Family of large biological molecules
Pronto para mais algumas gotas de conceitos para nosso cérebro? Neste audio pocket abordaremos: Como lidar com pessoas inseguras? 5 sinais de insegurança e como reconhece los? Premio nobel de medicina e fisiologia 2021 e suas implicações práticas Porquê a Vacina de RNA não ganhou o prêmio? Boa semana a todos!
Episode 70: HIV Prevention. Prevention is key in controlling HIV-AIDS. Listen to ways to prevent HIV, mainly by using condoms, PrEP and PEP.Introduction: HIV and AIDSBy Robert Dunn, MS3.Introduction: The Human Immunodeficiency Virus (HIV) is a retrovirus that is primarily transmitted via sex, needles or from mother to fetus. Once infected, the virus increases in its copies and decreases the individual's CD4+ cell count, thus leading to an immunocompromised state known as Acquired Immune Deficiency Syndrome (AIDS). Once with AIDS, the patient is susceptible to opportunistic infections. Prevention from AIDS includes several options. Condoms for safe sex practices are the least invasive and most readily accessible option for all patients. Pre-exposure prophylaxis (PrEP) is also an option for men who have sex with men (MSM) and transgender women. If the patient is also exposed to HIV, post-exposure prophylaxis (PEP) may also be an option to prevent infection but must be administer ideally 1-2 hours after exposure but no later than 72 hours after. Today we will briefly discuss how to prevent HIV infection.This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it's sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home.___________________________HIV Series IV: HIV Prevention. By Robert Dunn, MS3.Participation by Huda Quanungo, MS3; Bahar Hamidi, MS3; and Hector Arreaza, MD. HIV PreventionIntroductionThe Human Immunodeficiency Virus (HIV) is a retrovirus that is primarily transmitted via sex, needles or from mother to fetus. Once infected, the virus increases in its copies and decreases the individual's CD4+ cell count, thus leading to an immunocompromised state known as Acquired Immune Deficiency Syndrome (AIDS). Once with AIDS, the patient is susceptible to opportunistic infections. Prevention from AIDS includes several options. Condoms for safe sex practices are the least invasive and most readily accessible option for all patients. Pre-exposure prophylaxis (PrEP) is also an option for men who have sex with men (MSM) and transgender women. If the patient is also exposed to HIV, post-exposure prophylaxis (PEP) may also be an option to prevent infection, but it must be administered ideally 1-2 hours after exposure but no later than 72 hours after. We will concentrate in prevention during this episode. What is HIV?The Human Immunodeficiency Virus (HIV) is a retrovirus. When the virus gains access to our body via cuts on the skin or mucosa:The virus injects its 10kb sized RNA genome into our cells. The RNA is transcribed to DNA via viral reverse transcriptase and is incorporated into our cellular DNA genome. This causes our cells to become a virus producer. Viral proteins translated in the cell are transported to the edge of the cell and can bud off into new viruses without lysing the cell. Acute HIV symptoms. Some potential early symptoms of HIV can include fever, chills, rash, night sweats, muscle aches, sore throat, fatigue, lymphadenopathy, and mouth ulcers. The most common acute symptom is NO SYMPTOM. Many people do not feel sick with the acute infection of HIV. Some people can live years with HIV in “clinical latency” without knowing they are infected, but they can still be contagious during this time. As viral load (the amount of virus copies you have in your blood stream) increases, the CD4+ cells that contribute to our adaptive immunity continues to fall. That's why the best test during this period is not going to be HIV antibody but you should test for antigens. Specifically, the 4th Generation HIV test, which tests for both antibody and p24 antigens.Chronic symptoms. Once patients begin to present with opportunistic infections (i.e. Pneumocystis pneumonia – PCP), or have a CD4 count below 200, the patient is considered to have Acquired Immune Deficiency Syndrome (AIDS) and makes them susceptible to more serious infections. Without treatment, patients with AIDS typically survive about 3 years. Epidemiology of HIVHIV incidence: In 2019, there were 34,800 new HIV infections in the United States. This is an 8% decline from 2015. Amongst age groups: Age 25-34 had the highest rate of incidence (30.1 per 100,000)Age 35-44 had the second highest rate (16.5 per 100,000)Age 45-54 remained stableAge 13-24 had decreasing rates of incidence Amongst ethnic groups: Black/African-American groups has the highest rate of incidence (42.1 per 100,000)Hispanic/Latino had the second highest rate (21.7 per 100,000)Person of multiple races had the third highest (18.4 per 100,000) Amongst sex: Males had the highest rate of incidence (21 per 100,000)Females had the lowest rate of incidence (4.5 per 100,000) HIV Prevalence:In 2019, 1.2 million people (Ages 13 and older) in the US have HIV and 13% of them do not even know it. In 2020, there were an estimated 1.5 million people worldwide that acquired a new HIV infection. This is a 30% decline since 2020. An estimated 66% are receiving some HIV care and 57% were virally suppressed. Mortality: In 2019, there were 15,815 deaths among adults and adolescents diagnosed with HIV in the US. Preventative ScreeningThe USPSTF gives a Grade A recommendation for HIV screening for: Pregnant people and everyone between 15-65 years of age. All pregnant people at any point of their pregnancy, including those who present in labor or delivery and have an unknown status of HIV.The USPSTF only recommends a one-time screening and shows no benefit of repeat screening thereafter. Women may also be screened for subsequent pregnanciesAlso screen all Adolescents and adults ages 15-65. An effective approach is routine opt-out HIV screening. This approach includes HIV screening as part of the standard preventive tests. This approach removes the stigma associated with HIV testing, it promotes earlier diagnosis and treatment, reduces risk of transmission, and it is cost-effective. The determination for repeated screening of individuals should take into account the following risk factors: -Men who have sex with men (MSM)-Individuals who live in areas with high prevalence of HIVIncluding attending to tuberculosis clinics, stay in a correctional facility, or homelessness-Injection drug use-Transactional/commercial sex work-1 or more new sexual partners -History of previous STIs Annual screening for HIV is reasonable, however, clinicians may want to screen patients every 3-6 months if they have an increased risk of HIV. CondomsA simple and very effective method in HIV prevention is the use of condoms for safe sex practices. In 2009, the American College of Physicians (ACP) and the HIV medicine Association called for the wider availability of condoms and education to minimize HIV transmission. A meta-analysis of 12 HIV studies amongst heterosexual couples demonstrated the use of condoms in all penetrative sex acts reduced the risk of HIV transmission 7.4 times in comparison to those who never used condoms. Other studies show a 90-95% effectiveness in HIV prevention when “consistently” using condoms. A Cochrane review shoed that the use of a male latex condom in all acts of penetrative vaginal sex reduced HIV incidence by 80%. Overall, condoms are effective in HIV prevention.Pre-Exposure Prophylaxis (PrEP)Truvada and Descovy:Another option for prevention amongst HIV negative individuals is the use of Pre-Exposure Prophylaxis (PrEP). It is an anti-retroviral pill that is taken daily to maintain a steady-state level of the medication in the blood stream. The medication specifically a combination of 2 antiretroviral medications – Tenofovir and Emtricitabine. Both medications are nucleoside reverse transcriptase inhibitors (NRTIs) that work by blocking the viral reverse transcriptase from HIV and prevent the enzyme from copying the RNA genome into DNA. Therefore, it stops viral replications. There are 2 formulations of PrEP: Truvada and Descovy. Truvada's primary side effects are renal and bone toxicity with long-term use. Descovy's primary side effects are mild weight gain and dyslipidemia. Truvada is the most commonly prescribed PrEP because it has the most data since it has been around the longest. However, extra consideration should be taken for: Adolescents should weigh at least 35 kg before being prescribed PrEPDescovy may be preferred for adolescents by the prescribing physician as it is not associated with reduction in bone density, as Truvada is. Estimated GFR between 30 – 60Truvada is associated with acute and chronic kidney disease whereas Descovy is safe for patients with a GFR greater than 30Patients with osteoporosisTruvada is associated with bone toxicity, whereas Descovy is not. It is important to note that PrEP has only been studied in men or people who were assigned men at birth. So, its efficacy in vaginal sex and with vaginal fluids cannot be generalized at this time. Future of PrEP: In May 2020, the HIV Prevention Trials Network (HPTN) 083 randomized trial demonstrated the potential of an injectable PrEP. Carbotegravir, is an integrase inhibitor, which prevents the HIV integrase from incorporating the HIV genome into the cellular genome. This study demonstrated its efficacy as PrEP in comparison to Truvada with few new infections (13 versus 39, respectively). Carbotegravir would be given via injection once every 8 weeks. In September 2021, the pharmaceutical company Moderna will begin 2 human clinical trials for an HIV vaccine that use mRNA technology. Previous studies conducted with non-mRNA vaccines demonstrated that B cells can be stimulated to create antibodies against HIV. Since HIV becomes integrated in the cellular genome within 72 hours of transmission, a high level of antibodies must be produced and present in the body to offer an adequate level of immunity. Post-Exposure Prophylaxis (PEP)If an individual is exposed to blood or bodily fluids with high risk of HIV via percutaneous, mucus membrane or nonintact skin route, post-exposure prophylaxis (PEP) may be an option. PEP is indicated when the HIV status of the exposure source is unknown and are awaiting test results, or if the exposure source is HIV positive. Therapy should be started within 1 or 2 hours of exposure and it is not effective after 72 hours of initial exposure. The recommended duration of therapy is 4 weeks but no evidence has been shown for an optimal duration. Occupational exposure. There are 2 regimens for PEP: Truvada with Dolutegravir Truvada with Raltegravir Both Doltegravir and Raltegravir are integrase inhibitors which block the integration of the viral genome into the cellular DNA. The regiments are chosen based on efficacy, side effects, patient convenience, and completion rates. Dolutegravir is chosen because it is given once daily. While Raltegravir is taken twice daily, most experience with PEP has been with Raltegravir. Other risk with Raltegravir are potential skeletal muscle toxicity and systemic-cutaneous reactions resembling Steven-Johnson syndrome. One final word about prevention of vertical transmission is making sure pregnant women are treated during pregnancy and if the baby is delivered from a patient whose viral load is “detectable”, the baby needs to be treated, but we'll let that topic for another time to discuss. Joke: What do you call the patient zero of HIV? First Aids.HIV incidence is decreasing thanks to many prevention measures taken globally, and we discussed screening, condoms, PrEP and PEP as part of this prevention efforts. Stay tuned for more relevant medical information in our next episode. ____ Now we conclude our episode number 70 “HIV Prevention.” Robert, Huda and Bahar explained some ways to prevent HIV, mainly by screening those at risk, using condoms, PrEP (pre-exposure prophylaxis) and PEP (post-exposure prophylaxis). Let's also remember that having a monogamous relationship and avoiding high risk sexual behaviors confer significant protection against HIV. Even without trying, every night you go to bed being a little wiser.Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Robert Dunn, Huda Quanungo, and Bahar Hamidi. Audio edition: Suraj Amrutia. See you next week! References:About HIV. Center for Disease Control and Prevention, CDC.gov, June 1, 2021. https://www.cdc.gov/hiv/basics/whatishiv.html . Accessed September 21, 2021. Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet. 2006 Aug 5;368(9534):489-504. doi: 10.1016/S0140-6736(06)69157-5. PMID: 16890836; PMCID: PMC2913538. [https://pubmed.ncbi.nlm.nih.gov/16890836/] US Statistics. HIV.gov, June 2, 2021. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics . Accessed September 21, 2021. The global HIV/AIDS Epidemic. HIV.gov, June 25, 2021. https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics. Accessed September 21, 2021. Human Immunodeficiency Virus (HIV) Infection: Screening. U.S. Preventative Services Task Force, June 11, 2019. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/human-immunodeficiency-virus-hiv-infection-screening. Accessed September 21, 2021. Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ. 2004 Jun;82(6):454-61. PMID: 15356939; PMCID: PMC2622864. [https://pubmed.ncbi.nlm.nih.gov/15356939/] Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev. 2002;(1):CD003255. doi: 10.1002/14651858.CD003255. PMID: 11869658. [https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003255/full] Mayer, Kenneth H, MD, and Douglas Krakower, MD. Administration of pre-exposure prophylaxis against HIV infection. UpToDate, June 24, 2020. Accessed September 21, 2021. [https://www.uptodate.com/contents/administration-of-pre-exposure-prophylaxis-against-hiv-infection?search=8)%09Administration%20of%20pre-exposure%20prophylaxis%20against%20HIV%20infection&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1] Zachary, Kimon C, MD. Management of health care personnel exposed to HIV. UpToDate, June 07, 2019. Accessed September 21, 2021. [https://www.uptodate.com/contents/management-of-health-care-personnel-exposed-to-hiv?search=9)%09Management%20of%20health%20care%20personnel%20exposed%20to%20HIV&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1]
Episode Summary: When COVID-19 hit and society decided to use mRNA vaccines for the first time, many questions remained about whether RNA itself was ready for the challenge. But three scientists at Stanford University who had barely worked with each other before the pandemic realized that RNA's limitations were merely a design challenge and not an issue with the substrate itself. Through emails and zooms, Kathrin, Gun, and Hannah built a tool to massively test RNA designs. With it, they screened for RNA with better functionality, increasing the stability and expression of the protein they encode and ultimately creating a platform to improve these life-saving vaccines. Episode Notes:About the AuthorsHannah, Gun, and Kathrin had all been separately researching various aspects of genetics and RNA before the pandemic.When COVID hit and RNA vaccines were being built, the three realized they had newly complementary skill sets.They set aside their individual projects, leveraged their unique backgrounds, and worked in shifts to abide by social distance rules in order to solve multiple issues facing RNA as a substrate for vaccines.Key TakeawaysRNA holds great potential for therapies and vaccines as they are highly programmable, extremely flexible, and are much easier to scale than other options.But RNA is hard to deploy for vaccines because it is extremely unstable both in the body and on the shelf.Enhancing the expression and stability of RNA allows us to reduce the amount needed to give a person, increasing the number of people that can be vaccinated.The three designed PERSIST-seq to test a multitude of RNA designs in one-pot by leveraging synthetic biology and next generation sequencing.They also leveraged citizen science through a “game” called Eterna in order to optimize sequences using the collective brain power of humanity.With it in they found synonymous mutations and alterations to the untranslated regions that changed RNA folding and improved stability and translation.TranslationPERSIST-seq must still be validated in animal models to fully connect how improvements on stability and expression alter vaccine efficacy.The team is ready to leverage their approach through licensing to help RNA vaccine companies improve their designs.The design rules and method to discover them can be used to enhance any RNA therapeutic that will undoubtedly be coming through the pipeline soon.First Authors: Kathrin Leppek, Gun Woo Byeon, and Hannah Wayment-SteelePaper: Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics
On Breakthrough, a new series from the Prognosis podcast, we explore how the pandemic is changing our understanding of healthcare and medicine. We start with an examination of long Covid, a mysterious new illness that has stumped doctors attempting to treat symptoms that last for months and potentially years. It has changed the way hospitals work and forced healthcare officials to prepare for the next pandemic. Covid has also opened the door to revolutionary technology: messenger RNA vaccines. It's a technology that never could have been proven so quickly outside the crucible of that first pandemic year, 2020, and it holds big implications for the future of medicine. Breakthrough launches on Oct. 19. Subscribe today on Apple Podcasts, Spotify or wherever you get your podcasts. Learn more about your ad-choices at https://www.iheartpodcastnetwork.com
On Breakthrough, a new series from the Prognosis podcast, we explore how the pandemic is changing our understanding of healthcare and medicine. We start with an examination of long Covid, a mysterious new illness that has stumped doctors attempting to treat symptoms that last for months and potentially years. It has changed the way hospitals work and forced healthcare officials to prepare for the next pandemic. Covid has also opened the door to revolutionary technology: messenger RNA vaccines. It's a technology that never could have been proven so quickly outside the crucible of that first pandemic year, 2020, and it holds big implications for the future of medicine. Breakthrough launches on Oct. 19. Subscribe today on Apple Podcasts, Spotify or wherever you get your podcasts. Learn more about your ad-choices at https://www.iheartpodcastnetwork.com
Dr. Robert Malone visits with Sean. Dr. Malone is the Inventor of mRNA vaccines and RNA as a drug, and he is outraged by the government's decision to mandate people into a one size fits all medicinal solution. Malone is now working on a new media initiative that is just launching. The first rollout can be found at www.globalcovidsummit.org and https://doctorsandscientistsdeclaration.org/. This is an umbrella organization that is bringing together different physician groups from around the globe. Learn more about your ad-choices at https://www.iheartpodcastnetwork.com
In the field of bio-tech, it can take 10 years and millions of dollars to see if an experimental idea might turn into a life-saving treatment—if it ever does. Noubar Afeyan fully understood those risks when he co-founded Moderna in 2010. He and his colleagues were looking for a way to deploy the messenger RNA molecule to tackle life-threatening diseases. In January of 2020, an urgent opportunity presented itself in the form of a deadly virus that was spreading across the globe. At a breathtaking pace, Moderna produced a prototype for a COVID-19 vaccine, partnered with the NIH to test it, and produced millions of doses, becoming part of the most rapid vaccine roll-out in human history. While Moderna is the best known of Noubar's companies, he has launched many others in the bio-tech space as part of Flagship Pioneering, his multi-billion dollar venture studio.
In this episode, George D. Demetri, MD, and Alexander Drilon, MD, discuss the biologic rationale behind testing for NTRK fusions in patients with various solid tumors, along with clinical strategies for testing. Topics include:Differences between NTRK fusions vs gene mutationsFrequency of NTRK fusions by age and tumor typeWhen to test patients for NTRK fusions and interpreting reportsMethods of testing: multiplex gene testing, next-generation sequencing of DNA vs RNA, immunohistochemistry, and liquid biopsyPresenters:George D. Demetri, MDProfessor of MedicineHarvard Medical SchoolHarvard UniversityCo-Director, Ludwig Center at HarvardSenior Vice President for Experimental TherapeuticsDirector, Sarcoma CenterDana-Farber Cancer InstituteBoston, MassachusettsAlexander Drilon, MDChief, Early Drug DevelopmentAttending, ThoracicMemorial Sloan Kettering Cancer CenterNew York, New YorkLink to full program:https://bit.ly/2YFIPfrLink to slideset based on this podcast:https://bit.ly/3amgU6w
On Breakthrough, a new series from the Prognosis podcast, we explore how the pandemic is changing our understanding of healthcare and medicine. We start with an examination of long Covid, a mysterious new illness that has stumped doctors attempting to treat symptoms that last for months and potentially years. It has changed the way hospitals work and forced healthcare officials to prepare for the next pandemic. Covid has also opened the door to revolutionary technology: messenger RNA vaccines. It's a technology that never could have been proven so quickly outside the crucible of that first pandemic year, 2020, and it holds big implications for the future of medicine. Breakthrough launches on Oct. 19. Subscribe today on Apple Podcasts, Spotify or wherever you get your podcasts. Learn more about your ad-choices at https://www.iheartpodcastnetwork.com
Canadian biotech Providence Therapeutics CEO talks to Scrip on mRNA vaccines against COVID-19, cancer Shownotes – Providence Therapeutics CEO Brad Sorenson talks about his company's plans for Phase II, III clinical trials for an mRNA vaccine as well as marketing and manufacturing partnerships with Biological E, Everest Medicines, Emergent Biosolutions and Northern RNA. He also discusses Providence's m-RNA vaccines against cancer
New data on an oral antiviral treatment could have significant impact on the COVID treatment landscape. What's next for treatments, booster shots and child vaccines.----- Transcript -----Andrew Sheets Welcome to Thoughts on the Market. I'm Andrew Sheets, chief cross asset strategist for Morgan Stanley Research.Matthew Harrison And I'm Matthew Harrison, Biotechnology Analyst.Andrew Sheets And on this special edition of the podcast, we'll be talking about several new developments in the fight against COVID 19. It's Tuesday, October 5th at 3 p.m. in London,Matthew Harrison and it's 10:00 a.m. in New YorkAndrew Sheets So Matt. I really wanted to catch up with you today because there are a number of different storylines involving COVID 19 going on at the moment, from child vaccines to the situation with booster shots. But I suppose the headline story that's getting the most attention is data released last Friday on Merck's new oral COVID treatment pill Molnupiravir or I think I said that right. I'm sure I didn't. So maybe let's start there. What is this treatment and why does it matter?Matthew Harrison Yes. Thanks, Andrew. So Molnupiravir is an oral antiviral against COVID. The way it works is that it stops the virus from replicating effectively, and that reduces the amount of virus in someone's body. It was studied here in patients that were recently diagnosed with COVID 19. And it cut the rate of hospitalization in those patients by 50%. So those that didn't get treated with the drug went to hospital at a rate of 14%, and those that did get treated went to hospital rate of 7%. I think the thing I would want to highlight is that this is something you obviously take after you get infection and vaccines remain the primary way to prevent infection.Andrew Sheets So this is kind of one of the things I felt that was so fascinating when that news was announced. Because on the one hand, this seems like very good news, another treatment that appears highly effective against COVID 19. And yet the market reaction was actually to really punish many of the makers of the current COVID vaccines, so how much do you think this could influence the COVID treatment landscape? And do you think the market or people might be overreacting to some of the impact on whether or not people will still get vaccines or vaccines will remain important?Matthew Harrison Vaccines, their primary measure is prevention. Right? This is a drug to treat people once you get disease. But the hope is, and the way we get out of the pandemic, is still by vaccinating everybody to prevent disease from happening and disease from spreading. So, I think of this drug, along with antibodies as drugs that you use to treat people who either have breakthrough infections or those that aren't vaccinated. But you also have antibodies for people that are at higher risk, patients that might not be compliant with taking oral drugs. Or, you know, a whole another segment of the market that we haven't talked about is those that need to be protected either because they can't get a good response to the vaccine, because they're perhaps immunocompromised or otherwise, and those that need some sort of preventative treatment. Where Merck is studying this pill as a preventative treatment, but the antibodies are already authorized as preventative treatments. So, there's a different section of the landscape, I would say, for each of these drugs.Andrew Sheets So, Matt, what impact do these potentially positive results on a pill mean for vaccine hesitancy in the outlook for vaccinations?Matthew Harrison I think that's one of the things that the market is is struggling a lot with, and I think that's part of the reason you saw many of the vaccine stocks under pressure, right? There's definitely one segment of the market that thinks, if you have effective treatments, especially easy to use treatments like orals, that could give people another reason who don't want to have the vaccine to say, "Look, even if I do get sick, I do have an easy to take treatment." And so, on the margin, right, it may impact vaccination uptake, though the flip side is what I would say is I think what we're seeing in the U.S. is at least that you're seeing broad vaccination mandates and you and you are seeing those mandates lead to increases in vaccination, especially employer based mandates. And so, there are other factors driving vaccine uptake.Andrew Sheets So I think it's safe to say we care about the numbers here on this Thoughts of the Market podcast. Could you just run through the various costs of different treatments if we're thinking about vaccines, you know, potential thoughts on where an oral pill could be and then the antibody treatments, which are obviously another form of treatment that we're seeing being used. Just to give people some sense of how much the relative cost of each one of those things is.Matthew Harrison Yes, so vaccines per shot in the U.S., depending on manufacturer, run between $16.50 And $19.50 in the U.S. So a course of vaccination, let's say costs on average about $40. There are some administration fees and otherwise, but direct to drug costs. Merck has signed a contract with the US government for $1.2 Billion for 1.7 Million courses, so that runs about $700 per course for the oral right now. And then the U.S. government also has contracts with a variety of manufacturers for antibodies, which run about $2100 per course. So treatments are more expensive than vaccination and then usually with treatments, there are other associated medical costs which I didn't cover, and I don't have a great estimate for. But obviously, as those patients that might be getting treatments because they're also hospitalized, those costs are more significant.Andrew Sheets So I want to jump next to the topic of child vaccinations. Last week, Pfizer and BioNTech announced that they had submitted data to the Food and Drug Administration that their coronavirus vaccine is safe and effective in children ages 5-11. What do you think? Is the timeline ahead for the next steps here?Matthew Harrison Yes, right, so they have submitted preliminary data, but they have not submitted the final request for an emergency use authorization. The expectation here is that there will be some back and forth between Pfizer and the regulator to finalize the exact package of data after the FDA has reviewed the initial data. That will then trigger the final submission where they ask for the request for emergency use authorization. Most of us think that would occur sometime, let's say, in the next couple of weeks. And then historically right, the FDA, once they receive that final package, takes on order of two to three weeks to approve the EUA authorization. So, I think this ranges from maybe the earliest in late October towards sometime into early November.Andrew Sheets Matt, I also wanted to cover the issue of booster shots, which is the other kind of large development in the fight against COVID 19, and I think there's been a little bit of confusion on the topic. So, you know, what's the latest in terms of who is eligible for a booster in the U.S. and what the CDC is recommending?Matthew Harrison Originally the FDA had asked their external advisory committee whether or not boosters should be made available for everyone where the original vaccine was authorized, so that would be those 16 and up. The advisory committee then asked to narrow that slightly and specifically what the advisory committee asked was: those 65 years or older, as well as those at high risk, either because of underlying medical conditions or because of occupational hazard. So that would include, hospital workers or workers who are otherwise frontline workers in a high-risk scenario. The CDC has a separate committee called ACIP, which a few days later looked into this as well, and they had voted essentially for those at high medical risk and those 65 years and older. But they had said they were somewhat uncomfortable, and it was a very close vote to be clear, about those at increased occupational risk. After that meeting, the CDC themselves or the director of the CDC said that they believe the booster shot should be made available for all of those groups and essentially overrode the committee on the last piece around occupational risk. So right now, its 65 older, immunocompromised, those at high medical risk and those at high occupational risk.Andrew Sheets So Matt, the final thing I wanted to ask you about is one of the most positive things that seems to have come out of this this terrible pandemic is mRNA vaccination technology. It seems to be a type of medical technology that has really exceeded expectations for how quickly and how effectively a vaccine could be rolled out. Andrew Sheets So Matt, if you think about this technology looking ahead, what do you think are the applications that potentially could go beyond COVID? And also, at what point do you think some of these vaccinations might need to be updated and how difficult will that be?Matthew Harrison So in terms of applications and next steps for RNA, there's a wide variety of disease areas that they're looking at. But in general, the technology is being used to make missing proteins in your body, which occurs a lot with rare genetic diseases. To potentially help various tissues that may need certain proteins or enzymes to help them heal. And also looking at ways that you could, for example, with oncology patients that you could tell the body's own immune system for key flags or markers of the tumors versus normal tissue so that you could redirect the immune system to specifically go after the cancerous tumor. In terms of needing a updated COVID vaccine. I think that all depends on the variant outlook. Currently, what we see is just giving another dose of the current vaccine provides very good protection against Delta. And so, I think as we look out on the outlook, right, it's about if Delta combines with something else, then maybe there is the potential for an update. But the manufacturers are well primed for that, and that process is a couple months process, probably if they had to do that. So, they can adapt quickly.Andrew Sheets Something important to keep an eye on. As always, Matt, it's been great talking with you.Matthew Harrison Thanks, Andrew.Andrew Sheets As a reminder, if you enjoy Thoughts on the Market, please take a moment to rate and review us on the Apple Podcasts app. It helps more people find the show.
