Podcasts about ccr5

TBT- This week Let's Talk Micro is talking about virology, specifically about the Human Immunodeficiency Virus (HIV). This episode features an interview with Dr. Hsu, a stem cell specialist from the Weill Medical College at Cornell University in New York. She discusses an article about a patient that has been possibly cured from HIV after a stem cell transplant with cord blood cells. What is the CCR5 gene? What is its relationship to HIV? Tune in to find out about this interesting article. This episode was originally published on April 14th , 2022. Link to article:  https://news.weill.cornell.edu/news/2022/02/patient-possibly-cured-of-hiv-infection-by-special-stem-cell-transplant Questions? Feedback? Send those to letstalkmicro@outlook.com Want to support the podcast? Here's how: Venmo: https://venmo.com/u/letstalkmicro Buy me a Ko-fi: https://ko-fi.com/letstalkmicro  

This week we talk about gene-editing, CRISPR/Cas9, and ammonia.We also discuss the germ line, mad scientists, and science research funding.Recommended Book: The Siren's Call by Chris HayesTranscriptBack in November of 2018, a Chinese scientist named He Jiankui achieved global notoriety by announcing that he had used a relatively new gene-editing technique on human embryos, which led to the birth of the world's first gene-edited babies.His ambition was to help people with HIV-related fertility problems, one of which is that if a parent is HIV positive, there's a chance they could transmit HIV to their child.This genetic modification was meant to confer immunity to HIV to the children so that wouldn't be an issue. And in order to accomplish that immunity, He used a technology called CRISPR/Cas9 to modify the embryos' DNA to remove their CCR5 gene, which is related to immune system function, but relevant to this undertaking, also serves as a common pathway for the HIV-1 virus, allowing it to infect a new host.CRISPR is an acronym that stands for clustered regularly interspaced short palindromic repeats, and that refers to a type of DNA sequence found in all sorts of genomes, including about half of all sequenced bacterial genomes and just shy of 90% of all sequenced archaea genomes.Cas9 stands for CRISPR-associated protein 9, which is an enzyme that uses CRISPR sequences, those repeating, common sequences in DNA strands, to open up targeted DNA strands—and when paired with specific CRISPR sequences, this duo can search for selected patterns in DNA and then edit those patterns.This tool, then, allows researchers who know the DNA pattern representing a particular genetic trait—a trait that moderates an immune system protein that also happens to serve as a convenient pathway for HIV, for instance—to alter or eliminate that trait. A shorthand and incomplete way of thinking about this tool is as a sort of find and replace tool like you have in a text document on your computer, and in this instance, the gene sequence being replaced is a DNA strand that causes a trait that in turn leads to HIV susceptibility.So that's what He targeted in those embryos, and the children those embryos eventually became, who are usually referred to as Lulu and Nana, which are pseudonyms, for their privacy, they were the first gene-edited babies; though because of the gene-editing state of the art at the time, while He intended to render these babies' CCR5 gene entirely nonfunctional, which would replicate a natural mutation that's been noted in some non-gene-edited people, including the so-called Berlin Patient, who was a patient in Germany in the late-90s who was functionally cured of HIV—the first known person to be thus cured—while that's what He intended to do, instead these two babies actually carry both a functional and a mutant copy of CCR5