This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue. Dr. James de Lemos: Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue. Dr. Marc Ruel: Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward. Dr. Marc Ruel: Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery. Dr. Marc Ruel: Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation. Dr. James de Lemos: Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece? Dr. Marc Ruel: It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery. Dr. Marc Ruel: It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage. Dr. Marc Ruel: And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far. Dr. Marc Ruel: Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well? Dr. Michael Fischbein: Yeah. Thanks, Marc. I think that's an excellent question. Yeah, now, every patient after this trial, I talk to them ahead of time and offer them to have their appendage ligated in this setting if they have a history of atrial fibrillation. I don't think this adds much to our operation, it doesn't increase much the clamp time. And especially, although the trial was more surgically excising with some of the newer clips out there, it really doesn't add much time to the operation. So I think this is really an important paper that will change what we do as surgeons. Dr. James de Lemos: Can I just comment that I think the trial has indirect implications well beyond surgery, because the demonstration of combined benefit for oral anticoagulation with left atrial appendage occlusion really suggests that, even for patients not going for cardiac surgery, at some point in the future, we may be thinking about not and either/or between the devices and anticoagulation, but maybe both. Dr. James de Lemos: Mike, let me come back to you. There's a really fascinating paper by DeCarlo evaluating penetrating aortic ulcers that really change my thinking on this. Can you talk a little bit about this paper and your thoughts? Dr. Michael Fischbein: Thanks very much, James. I think this is really an important paper that's going to change what we do as surgeons. As you know, symptomatic penetrating aortic ulcers are grouped with dissections in tremula hematoma where we treat those patients immediately. None of us know what to do though with the asymptomatic aortic ulcer, which is actually more common. A lot of us are basing our reports on some observational studies. Many of these studies are mixed, symptomatic and asymptomatic. And so the treatment really varies, from watching them conservatively to treating them with open or endovascular approaches. Dr. Michael Fischbein: However, this paper by DeCarlo's really excellent. They followed 273 asymptomatic penetrating ulcer patients over time following their CT scans. And they really had two key important findings. One that these ulcers really didn't change much over time, and two, the risk of some complication occurring, whether that's rupture, symptoms or progression of disease was very low at 6.5% over 10 years. And so I think this is really going to be important, because we know that these asymptomatic penetrating ulcers, we can watch them conservatively. They do have to be still followed, but we don't have to go immediately to perform some surgical procedure. Dr. James de Lemos: Marc, any thoughts from you on this paper? Does this change what you guys will be doing in Ottawa? Dr. Marc Ruel: Absolutely. Yeah, I think this is, as Mike was saying, a very germane finding that's very helpful. I think the key word here, as Mike was alluding to, is really the word asymptomatic and how do you define that? Right? I mean, many of these findings are incidental findings. Someone comes in with a bit of shortness of breath or this or that, gets a PE protocol CT scan and then a penetrating aortic ulcer is found. Dr. Marc Ruel: So where do you draw the line between symptoms that may be a small left lateral effusion or a bit of shortness of breath. And it's also, I think that nuance will have to be determined going forward, what is truly asymptomatic versus a few symptoms that may be less specific and perhaps not relate to the penetrating aortic ulcer. But I think it's tremendously helpful in guiding practice going forward. Dr. James de Lemos: Fantastic. Thank you both. Mike, I want to come back to you on another really important paper from the vascular surgery standpoint, which is the paper from the Voyager investigators on the combination of rivaroxaban and aspirin for patients with surgical treatment of peripheral arterial disease. Dr. Michael Fischbein: Yeah, no, I think this is another or provocative paper. And as you know, peripheral arterial disease is a really highly-significant clinical problem. We say that affects 200 million people globally. And this includes patients with claudication, arrest pain, limb threat ischemia. And currently, the treatment for this is to either a open surgical or endovascular revascularization of the lower extremity. And the problem is while these patients, they have immediate symptomatic relief where you can save their limb, we say that one out of five will develop some sort of symptom or limb ischemia by three years. Dr. Michael Fischbein: And so the field is really looking for some sort of adjuvant therapy to help prevent these occurrences later on. And so the Voyager trial randomized over 6,000 patients who underwent surgery, whether it was open or endovascular, and then they randomized to either receiving rivaroxaban plus aspirin, versus aspirin and a placebo. And they showed that if you received riva, that those patients had a significant reduction in the instance of their primary endpoint, which included ischemia, limb loss or symptoms. And importantly, there was not an increase in major bleeding risk in these individuals. Dr. James de Lemos: So fascinating. I mean, this does this change practice and is this now the standard for surgically-treated peripheral arterial disease? Dr. Michael Fischbein: Yeah, I think there's still some questions that we have to answer. Yeah, I think definitely this, I think will be used after the bypass surgery, but some of the things in the trial that we would have to figure out is how applicable is this to everyone. In the trial, the open surgical arm had patients with less risks. Also, some patients received vein conduit versus a prosthetic conduit. And so, I think we'll have to look at some of the sub-analysis to see who we can apply this to. Dr. James de Lemos: Fantastic. Marc, any thoughts from your perspective on this one? Dr. Marc Ruel: Yeah. Mike provided a great summary. I think one other take-home message to me is that, really, these patients should be viewed as having panvascular disease, a little bit like our CABG patients. And essentially rivaroxaban or DOACs in general have a role, like in the COMPASS trial, in preventing other complications. So here, part of the composite endpoint was myocardial infarction, right? And we know that these peripheral vascular disease patients are very much at risk of it. So it may have an effect locally, but it really, probably, has most of its effect with regards to the panvascular disease that these patients present. Dr. James de Lemos: Excellent. And I'll just point out that just today, the FDA released news that they've granted an indication for this combination therapy for patients with peripheral arterial disease. Let me come back to Marc for a really interesting randomized controlled trial, from China, evaluating no-touch vein graft interventions for cardiac surgery. Marc, can you talk to us about this trial and your impressions on this? Dr. Marc Ruel: Absolutely. Thank you, James. So this is a trial from seven hospitals in China that randomized 2,600 patients between April, 2017 and June, 2019. And patients were randomized with the use of saphenous vein grafts between a no-touch technique and a conventional saphenous vein graft harvest technique. And I'll explain a little bit what this no-touch technique is. It actually consists of two things. You take the vein by a complete incision. Often, in fact, it's more invasive, and you take the actual saphenous vein with a surrounding layer of fat and connective tissue around it. And because of that, it's not easily amenable to endoscopic vein harvest or even using small incisions. Dr. Marc Ruel: The other component of no touch of vein harvesting is to really preserve the anterior layer by not using any syringe inflation and letting the conduit be rinsed, but flow naturally and not be distended at all. So the trial was positive, and the trial already showed a lesser incidence of saphenous vein graft closure at both three months and 12 months on CT scan. So to give you an example, the three months saphenous vein closure was 4.8% in the conventional harvest group, versus 2.8% in the no-touch group. Dr. Marc Ruel: Now what's interesting to here is twofold. There may be a couple of aspects in the benefits of the therapy, and one may relate, in fact, to the lack of pressure syringe dilatation. So it's hard to tease out, is it really the surrounding layer of fat or is it the fact that the syringe dilatation procedure is not being performed in the no-touch group? The second issue is the technique is definitely more invasive. The authors found in the trial more local complications, about 50 to a hundred percent increase in terms of a local numbness, exudation, et cetera, delayed wound healing. Because you have to make bigger incisions and you have to take more tissue around where the vein that you're harvesting. Dr. Marc Ruel: So it is a very intriguing trial. Obviously, graph patency is something that's tremendously important around the CABG operation. But unfortunately, it steers us towards a more invasive approach. In a nutshell, it is a positive trial, but it does require the surgery to be slightly more invasive, albeit, in most cases, with addressable issues with regards to delayed wound healing and exudation. But it would be ideal if we could combine the benefits of a no-touch technique with a less invasive approach to harvesting. Dr. James de Lemos: Mike, this is fascinating to me because you've got a procedure that probably improves the long-term outcomes of the operation, but is associated with a longer surgical time and more local complications. Mike, I'm wondering, what are your surgeon's going to do at Stanford? Are they going to adopt this or is this too difficult and associated with too much inconvenience for the patient to become something that's done routinely? Dr. Michael Fischbein: Brilliant, great question, James. Because I think, often, our patients, previous to endoscopic vein harvesting, they often complained more issues with their leg incisions than their actual sternotomy. And I always tell my patients now, though, one of the incredible things is that we can take their vein endoscopically. And now, we're talking about, while we do have improvement in graft patency for the vein, we're going to go backwards and maybe have some of these wound issues again. And I'd be curious what Marc thinks, though. We are trying to do more and more arterial grafts. And so, if we're just using one vein, is it worth accepting these higher wound complications? Dr. Marc Ruel: It's a great point, Mike, and perhaps exactly, as you say, perhaps an increased use of arterial grafts can be combined with lack of a pressure syringe dilatation of the vein after harvest, right? And there's already some data suggesting, as provided in the excellent editorial by Vidal, that this may be mechanistically important to enhance patency. So the study is very intriguing and still remains to completely unfold. Dr. James de Lemos: Excellent. Really important contribution to the surgical science. Marc, I want to come back to you with another important randomized control trial, this with a really novel therapeutic compound designed to address kidney injury after cardiac surgery. Marc, can you talk about the trial with the small interfering mRNA for renal protection? Dr. Marc Ruel: Absolutely. Thank you, James. This is an important trial, in my opinion. It's a Phase II study of a compound named, teprasiran, which is a interfering RNA, which modifies the p53 mediated cell death response in the renal tubal cells. So what does that do, essentially, is that the thought is that it may prevent acute renal injury after cardiac surgery. We know that's a tremendous problem. Most busy cardiosurgical ICUs would have at least between 15 to 25% of the patients requiring dialysis postop, depending on the level of risk acuity that your unit is presenting. Dr. Marc Ruel: And it's no different whether you're in Stanford or Ottawa or Germany, in my opinion. So we need solutions here. And this is a relatively simple compound, which is administered within four hours of completion of surgery. So for instance, if the surgery was performed on pump, it was given within four hours of completion of surgery. So, for instance, if the surgery was on-pump, it was given within four of hours completion of CPB, cardiopulmonary bypass. If it had been performed off-pump, it was within four hours of the last anastomosis. Dr. Marc Ruel: It's a two-minute infusion, 10 milligrams per kilo, and essentially in the trial, it was not associated with any safety concerns. And quite conversely, it was actually associated with the benefit, with regards to the development of early acute kidney injury, which was 50% prevalence in the patients who were treated with placebo, versus 37% in patients who received the compound, again, named teprasiran. So I think this is quite important. It has led to a Phase III which is currently ongoing, and I think this is a very instrumental finding in the field. Dr. James de Lemos: Fantastic. I mean really a testament to the progress in clinical science for cardiac surgery, that we've got these randomized controlled trials moving through a development phase that may be actionable in years to come. Let's finish the discussion of the original research articles, Mike, with a review of the Yang paper, really, which also, I think, is in Circulation's real sweet spot, where we're highlighting the very best of basic and translational science coming from Surgeon Laboratories. Can you talk about that paper for us? Dr. Michael Fischbein: Thanks very much, James. I think this is really an exciting paper. Qiong Yang's lab at University of Michigan, they're studying Loeys-Dietz syndrome. As you know, Loeys-Dietz syndrome is one of the connective tissue disorders. There's five subtypes, and these individuals form aortic root aneurysms. Importantly, it's specific to the aortic root that these aneurysms primarily develop. Although later on, you can see them in other locations, including intracranial and some of the branch vessels. Dr. Michael Fischbein: But these root aneurysms can dissect and this is life threatening. Currently, the only treatment strategy for these individuals is surgical, where you perform a prophylactic replacement of the aortic root. Unfortunately, there are no real medical therapies, primarily because we don't understand the mechanisms why these aneurysms form. So Dr. Yang's lab, they model this disease using a induced pluripotent stem cell model, where cells are differentiated into the different embryologic origins of the aorta. Dr. Michael Fischbein: The aortic group comes primarily from the second heart field. And so, when they studied these smooth muscle cells, they were able to show that there is lineage-specific smooth muscle cell defects, and they discovered some interesting pathways that might explain why aneurysms form specifically in the root in these in individuals. They also came up with some potential pharmacologic strategies to block some of these mechanisms. Dr. Michael Fischbein: And so, I think this is really exciting because this is using pluripotent stem cells more as a model to study disease states. And I could see the potential, also, for precision medicine, where you take an individual cells, make their iPSCs and study that individual's mechanisms, and perhaps come up with unique medical strategies for that individual. Dr. James de Lemos: So let's, Marc, finish, that's really all of the original research articles we covered. Really, an amazing spectrum of clinical translational and basic science that is a Testament, both to what you all have done to recruit content, but the tremendous growth in science and the surgical specialties. Marc, let's talk a little bit about the two terrific in-depth reviews that you picked for this issue and what their contributions are. Dr. Marc Ruel: Thank you again, James. We have two excellent reviews in this themed issue of Circulation. One is a frontiers piece about cardiac surgery in women in the current era, going over what are the gaps in care. And this is spearheaded by Leslie Cho, from the Cleveland Clinic, and it really goes over, very comprehensively, many of the issues around not only clinical trial enrollment of women, but specific issues pertaining to the care, and which goes back even to basic science of the sex and gender of animals being used in research for reasons that I said, that are very comprehensively, again, I want to emphasize highlighted by the authors. Dr. Marc Ruel: And I'll give you an example, for instance. In off-pump surgery, there are some discrepancies with regards to the use of off-pump versus on-pump surgery between males and females. And we off-pump surgeons know that there are really two very different ways from the surgery. Women, for instance, have a smaller heart which is easier to expose, for instance, for lateral and inferior territories. But in the same token, the coronary targets can be smaller. So there's really a number of discrepancies here, which can be anatomic, it can be sometimes due to the disease presentations. Dr. Marc Ruel: For instance, women have more tricuspid valve disease, and at a certain age start having an increased incidence of aortic problems versus males. And there's also some what I would call logistical issues with regards, for instance, to clinical trial recruitments from VA centers that typically have very, very few women being eligible for enrollment there. So these issues, again, are comprehensively addressed by Dr. Cho and her colleagues. And it's a very interesting read. Dr. Marc Ruel: The other piece you were referring to is a state-of-the-art paper around the use of transit time flow measurements during coronary bypass. And I think our cardiology colleagues and everyone in the cardiovascular field will be very interested to learn a bit more about this. Because essentially, when we perform bypass surgery, we don't have a validated easy way to ascertain whether the grafts that we just built are doing their job. And you may say, "Well, the surgeon's great at cutting and doing anastomosis," but as I like to tell my trainees, there's much more than suturing that might be happening. Dr. Marc Ruel: An anastomosis may have an unforeseen flap into it. There could be a small clot that's blocking something. There could be a kink or a twist in the graft that's not readily recognized. So I think it's very important to have a thorough assessment in everybody. I'm the last author of this piece, so I'm obviously somewhat partial to it. But I think it is important for the field to have quality checking of all grafts that are performed at something, especially something as invasive as bypass surgery. The patient should come out with functional grafts and that should be validated and objectively verified. Dr. James de Lemos: Fantastic. Marc, and we also have two research letters in this issue of Circulation. These are small pieces, but they pack a really powerful punch. Do you want to just briefly tell us about those two? Dr. Marc Ruel: Absolutely. Thank you, James. As a surgeon, I love research letters. I think they are a great venue. They're under a thousand words. Certain, sometimes we're busy, we don't want to always read a 5,000-word manuscript. And they're really, they are well-suited to what I would say are surgical follow-up studies. Once a technique has been described and you want to look at what are the late outcomes of this technique, I think they're an excellent format for that. And precisely, this corresponds to the two research letters that we have in the 2021-themed issue. Dr. Marc Ruel: One is a long-term, 10 year analysis of the SAVE RITA trial by Kim and Kim in South Korea. The SAVE RITA trial is a fairly famous trial in our specialty, which essentially, randomized patients to have a Y graft on the left internal thoracic artery, using either a saphenous vein conduit or the right internal thoracic itself. And essentially the early results were neutral. So the two groups were comparable, which is naturally neutral. I would say non-inferior for the saphenous vein graft. Dr. Marc Ruel: Now we have 10-year data in over 200 patients, equally randomized between receiving a saphenous vein graft versus the right internal thoracic artery. And the results are 10 years are equally excellent between the saphenous vein graft and the right internal thoracic artery. So this is quite non-intuitive to many. Essentially, what we're showing here is that a vein graft at 10 years has amazing patency. We're talking 90%-plus in those patients who received an angiogram. So I think there's a couple of messages to remember here. Dr. Marc Ruel: There may be a biologic role of connecting a saphenous vein graft onto the left internal thoracic artery with regards to nitric oxide dilution. Also, technically, the authors have readily acknowledged that the harvest the vein, again, back to this saphenous vein harvest issue, they harvest it from the lower leg. Therefore, the diameter of the vein is more suited to a Y graft. And, in fact, using a vein over right internal thoracic artery may have technical advantages, because the diameter is a little bit more facile to use with regards to complex composite grafting. So it may actually be something that, if you can maintain it with patency based on say, nitric oxide dilution, is a little bit easier to maneuver and build at the time of surgery. Dr. James de Lemos: Marc, can I ask a question here? Does this change your practice with regard to how often you're using Y graphs, in general, and the vein on artery Y? Because, Mike, outsiders experiences that these graphs aren't used and do these data suggest that we should be using why Y graphs, in general, and this particular type of Y more often in surgery? Dr. Marc Ruel: Absolutely. I think these data suggest precisely that. Whether the adoption will follow is another story. There's not a lot of groups, much to your point, that are using this configuration, but it's used commonly as a bailout strategy. Let's say, one of the arteries has been injured or is not available, or you have a porcelain aorta, I think based on these important data, you can now know that you can, if well-constructed, use a saphenous vein graft as a Y graft onto the LITA with relative impunity. In fact, excellent results, if done in the way that Kim and Kim are reporting. Dr. Marc Ruel: Our second research letter is actually a follow-up of hybrid palliation for hypoplastic left heart syndrome. This comes from the UK, where a number of centers had used several years ago the concept of a hybrid palliation in patients who were mostly high risk for hypoplastic left heart. So here, again, much to the research letter format, we have a follow-up series with regards to following all these children who had received either a initial Norwood approach or a hybrid approach progressing to a Norwood stage two. And essentially, the overall survival, which is about, between two thirds to 75% of children at three, four years, is no different between an initial Norwood stage one approach versus hybrid palliation. Dr. Marc Ruel: So I think this is obviously very intriguing data. It's used to be that a hybrid palliation would only be used in very high-risk cases. I think this would provide credence to using it in a more liberal fashion. There's still the possible caveat that the centers that use hybrid palliation have a little bit of a "expertise bias," if you will, because they have both modalities being available. But I think this is a very important and very intriguing data for this extremely challenging condition. Dr. James de Lemos: Well, thank you. And I'd like to thank both you, Marc, and Mike for just tremendous insight. I think for somebody that doesn't live in the cardiac surgery world, having the privilege, not just to hear you explain these terrific studies, but also provide your insights in pearls about cardiac surgery and vascular surgery care in 2021 has been invaluable. And I think our listeners will feel the same way. I'd like to turn it over to you, Marc, as our leader in cardiovascular surgery to close us out today from a wonderful podcast. Dr. Marc Ruel: Well, thank you very much, James. Again, I want to reiterate, I think this is really a tremendous issue. It's our best ever. And I want to thank you, James and Joe Hill, as well, our Editor-in-Chief, for your support of surgery within Circulation. I also want to thank Sarah, Molly, Nick, and Augie, really, for their in their indefatigable support of our issue. I want to, again, extend our gratitude to Tim Gardner and to Mike for their tremendous help with this issue. I think this is, again, very important. Do send your best work, and I'm speaking to our readership community and all surgeons to Circulation. Dr. Marc Ruel: Circulation is our premier journal and surgery's tremendously important. And the interface together is a strong one, because Circulation realizes that surgery provides, and I'm a bit biased when I say this, but I think it is true. It provides the most robust and durable treatment for advanced heart disease, so it is very important to be featured prominently in Circulation. And I think this is what our current leadership and staff at Circulation are supporting, and I'm tremendously thankful on behalf of all surgeons. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Nesta semana falei dos seguintes tópicos neste episódio: O que é e como agem os hormônios esteróides? O que é testo e Quais consequências dela baixa? 10 Condições que abaixam sua testosterona.... O que vc acha de ressuscitarmos o Mamute? Quais eram os objetivos da Cientista ( Katalin Karico) que inventou a Vacina de RNA?
What makes a virus mutate? Why does bladder control become so much harder to achieve the closer I get to a toilet? How does sneezing work? How are vaccines quality controlled and assured around the world? What happens to Covid-19 vaccines if the cold-chain is broken? Dr Chris and Africa Melane have the answers... Like this podcast? Please help us by supporting the Naked Scientists
What makes a virus mutate? Why does bladder control become so much harder to achieve the closer I get to a toilet? How does sneezing work? How are vaccines quality controlled and assured around the world? What happens to Covid-19 vaccines if the cold-chain is broken? Dr Chris and Africa Melane have the answers... Like this podcast? Please help us by supporting the Naked Scientists
https://magtein.com/products/magtein-orginal-formula enter code DREW Today's show is packed with value. From a track athlete and wrestler, to a community pharmacist, and now a cardiovascular research scientist, doctor of pharmacy, and author of at least 5 life-changing books, Dr. James Dinicolantonio is here to help blow the lid off of nutrition myths and legends. 0:57 "A lot of my patients were suffering from symptoms when their doctor put them on a diuretic to lower their blood pressure, or told them to reduce their salt intake. They felt terrible." Dr. James has hundreds of positive reviews on his books The Mineral Fix, The Salt Fix, The Longevity Solution, and others. Many of these reviews are very personal stories of people sharing how their lives have been changed and improved after following his research and advice. 2:17 "Being more omnivorous optimizes all minerals, better than being a vegan or a carnivore." The average American is not only missing out on the quantity of vegetables they need daily, but they're also not eating enough variety of fruits and vegetables. Our diet does affect our pH balance in the body. Yes, the body does regulate pH on its own, but our bicarbonate levels can go down if we eat high acidic foods without offsetting them with some type of base. 3:28 "Two different waters that are pretty high in bicarbonate and minerals, one is Gerolsteiner, and the other is San Pellegrino." If you have a diet higher in animal foods, your body might struggle a bit to maintain the proper acid levels. So fruits and vegetables or at least bicarbonate mineral water are essential for helping the body balance itself. "5:09 "In order for a neuron to fire and for muscles to move, sodium has to go into the cell, potassium gets kicked out and it's called sodium-potassium ATPase, and it requires ATP and magnesium to do that. So we're alive because we're these electrical, basically these walking bags of salt, fluids, and electrolytes." Both physical performance and cognitive abilities depend heavily on minerals and electrolytes. There's so much information and electrical transfer that happens throughout our body. None of our cells would be proper conductors for that electrical transfer without minerals. Magnesium is required for over 600 enzymatic functions in the body, to produce ATP, to create protein and DNA and RNA. They're necessary for hormones and neurotransmitters. So life really doesn't exist without magnesium. Most people aren't even getting the recommended daily allowance of magnesium, let alone the right VARIETY of magnesiums. Further Resources: The Salt Fix: Why the Experts Got It All Wrong--and How Eating More Might Save Your Life - Dr. James DiNicolantonio The Mineral Fix: How to Optimize Your Mineral Intake for Energy, Longevity, Immunity, Sleep and More - Dr. James DiNicolantonio http://drjamesdinic.com/ https://www.instagram.com/drjamesdinic Follow Drew: @Twitter https://twitter.com/drewcanole @Instagram https://www.instagram.com/drewcanole/ @Facebook https://www.facebook.com/people/Drew-Canole/100044261357988/ Visit www.mysoulcbd.com/drew and get 15% off your next order!
On this week's Unsupervised Learning Podcast, Razib sits down with Mahan Ghafari, a doctoral candidate at Oxford's department of zoology to discuss his ongoing research in the area of viral evolution. They discuss the difference between RNA viruses and DNA viruses and how viral evolution differs from that of more complex life forms – accentuated by a virus's short reproduction cycle and high mutation rate - particularly in RNA viruses like SARS-CoV-2 which can mutate orders of magnitude faster than DNA based viruses. Mahan also discusses his involvement in SARS-CoV-2 research and the particular challenges that the virus poses, including what caught virologists off guard and where they got it wrong – particularly about the emergence of variants. He emphasizes how much is yet to be understood about SARS-CoV-2, particularly in how mutations are evolving and in which populations they may incubate and emerge, and the importance of understanding the dynamics between virus and host. Mahan goes on to dispel some common misconceptions floating around the Twittersphere regarding mutation and viral virulence and emphasizes the important distinction between virulence and infectiveness. The conversation concludes with a discussion of the effect of vaccination on the transmission and evolution of SARS-CoV-2 and how having a partially vaccinated population may potentially serve as a viral incubator, making the likelihood of mutation and breakthrough infection far more likely because it gives the virus an opportunity to replicate and maximize its diversity within non vaccinated individuals, while simultaneously exposing it to the selective pressure of the vaccinated – thus driving adaptation and increasing the odds of breakthroughs that are resistant to vaccination and treatment.
Dr. Robert Malone, is the Inventor of mRNA vaccines and RNA as a drug, and he is outraged by the government's decision to mandate people into a one size fits all medicinal solution. Malone is now working on a new media initiative that is just launching. Learn more about your ad-choices at https://www.iheartpodcastnetwork.com
In this episode Keta & Dani of the East Oakland Collective and I talk about the changes they're creating in Oakland to increase accessibility. We all know there's no damn reason for communities of color to be under-resourced other than whyteness doing what it does! And Dani let us know that no community, even if it's underdeveloped, ever goes unmapped or unplanned. So what can we do about houselessness, transportation, and making sure our communities thrive? How can we be the ones to stand up for our cities to increase access? Bc let's face it, we've always known WE gotta take care of US.! How can we create what we want to see and get the resources for it? Listen, learn, and get involved! ABOUT WEEZE Louiza Doran, known and referred to as Weeze, is a cis-het Amazigh* female-identifying human who uses she/her/they/them pronouns. She's known as a coach, podcast host, advocate, agent of change, strategist, and educator (to name a few) but is ultimately a compassionate provocateur that is out to help folks uncover their path of possibility. ABOUT KETA & DANI Marquita “Keta” Price (she/her/Goddess), aka “The Hood Planner,” is a third-generation East Oakland native serving as the Director of Urban and Regional Planning for The East Oakland Collective. Keta's formal passion for urbanism came about during recreational research on how gentrification has impacted low-income Black “hoods” across the nation. As director, Keta is the lead on several East Oakland neighborhood & transportation planning projects, participates in the development of local urban and regional planning, and holds the city of Oakland accountable to equitable zoning and land use in East Oakland. Her early activism and care for community is rooted at Merritt College, where she served as the Vice President of The Black Student Union, President of the Kem(istry) Club, President of the Associated Students of Merritt College (ASMC), and served as a Student Trustee of the Peralta Community College School District. Keta's initial goals were to restore the intellect and militancy of Merritt's student government. Seeded by Chairman Bobby Seale and other former Black Panthers, ASMC focused on leveraging the institution's resources to address the socioeconomic issues from the flatlands prohibiting students from thriving academically. Keta's political and social goals pulled her away from studying chemistry to deeply exploring how societies, communities, and cities are planned, designed and constructed. As a chemistry major, Keta received an achievement award for the completion of The Center for Educational Partnerships NIH-UCB internship. During this project Keta synthesized pro-fluorophores used for live-cell RNA imaging. Keta also received recognition and commendation from the California Legislature Assembly and State of California Senate and the Alameda County Board of Supervisors for her student advocacy work with the Tobacco-less Club at Merritt College. Keta has an Associates of Science in Mathematics and Natural Science. When the opportunity presents itself, Keta plans to further her education in Urban Studies, Data Analysis and Design. Danielle "Dani" Dynes is a dedicated community planner who was born in East Oakland and raised in West Oakland. As a planner, she focuses on the present needs of residents and while creating strategies to deal with the challenges of the future. She works to bring more resources and infrastructure to Oakland and ensure we have safer, healthier, and well-connected communities moving forward. Danielle has a B.A. in Urban Studies and Planning from San Francisco State University. She has previously worked at the Oakland Department of Transportation (OakDOT) in their Planning and Project Development section. Several of Danielle's projects at OakDOT prioritized equitable and culturally relevant change in the East Oakland community. She facilitated events around the 90th Avenue Scraper Bike Way and conducted community outreach for the East Oakland Mobility Action Plan. She also helped manage Sustainable Transportation Planning grants while interning at the California Department of Transportation. Before she studied planning Danielle taught website design and visual communication to students in Oakland and Richmond. In 2016 she was honored as a Youth Development Fellow by Coro, a civic leadership training organization. In her leisure, Danielle enjoys photography, crafting, hiking, and gardening. IN THIS EPISODE, WE TALK ABOUT How EOC's founder, Candace Elder, said hell nah to the ways her community was deteriorating due to gentrification and decided to address issues like pollution + houselessness. The fuckery with folks seeing systemic challenges and thinking it's random or beyond our control, but it's not! We knowwww this! Why disparities and underdeveloped communities even exist, when communities are always mapped out and planned. How the white flight outta of East Oakland and left the whole area for dead!. There's no designated funding to give to communities to plan their own communities surprise surprise, so a lot of that grunt work falls on nonprofits, grassroots people, and individuals to fill that gap. How a lack of economics, transportation, and accessibility affects communities + what we can do to help! CALL TO ACTION Support the East Oakland Mobility Action Plan. Get involved with the Mobility 4 All program, their new clean mobility fellows, and an upcoming project funded by the STEP Grant to explore the feasibility of implementing a zero-emission bus shuttle to bridge access to nearby local/regional park-The Martin Luther King Jr. Shoreline. EPISODE TRANSCRIPT https://drive.google.com/file/d/1eq-twyoJeB5ipLs7kbAWjF0Kgq210WRO/view?usp=sharing FOLLOW WEEZE TO STAY ENGAGED Website: https://www.accordingtoweeze.com Instagram: https://www.instagram.com/accordingtoweeze Podia: https://accordingtoweeze.podia.com/weeze FOLLOW KETA & DANI TO STAY ENGAGED Website: https://www.eastoaklandcollective.com/ Instagram: https://www.instagram.com/eastoaklandcollective/ Twitter: https://twitter.com/eoakcollective Facebook: https://www.facebook.com/eoakcollective
Todd opens the hour playing the daily rants, with topics regarding Lamont, Biden, RNA, and more. Todd then is joined by CT State Senator Ryan Fazio to speak on his first month in office, and how that has gone, and what is on the to-do list now that he is in office. Tune on weekdays 2-6 PM EST on WTIC Newstalk 1080 ;or on the new Audacy app! See omnystudio.com/listener for privacy information.
Sophie St-Cyr, PhD of Children's Hospital of Philadelphia joins us to talk about the heart. Heart disease is the second cause of mortality from Huntington'sand patients present an increased incidence of heart failure and a smaller heart. This heart pathology will need solving to improve the longevity and quality of life of HD patients. Dr. St-Cyr will explore the contribution of two RNA-binding proteins (RBPs) in the HD-associated cardiac pathology. RBPs are responsible for regulating the RNA splicing of hundreds of genes, a phenomenon by which different proteins are produced from the same gene and serve different functions. CELF1 is responsible for heart splicing during development while MBNL1 does so in adulthood. Dr. St-Cyr hypothesizes that imbalance between these two RBPs is in part responsible for the HD heart pathology. To test this, she will identify all the RNA isoforms abnormally expressed in the heart in a HD mouse model and determine whether increasing MBNL1 expression ameliorates heart size and contractile function.
This month on Episode 28 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the August 20th and September 3rd issues of Circulation Research. This episode also features an in-depth conversation with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. Article highlights: Gupta, et al. Electronic Cigarettes and Oxidized Lipids Bartosova, et al. Glucose Derivative Induced Vasculopathy in CKD Atmanli, et al. DMD Correction Attenuates Cardiac Abnormalities Ma, et al. Length Dependent Activation in Porcine Myocardium Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast for the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I will be highlighting articles presented in our August 20th and September 3rd issues of Circulation Research. I also will speak with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. Cindy St. Hilaire: The first article I want to share is titled Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers. The first author is Rajat Gupta and the corresponding author is Jesus Araujo from UCLA. E-cigarettes have surged in popularity in the last decade and while many people switching from traditional cigarettes to smokeless ones view the latter as a safe alternative to smoking tobacco, emerging data shows that E-cigarettes cause adverse effects such as oxidative stress, inflammation and endothelial dysfunction in users. The aerosols produced during vaping contain similar levels of reactive oxygen species, also called ROS, as the vapors of tobacco smoke. However, data on the extent to which E-cigarettes, E-cigarette ROS, influences cardiovascular health is lacking. Cindy St. Hilaire: To address this, this group recruited 32 chronic users of E-cigarettes, 29 chronic tobacco smokers, and 45 individuals that used neither and they measured their plasma levels of oxidative biomarkers. The team found both similarities and differences between the E-cigarettes and the tobacco users. For example, both smoking groups had increased plasma antioxidant capacity and decreased levels of oxidized linoleic acid compared with the levels seen in non-users, while arachidonic acid levels were raised in tobacco smokers and reduced in E-cigarette users. Overall, however, the biomarker levels were deemed to be intermediate for E-cigarette users between the non-users and the tobacco users. This study suggests that while E-cigarettes carry a lower health risk than tobacco, they are by no means safe. Cindy St. Hilaire: The second article I want to share is titled Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis. The first author is Maria Bartosova and the corresponding author is Claus Schmitt and they're from the University of Heidelberg. Diabetes, high blood pressure and obesity are risk factors for both cardiovascular disease and chronic kidney disease. Worse still, loss of kidney function and even dialysis itself are thought to exacerbate cardiovascular issues. In the case of dialysis, it's thought that high levels of glucose degradation products, or GDPs, in the dialysis fluids can promote the addition of sugar moieties to vascular proteins and lipids causing vascular damage. To investigate this theory, Bartosova and colleagues studied vascular tissue from children with chronic kidney disease receiving dialysis fluids with either high levels or low levels of glucose degradation products and compared these to tissues from children not on dialysis at all. Cindy St. Hilaire: Proteome and transcriptome analysis of the vessel tissues revealed that compared with patients or no to low GDP fluids, patients receiving high GDP fluids had higher levels of damaging glycation, increased transcription of genes involved in cell death, and decreased transcription of genes involved in cell survival and cytoskeletal reorganization. In line with these findings, vessels from high GDP patients displayed considerable evidence of damage, such as markers of apoptosis, skeletal disintegration and thickened intimas. The results confirmed GDPs can cause vasculopathy and suggest low GDP fluids should be used for dialysis patients. Cindy St. Hilaire: The next article I want to share is titled Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy. The first author is Ayhan Atmanli and the corresponding author is Eric Olson from UT Southwestern. Duchenne Muscular Dystrophy, or DMD, affects one in 5,000 baby boys and is caused by mutations in gene for dystrophin, an architectural protein essential for muscle cell integrity. Patients display profound muscle degeneration and weakness, with respiratory and heart muscle dysfunction being a major cause for death. With the recent improvements in respiratory medicine that extend the lives of patients, this group now focused on heart dysfunction and specifically, whether gene editing could mitigate it. The team created induced pluripotent stem cells, or iPSCs, from Duchenne Muscular Dystrophy patient and his healthy brother and showed that gene editing from the DMD cells enabled their development into normal-looking cardiomyocytes with normal contractile function and calcium handling, equivalent to that seen in healthy control cells. The unedited DMD cells, by contrast, did not develop normally. For great clinical relevance, the team edited DMD cells after cardiomyocyte differentiation showing that this reduced their propensity for arrhythmia, compared with that of unedited cells. Cindy St. Hilaire: Lastly, the team provided evidence to suggest gene editing may improve heart abnormalities in mice with the same mutation. All together the results are proof of principle and support of the development of gene editing therapy as treatment for DMD. Cindy St. Hilaire: The last article I want to share is titled The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium. The first authors are Weikang Ma and Marcus Henze and the corresponding author is Thomas Irving and they're from the Illinois Institute of Technology. Myofilament length-dependent activation or LDA is the fundamental mechanism coupling the force of the heart's contraction to it's proceeding diastolic volume. In other words, LDA ensures that the more the heart fills, the stronger it contracts. Studies of rodent hearts have given insights into LDA mechanics. However, how it operates in large mammalian hearts is unknown. Using structural and biochemical analysis of pig myocardial fibers, this group found that compared with small stretches of the fibers which were equivalent to small diastolic volumes, long stretches induced greater ATP turnover and greater numbers of cross bridges between myosin and actin filaments which are critical contractile machinery proteins. Cindy St. Hilaire: Myosin motors can be found in three stages, engaged with actin, unengaged in a disordered, relaxed state but ready to engage, or super-relaxed state where they are essentially switched off. The team showed that as muscle stretch increased, the amount of super-relaxed myosin motors diminished with more myosin motors becoming engaged to enable a stronger contraction. When the fibers were treated with a myosin motor inhibitor, these stretch effects were impaired. In revealing the mechanisms of myofilament length-dependent activation, this study provides a platform for studying cardiomyopathies in which this system goes awry. Cindy St. Hilaire: So today, Dr Scott Cameron from the Cleveland Clinic and corresponding author of the paper, Dr Milka Koupenova from the University of Massachusetts Medical Center, are both with me to discuss their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. And this article is in our September 3rd issue of Circ Research and for full disclosure, the editor of Circ Res, Dr Jane Freedman is also an author on this manuscript. And for full double disclosure, I know Dr Koupenova quite well as we were both graduate students together back in the Ravid Lab at Boston University. However, the full Editorial Board selects these articles, not just me alone and this one is timely, novel, and an amazing story. So thank you both for joining me today. Milka Koupenova: Thank you for having us. Scott Cameron: Privileged to be here. Cindy St. Hilaire: So before we jump into the story that is your paper, can you give us a little bit of background about platelets? I know for years, I guess certainly before Katya's lab, I just thought of platelets as little nucleus-free particles that clot. But we know they are so much more than that. So why are they so important? And how do they function to do more than just stop a bleed? Milka Koupenova: So this is a great question, Cindy, and I am happy that you alluded exactly to the anucleated nature of platelets. So platelets are cell fragments. They're precursors in the bone marrow, the megakaryocyte. They are the second most abundant blood component after the red blood cells. And traditionally, platelets have been known, as what you pointed out, as these little units that change their conformation once there is some form of a problem with either the vascular, which we have a cut, they come together, they form this clot, and bleeding is prevented. But as we have learned perhaps in the past 20 years that platelets have a profound immune role during various immune processes and infections for different kind of microbes. And particularly relevant to this paper is that we understand that platelets have clearly a role responding to the viruses and activating the immune system. Cindy St. Hilaire: Yeah, and that was actually my next question. You and Jane are the world-leading experts on platelets and viral responses. So what was known about that interaction, I guess before we started looking at SARS-CoV-2, what was known about that platelet virus or even type of virus interaction? Milka Koupenova: So SARS-CoV-2 is a RNA virus--respiratory virus that we actually thought similarly to influenza that it mostly stays in the lower respiratory tract where it becomes problematic. However, from our work with influenza, when we saw that in certain patients you actually can detect the virus in platelet. In the beginning of the pandemic, we hypothesized that perhaps, in some people, the virus crosses over into the circulation. And based on our previous studies with influenza, we wanted to see if that indeed is the case. Hence we initiated a study here at UMass with the department head who is also on the paper, Dr Finberg, who is a leading expert in influenza and novel virus and we collected platelets from people to see if we can detect it. And so in the beginning, we were not able to detect SARS-CoV-2 in platelets. So we collected platelets from 17 patients and by qPCR with the primers that the CDC has, for whatever reason I couldn't detect anything. And I was really frustrated because previous reports have shown that about 25%, in some people even 35% of the study population, SARS can be detected. So very interesting observations. Milka Koupenova: I could see it by immunofluorescence but I couldn't detect the RNA. And the story goes, that I attended a seminar on SARS-CoV-2 and the person was actually referencing a company that started from University of Pitt where you are. Cindy St. Hilaire: Oh, very nice. Milka Koupenova: And they do specific, it's called amplicon ARTIC v3 sequencing so they enrich for the SARS-CoV-2 RNA and screen by sequencing. And when we did that, we were able to detect it in all patients. So I freaked out and I said, "Oh my gosh, something is wrong." Milka Koupenova: And so I sent plasma, and I sent controls, and actually RNA from the virus and you can see beautifully that it's only in platelets. Four of the 17 people actually had RNA in the plasma, but what you can observe in all these people is that the virus is fragmented, meaning it's not infectious. And in a way what this tells us, it suggests that platelets are super important in the removing it from the circulation and they probably serve as a dead-end for the virus because you cannot find virus coming out of platelets and the RNA is chopped off. So what I would say, is that platelets are these amazing little units that serve as removal of the viral RNA for these particular viruses, respiratory viruses that are RNA viruses. Cindy St. Hilaire: I think that is so interesting. So essentially, they're almost like little composters that are chewing it up and preventing it from spreading in the organism. Milka Koupenova: Yes, and as a result there is a response. Cindy St. Hilaire: Scott, probably the most common thing that people know with SARS is that loss of smell, or taste, and things like that, but really that doesn't send anybody to the hospital. So really what are the symptoms of COVID-19 patients that tie in with platelets specifically? I feel like that's a lot of things that we maybe in the public, or on Twitter, and things didn't hear as much about. So really what are those big symptoms linking COVID and platelets and what are the implications of platelet death in the pathogenesis of COVID? Scott Cameron: So certainly I think several investigators are in the world of now showing that platelets are hyperactivated, Robbie Campbell and Matt Rondina put a really nice paper in Blood last year showing that platelets are hyperactive and there are other investigators who found something similar. And so the question is, what are the symptoms of hyperactive platelets in the SARS-CoV-2 patient? So what most of them would find is shortness of breath or dyspnea, and when they present to the emergency department, and certainly we saw this, the oxygen saturation which should be in the mid to high 90s on room air on an average person, was quite often low. It was in the 80s or 70s, sometimes even the 60s. Scott Cameron: And the real surprising thing was those are patients that would normally immediately be on a ventilator, but yet they could still be talking to you. And so if you have a platelet that's activated in a hyperthrombotic condition, like SARS-CoV-2, COVID-19, and then that forms a blood clot, you have a situation where the amount of oxygen the patients taking in and the amount of oxygen you're measuring in the artery is quite discrepant and we call that the alveolar arterial or oxygen gradient. So if you've got lots of platelet plugs through the microvasculature, it's going to take up some space the oxygen should be using for diffusing in. And so that would be manifested as shortness of breath and that's certainly one of the biggest tip-offs that a patient might have a blood clot, particularly in the lung. Cindy St. Hilaire: Some of these symptoms of COVID-19 are really worse in patients with comorbidities, diabetes, obesity and heart failure. Are platelets central to kind of the pathogenesis of those disease or the symptoms of those diseases? I guess the root of my question is, why do the comorbidities of diabetes, obesity, and heart failure make COVID worse? Is it something about those disease states themselves or is there a role for platelet? Scott Cameron: That's a brilliant question, no one's ever asked that before. And as Dr Koupenova said, I'm a little bit biased too because I firmly believe that in different disease states, the disease educates the platelets so you've got a different platelets phenotype. So focusing on diabetes, we know the platelet phenotype is different in diabetic patients. We know that platelet reactivity seems to be higher through the P2Y12 receptor. In terms of obesity, it is true, we know that, and this has been published also, and we know that the platelet phenotype is hyperactive in a patient with obesity and so that tells me that, that's a comorbidity that might affect platelet function and also vice versa for that case. And then in terms of why is it affecting males more prominently and more severely than females, well one of the beefs, I guess, that I had is that we treat diseases in women the same as we do in men assuming that the platelet phenotype in disease must be the same, but that's absolutely not true. And that's actually a theme that we have in our lab right now, we know that the behavior of platelets, and how platelets are educated in diseases is not all the same in women as in men and I think it's a huge disservice that we really had to have a pandemic that would make that quite clear to us. Cindy St. Hilaire: You kind of hit onto something that's really, I think it's now becoming more recognized certainly in the cardiovascular field and that is so many studies are really only on male mice, or only younger or older men, and we are missing not only a huge patient population, but probably some really interesting biology that is distinct. Milka Koupenova: So expanding on that, we know that in platelets, the toll-like receptors, and we've looked at the expression of all 10 in a study that we published in ATVB in 2015, actually, significantly if you look at Farmingham Heart Study data and the expression of these toll-like receptors they are increased in women versus men. And also, an interesting observation that never got published, once upon a time when I was doing studies with TLR7 mice is that if you inject TLR7 agonists, male mice would have a higher level of reduced platelet count than female mice at the same time points, right? And at that time it wasn't published. Definitely there are differences, but I also want to extrapolate a little bit on what was said at the beginning. We have to understand that when it comes to these comorbidities, everything affects a unit that doesn't have a nucleus, right? And diabetes and obesity have the so called profound, chronic inflammation of cytokines, such as IL6, that keep circulating. These things have effect on platelets. So we have two responses, we have the environment that affects platelets and we have the direct response of the virus that affects platelets. And that cumulative response truly can exhaust them and once they become exhausted, once they release their contents, as we show in this paper, then you're compromising their function and you will be compromising taking out the virus from one side and from the other side you're going to be compromising the environment because all of the content that comes out from a unit that already has free form proteins, it exhibits a true insult on what's being surrounded. So these clots that form in the lung or the platelets that circulate they no longer can be resolved properly. Cindy St. Hilaire: Yeah. Milka Koupenova: It's a balance. Cindy St. Hilaire: Yeah, so really it's like destroying the platelet not only are you destroying the vacuum that has to suck up those particles, you're then just dumping a whole bunch of pro-inflammatory things on all of the endothelial cell vasculature that those platelets are nearby. Cindy St. Hilaire: Actually that was one thing that I thought you spent a decent portion of the discussion on, and that is the method by which the blood is collected really impacts the outputs you observe in quote unquote platelets. Can you talk about the importance of that because I think that's one thing, certainly as a PhD who's just like, "Oh, yeah. I'm just going to collect blood from my mice and do this thing," how critical is that point in the experiment, in the blood collection? Milka Koupenova: So I am very adamant when it comes to platelets for the blood to be drawn in citrate. And I have to say that a lot of the studies that you would see in the literature are done using EDTA blood or serum. They all have their importance. I'm not going to dismiss it, but if you want to truly measure what's inside in plasma, versus what's inside in platelets, or what's inside in any cell for that matter, you got to go for citrate. You have to be very careful not to shake the blood. You have to be very careful not to cool down the blood. So the nurses probably hated me because often I would be like, "You can't do this. You can't put it on ice. You can't warm it up to above certain degrees. Everything has to be controlled and done correctly." Milka Koupenova: And so I had done in the past studies in which I would take plasma from the same patient in EDTA, in citrate and then isolate the RNA, have my tech isolate the RNA, and we send it to a fragment analyzer, and you can see how much more RNA you will get in the EDTA plasma. I'm not even talking about serum. Milka Koupenova: Serum is a very different thing, then you're definitely going to get platelet content in it, in the serum, right? So it's important to distinguish that perhaps when you're getting EDTA plasma you are looking at a content that could have been inside in platelet and I can't stress enough that when it comes to these particular studies, citrate, dextrose, phosphate is your place to go and be. Cindy St. Hilaire: So in terms of translational potential, what do your findings suggest about future therapies or targets to investigate as therapy? And is modulating platelets a potential for combating viral infections or mitigating their severity? Milka Koupenova: Well, Scott and I actually talk a lot about that. Scott Cameron: That's right. Milka Koupenova: I personally would say, control the inflammation, never let it go to platelet. Let me back up a little bit, if you have to, you have to, right? But your go to method should be inflammation, if you don't get to the point that you need to control platelets then you're in a better place because it becomes very fickle. From everything that you hear me say, you push it to one side and the balance is destroyed. You deactivate platelets or inhibit platelets well, are they now not able to pick up the virus and then you're now having the virus circulating somewhere. Now, if you don't treat platelets that's also not good. So you're in the very fickle situation if you get to the point that you need to control the activation of platelets and there are trials currently that are trying to look at those things. Scott, I'm going to refer this a little bit more to you because you have done some interesting things with that particular point. Scott Cameron: No, it's a great question, Milka, and I think that as platelet biologists, nobody more than I wanted it to be true that platelets would be the ultimate target. I mean, clearly patients with SARS-CoV-2 have thrombosis, clearly platelets are activated, so should we inactivate them? That was the whole point of the RECOVERY trial and one of the benefits I'll tell you before I sort of go into that is, working in a large organization like the Cleveland Clinic and we have access to data and lots of it extremely quickly, and so because of that I of course could see how many patients were coming into our hospital with thrombotic events. And I could see what the independent predictors of thrombotic events was and it wasn't the platelet count, sometimes platelet count was low, sometimes it's high in the SARS-CoV-2 patient. And if you took those individuals that were on aspirin, comparing them to those that are not in a propensity match study, one of the things that we find is that aspirin doesn't seem to affect or improve mortality or the number of blood clots in the patient with SARS-CoV-2. Scott Cameron: We compared that to all non-steroidal anti-inflammatory medications that patients may have been taking also in a propensity match study just in case it was the mechanism action of the drug, rather than the drug itself, and we found that NSAIDs not only did not protect patients, but they were not necessarily harmful either, which was one of the things that came out at the start of the pandemic. Among, I'll add, the absence of evidence based medicine and a lot of cases where naturally people, including clinicians, were scared and so they were going off label and they were trying a lot of different medications with really not a shred of randomized controlled data. Scott Cameron: But now that we're 18 months into it, the first and biggest study that came back was the RECOVERY trial, which we were all waiting on, where patients were given aspirin and short term mortality was examined over an observational period of one month. And just like we found in a propensity match study, which is as close as you'll get to a clinical trial in a retrospective manner, the prospect of RECOVERY trial actually showed the curves were almost super imposeable, those that got aspirin versus those that didn't. So I think low dose aspirin clearly is not going to be enough for those patients, but I'll also add that over the observational period of one month they also didn't see a higher incidence of death in those patients. And I think Milka's point is really well taken that you have to remember that as well being an entity of thrombosis, platelets are immunological entities and so you've got to really consider should we be inhibiting them and if you are inhibiting them, I think the time point at which you should inhibit them is what we should examine, not just an all or nothing, inhibited or not. Milka Koupenova: It's just in our linear brains we prefer to think of it as one straight, linear pathway, but it isn't, and I think platelets are actually a great example of how many pathways are feeding into one tiny fragment and that particular blood cell is inducing this profound response during these infections. Cindy St. Hilaire: I think most people have heard that angiotensin-converting enzyme 2, also called ACE2 is the receptor of SARS-CoV-2. The virus itself uses it to bind and become internalized into the cell, but there's been some discussion or even some discrepancy of data as to whether platelets truly express ACE2 and if that is the means for the virus to enter the platelets. So can you share with us what is the current state of knowledge about that? Scott Cameron: Yeah, just as a segue of some of the things that Milka said, I think the preparation of your sample is part of the answer. If you draw in the incorrect tube, if you the tube is not completely filled, and the ratio of citrates to whole blood isn't correct you're going to have discrepant results. If you biomechanically activate the platelets by drawing through a short needle, in a small-bore needle for example, that's going to activate the platelets. If you cool them, it's going to activate them. But then also, depending on how you decide to separate them, we always washed platelets in my lab, we wash them two or sometimes three times, and I can tell you if you use flow cytometer we get one white blood cell for every 12,000 platelets. Scott Cameron: And some investigators might go one step further and they'll a CD45 depletion set, which is certainly important if you're studying RNA. But one of the issues, as you well know, a CD45 is also on the surface of platelets, so if you start with a low expressing protein and you CD45 deplete them, you are actually going to get a decrease in your platelet yields. I've seen it, I think Milka's seen it, various other investigators have, and you might find yourself at the threshold of what your antibody can detect. It's also variably expressed. If you look at even healthy individuals, some of them have almost none. So if you look at 10 individuals, you might actually find none, but then if you look at another 10, the amount of expression that we see is kind of all over the place. It's not like other receptors where one tends to express a certain amount and that's the way it is in health. ACE2 doesn't seem to be that way for whatever reason. Milka Koupenova: We were able to detect in some of the people by qPCR, but what was interesting is that from the three primers that I used there was never the same person who we were able to detect all three primers with for that receptor. That tells you that maybe they are changes of one base that is not enough for the primer to detect it, right? That becomes another possibility of not being able to detect. Milka Koupenova: And so I go to confocal microscopy where I use 100 lens and tons of hours in the microscope room, and Scott is completely right, it's really hard to see it particularly in healthy people. And it starts to pick a little bit more in people with cardiovascular disease or people with COVID that are old. So it's a bit complicated, but the important thing here is, besides the fact that we are detecting ACE2 and we're detecting proteins and I use controls, biological controls to prove that this is the case and it's not just an antibody problem, is that the virus will get picked up by platelets even if you don't have ACE2. That is the take home message from this paper is that the platelet has evolved various mechanisms by which is utilizes getting it inside. It is that important for this virus. This type of virus is not recirculating. In this case, what we observed is that the virus is attached to microparticles that are of platelet origin for that matter. Cindy St. Hilaire: So really what you're saying, what I'm hearing is the platelet is the superhero of the body. Milka Koupenova: Definitely. Absolutely. No bias, absolutely. Cindy St. Hilaire: Unbiasedly, it is a superhero. Well, Dr Cameron and Dr Koupenova, thank you so much not only for this amazing discussion, but for really an elegant, elegant paper that is really bringing to light the complex interaction between SARS-CoV-2 and platelets. So thank you so much for joining me and keep publishing amazing stories like this. Milka Koupenova: Thank you for having us. Scott Cameron: Thank you, an honor to be here. Thanks again. Cindy St. Hilaire: That's it for the highlights from August 20th and September 3rd issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Scott Cameron and Dr Milka Koupenova. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.
Episode Summary: Novel drugs that boost the immune system to fight cancer have become pharma darlings in the few short years since their approval. These drugs, known as immunotherapies, have so far focused on improving T cell responses and can be used to cure a multitude of different cancer types. Yet more often than not, immunotherapies have no effect on a patient, leaving doctors guessing on whether to prescribe the drug. To find the reason why some people respond while others don't, Kevin and his team create a huge database of sequences derived from immunotherapy-treated patients. With it, he discovers biomarkers, mutational signatures, and immune profiles that correlate to response with the hopes that one day, these measurements form a diagnostic to ensure we treat the right patients.Episode Notes:About the AuthorKevin is a group leader at University College London and performed this work in the lab of Charles Swanton at the Francis Crick Institute. Dr. Swanton and his group are experts in studying the genome instability and evolution of cancer.Kevin started his career as a mathematician but was always driven to apply his skills to improving medicine.Key TakeawaysImmunotherapies aim to cure cancer by “taking the breaks off” your immune system, supercharging it to attack tumors.Two immunotherapies known as checkpoint inhibitors (CPI), anti-CTLA-4 and anti-PD-1, work by enhancing T cells and have recently become blockbuster drugs for the treatment of multiple different cancer types.These immunotherapies don't work in many patients and medicine has yet to understand why.Kevin aggregated DNA and RNA sequencing data across multiple studies to generate a dataset that contained over 1,000 CPI treated patients who did and did not benefit from treatment.With this data, Kevin discovers mutational signatures, biomarkers, and immune profiles that correlate to whether a patient will respond to treatment.TranslationKevin finds measurable signatures of a patient's cancer that could be used to determine whether a patient should receive CPIs.This retrospective analysis will need to be validated as a prospective study to determine whether Kevin's findings actually predict response.More tumor data as well as information about the patient's genetics is being brought in to improve the accuracy of this prediction.Collaborations between academics, medical centers, non-profits, and industry partners will enable the findings to make an impact on patient outcomes.First Author: Kevin LitchfieldPaper: Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition
The founders of German biotechnology company BioNTech were researching how to fight cancers using messenger RNA, "the unloved cousin of DNA", when covid-19 first appeared and they realised mRNA could be used to make a vaccine for the disease. Financial Times journalist Joe Miller has been following the company since just before the pandemic and tells Rebecca Kesby how they created the first covid-19 vaccine. Could mRNA help cure other diseases and improve vaccine access to low income countries? We ask Oksana Pyzik of the UCL School of Pharmacy. And how might the technology change the whole pharmaceutical industry? We hear from Dr Richard Torbett, CEO of the Association of the British Pharmaceutical Industry. Producer: Benjie Guy (Picture: a collection of mRNA covid vaccines. Credit: Getty Images.)
Protein is a word in nutrition that horse owners have difficulty understanding. There is good reason for this - because it is more complicated than carbohydrates (sugar) and fat. But why? Horse owners aren't stupid and on top of this, they want to do the "best" for their horses. Protein is used to make the hair coat, top line muscles, hooves, suspensory ligaments, neurotransmitters (Cushing's disease), the immune system (allergies, skin conditions, disease), enzymes (digestive disorders) and hormones (hormone disorders). In addition, the DNA, RNA and all viruses are all made up of the stuff proteins are made of - amino acids. I explain what a protein is and the amino acids that make up all proteins. Then I describe the two reasons why horses are chronically deficient in protein: 1) lack of intake of high quality protein having all the essential amino acids and 2) increased destruction of proteins by the body trying to survive living in a high sugar world. TheHorsesAdvocate.com - Helping Horses Thrive In A Human World
Florida's Senate Democrats called on a critical care nurse to clear up misinformation on whether the COVID-19 vaccine changes your RNA. Also on today's Sunrise: — Gov. Ron DeSantis announces an end to high-stakes testing. — And while preparing to fight off a Texas-style abortion law, Rep. Anna Eskamani files a bill to repeal Florida's 24-hour abortion waiting period law. Eskamani is on the Sunrise interview.
The Corner welcomes back our friend Justin Wagoner to talk about an event that John, Eric and Jason can't wait to attend! This is Rally North America. Take one part Cannonball Run, one part scavenger hunt, throw in a deadline to add a little competition, and you've got a rally that any car can participate in. Have an amazingly great time, while supporting charities (almost $2M raised to date!). From the RNA website: "Routes are chosen that deliver history, scenic beauty, and a driving experience that will prove to be second to none." This show got us excited to want to participate in the next rally and we think you will too! This episode is brought to you in part by Springdale Automotive. With over 25 years in the auto repair and maintenance business, Springdale Automotive is the perfect place to care for the vital workings of your treasured classic cars. Classic Car Corner is proudly sponsored by G.D. Herring, providing insurance for not only your classic cars, but all your life's most valuable treasures, including life, home and collectibles. Visit them today for a customized quote.
Listen to this interview or check out bestbusinesscoach.ca for FULL show notes & the video version of this call. 4 Steps to Stop the Pandemic 1. Vaccinate people who are at high risk. But not everyone like we're doing. 2. Provide self-assessment tools to help people identify if they are high risk. 3. Provide early treatments - purge the parasitic entities suppressing them. 4. Create a home diagnostics system to test if you're infected. About Our Guest Dr. Robert Malone, inventor of the core mRNA vaccine technologies & RNA transfection. He has done extensive research and development work in: Preclinical discovery research, Clinical trials, Gene therapy, Vaccines, Immunology, and bio-defense. Dr. Robert Malone trained at UC Davis, UC San Diego. At the Salk Institute of Molecular Biology & Virology Laboratories. He received medical training from Northwestern University (MD), Harvard Medical School (Clinical Research Post Graduate), and UC Davis (Pathology). To date, he has written close to 100 peer-reviewed publications. These have 12489 citations. 31 are h-index & 50 are i10-index [it's a big deal]. Dr. Robert Malone has been involved in developing, designing, and providing oversight to around: 40 phase-1 clinical trials, 20 phase-2 clinical trials, and 5 phase-3 clinical trials. Plus vaccine-focused clinical research organizations In most of those as medical director & medical monitor. With 20+ years of management and leadership experience in pharmaceutical, biotechnology industries, academia, government and non-government organizations. He is one of the most experienced & credible experts you can find on this subject. His prescription to end this pandemic quickly? 1. Only vaccinate the high-risk groups. Not everyone. Natural immunity is 10x better, stronger, faster, longer-lasting. So if you're not high risk, it should be a choice to not get vaccinated. Vaccine effectiveness is diminishing fast. Covid-19 is mutating way more each week than they anticipated. Vaccine-induced disease enhancement is a real thing. Mass vaccination campaigns are only encouraging this. Based on current rates of reduced vaccine effectiveness. Estimates are current vaccines will be ineffective within 6-12 months. Meaning new ones will replace them. There are legitimate risks involved from vaccination. If vaccines synthesize a misfolded protein, we wouldn't know. Misguided spike proteins CAN cause problems with Prion Diseases. Lipid-nanoparticles with mRNA can pass the blood-brain barrier. The covid vaccines went out fast. We don't have good long-term data. There HAVE been production contamination issues. [See Moderna + Japan as an example]. Alphabet agencies could do better tracking & reporting adverse events. Many things significant to an individual, don't register as clinically significant. Like a 3% drop in fitness for an NFL player]. Recently 2 top brass left the FDA. For reasons related to the third shot rollout. My questions, not his, are: Will a third shot meaningfully boost immunity? Or are they moving big pharma inventory before the new vaccines come in? #ProductLifecycles Did anyone use a fax machine lately? 8 track? CDs? Just curious. Each year some major pharmaceutical company is paying hundreds of millions in criminal and civil settlements. Often for marketing dangerous drugs or paying kickbacks to incentivize prescriptions. 2. Early Detection. Provide home test kits. Apps. Tools to help people make data-driven decisions. If they should get vaccinated or not. Some people need to be vaccinated. Vaccines aren't perfect, but they do serve a purpose. 3. Early Treatment: This is a virus best battled early. Ivermectin, HCQ, Vitamin D & even Aspirin have GREAT data they're effective - if used early. 4. Follow Good Health Science. Allow open discussions about: - Risk Mitigation - Leading Indicators - Black Swans Right now the major alphabet agencies fly in the face of good health science. There is no room for discussion on any of these things. It's either: Follow the narrative of vaccines are our saving grace - or your career is gone. They want 100% irrefutable, giant study data it 100% works. Proof so solid, it's cost & time prohibitive in an evolving pandemic. These emergency use Vaccines have NOT been studied as well as some PRE-existing drugs we could use as therapeutics. Conversations are being shut down as if they're lethal. When it's these NEW vaccines we have no long-term safety data on. He believes in this climate - no one can publish papers saying anything against the narrative. Only if it's a giant study with immaculate outcomes. There is little space for open dialogue or exchange. Careers are being ended for trying to open discourse. Misc items which came up: We don't know enough about Viral Reactivation of Covid-19. Despite years of trying, there are no successful vaccines for a coronavirus. For a successful vaccine, viruses must activate a strong immune response. There have been many problems with corona vaccines in the past. For example, the original SARS vaccine. It actually increased the pathology rather than reducing it. So the first SARS corona vaccine caused, in animals, inflammation in the lungs. Inflammation which wouldn't otherwise have been there if the vaccine hadn't been given. Vaccines can also create hyper-sensitivity in certain cases. This means they work well against main target virus. But when a wildly mutated virus comes along.. The immune system response kills the host. Vaccines in general are very safe. But these COVID vaccines lack sufficient long-term data. In 1976 there was a swine flu outbreak. Mass vaccination campaigns like this rolled out and were stopped due to adverse effects causing neurological issues. Rushing vaccine due process can have severe consequences. August 22nd 2021, a paper was published saying: https://www.biorxiv.org/content/10.1101/2021.08.22.457114v1 "Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor-binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity." But there's no space for discussion... The propaganda machine is running bigger and harder than it ever has historically. Shutting any doubt down. Censorship is rampant. It's really crazy what's going on right now. Some say it's because there is so much profit to be made. According to the FDA website: FDA may authorize unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN threat agents when certain criteria are met, including there are no adequate, approved, and available alternatives. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization Again, Listen to this interview or check out bestbusinesscoach.ca for FULL show notes & the video version of this call. Be safe everyone. As always, thank you for your time & attention.
Artificial Intelligence Podcast Podcast Notes Key Takeaways Viruses can diversify to infect anything because they can break into cells and steal proteinsThe most lethal virus is actually rabies which will kill you if you get it; fortunately, it's slow to develop and also also the only virus that can be treated after exposure (bite)SARS-CoV-2 is different than SARS-CoV-1 because shedding and transmission occurs before symptoms developThe mRNA vaccine mechanism: RNA is put into lipid capsule for protection and injected into muscle then taken up into the cellVaccine hesitancy exists for a variety of reasons – the truth is we don't know anything with 100% certainty so you have to weigh the effects of vaccine versus the effects of virusAntiviral treatments must be administered quickly after the first sign and positive test – by the time you are in the hospital, it's too late to workIt's shocking that we have not put money into widespread, regular antigen testing at homeWe need to stay vigilant to prepare for future pandemics – we have all the information to do what we need (study masks, antivirals, vaccines) – but we have short memoriesRead the full notes @ podcastnotes.orgVincent Racaniello is a virologist, immunologist, and microbiologist at Columbia. He is a co-author of the textbook Principles of Virology and co-host of This Week in Virology podcast. Please support this podcast by checking out our sponsors: – Privacy: https://privacy.com/lex to get $5 added to your account – Justworks: https://justworks.com – Sun Basket: https://sunbasket.com/lex and use code LEX to get $35 off – The Information: https://theinformation.com/lex to get 75% off first month – Athletic Greens: https://athleticgreens.com/lex and use code LEX to get 1 month of fish oil EPISODE LINKS: Vincent's Twitter: https://twitter.com/profvrr Vincent's YouTube: https://www.youtube.com/c/vincentracaniello Vincent's Podcast: https://www.microbe.tv/ Vincent's Website:
Dr Rob reveals several new studies that are challenging the fundamental assumptions that underlie the neo-Darwinian synthesis. Specifically. the 'central dogma of molecular biology' (the thought that information only flows from DNA to RNA to protein) and the Weismann barrier (the thought that only the DNA 'information' in sperm and egg cells is inherited) are both wrong. Recent revelations have shown us that sperm actively absorb and use body-cell-sourced RNA in the epididymis, and one polymerase uses RNA templates in a newly discovered DNA repair system. Neither of these are supposed to be true. Can a vague idea from the 19th century withstand the assault of 21st century knowledge? Hardly. The simplifying assumptions made by Darwin and his contemporaries no longer hold up. Notes and links: Main article: Carter R., The barrier has been breached! Making a fool out of Professor Wise-man, Creation.com, 7 September 2021. Wilhelm D, Palmer S, Koopman P, Sex determination and gonadal development in mammals, Physiol. Rev. 87(1):1–28, 2007; doi: 10.1152/physrev.00009.2006. Crow JF, Age and sex differences on human mutation rates: an old problem with new complexities, J. Radiat. Res. 47(Suppl.):B75–B82, 2006; doi: 10.1269/jrr.47.b75. James ER, et al., The role of the epididymis and the contribution of epididymosomes to mammalian reproduction, Int. J. Mol. Sci. 21:5377, 2020; doi: 10.3390/ijms21155377. Chandramouly G, et al., Polθ reverse transcribes RNA and promotes RNA-templated DNA repair. Science Advances 7(24):eabf1771; doi: 10.1126/sciadv.abf1771. See also the press release from Thomas Jefferson University “New discovery shows human cells can write RNA sequences into DNA”, Phys.org, 11 June 2021. King TE, et al., Africans in Yorkshire? The deepest-rooting clade of the Y phylogeny within an English genealogy, Eur J. Hum. Genet. 15:288–293, 2007; doi: 10.1038/sj.ejhg.5201771. Filming locations: Kennesaw National Battlefield Park and Kennesaw Memorial Park.
We have heard a lot about RNA this past year as messenger RNA vaccine technology has been used for the first time to combat the Covid-19 pandemic. Now RNA-based technology has shown promise to make major contributions to agriculture. A group of researchers at the University of Chicago and two Chinese universities have announced that […]
“Omics”, “differential expression” and “biomarker discovery” – Are these phrases you commonly use in your research? Or have you come across them and wondered what they meant in the context of AD? If you're nodding your head at either of those, this episode is just for you. Join Marcia as she brings you the latest research published in July 2021 on ‘RNA, Transcription and translation in AD'! Sections in this episode: Gene expression and transcriptomics (02:26) Proteomics (17:38) -------------------------------------------------------------- You can find the numbered bibliography for this episode by clicking here, or the link below:https://drive.google.com/file/d/1ynR7Sw7rqiCs_d8ZePpp325nGq87QRFE/view?usp=sharingTo access the folder with all the bibliographies for 2021 so far, follow this link (it will be updated as we publish episodes and process bibliographies), or click the following link below:https://drive.google.com/drive/folders/1N1zx_itPkCDNYE1yFGZzQxDDR-NiRx3p?usp=sharingYou can also join our mailing list to receive a newsletter by filling this form. Or tweet at us: @AMiNDR_podcast --------------------------------------------------------------Follow-up on social media for more updates!Facebook: AMiNDR Twitter: @AMiNDR_podcastInstagram: @AMiNDR.podcastYoutube: AMiNDR PodcastLinkedIn: AMiNDR PodcastIf you have any questions or concerns, do not hesitate to contact us at: email@example.com -------------------------------------------------------------- Please help us by spreading the word about AMiNDR to your friends, colleagues, and networks! Another way you can help us reach more researchers is by leaving us a review on Apple Podcasts or wherever you listen to podcasts. It helps us a lot and we thank you in advance for leaving a review! Every episode of AMiNDR is the result of a huge team effort. Today's episode was scripted and hosted by Marcia Jude, edited by Lara Onbasi, and reviewed by Anusha Kamesh and Ellen Koch. The bibliography and the wordcloud (wordart.com) were generated by Sarah Louadi. Big thanks to the sorting team for sorting all the papers published in June into themes for our episodes: Jacques Ferreira, Elyn Rowe, Ellen Koch, Christy Yu, Nicole Corso, Sarah Louadi, and Naila Kuhlmann. Also, props to our management team, which includes Sarah Louadi, Ellen Koch, Naila Kuhlmann, Elyn Rowe, Anusha Kamesh, and Jacques Ferreira, for keeping everything running smoothly.Our music is from "Journey of a Neurotransmitter" by musician and fellow neuroscientist Anusha Kamesh; you can find the original piece and her other music on soundcloud under Anusha Kamesh or on her YouTube channel, AKMusic. https://www.youtube.com/channel/UCMH7chrAdtCUZuGia16FR4w -------------------------------------------------------------- If you are interested in joining the team, send us your CV by email. We are specifically looking for help with sorting abstracts by topic, abstract summaries and hosting, creating bibliographies, and promotions. However, if you are interested in helping in other ways, don't hesitate to apply anyways. --------------------------------------------------------------*About AMiNDR: * Learn more about this project and the team behind it by listening to our first episode: "Welcome to AMiNDR!"
We are excited to bring you a fascinating interview about our microbiome with Pedram Shojai from Well.org this week! Tune in to understand how our microbiome is the ecosystem of our lives. You'll learn how your gut health affects your immunity and mental health. And the new fascinating discoveries being made about the bacteria in our tissues and organs and how they support healthy function. You don't want to miss Pedram's tips for ensuring you tend a happy healthy microbiome. It all starts in 3…2…1! Dr. Pedram Shojai is a man with many titles. He is the founder of Well.Org, the NYT Best Selling author of The Urban Monk, Rise and Shine, and The Art of Stopping Time. He's the producer and director of the movies “Vitality,” “Origins.” And “Prosperity.” In his spare time, he's also a Taoist Abbot, a doctor of Oriental medicine, a Kung Fu world traveler, a fierce global green warrior, an avid backpacker, a devout alchemist, a Qi Gong Master, and an old school Jedi bio-hacker working to preserve our natural world and wake us up to our full potential. The Ecosystem of Life – Your Microbiome Science has now shown is that we are much more intimately connected with all the life on the planet than we ever knew through the bacteria, viruses, protozoa, nematodes, even parasites that live inside our body. There's RNA and DNA that we can now analyze on these bugs and understand how they support many human functions. These functions are actually attributed to these bacteria that are co-existing with us. The word is symbiosis. All of this life in and around us is part of what makes us human and without it, we collapse, and we fall ill. If you don't have proper gut health and you're not supporting the life inside of you, there are entire systems that are collapsing that are leading to inflammation and chronic disease. Where It All Begins The first inoculation of our microbiome is as we come through the birth canal. 30% of mom's breast milk are these oligosaccharides that get secreted by mom. They are indigestible by baby. They're specifically designed to feed the bacteria in the baby's gut. Now fast forward here, you need to eat the fiber, vegetables, phytonutrients, and all these things that these bacteria eat, not for you but for the bacteria. If we put them first and understand how to feed them, they take care of us and in turn we get less illness, less chronic disease, we have more energy, things work. Every Tissue, Every Organ In The Body Has Bacteria Associated With It Researchers found that women with tumors in their breasts had a different mix of bacteria living in the tissue compared with women who did not have tumors. The research team discovered for the first time that healthy breast tissue contains more of the bacterial species Methyl bacterium. It is blowing the doors open on everything we know about medicine and this is just the beginning. The Microbiome and Your Immunity About 70% or so of our immune system is around our guts, it's called the gut associated lymphatic tissue. The bacteria are acting as the sentinels between the outside world and the inside world and telling the immune system that everything is good. You can't heal if your immune system is constantly battling and that all starts in the gut and that all has to do with how the microbiome is informing the immune system to either attack or to relax and it will do so based on what is in there. What Lifestyles Are Destroying Our Microbiome and Causing Leaky Gut? Standard American Diet Not enough prebiotics to feed the good bacteria. Food allergies like gluten and dairy. Why Leaky Gut Matters Once you start creating inflammation and tears in the lining of the gut, there are food particles that will sneak through and the immune system says, “Hey, you're not supposed to be on this side.” It will start to create antibodies to those food particles as foreign invaders. This is how food allergies are created. Creates systemic inflammation throughout the body. How to Improve Your Microbiome Work with a Functional Medicine Doctor. Analysis of your microbiome. You look at how we need to eat and ‘who' we need to feed. Include indigestible fiber in your daily diet. You consume a variety of fermented foods and prebiotic foods with every single meal and you adjust for feeding the bacteria that help you thrive. Reduce sugar in your diet. By bringing down the bacteria, specifically like the yeast and bad bacteria that thrive on sugars in particular, you'll start to notice a difference very quickly. Increase fiber intake. Benefits of a Healthy Microbiome Brain fog dissipates. Anxiety and depression reduced. Energy levels increase. Excess weight is released. What Role Do Parasites Play in Gut Health? We're finding that there's certain parasites that help bring down your blood sugar. Certain parasites will help you offset certain disease processes. The research in new and ongoing in this area. Resources: Interconnected Docuseries Well.org Viome - At Home Gut Microbiome Testing Metabolome Symbiosis Cleveland Clinic Researchers Find Link Between Bacterial Imbalances and Breast Cancer What prebiotic foods should people eat? 11 Probiotic Foods That Are Super Healthy Gut-associated lymphoid tissue Intestinal permeability Candidiasis The Institute for Functional Medicine The Hygiene Hypothesis Probiotics Benefits for Women: 7 Reasons You Need Probiotics & What to Look For L. Plantarum Probiotic: 5 Benefits for Managing Weight, Cholesterol & Metabolic Disorders 3 Reasons Why People Over 60 Need Probiotics
Mauro Calabrese, Associate Professor at UNC Chapel Hill and Director of Graduate Studies in the Department of Pharmacology, discusses the future of RNA-based therapeutics and the role of lncRNA in gene transcription. The Bioinformatics CRO is a fully distributed contract research company that serves the computational biology needs of biotechnology companies, with a focus on genomics. https://www.bioinformaticscro.com/
Welcome back to Zillennials Podcast Book Club! This month we read The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race by Walter Isaacson. This is a nonfiction pick that covers the history of DNA & RNA, the life of Jennifer Doudna, and how we came to a world where gene editing is possible. Kaylee and Lian will discuss the parts of the book that they found most interesting, their personal opinions on gene editing, and their overall impression of the book in this episode.
Thank you for joining us for our 2nd Cabral HouseCall of the weekend! I'm looking forward to sharing with you some of our community's questions that have come in over the past few weeks… Let's get started! Sarah: Hi Dr. Cabral! I listened to your podcast regarding new evidence showing that RNA segments can be written back into DNA and influence its sequencing. I've heard some suggest concerns over the Covid 19 v delivery method, via mRNA, affecting one's DNA. Thoughts? Thanks in advance! Learning so much from your podcasts! Tim: Dr. Cabral, We appreciate your show and teachings. Regarding the current unmentionable virus, we have read that viruses can stay alive on different surfaces for varying amounts of time. My wife is a germaphobe/over-thinker, and to be cautious, we have either been wiping down everything that we bring into our house or letting it sit for a few days before using it. However, we have read that getting sick from surface contact is not as likely to happen as from airborne exposure. Would you recommend wiping/quarantining items, or is the risk simply too low to not make the effort worthwhile? I am hoping to stop and have her feel comfortable. Thank you! Michaela: Hi, I love your podcast! Thank you for answering people's questions, its awesome. 2 years ago while pregnant with my second child I started getting greyish brownish spots on my torso, neck, and a few on my arms. The dermatologist diagnosed it as CARP, confluent and reticulated papillomatosis. There really isn't much information about this online. I won't take antibiotics for this, I am curious if you have any idea where this is stemming from (liver, kidneys?) and how to treat it from a functional medicine perspective. Could it be from magnesium overdose? I never took more than 400mg a day. I am a healthy 30 year old female, used to have insulin resistance but now eat a mostly paleo / low carb type of diet. (I am now pregnant with our third, and don't mind waiting until done nursing this next one to heal this if it wouldn't be safe now! I'm assuming it wouldn't be.) Ryan: First, I would like to say thank you for all that you do for the community, I know you have helped thousands of people including myself become happier healthier beings. As far as questions, I have a couple of random rapid fire questions, when I do 24 hour fasts weekly or the beginning of the quarterly detox I notice my eyes get very dry until I eat, is this normal or am I missing something? I have been doing weekly 24 hour fasts and quarterly detoxes for a couple of years and it happens every time. During my 24 hour fasts I only consume water, usually with lemon or lime and salt and tea. Next, for using an IR sauna I know you suggest 40 minutes, would you or could you lower this time and maintain benefits if it was directly after a workout, either cardio or weight lifting since your internal temperature is already elevated? When I get into the sauna cold it takes 15 minutes to start sweating, if I go immediately following a workout I'm sweating the moment I step in, I'm just trying to optimize my time. Thanks again and have a wonderful rest of your weekend! Julie: Hey Dr C. I'm an IHP and am a little stumped with an issue one of my clients is having. She is 25 and just started month 2 of the CBO protocol after having completed the food sensitivity test, minerals & metals & OAT test. (She also did the 21-day detox). She's feeling amazing with an incredible boost in energy levels, clearer skin & far less anxiety. She hasn't felt this good in many years! We have a long way to go but it's very positive. One of the things that hasn't improved yet are the frequent bouts of really hot hands & feet which she has suffered with since she was a little girl. I've looked for this in your podcasts but can't seem to find any info. Have you seen this before? So grateful for any ideas or help. Mary: I've been hearing about Ketamine infusions for treatment resistant depression and PTSD. Do you have any thoughts on this or do you recommend this type of treatment? It was legalized in the US in 2019, I believe. Thanks for all your help today and always! Thank you for tuning into this weekend's Cabral HouseCalls and be sure to check back tomorrow for our Mindset & Motivation Monday show to get your week started off right! - - - Show Notes & Resources: http://StephenCabral.com/2039 - - - Dr. Cabral's New Book, The Rain Barrel Effect https://amzn.to/2H0W7Ge - - - Join the Community & Get Your Questions Answered: http://CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Stress, Sleep & Hormones Test (Run your adrenal & hormone levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels)
Let's continue thinking through the steps that would have to happen for evolve naturally. We'll look at the popular “RNA world” hypothesis, which claims that life first evolved from RNA-like molecules, and see why even some evolutionists now argue this would have been impossible. --- Send in a voice message: https://anchor.fm/answerstv/message Support this podcast: https://anchor.fm/answerstv/support
TOPICS by TIMECODE2:26 Constitutional carry in Texas, antifa teacher training kids to revolt is fired, Trump finally tells the truth about what's needed for elections to be honest, police rob a man of $87,000 w/o charging him with a crime17:31 Biden is pushing the biggest tax increase since 1968…here's the list, including a “wealth tax”.20:48 Central Bank Digital Currencies are moving rapidly to implementation with (BIS) Bank of International Settlements' Project Dunbar35:13 Now They Want to Tell You What You Can Eat. When will we stop letting them fence us in? First FDA prohibited certain natural medicines, now you're coerced to take jabs you don't want — the same will happen with food. The principle has been established says a CEO and you shouldn't be allowed to eat certain foods.48:11 CDC Power Grab Makes Middle Class Homeless. Just as intended — the CDC prohibition on foreclosures & evictions is destroying lives, not just private property rights1:03:09 A nauseating trailer for National Geographic's upcoming documentary/hagiography of Fauci1:12:24 CDC Test Change Reveals They Were NEVER Testing for COVID-19. The fraud is worse than the magnification factor. FDA can't even compare effectiveness of the tests since the 59 tests were looking for different things. Some were looking for synthetic RNA, some for gene specific RNA, some for whole genome RNA. CDC says that since they didn't have a sample, they used “contrived samples”. 1:33:01 Will Australia Be Able to Pull Back from the Police State? Will the World? Text messages will be sent out and you'll have 15 minutes to reply with a picture of your face, tagged for geolocation. It's a prison. A model of what the globalists want want for the entire world.2:13:44 “After Birth Abortion”: From Abortion to Eugenics. The views are getting more extreme and defiant and a new label has been created to make it acceptable. Not only is physical and mental “development” a continum, so is depopulation. 2:44:38 Listeners' letters — lockdown in Australia, Caribbean Island of St. Lucia enacts 24 hr curfew on Sundays to stop all church worship, EMS update on front line nurses refusing jab — what does THAT say about risk?2:49:09 Media touts literal snake oil for Covid, as they continue to falsely characterize Ivermectin as “horse medicine” even though it won a Nobel Prize for human use2:56:15 Lots of speculation about why the top 2 vaccine people at the FDA would suddenly leave. Now we know the exact reason…Find out more about the show and where you can watch it at TheDavidKnightShow.comIf you would like to support the show and our family please consider subscribing monthly here: SubscribeStar https://www.subscribestar.com/the-david-knight-showOr you can send a donation throughZelle: @DavidKnightShow@protonmail.comCash App at: $davidknightshowBTC to: bc1qkuec29hkuye4xse9unh7nptvu3y9qmv24vanh7Mail: David Knight POB 1323 Elgin, TX 78621
TOPICS by TIMECODE 2:26 Constitutional carry in Texas, antifa teacher training kids to revolt is fired, Trump finally tells the truth about what's needed for elections to be honest, police rob a man of $87,000 w/o charging him with a crime 17:31 Biden is pushing the biggest tax increase since 1968…here's the list, including a “wealth tax”. 20:48 Central Bank Digital Currencies are moving rapidly to implementation with (BIS) Bank of International Settlements' Project Dunbar 35:13 Now They Want to Tell You What You Can Eat. When will we stop letting them fence us in? First FDA prohibited certain natural medicines, now you're coerced to take jabs you don't want — the same will happen with food. The principle has been established says a CEO and you shouldn't be allowed to eat certain foods. 48:11 CDC Power Grab Makes Middle Class Homeless. Just as intended — the CDC prohibition on foreclosures & evictions is destroying lives, not just private property rights 1:03:09 A nauseating trailer for National Geographic's upcoming documentary/hagiography of Fauci 1:12:24 CDC Test Change Reveals They Were NEVER Testing for COVID-19. The fraud is worse than the magnification factor. FDA can't even compare effectiveness of the tests since the 59 tests were looking for different things. Some were looking for synthetic RNA, some for gene specific RNA, some for whole genome RNA. CDC says that since they didn't have a sample, they used “contrived samples”. 1:33:01 Will Australia Be Able to Pull Back from the Police State? Will the World? Text messages will be sent out and you'll have 15 minutes to reply with a picture of your face, tagged for geolocation. It's a prison. A model of what the globalists want want for the entire world. 2:13:44 “After Birth Abortion”: From Abortion to Eugenics. The views are getting more extreme and defiant and a new label has been created to make it acceptable. Not only is physical and mental “development” a continum, so is depopulation. 2:44:38 Listeners' letters — lockdown in Australia, Caribbean Island of St. Lucia enacts 24 hr curfew on Sundays to stop all church worship, EMS update on front line nurses refusing jab — what does THAT say about risk? 2:49:09 Media touts literal snake oil for Covid, as they continue to falsely characterize Ivermectin as “horse medicine” even though it won a Nobel Prize for human use 2:56:15 Lots of speculation about why the top 2 vaccine people at the FDA would suddenly leave. Now we know the exact reason… Find out more about the show and where you can watch it at TheDavidKnightShow.com If you would like to support the show and our family please consider subscribing monthly here: SubscribeStar https://www.subscribestar.com/the-david-knight-show Or you can send a donation through Zelle: @DavidKnightShow@protonmail.com Cash App at: $davidknightshow BTC to: bc1qkuec29hkuye4xse9unh7nptvu3y9qmv24vanh7 Mail: David Knight POB 1323 Elgin, TX 78621
*Today we present the return of a classic show. Bob Enyart builds on last week's intro to our 2021 presentation of Nicer than God and promos the next few scheduled Real Science Radio programs including this week's interview of molecular biologist Dr. Kevin Anderson on both the covid and on RNA vaccines, next week's interview with Alan Bunning who has wrested the cutting edge of New Testament textual analysis away from unbelievers, and following that, an interview with Mark Armitage, the scientist who's published again in a prestigious peer-reviewed science journal yet another discovery of dinosaur soft tissue (as at bflist.rsr.org). * This Just in from an Ex-gay: After Bob mentioned on yesterday's program that homosexuals do reproduce sexually, by molesting children, we received this sad but at the same time, celebratory message from Jonah Weller... I was recruited into the 'gay' life by an older man when I was seventeen. I was homosexual with my piano teacher for nine years, and thought I should have been a girl. Now, here in Oregon, (even though I was 'raped') if I refused to play love songs for a gay wedding, I would be breaking the law! This is against my rights as a Christian. It is not 'equality,' but homosexual supremacy! They are not persecuted! There are many like me who were feminine and gay, but Jesus changed my life. I am much happier now, even though people 'discriminate' against me! God bless you. Keep up the good work Bob. Honesty set me free! Today's Resource: Nicer Than God Enjoy this fast-paced critique of religion where Bob Enyart presents questions such as: When should a Christian lie? Should he ever mock? How about name-calling? Does sarcasm belong in the Christian's repertoire? How about ridicule? Learn why nice is not in the Bible and how to identify a Nicer-Than-God Christian. If Christians are not supposed to judge, then why does Jesus command us to judge rightly? And if only God will judge, then why does Paul say that we believers will judge the angels, and judge the world? If Jesus logged onto a website forum under a pseudonym, would we recognize Him, or condemn Him? This album communicates well Bob Enyart's unique style. But, warning, warning, warning, Will Robertson, it is not for the faint of heart. The Bible tells the story of human history and the work of God for His creation. And as all good stories do, Scripture has a plot! Grasping the big picture will help you reconcile many seemingly contradictory and controversial Bible passages. So consider listening to The Plot series based on Bob's manuscript of the same title. Then enjoy these book studies and see how the big picture can help you to better know the living God.
People are constantly asking me, "Is Covid-19 evolving?" So I went ahead and recorded my answer. In short, no, there is nothing to suggest that it is on its way to becoming anything but a coronavirus. In fact, it should be picking up enough mutations over time that it slowly degrades. In other words, it is on its way to becoming a decrepit coronavirus, given a decade or two. But this does not mean that it won't find that lucky mutation that makes it spread faster or that makes is more deadly in the meantime. Links: Loess Hills, Iowa Preparation Canyon State Park Darwin's finches: see Lightner J, Finch beaks point to a Creator who provides, Journal of Creation 26(2):8–10, 2012. Tay J, Reclaiming the peppered moth: designed to adapt, Creation 42(3):18–21, 2020. Eacock A, et al., Adaptive colour change and background choice behaviour in peppered moth caterpillars is mediated by extraocular photoreception, Communications Biology 2:286, 2019. Carter RW, More evidence for the reality of genetic entropy, Journal of Creation 28(1):16–17, 2014. [Deals with the extinction of the human H1N1 influenza] Carter RW, Sanford JC, A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918, Theor Biol Med Model 9:42, 2012. Carter R, Is Covid-19 Evolving? No, but it is changing rapidly, Creation.com, 24 Aug 2021. [also a discussion on APOBEC enzymes] Carter R, RNA vaccines: harnessing God's design to help prevent sickness, but will the new vaccine technology alter our DNA?, Creation.com, 3 Dec 2020. Sarfati J, CMI, vaccines, and vaccination, Creation.com, 24 Aug 2021 update. Coronavirus videos on Creation.com Main thumbnail image: Daniel Schludi via Unsplash.com
This week Harry is joined by Kevin Davies, author of the 2020 book Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing. CRISPR—an acronym for Clustered Regularly Interspaced Short Palindromic Repeats—consists of DNA sequences that evolved to help bacteria recognize and defend against viral invaders, as a kind of primitive immune system. Thanks to its ability to precisely detect and cut other DNA sequences, CRISPR has spread to labs across the world in the nine years since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking 2012 Science paper describing how the process works. The Nobel Prize committee recognized the two scientists for the achievement in 2020, one day after Davies' book came out. The book explains how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused. Today's interview covers all of that ground and more.Davies is a PhD geneticist who has spent most of his career in life sciences publishing. After his postdoc with Harvey Lodish at the Whitehead Institute, Davies worked as an assistant editor at Nature, the founding editor of Nature Genetics (Nature's first spinoff journal), editor-in-chief at Cell Press, founding editor-in-chief of the Boston-based publication Bio-IT World, and publisher of Chemical & Engineering News. In 2018 he helped to launch The CRISPR Journal, where he is the executive editor. Davies' previous books include Breakthrough (1995) about the race to understand the BRCA1 breast cancer gene, Cracking the Genome (2001) about the Human Genome Project, The $1,000 Genome (2010) about next-generation sequencing companies, and DNA (2017), an updated version of James Watson's 2004 book, co-authored with Watson and Andrew Berry.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to the page of the MoneyBall Medicine podcast. You can find it by searching for it or selecting it from your library. Just note that you'll have to go to the series page which shows all the episodes, not just the page for a single episode.3.Scroll down to find the subhead titled "Ratings & Reviews."4.Under one of the highlighted reviews, select "Write a Review."5.Next, select a star rating at the top — you have the option of choosing between one and five stars. 6.Using the text box at the top, write a title for your review. Then, in the lower text box, write your review. Your review can be up to 300 words long.7.Once you've finished, select "Send" or "Save" in the top-right corner. 8.If you've never left a podcast review before, enter a nickname. Your nickname will be displayed next to any reviews you leave from here on out. 9.After selecting a nickname, tap OK. Your review may not be immediately visible.Full TranscriptHarry Glorikian: I'm Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.Harry Glorikian: We talk a lot on the show about how computation and data are changing the way we develop new medicines and the way we deliver healthcare. Some executives in the drug discovery business speak of the computing and software side of the business as the “dry lab” —to set it apart from the “wet labs” where scientists get their hands dirty working with actual cells, tissues, and reagents.But the thing is, recent progress on the wet lab side of biotech has been just as amazing as progress in areas like machine learning. And this week, my friend Kevin Davies is here to talk about the most powerful tool to come along in the last decade, namely, precise gene editing using CRISPR.Of course, CRISPR-based gene editing has been all over the news since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking Science paper in 2012 describing how the process works in the lab. That work earned them a Nobel Prize in medicine just eight years later, in 2020.But what's not as well-known is the story of how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused.Kevin put that whole fascinating story together in his 2020 book Editing Humanity. And as the executive editor of The CRISPR Journal, the former editor-in-chief of Bio-IT World, the founding editor at Nature Genetics, and the author of several other important books about genomics, Kevin is one of the best-placed people in the world to tell that story. Here's our conversation.Harry Glorikian: Kevin, welcome to the show. Kevin Davies: Great to see you again, Harry. Thanks for having me on.Harry Glorikian: Yeah, no, I mean, I seem to be saying this a lot lately, it's been such a long time since, because of this whole pandemic, nobody's really seeing anybody on a regular basis. I want to give everybody a chance to hear about, you had written this book called Editing Humanity, which is, you know, beautifully placed behind you for, for product placement here. But I want to hear, can you give everybody sort of an overview of the book and why you feel that this fairly technical laboratory tool called CRISPR is so important that you needed to write a book about it?Kevin Davies: Thank you. Yes. As you may know, from some of my previous “bestsellers” or not, I've written about big stories in genetics because that's the only thing I'm remotely qualified to write about. I trained as a human geneticist in London and came over to do actually a pair of post-docs in the Boston area before realizing my talents, whatever they might be, certainly weren't as a bench researcher. So I had to find another way to stay in science but get away from the bench and hang up the lab coats.So moving into science publishing and getting a job with Nature and then launching Nature Genetics was the route for me. And over the last 30 years, I've written four or five books that have all been about, a) something big happening in genomics, b) something really big that will have both medical and societal significance, like the mapping and discovery of the BRCA1 breast cancer gene in the mid-90s, the Human Genome Project at the turn of the century, and then the birth and the dawn of consumer genetics and personalized medicine with The $1,000 Genome. And the third ingredient I really look for if I'm trying to reach a moderately, significantly large audience is for the human elements. Who are they, the heroes and the anti heroes to propel the story? Where is the human drama? Because, you know, we all love a good juicy, gossipy piece of story and rating the good guys and the bad guys. And CRISPR, when it first really took off in 2012, 2013 as a gene editing tool a lot of scientists knew about this. I mean, these papers are being published in Science in particular, not exactly a specialized journal, but I was off doing other things and really missed the initial excitement, I'm embarrassed to say. It was only a couple of years later, working on a sequel to Jim Watson's DNA, where I was tasked with trying to find and summarize the big advances in genomic technology over the previous decade or whatever, that I thought, well, this CRISPR thing seems to be taking off and the Doudnas and the Charpentiers are, you know, winning Breakthrough Prizes and being feted by celebrities. And it's going on 60 Minutes. They're going to make a film with the Rock, Dwayne Johnson. What the heck is going on. And it took very little time after that, for me to think, you know, this is such an exciting, game-changing disruptive technology that I've got to do two things. I've gotta, a) write a book and b) launch a journal, and that's what I did. And started planning at any rate in sort of 2016 and 17. We launched the CRISPR Journal at the beginning of 2018. And the book Editing Humanity came out towards the end of 2020. So 2020, literally one day before the Nobel Prize—how about that for timing?—for Doudna and Charpentier for chemistry last year. Harry Glorikian: When I think about it, I remember working with different companies that had different types of gene editing technology you know, working with some particularly in the sort of agriculture space, cause it a little bit easier to run faster than in the human space. And you could see what was happening, but CRISPR now is still very new. But from the news and different advances that are happening, especially here in the Boston area, you know, it's having some real world impacts. If you had to point to the best or the most exciting example of CRISPR technology helping an actual patient, would you say, and I've heard you say it, Victoria Gray, I think, would be the person that comes to mind. I've even, I think in one of your last interviews, you said something about her being, you know, her name will go down in history. Can you explain the technology that is helping her and what some of the similar uses of CRISPR might be?Kevin Davies: So the first half of Editing Humanity is about the heroes of CRISPR, how we, how scientists turned it from this bizarre under-appreciated bacterial antiviral defense system and leveraged it and got to grips with it, and then figured out ways to turn it into a programmable gene editing technology. And within a year or two of that happening that the classic Doudna-Charpentier paper came out in the summer of 2012. Of course the first wave of biotech companies were launched by some of the big names, indeed most of the big names in CRISPR gene editing hierarchies. So Emmanuel Charpentier, Nobel Laureate, launched CRISPR Therapeutics, Jennifer Doudna co-founded Editas Medicine with several other luminaries. That didn't go well for, for reasons of intellectual property. So she withdrew from Editas and became a co-founder of Intellia Therapeutics as well as her own company, Caribou, which just went public, and Feng Zhang and others launched Editas Medicine. So we had this sort of three-way race, if you will, by three CRISPR empowered gene editing companies who all went public within the next two or three years and all set their sights on various different genetic Mendelian disorders with a view to trying to produce clinical success for this very powerful gene editing tool. And so, yes, Victoria Gray is the first patient, the first American patient with sickle cell anemia in a trial that is being run by CRISPR Therapeutics in close association with Vertex Pharmaceuticals. And that breakthrough paper, as I think many of your listeners will know, came out right at the end of 2020 published in the New England Journal of Medicine. Doesn't get much more prestigious than that. And in the first handful of patients that CRISPR Therapeutics have edited with a view to raising the levels of fetal hemoglobin, fetal globin, to compensate for the defective beta globin that these patients have inherited, the results were truly spectacular.And if we fast forward now to about two years after the initial administration, the initial procedures for Victoria Gray and some of her other volunteer patients, the results still look as spectacular. Earlier this year CRISPR Therapeutics put out of sort of an update where they are saying that the first 20 or 24 patients that they have dosed with sickle cell and beta thallasemia are all doing well. There've been little or no adverse events. And the idea of this being a once and done therapy appears very well founded. Now it's not a trivial therapy. This is ex-vivo gene editing as obviously rounds of chemotherapy to provide the room for the gene edited stem cells to be reimplanted into the patient. So this is not an easily scalable or affordable or ideal system, but when did we, when will we ever able to say we've pretty much got a cure for sickle cell disease? This is an absolutely spectacular moment, not just for CRISPR, but for medicine, I think, overall. And Victoria Gray, who's been brilliantly profiled in a long running series on National Public Radio, led by the science broadcaster Rob Stein, she is, you know, we, we can call her Queen Victoria, we can call it many things, but I really hope that ,it's not just my idea, that she will be one of those names like Louise Brown and other heroes of modern medicine, that we look and celebrate for decades to come.So the sickle cell results have been great, and then much more recently, also in the New England Journal, we have work led by Intellia Therapeutics, one of the other three companies that I named, where they've been also using CRISPR gene editing, but they've been looking at a rare liver disease, a form of amyloidosis where a toxic protein builds up and looking to find ways to knock out the production of that abnormal gene.And so they've been doing in vivo gene editing, really using CRISPR for the first time. It's been attempted using other gene editing platforms like zinc fingers, but this is the first time that I think we can really say and the New England Journal results prove it. In the first six patients that have been reported remarkable reductions in the level of this toxic protein far, not far better, but certainly better than any approved drugs that are currently on the market. So again, this is a very, very exciting proof of principle for in vivo gene editing, which is important, not just for patients with this rare liver disorder, but it really gives I think the whole field and the whole industry enormous confidence that CRISPR is safe and can be used for a growing list of Mendelian disorders, it's 6,000 or 7,000 diseases about which we know the root genetic cause, and we're not going to tackle all of them anytime soon, but there's a list of ones that now are within reach. And more and more companies are being launched all the time to try and get at some of these diseases.So as we stand here in the summer of 2021, it's a really exciting time. The future looks very bright, but there's so much more to be done. Harry Glorikian: No, we're just at the beginning. I mean, I remember when I first saw this, my first question was off target effects, right? How are we going to manage that? How are they going to get it to that place that they need to get it to, to have it to that cell at that time, in the right way to get it to do what it needs to do. And you know, all these sorts of technical questions, but at the same time, I remember I'm going to, trying to explain this to my friends. I'm like, “You don't understand, this can change everything.” And now a high school student, I say this to people and they look at me strangely, a high school student can order it and it shows up at your house.Kevin Davies: Yeah, well, this is why I think, and this is why one reason why CRISPR has become such an exciting story and receives the Nobel Prize eight years after the sort of launch publication or the first demonstration of it as a gene editing tool. It is so relatively easy to get to work. It's truly become a democratized or democratizing technology. You don't need a million-dollar Illumina sequencer or anything. And so labs literally all around the world can do basic CRISPR experiments. Not everyone is going to be able to launch a clinical trial. But the technology is so universally used, and that means that advances in our understanding of the mechanisms, new tools for the CRISPR toolbox new pathways, new targets, new oftware, new programs, they're all coming from all corners of the globe to help not just medicine, but many other applications of CRISPR as well.Harry Glorikian: Yeah. I always joke about like, there, there are things going on in high school biology classes now that weren't, available, when I was in college and even when we were in industry and now what used to take an entire room, you can do on a corner of a lab bench.Kevin Davies: Yeah. Yeah. As far as the industry goes we mentioned three companies. But you know, today there's probably a dozen or more CRISPR based or gene editing based biotech companies. More undoubtedly are going to be launched before the end of this year. I'm sure we'll spend a bit of time talking about CRISPR 2.0, it seems too soon to be even thinking about a new and improved version of CRISPR, but I think there's a lot of excitement around also two other Boston-based companies, Beam Therapeutics in Cambridge and Verve Therapeutics both of which are launching or commercializing base editing. So base editing is a tool developed from the lab of David Lu of the Broad Institute [of MIT and Harvard]. And the early signs, again, this technology is only five or six years old, but the early signs of this are incredibly promising. David's team, academic team, had a paper in Nature earlier this year, really reporting successful base editing treatment of sickle cell disease in an animal model, not by raising the fetal globin levels, which was sort of a more indirect method that is working very well in the clinic, but by going right at the point mutation that results in sickle cell disease and using given the chemical repertoire of base editing.Base editing is able to make specific single base changes. It can't do the full repertoire of single base changes. So there are some limitations on researchers' flexibility. So they were unable to flip the sickle cell variant back to the quote unquote wild type variants, but the change they were able to make is one that they can live with, we can live with because it's a known benign variant, a very rare variant that has been observed in other, in rare people around the world. So that's completely fine. It's the next best thing. And so that looks very promising. Beam Therapeutics, which is the company that David founded or co-founded is trying a related approach, also going right at the sickle cell mutation. And there are other companies, including one that Matthew Porteus has recently founded and has gone public called Graphite Bio.So this is an exciting time for a disease sickle cell disease that has been woefully neglected, I think you would agree, both in terms of basic research, funding, medical prioritization, and medical education. Now we have many, many shots on goal and it doesn't really, it's not a matter of one's going to win and the others are going to fall by the wayside. Just like we have many COVID vaccines. We'll hopefully have many strategies for tackling sickle cell disease, but they are going to be expensive. And I think you know the economics better than I do. But I think that is the worry, that by analogy with gene therapies that have been recently approved, it's all, it's really exciting that we can now see the first quote, unquote cures in the clinic. That's amazingly exciting. But if the price tag is going to be $1 million or $2 million when these things are finally approved, if and when, that's going to be a rather deflating moment. But given the extraordinary research resources that the CRISPRs and Intellias and Beams and Graphites are pouring into this research, obviously they've got to get some return back on their investment so that they can plow it back into the company to develop the next wave of of gene editing therapies. So you know, it's a predicament Harry Glorikian: One of these days maybe I have to have a show based on the financial parts of it. Because there's a number of different ways to look at it. But just for the benefit of the listeners, right, who may not be experts, how would you explain CRISPR is different from say traditional gene therapies. And is CRISPR going to replace older methods of, of gene therapy or, or will they both have their place? Kevin Davies: No, I think they'll both have their place. CRISPR and, and these newer gene editing tools, base editing and another one called prime editing, which has a company behind it now called Prime Medicine, are able to affect specific DNA changes in the human genome.So if you can target CRISPR, which is an enzyme that cuts DNA together with a little program, the GPS signal is provided in the form of a short RNA molecule that tells the enzyme where to go, where to go in the genome. And then you have a couple of strategies. You can either cut the DNA at the appropriate target site, because you want to inactivate that gene, or you just want to scramble the sequence because you want to completely squash the expression of that gene. Or particularly using the newer forms of gene editing, like base editing, you can make a specific, a more nuanced, specific precision edit without, with one big potential advantage in the safety profile, which is, you're not completely cutting the DNA, you're just making a nick and then coaxing the cell's natural repair systems to make the change that you sort of you're able to prime.So there are many diseases where this is the way you want to go, but that does not in any way invalidate the great progress that we're making in traditional gene therapy. So for example today earlier today I was recording an interview or for one of my own programs with Laurence Reid, the CEO of Decibel Therapeutics, which is looking at therapies for hearing loss both genetic and other, other types of hearing disorders.And I pushed him on this. Aren't you actually joinomg with the gene editing wave? And he was very circumspect and said, no, we're very pleased, very happy with the results that we're getting using old fashioned gene replacement therapy. These are recessive loss of function disorders. And all we need to do is get the expression of some of the gene back. So you don't necessarily need the fancy gene editing tools. If you can just use a an AAV vector and put the healthy gene back into the key cells in the inner ear. So they're complimentary approaches which is great.Harry Glorikian: So, you know, in, in this podcast, I try to have a central theme when I'm talking to people. The relationships of big data, computation, advances in new drugs, and other ways to keep people healthy. So, you know, like question-wise, there's no question in my mind that the whole genomics revolution that started in the ‘90s, and I was happy to be at Applied Biosystems when we were doing that, would have been impossible in the absence of the advances in computing speed and storage in the last three decades. I think computing was the thing that held up the whole human genome, which gave us the book of life that CRISPR is now allowing us to really edit. But I wonder if you could bring us sort of up-to-date and talk about the way CRISPR and computation are intertwined. What happens when you combine precision of an editing tool like CRISPR with the power of machine learning and AI tools to find meaning and patterns in that huge genetic ball? Kevin Davies: Yeah. Well, yeah. I'm got to tread carefully here, but I think we are seeing papers from some really brilliant labs that are using some of the tools that you mentioned. AI and machine learning with a view to better understanding and characterizing some of the properties and selection criteria of some of these gene editing tools. So you mentioned earlier Harry, the need to look out for safety and minimize the concern of off-target effects. So I think by using some of these some algorithms and AI tools, researchers have made enormous strides in being able to design the programmable parts of the gene editing constructs in such a way that you increase the chances that they're going to go to the site that you want them to go to, and nnot get hung up latching onto a very similar sequence that's just randomly cropped up on the dark side of the genome, across the nucleus over there. You don't want that to happen. And I don't know that anybody would claim that they have a failsafe way to guarantee that that could never happen. But the you know, the clinical results that we've seen and all the preclinical results are showing in more and more diseases that we've got the tools and learned enough now to almost completely minimize these safety concerns. But I think everyone, I think while they're excited and they're moving as fast as they can, they're also doing this responsibly. I mean, they, they have to because no field, gene therapy or gene editing really wants to revisit the Jesse Gelsinger tragedy in 1999, when a teenage volunteer died in volunteering for a gene therapy trial at Penn of, with somebody with a rare liver disease. And of course that, that setback set back the, entire field of gene therapy for a decade. And it's really remarkable that you know, many of the sort of pioneers in the field refuse to throw in the towel, they realized that they had to kind of go back to the drawing board, look at the vectors again, and throw it out. Not completely but most, a lot of the work with adenoviruses has now gone by the wayside. AAV is the new virus that we hear about. It's got a much better safety profile. It's got a smaller cargo hold, so that's one drawback, but there are ways around that. And the, the explosion of gene therapy trials that we're seeing now largely on the back of AAV and now increasingly with, with non-viral delivery systems as well is, is very, very gratifying. And it's really delivery. I think that is now the pain point. Digressing from your question a little bit, but delivery, I think is now the big challenge. It's one thing to contemplate a gene therapy for the eye for rare hereditary form of blindness or the ear. Indeed those are very attractive sites and targets for some of these early trials because of the quantities that you need to produce. And the localization, the, the physical localization, those are good things. Those help you hit the target that you want to. But if you're contemplating trying something for Duchenne muscular dystrophy or spinal muscular atrophy, or some of the diseases of the brain, then you're going to need much higher quantities particularly for muscular disorders where, you run into now other challenges, including, production and manufacturing, challenges, and potentially safeguarding and making sure that there isn't an immune response as well. That's another, another issue that is always percolating in the background.But given where we were a few years ago and the clinical progress that we've talked about earlier on in the show it, I think you can safely assume that we've collectively made enormous progress in, in negating most, if not all of these potential safety issues.Harry Glorikian: No, you know, it's funny, I know that people will say like, you know, there was a problem in this and that. And I look at like, we're going into uncharted territories and it has to be expected that you just…you've got people that knew what they were doing. All of these people are new at what they are doing. And so you have to expect that along the way everything's not going to go perfectly. But I don't look at it as a negative. I look at it as, they're the new graduating class that's going to go on and understand what they did right. Or wrong, and then be able to modify it and make an improvement. And, you know, that's what we do in science. Kevin Davies: Well, and forget gene editing—in any area of drug development and, and pharmaceutical delivery, things don't always go according to plan. I'm sure many guests on Moneyball Medicine who have had to deal with clinical trial failures and withdrawing drugs that they had all kinds of high hopes for because we didn't understand the biology or there was some other reaction within, we didn't understand the dosing. You can't just extrapolate from an animal model to humans and on and on and on. And so gene editing, I don't think, necessarily, should be held to any higher standard. I think the CRISPR field has already in terms of the sort of market performance, some of the companies that we've mentioned, oh my God, it's been a real roller coaster surprisingly, because every time there's been a paper published in a prominent journal that says, oh my God, there's, there's a deletion pattern that we're seeing that we didn't anticipate, or we're seeing some immune responses or we're seeing unusual off target effects, or we're seeing P53 activation and you know, those are at least four off the top of my head. I'm sure there've been others. And all had big transient impact on the financial health of these companies. But I think that was to be expected. And the companies knew that this was just an overreaction. They've worked and demonstrated through peer review publications and preclinical and other reports that these challenges have been identified, when known about, pretty much completely have been overcome or are in the process of being overcome.So, you know, and we're still seeing in just traditional gene therapy technologies that have been around for 15, 20 years. We're still seeing reports of adverse events on some of those trials. So for gene editing to have come as far as it's common, to be able to look at these two big New England Journal success stories in sickle cell and ATTR amyloidosis, I don't think any very few, except the most ardent evangelists would have predicted we'd be where we are just a few years ago. [musical transition]Harry Glorikian: I want to pause the conversation for a minute to make a quick request. If you're a fan of MoneyBall Medicine, you know that we've published dozens of interviews with leading scientists and entrepreneurs exploring the boundaries of data-driven healthcare and research. And you can listen to all of those episodes for free at Apple Podcasts, or at my website glorikian.com, or wherever you get your podcasts.There's one small thing you can do in return, and that's to leave a rating and a review of the show on Apple Podcasts. It's one of the best ways to help other listeners find and follow the show.If you've never posted a review or a rating, it's easy. All you have to do is open the Apple Podcasts app on your smartphone, search for MoneyBall Medicine, and scroll down to the Ratings & Reviews section. Tap the stars to rate the show, and then tap the link that says Write a Review to leave your comments. It'll only take a minute, but it'll help us out immensely. Thank you! And now back to the show.[musical transition]Harry Glorikian:One of your previous books was called The $1,000 Genome. And when you published that back in 2010, it was still pretty much science fiction that it might be possible to sequence someone's entire genome for $1,000. But companies like Illumina blew past that barrier pretty quickly, and now people are talking about sequencing individual genome for just a few hundred dollars or less. My question is, how did computing contribute to the exponential trends here. And do you wish you'd called your book The $100 Genome?Kevin Davies: I've thought about putting out a sequel to the book, scratching out the 0's and hoping nobody would notice. Computing was yes, of course, a massive [deal] for the very first human genome. Remember the struggle to put that first assembly together. It's not just about the wet lab and pulling the DNA sequences off the machines, but then you know, the rapid growth of the data exposure and the ability to store and share and send across to collaborators and put the assemblies together has been critical, absolutely critical to the development of genomics.I remember people were expressing shock at the $1,000 genome. I called the book that because I heard Craig Venter use that phrase in public for the first time in 2002. And I had just recently published Cracking the Genome. And we were all still recoiling at the billions of dollars it took to put that first reference genome sequence together. And then here's Craig Venter, chairing a scientific conference in Boston saying what we need is the $1,000 genome. And I almost fell off my chair. “what are you? What are you must you're in, you're on Fantasy Island. This is, there's no way we're going to get, we're still doing automated Sanger sequencing. God bless Fred Sanger. But how on earth are you going to take that technology and go from billions of dollars to a couple of thousand dollars. This is insanity.” And that session we had in 2002 in Boston. He had a local, a little episode of America's Got Talent and he invited half a dozen scientists to come up and show what they had. And George Church was one of them. I think Applied Biosystems may have given some sort of talk during that session. And then a guy, a young British guy from a company we'd never heard of called Celexa showed up and showed a couple of pretty PowerPoint slides with colored beads, representing the budding DNA sequence on some sort of chip. I don't know that he showed any data. It was all very pretty and all very fanciful. Well guess what? They had the last laugh. Illumina bought that company in 2006. And as you said, Harry you know, I think when, when they first professed to have cracked the $1,000 dollar genome barrier, a few people felt they needed a pinch of salt to go along with that. But I think now, yeah, we're, we're, we're well past that. And there are definitely outfits like BGI, the Beijing Genomics Institute being one of them, that are touting new technologies that can get us down to a couple of hundred. And those were such fun times because for a while there Illumina had enormous competition from companies like 454 and Helicose and PacBio. And those were fun heady times with lots and lots of competition. And in a way, Illumina's had it a little easy, I think over the last few years, but with PacBio and Oxford Nanopore gaining maturity both, both in terms of the technology platforms and their business strategy and growth, I think Illumina' gonna start to feel a little bit more competition in the long read sequence space. And one is always hearing whispers of new companies that may potentially disrupt next-gen sequencing. And that would be exciting because then we'd have an excuse to write another book. Harry Glorikian: Well, Kevin, start writing because I actually think we're there. I think there are a number of things there and you're right, I think Illumina has not had to bring the price down as quickly because there hasn't been competition. And you know, when I think about the space is, if you could do a $60 genome, right, it starts to become a rounding error. Like what other business models and opportunities now come alive? And those are the things that excite me. All right. But so, but you have a unique position as editor of the journal of CRISPR and the former editor of a lot of prominent, you know, publications, Nature Genetics, Bio-IT World, Chemical & Engineering News. Do you think that there's adequate coverage of the biological versus the computing side of it? Because I, I have this feeling that the computing side still gets a little overlooked and underappreciated. Kevin Davies: I think you're right. I mean I think at my own company Genetic Engineering News, we still have such deep roots in the wet lab vision and version of biotechnology that it takes a conscious effort to look and say, you know, that's not where all the innovation is happening. Bio-IT World, which you mentioned is interesting because we launched that in 2002. It was launched by the publisher IDG, best-known from MacWorld and ComputerWorld and this, this whole family of high-tech publications.And we launched in 2002 was a very thick glossy print magazine. And ironically, you know, we just couldn't find the advertising to sustain that effort, at least in the way that we'd envisioned it. And in 2006 and 2007, your friend and mine Phillips Kuhl, the proprietor of Cambridge Healthtech Institute, kind of put us out of our misery and said, you know what I'll, take the franchise because IDG just didn't know what to do with it anymore. But what he really wanted was the trade show, the production. And even though at the magazine eventually we fell on our sword and eventually put it out of its misery, the trade show went from strength to strength and it'll be back in Boston very soon because he had the vision to realize there is a big need here as sort of supercomputing for life sciences.And it's not just about the raw high-performance computing, but it's about the software, the software tools and data sharing and management. And it's great to go back to that show and see the, you know, the Googles and Amazons and yeah, all the big household names. They're all looking at this because genome technology, as we've discussed earlier has been one of the big growth boom areas for, for their services and their products.Harry Glorikian: Right. I mean, well, if you look at companies like Tempus, right. When I talked to Joel Dudley over there on the show it's, they want to be the Amazon AWS piping for all things genomic analysis. Right. So instead of creating it on your own and building a, just use their platform, basically, so it's definitely a growth area. And at some point, if you have certain disease states, I don't see how you don't get you know, genomic sequencing done, how a physician even today in oncology, how anybody can truly prescribe with all the drugs that are being approved that have, you know, genomic biomarkers associated with them and not use that data.Kevin Davies: On a much lower, lo-fi scale, as I've been doing a lot of reading about sickle cell disease lately, it's clear that a lot of patients who are, of course, as you, as you know, as your listeners know, are mostly African-American because the disease arose in Africa and the carrier status gives carriers a huge health advantage in warding off malaria. So the gene continues to stay, stay high in in frequency. Many African-American patients would benefit from some generic drugs that are available in this country that provide some relief, but aren't aware of it and maybe their physicians aren't completely aware of it either. Which is very sad. And we've neglected the funding of this disease over many decades, whereas a disease like cystic fibrosis, which affects primarily white people of Northern European descent that receives far more funding per capita, per head, than than a disease like sickle cell does. But hopefully that will begin to change as we see the, the potential of some of these more advanced therapies.I think as far as your previous comment. I think one of the big challenges now is how we tackle common diseases. I think we're making so much progress in treating rare Mendelian diseases and we know thousands of them. But it's mental illness and asthma and diabetes you know, diseases that affect millions of people, which have a much more complicated genetic and in part environmental basis.And what can we learn, to your point about having a full genome sequence, what can we glean from that that will help the medical establishment diagnose and treat much more common diseases, not quite as simple as just treating a rare Mendelian version of those diseases? So that's, I think going to be an important frontier over the next decade.Harry Glorikian: Yeah. It's complicated. I think you're going to see as we get more real-world data that's organized and managed well, along with genomic data, I think you'll be able to make more sense of it. But some of these diseases are quite complicated. It's not going to be find one gene, and it's going to give you that answer.But I want to go back to, you can't really talk about CRISPR without talking about this specter of germline editing. And a big part of your book is about this firestorm of criticism and condemnation around, you know, the 2018 when the Chinese researcher He Jankui, I think I said it correctly.Yep.Kevin Davies: He Jankui is how I say it. Close. Harry Glorikian: He announced that he had created twin baby girls with edits to their genomes that were intended to make them immune to HIV, which sort of like—that already made me go, what? But the experiment was, it seems, unauthorized. It seems that, from what I remember, the edits were sloppy and the case spurred a huge global discussion about the ethics of using CRISPR to make edits that would be inherited by future generations. Now, where are we in that debate now? I mean, I know the National Academy of Sciences published a list of criteria, which said, don't do that. Kevin Davies: It was a little more nuanced than that. It wasn't don't do that. It was, there is a very small window through which we could move through if a whole raft of criteria are met. So they, they refuse to say hereditary genome editing should be banned or there should be a moratorium. But they said it should not proceed until we do many things. One was to make sure it is safe. We can't run before we can walk. And by that, I mean, we've got to first demonstrate—because shockingly, this hasn't been done yet—that genome editing can be done safely in human embryos. And in the last 18 months there've been at least three groups, arguably the three leading groups in terms of looking at genetic changes in early human embryos, Kathy Niakan in London, Shoukhrat Mitalipov in Oregon, and Dieter Egli in New York, who all at roughly the same time published and reports that said, or posted preprints at least that said, when we attempt to do CRISPR editing experiments in very early human embryos, we're seeing a mess. We're seeing a slew of off-target and even on-target undesirable edits.And I think that says to me, we don't completely understand the molecular biology of DNA repair in the early human embryo. It may be that there are other factors that are used in embryogenesis that are not used after we're born. That's speculation on my part. I may be wrong. But the point is we still have a lot to do to understand, even if we wanted to.And even if everybody said, “Here's a good case where we should pursue germline editing,” we've gotta be convinced that we can do it safely. And at the moment, I don't think anybody can say that. So that's a huge red flag.But let's assume, because I believe in the power of research, let's assume that we're going to figure out ways to do this safely, or maybe we say CRISPR isn't the right tool for human embryos, but other tools such as those that we've touched on earlier in the show base editing or prime editing, or maybe CRISPR 3.0 or whatever that is right now to be published somewhere. [Let's say ] those are more safe, more precise tools. Then we've got to figure out well, under what circumstances would we even want to go down this road? And the pushback was quite rightly that, well, we already have technologies that can safeguard against families having children with genetic diseases. It's called IVF and pre-implantation genetic diagnosis. So we can select from a pool of IVF embryos. The embryos that we can see by biopsy are safe and can therefore be transplanted back into the mother, taken to term and you know, a healthy baby will emerge.So why talk about gene editing when we have that proven technology? And I think that's a very strong case, but there are a small number of circumstances in which pre-implantation genetic diagnosis will simply not work. And those are those rare instances where a couple who want to have a biological child, but have both of them have a serious recessive genetic disease. Sickle cell would be an obvious case in point. So two sickle cell patients who by definition carry two copies of the sickle cell gene, once I have a healthy biological child preimplantation genetic diagnosis, it's not going to help them because there are no healthy embryos from whatever pool that they produce that they can select. So gene editing would be their only hope in that circumstance. Now the National Academy's report that you cited, Harry, did say for serious diseases, such as sickle cell and maybe a few others they could down the road potentially see and condone the use of germline gene editing in those rare cases.But they're going to be very rare, I think. It's not impossible that in an authorized approved setting that we will see the return of genome editing, but that's okay. Of course you can can issue no end of blue ribbon reports from all the world's experts, and that's not going to necessarily prevent some entrepreneur whose ethical values don't align with yours or mine to say, “You know what, there's big money to be made here. I'm going offshore and I'm going to launch a CRISPR clinic and you know, who's going to stop me because I'll be out of the clutches of the authorities.” And I think a lot of people are potentially worried that that scenario might happen. Although if anyone did try to do that, the scientific establishment would come down on them like a ton of bricks. And there'll be a lot of pressure brought to bear, I think, to make sure that they didn't cause any harm.Harry Glorikian: Yeah. It's funny. I would like to not call them entrepreneurs. I like entrepreneurs. I'd like to call them a rogue scientist. Kevin Davies: So as you say, there's the third section of four in Editing Humanity was all about the He Jankui debacle or saga. I had flown to Hong Kong. It's a funny story. I had a little bit of money left in my travel budget and there were two conferences, one in Hong Kong and one in China coming up in the last quarter of 2018. So I thought, well, okay, I'll go to one of them. And I just narrowed, almost a flip of a coin, I think. Okay, let's go to the Hong Kong meeting.It's a bioethics conference since I don't expect it to be wildly exciting, but there are some big speakers and this is an important field for the CRISPR Journal to monitor. So I flew there literally, you know, trying to get some sleep on the long flights from New York and then on landing, turn on the phone, wait for the new wireless signal provider to kick in. And then Twitter just explode on my feed as this very, very astute journalists at MIT Technology Review, Antonio Regalado, had really got the scoop of the century by identifying a registration on a Chinese clinical trial website that he and only he had the foresight and intelligence to sort of see. He had met He Jankui in an off the record meeting, as I described in the book, about a month earlier. A spider sense was tingling. He knew something was up and this was the final clue. He didn't know at that time that the Lulu and Nana, the CRISPR babies that you mentioned, had actually been born, but he knew that there was a pregnancy, at least one pregnancy, from some of the records that he'd seen attached to this registration document. So it was a brilliant piece of sleuthing. And what he didn't know is that the Asociated Press chief medical writer Marilynm Marchion had confidentially been alerted to the potential upcoming birth of these twins by an American PR professional who was working with He Jankui in Shenzhen. So she had been working on an embargoed big feature story that He Jankui and his associates hoped would be the definitive story that would tell the world, we did this quote unquote, “responsibly and accurately, and this is the story that you can believe.” So that story was posted within hours.And of course the famous YouTube videos that He Jankui had recorded announcing with some paternal pride that he had ushered into the world these two gene edited, children, screaming and crying into the world as beautiful babies I think was [the phrase]. And he thought that he was going to become famous and celebrated and lauded by not just the Chinese scientific community, but by the world community for having the ability and the bravery to go ahead and do this work after Chinese researchers spent the previous few years editing human embryos. And he was persuaded that he had to present his work in Hong Kong, because he'd set off such a such an extraordinary firestorm. And I think you've all seen now you're the clips of the videos of him nervously walking onto stage the muffled, the silence, or the only sound in the front row, the only sound in the big auditorium at Hong Kong university—[which] was absolutely packed to the rim, one side of the auditorium was packed with press photographers, hundreds of journalists and cameras clicking—and the shutters clattering was the only, that was the applause that he got as he walked on stage.And to his credit, he tried to answer the questions directly in the face of great skepticism from the audience. The first question, which was posed by David Liu, who had traveled all the way there, who just asked him simply, “What was the unmet medical need that you are trying to solve with this reckless experiment? There are medical steps that you can do, even if the couple that you're trying to help has HIV and you're trying to prevent this from being passed on. There are techniques that you can use sperm washing being one of them. That is a key element of the IVF process to ensure that the no HIV is transmitted.”But he was unable to answer the question in terms of I'm trying to help a family. He'd already moved out and was thinking far, far bigger. Right? And his naiveté was shown in the manuscript that he'd written up and by that point submitted to Nature, excerpts of which were leaked out sometime later.So he went back to Shenzhen and he was put under house arrest after he gave that talk in Hong Kong. And about a year later was sentenced to three years in jail. And so he's, to the best of my knowledge that's where he is. But I often get asked what about the children? As far as we know, there was a third child born about six months later, also gene-edited. We don't even know a name for that child, let alone anything about their health. So one hopes that somebody in the Chinese medical establishment is looking after these kids and monitoring them and doing appropriate tests. The editing, as you said, was very shoddily performed. He knocked out the gene in question, but he did not mimic the natural 32-base deletion in this gene CCR5 that exists in many members of the population that confers, essentially, HIV resistance. So Lulu and Nana on the third child are walking human experiments, sad to say. This should never have been done. Never should have been attempted. And so we hope that he hasn't condemned them to a life of, you know, cancer checkups and that there were no off-target effects. They'll be able to live, hopefully, with this inactivated CCR5 gene, but it's been inactivated in a way that I don't think any, no other humans have ever been recorded with such modifications. So we, we really hope and pray that no other damage has been done. Harry Glorikian: So before we end, I'd love to give you the chance to speculate on the future of medicine in light of CRISPR. Easy, fast, inexpensive genome sequencing, give us access to everybody's genetic code, if they so choose. Machine learning and other forms of AI are helping understand the code and trace interactions between our 20,000 genes. And now CRISPR gives us a way to modify it. So, you know, it feels like [we have] almost everything we need to create, you know, precise, targeted, custom cures for people with genetic conditions. What might be possible soon, in your view? What remaining problems need to be solved to get to this new area of medicine? Kevin Davies: If you know the sequence that has been mutated to give rise to a particular disease then in principle, we can devise a, some sort of gene edit to repair that sequence. It may be flipping the actual base or bases directly, or maybe as we saw with the first sickle cell trial, it's because we understand the bigger genetic pathway. We don't have to necessarily go after the gene mutation directly, but there may be other ways that we can compensate boost the level of a compensating gene.But I think we, we should be careful not to get too carried away. As excited as I am—and hopefully my excitement comes through in Editing Humanity—but for every company that we've just mentioned, you know, you can go on their website and look at their pipeline. And so Editas might have maybe 10 diseases in its cross hairs. And CRISPR [Therapeutics] might have 12 diseases. And Intellia might have 14 diseases and Graphite has got maybe a couple. And Beam Therapeutics has got maybe 10 or 12. And Prime Medicine will hasn't listed any yet, but we'll hopefully have a few announced soon. And so I just reeled off 50, 60, less than a hundred. And some of these are gonna work really, really well. And some are going to be either proven, ineffective or unviable economically because the patient pool is too small. And we've got, how many did we say, 6,000 known genetic diseases. So one of the companies that is particularly interesting, although they would admit they're in very early days yet, is Verve Therapeutics. I touched on them earlier because they're looking at to modify a gene called PCSK9 that is relevant to heart disease and could be a gene modification that many people might undergo because the PCSK9 gene may be perfectly fine and the sequence could be perfectly normal, but we know that if we re remove this gene, levels of the bad cholesterol plummet, and that's usually a good thing as far as heart management goes. So that's an interesting, very interesting study case study, I think, to monitor over the coming years, because there's a company looking at a much larger patient pool potentially than just some of these rare syndromes with unpronounceable names. So the future of CRISPR and gene editing is very bright. I think one of the lessons I took away from CRISPR in Editing Humanity is, looking at the full story, is how this technology, this game-changing gene-editing technology, developed because 25 years ago, a handful of European microbiologists got really interested in why certain microbes were thriving in a salt lake in Southeastern Spain. This is not exactly high-profile, NIH-must-fund-this research. There was a biological question that they wanted to answer. And the CRISPR repeats and the function of those repeats fell out of that pure curiosity, just science for science's sake. And so it's the value of basic investigator-driven, hypothesis-driven research that led to CRISPR being described and then the function of the repeats.And then the story shifted to a yogurt company in Europe that was able to experimentally show how having the right sequence within the CRISPR array could safeguard their cultures against viral infection. And then five years of work people in various groups started to see, were drawn to this like moths to a flame. Jennifer Doudna was intrigued by this from a tip-off from a coffee morning discussion with a Berkeley faculty colleagues, Jill Banfield, a brilliant microbiologist in her own. And then she met meets Emmanuelle Charpentier in Puerto Rico at a conference, and they struck up a friendship and collaboration over the course of an afternoon. And that, why should that have worked? Well, it did, because a year later they're publishing in Science. So it's serendipity and basic research. And if that can work for CRISPR, then I know that there's another technology beginning to emerge from somewhere that may, yet trump CRISPR.And I think the beauty of CRISPR is its universal appeal. And the fact is, it's drawn in so many people, it could be in Japan or China or South Korea or parts of Europe or Canada or the U.S. or South America. Somebody is taking the elements of CRISPR and thinking well, how can we improve it? How can we tweak it?And so this CRISPR toolbox is being expanded and modified and updated all the time. So there's a hugely exciting future for genome medicine. And you know, whether it's a new form of sequencing or a new form of synthetic biology, you know, hopefully your show is going to be filled for many years to come with cool, talented, young energetic entrepreneurs who've developed more cool gadgets to work with our genome and other genomes as well. We haven't even had time to talk about what this could do for rescuing the wooly mammoth from extinction. So fun things, but maybe, maybe another time. Harry Glorikian: Excellent. Well, great to have you on the show. Really appreciate the time. I hope everybody got a flavor for the enormous impact this technology can have. Like you said, we talked about human genome, but there's so many other genomic applications of CRISPR that we didn't even touch. Kevin Davies: Yup. Yup. So you have to read the book. Harry Glorikian: Yeah. I will look forward to the next book. So, great. Thank you so much. Kevin Davies: Thanks for having me on the show, Harry. All the best.Harry Glorikian: Take care.Harry Glorikian: That's it for this week's show. You can find past episodes of MoneyBall Medicine at my website, glorikian.com, under the tab “Podcast.” And you can follow me on Twitter at hglorikian. Thanks for listening, and we'll be back soon with our next interview.
Today on the Mushroom Hour Podcast we are joined by Bryce Alex, Doctoral Student at the University of Wisconsin Madison. Bryce is originally from Utah and he spent time working as a graduate student and Masters Candidate in the legendary Dentinger Lab at the University of Utah. His mycological research work has involved important players when it comes to fungal ecology that are largely invisible and many of us may have never heard of. He has worked on projects involving metabarcoding fungal propagules carried on bird feathers and mining transcriptomic datasets for hidden mycoviruses. He began his PhD in Plant Pathology at University of Wisconsin Madison in Fall 2020. I am excited for him to share his expertise with the emerging field of mycoviruses and how they relate to fungal, plant and even animal populations. TOPICS COVERED: Entering the World of Mycology by Chance Research in Legendary Dentinger Lab What is a Mycovirus? How do Mycoviruses Effect Their Hosts? Hypovirulence in Pathogenic Fungi Cryphonectria parasitica Mycovirus Transference to Plants & Animals? Agaricus bisporous Dieback Disease Theories on Origins and Evolution of Mycoviruses Changing Paradigm of Virology Bryce's Current PhD Research Advice for Pursuing Academic Mycology Embracing the Mycology Community Future of Bryce's Work EPISODE RESOURCES: Bryce Alex LinkedIn: https://www.linkedin.com/in/bryce-alex-5799b8169 UW-Madison Rakotondrafara Lab: https://rakotondrafaralab.russell.wisc.edu/ Utah Dentinger Lab: https://www.biology.utah.edu/faculty/bryn-dentinger/ Cryphonectria parasitica: https://en.wikipedia.org/wiki/Chestnut_blight "50-Plus Years of Fungal Viruses": https://pubmed.ncbi.nlm.nih.gov/25771805/ "Five Questions About Mycoviruses": https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005172 "Mycoviruses of filamentous fungi and their relevance to plant pathology": https://bsppjournals.onlinelibrary.wiley.com/doi/10.1111/j.1364-3703.2008.00503.x
Learn how COVID tests work; how math can help you with major life decisions; and how some dogs have natural talent. How COVID PCR tests work by Ashley Hamer (Listener question from Lydia) Tiner, S. (2020, March 27). The Science Behind the Test for the COVID-19 VirusDiscovery's Edge. Https://Discoverysedge.mayo.edu/. https://discoverysedge.mayo.edu/2020/03/27/the-science-behind-the-test-for-the-covid-19-virus/ Amoeba Sisters. (2020). PCR (Polymerase Chain Reaction) [YouTube Video]. In YouTube. https://www.youtube.com/watch?v=a5jmdh9AnS4 PCR: Thirty-five years and counting. (2018, May 10). PCR: Thirty-five years and counting. Science | AAAS. https://www.sciencemag.org/features/2018/05/pcr-thirty-five-years-and-counting Ask A Scientist Staff. (2020, October 23). Why qPCR is the gold standard for COVID-19 testing. Ask a Scientist; Thermo Fisher Scientific. https://www.thermofisher.com/blog/ask-a-scientist/why-qpcr-is-the-gold-standard-for-covid-19-testing/ Additional resources from David Sumpter: Pick up "The Ten Equations that Rule the World and How You Can Use Them Too": https://www.penguin.co.uk/books/314/314406/the-ten-equations-that-rule-the-world/9780241404546.html Faculty page: https://katalog.uu.se/profile/?id=N7-525 Twitter: https://twitter.com/soccermatics?lang=en Dogs have talent, yes they do by Steffie Drucker Not only humans got talent, dogs got it too! (2021, July 7). EurekAlert! https://www.eurekalert.org/news-releases/553737 Fugazza, C., Dror, S., Sommese, A., Temesi, A., & Miklósi, Á. (2021). Word learning dogs (Canis familiaris) provide an animal model for studying exceptional performance. Scientific Reports, 11(1). https://doi.org/10.1038/s41598-021-93581-2 Genius Dog Challenge. (2021). Exceptional DOGS & what they can TEACH us [YouTube Video]. In YouTube. https://www.youtube.com/watch?v=WF6ZpjdH2Sc Follow Christina Hunger, Speech Pathologist, on Instagram @Hunger4Words https://www.instagram.com/hunger4words/?hl=en Follow Curiosity Daily on your favorite podcast app to learn something new every day withCody Gough andAshley Hamer. Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers. See omnystudio.com/listener for privacy information.
News Intern Rachel Fritts talks with host Sarah Crespi about a new way to think about endometriosis—a painful condition found in one in 10 women in which tissue that normally lines the uterus grows on the outside of the uterus and can bind to other organs. Next, Raphael Townshend, founder and CEO of Atomic AI, talks about predicting RNA folding using deep learning—a machine learning approach that relies on very few examples and limited data. Finally, in this month's edition of our limited series on race and science, guest host and journalist Angela Saini is joined by author Lundy Braun, professor of pathology and laboratory medicine and Africana studies at Brown University, to discuss her book: Breathing Race into the Machine: The Surprising Career of the Spirometer from Plantation to Genetics. This week's episode was produced with help from Podigy. Listen to previous podcasts. About the Science Podcast Download a transcript (PDF). [Image: C. Bickel/Science; Music: Jeffrey Cook] [Alt text: folded RNA 3D structures] Authors: Sarah Crespi; Rachel Fritts See omnystudio.com/listener for privacy information.
News Intern Rachel Fritts talks with host Sarah Crespi about a new way to think about endometriosis—a painful condition found in one in 10 women in which tissue that normally lines the uterus grows on the outside of the uterus and can bind to other organs. Next, Raphael Townshend, founder and CEO of Atomic AI, talks about predicting RNA folding using deep learning—a machine learning approach that relies on very few examples and limited data. Finally, in this month's edition of our limited series on race and science, guest host and journalist Angela Saini is joined by author Lundy Braun, professor of pathology and laboratory medicine and Africana studies at Brown University, to discuss her book: Breathing Race into the Machine: The Surprising Career of the Spirometer from Plantation to Genetics. This week's episode was produced with help from Podigy. Listen to previous podcasts. About the Science Podcast Download a transcript (PDF).
In this episode, Paul E. Sax, MD, discusses emerging drug therapies and treatment options for patients with HIV, including rapid initiation of ART, long-acting ART, and 2-drug ART regimens. The overview will include analyses from:The RAPID ART program in San Francisco, where same-day initiation of ART led to faster HIV-1 RNA suppression that was maintained at greater than 92% during a 3-year periodThe DIAMOND study analyzing virologic efficacy and safety at 48 weeks after initiating DRV/COBI/FTC/TAF within 24 hours of HIV infection diagnosisA rapid ART start program in young PWH in New Orleans that demonstrated achievement of viral suppression in fewer than 30 days and no discontinuations due to adverse eventsThe ATLAS (including ATLAS-2M) and FLAIR studies that demonstrated efficacy and safety of long-acting injectable CAB plus RPVSWORD-1 and SWORD-2 that demonstrated switching to a 2-drug regimen of DTG plus RPV in virologically suppressed adults was safe and effectiveGEMINI-1 and GEMINI-2 that demonstrated noninferiority of DTG plus 3TC compared with DTG plus FTC/TDFTANGO that demonstrated safety and efficacy of switching to DTG/3TC in virologically suppressed adults receiving a TAF-based regimenIn addition, Dr. Sax reviews current recommendations by the DHHS, WHO, and IAS-USA regarding these emerging therapies and treatment paradigms. Presenter:Paul E. Sax, MDClinical DirectorHIV Program and Division of Infectious DiseasesBrigham and Women's HospitalProfessor of MedicineHarvard Medical SchoolBoston, MassachusettsFollow along with the slides at:https://bit.ly/3zdPwm2 Content based on an online CME program supported by an educational grant from ViiV Healthcare.Link to full program:https://bit.ly/3ux6FF8
Two Top Virologists' Frightening Warnings About COVID Injections: Ignored by Government and Big Media By Joel S. Hirschhorn NOQ Report, August 21 2021 When two great minds come to similar conclusions about the current global push to vaccinate everyone with the COVID experimental vaccines, we should pay close attention. Both highly experienced scientists have a totally negative view of the vaccination effort. Worse than being ineffective, they point to negative health outcomes for the global population. These two truth-telling acclaimed medical researchers make Fauci look as inept, deceitful and dangerous as he is. The point made in this article is not only has Fauci pushed the wrong potentially disastrous pandemic solution, he has blocked the right one. Much of what the two virologists say is very technical in nature. This article simplifies their controversial messages without losing their essential meanings. The public needs to understand their warnings that refute all the propaganda pushing vaccines from government and public health agencies as well as big media. Warning: Keep reading and you may become depressed. * Dr. Luc Montagnier First considered is the thinking of Dr. Luc Montagnier, a French virologist and recipient of the 2008 Nobel Prize in Medicine for his discovery of the human immunodeficiency virus (HIV). He has a doctorate in medicine. But there is a lot more to conclude he is a great expert: He has received more than 20 major awards, including the French National Order of Merit and the Légion d'honneur. He is a recipient of the Lasker Award, the Scheele Award, the Louis-Jeantet Prize for medicine , the Gairdner Award the Golden Plate Award of the American Academy of Achievement, King Faisal International Prize (known as the Arab Nobel Prize), and the Prince of Asturias Award. He has worked hard to expose the dangers of the COVID-19 vaccines, still experimental but sadly may soon be fully approved. The vaccines don't stop the virus, argues the prominent virologist, they do the opposite — they “feed the virus,” and facilitate its development into stronger and more transmittable variants. These new virus variants will be more resistant to vaccination and may cause more health implications than their “original” versions. Montagnier refers to the mass vaccine program as an “unacceptable mistake” and are a “scientific error as well as a medical error.” His assertion is that “The history books will show that…it is the vaccination that is creating the variants.” In other words: “There are antibodies, created by the vaccine,” forcing the virus to “find another solution” or die. “This is where the variants are created. It is the variants that “are a production and result from the vaccination.” Stop and think about these thoughts. Have you heard a better explanation of variant creation? I doubt it. He is talking about the mutation and strengthening of the virus from a phenomenon known as Antibody Dependent Enhancement (ADE). ADE is a mechanism that increases the ability of a virus to enter cells and cause a worsening of the disease. Data from around the world confirms ADE occurs in SARS-CoV-2, which causes COVID-19, says Montagnier. “You see it in each country, it's the same: the curve of vaccination is followed by the curve of deaths.” Sounds like what we are now hearing more about, namely escalating breakthrough infections that kill some people. And this spiral into disaster may have no end. In a November 2020 documentary he emphasized harmful and irrational mask mandates as well as lockdowns, quarantines, abuses of government overreach, and supported use of effective COVID treatments such as hydroxychloroquine. The film was banned by YouTube and most other mainstream outlets. At that time Fauci had succeeded in blocking wide use of the cheap generic based treatments for COVID and pursued the wait for the vaccine strategy. Montagnier has been a vocal critic of the mass vaccination campaign. In a letter to the President and Judges of the Supreme Court of the State of Israel, which unrolled the world's speediest and the most massive vaccination campaign, Montagnier argued for its suspension. He said: “I would like to summarize the potential dangers of these vaccines in a mass vaccination policy.” Here they are: 1. Short-term side effects: these are not the normal local reactions found for any vaccination, but serious reactions involve the life of the recipient such as anaphylactic shock linked to a component of the vaccine mixture, or severe allergies or an autoimmune reaction up to cell aplasia. In this group we should include a number of lethal blood problems involving clots and loss of platelets that cause strokes, brain bleeds and other impacts. Lack of vaccine protection: 2.1 In induced antibodies do not neutralize a viral infection, but on the contrary facilitate it depending on the recipient. The latter may have already been exposed to the virus asymptomatically. Naturally induced antibodies may compete with the antibodies induced by the vaccine. 2.2 The production of antibodies induced by vaccination in a population highly exposed to the virus will lead to the selection of variants resistant to these antibodies. These variants can be more virulent or more transmissible. This is what we are seeing now. An endless virus-vaccine race that will always turn to the advantage for the virus. Long-term effects: Contrary to the claims of the manufacturers of messenger RNA vaccines, there is a risk of integration of viral RNA into the human genome. Our cells have the ability to reverse transcriptase from RNA into DNA. Although this is a rare event, its passage through the DNA of germ cells and its transmission to future generations cannot be excluded. His bottom line: “Faced with an unpredictable future, it is better to abstain.” But most people will find it extremely difficult to resist all the coercion and vaccine mandates. Back in April 2020, before all the talk of variants and before the rollout of the experimental vaccines, Montagnier urged people to refuse vaccines against COVID-19 when they become available. His main point should always be remembered: “instead of preventing the infection, they [would] accelerate infection.” Today, the newly occurring variants of SARS-CoV-2 that affect vaccinated people prove his thesis. With his scientific thinking, mass vaccination may cause a new, more deadly wave of pandemic infection. As to the much talked about and hope for herd immunity, he has said: “the vaccines Pfizer, Moderna, Astra Zeneca do not prevent the transmission of the virus person-to-person and the vaccinated are just as transmissive as the unvaccinated. Therefore the hope of a ‘collective immunity' by an increase in the number of vaccinated is totally futile.” On the positive side, he advocated this: “The early treatment of infection with ivermectin and bacterial antibiotic because there is a bacterial cofactor that amplifies the effects of the virus. “ Dr. Vanden Bossche The stark views of Montagnier have been shared by the esteemed Belgium virologist Dr. Vanden Bossche. He too has considerable credentials that make his views worth consideration. He has PhD degree in Virology from the University of Hohenheim, Germany. He held faculty appointments at universities in Belgium and Germany. He was at the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He has been in the private sector at several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) where he worked on vaccine R&D as well as vaccine development. He also worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. His views have been analyzed in a recent article. He too has loudly called for a halt to mass-vaccination programs. He believes that if the jabs are not halted, they could lead to the evolution of stronger and stronger variants of the virus until a “supervirus” takes hold and wipes out huge numbers of people. This is his bold view: “Given the huge amount of immune escape that will be provoked by mass vaccination campaigns and flanking containment measures, it is difficult to imagine how human interventions would not cause the COVID-19 pandemic to turn into an incredible disaster for global and individual health.” Here is an essential element of his thinking. Pretty much everything being done in the pandemic doesn't guarantee elimination of the virus. What is happening is selective viral ‘immune escape' where viruses continue to be shed from those who are infected [both vaccinated and nonvaccinated] because neutralizing antibodies fail to prevent replication and elimination of the virus. The evolutionary selection pressure on the virus through ‘immune escape,' creates ever more virulent strains of the virus that have a competitive advantage over other variants and will increasingly have the potential to break through the antibody defenses. Defenses provided by the vaccine induced immune system. This is ‘vaccine resistance.' What happens is that vaccine makers keep trying to outsmart variants, but fail. So, they keep pushing boosters and yearly vaccine shots. This is the more is better approach. This is aided by suppression of many negative facts about the vaccines by big media. A frightening forecast by Bossche is that the worst of the pandemic is still to come. Hard to believe considering all the bad news propaganda about cases, hospitalizations and deaths. But he thinks we are now experiencing the calm before the ultimate storm. Imagine a new wave of infection far worse than anything we've seen so far is how Bossche thinks. How does this happen? There will be more mutants or variants to which the adaptive immune system from vaccine shots provides little resistance. At the same time there will be decreased innate or natural immune effectiveness. Unless people take a number of steps to boost their natural immunity. Bossche consistently points to a lack of evidence that the existing global, mass vaccination program that has been mounted while there is still significant infection around, is unprecedented and there is no scientific evidence that this will work. This is why he is largely ignored. He stresses that historic vaccination programs have always emphasized the importance of vaccinating populations prophylactically in the absence of infection pressure. He also argues that if different types of vaccine were used that provided sterilizing immunity i.e., that prevented immune escape and killed all viruses in those vaccinated, the situation would be entirely different. Most people do not understand that the current experimental vaccines do not actually kill the virus; and that both the vaccinated and nonvaccinated shed the virus. These vaccines do not stop viral transmission. And all the contagion control measures simply to not work effectively enough to stop wide spread of the virus in its various forms. Here is his big picture view: “There is only one single thing at stake right now and that is the survival of our human race, frankly speaking.” But there are more strong words recently said by Bossche to pay attention to: “every person out there who is ‘partially' or ‘fully' vaccinated is a walking disease incubation system that puts everyone else at risk of contracting a deadly, vaccine-caused ‘variant' that could kill them. The ‘vaccinated' are walking murderers spreading disease to others. Getting injected for the Fauci Flu is not only foolish; it is also a form of murder in that unvaccinated people are now at risk of contracting the deadly diseases being manufactured inside the bodies of the vaccinated. If Trump had never introduced the vaccine in the first place, the pandemic would have long ago fizzled out. Since his vaccines continue to be pushed … however, the ‘Delta' variant is spreading like wildfire, soon to be followed by other ‘variants' as we enter the fall season.” This too is a very strong view. The “mass vaccination program is…unable to generate herd immunity.” If true, there is little hope of seeing the COVID pandemic ending. What is the solution? Bossche has identified the needed alternative to the current massive vaccine effort. It is this; “This first critical step can only be achieved by calling an immediate halt to the mass vaccination program and replacing it by widespread use of antiviral chemoprophylactics while dedicating massive public health resources to scaling early multidrug treatments of Covid-19 disease.” This is referring to the early home/outpatient treatment protocols based on cheap, safe and fully approved generics like ivermectin and hydroxychloroquine; these also work as preventatives. Pandemic Blunder provides much data and advice on using this treatment approach. So, both virologists support use of what Fauci has blocked. These action recommendations were also made by Bossche “Provide – at no cost – early multidrug treatment to all patients in need. Roll out campaigns to promote healthy diets and lifestyle.” In other words, people need to take actions to boost their natural immunity, this should include vitamins and supplements, including this cocktail: vitamin C, vitamin D, zine and quercetin. Conclusions Take a moment to consider that Patrick Wood on the Bannon show on August 21 concluded that all the available data from the US and Europe shows some 100,000 people have died from the COVID experimental vaccines. I agree with that assessment. And by the time you read this FDA may have given full approval to the Pfizer vaccine. After considering what these two experts have said it is appropriate to criticize what current government officials say, namely blame the unvaccinated for the surges in COVID cases, hospitalizations and deaths. The major alternative to this thinking is that it is the vaccinated people who are creating pandemic problems, including the variants. The strong conclusion is that the current vaccines are ineffective, nonprotective and dangerous. What is needed is an entirely new approach to COVID vaccines. Perhaps there are companies working on this. This would threaten the trillion-dollar business of the current vaccine makers. If the people, agencies and institutions with all the power listening to these two very smart people they would devote all their energies to using alternatives to the current vaccines. We have them. Notably, the treatment protocols that so many great doctors have created and used to help their patients. Many other physicians and medical researchers have called for a halt to the current vaccine bonanza for big drug companies. In the meantime, on a daily basis for all those willing to look at the facts, it is clearer and clearer that the experimental vaccines are not effective. It is insanity to keep doing or expanding what is not working. That is the insane world we are now experiencing even as more and people die from breakthrough infections, blood problems and other bad vaccine health impacts. Perhaps the ugly truth about the vaccines will be widely revealed only when there are massive, widespread deaths despite all the shots and jabs. That will be too late to change pandemic management from money-driven stupidity to life-saving, medically moral actions. * Dr. Joel S. Hirschhorn, author of Pandemic Blunder and many articles on the pandemic, worked on health issues for decades. As a full professor at the University of Wisconsin, Madison, he directed a medical research program between the colleges of engineering and medicine. As a senior official at the Congressional Office of Technology Assessment and the National Governors Association, he directed major studies on health-related subjects; he testified at over 50 U.S. Senate and House hearings and authored hundreds of articles and op-ed articles in major newspapers. He has served as an executive volunteer at a major hospital for more than 10 years. He is a member of the Association of American Physicians and Surgeons and America's Frontline Doctors and has been a long-time contributor to the sites of Kettle Moraine.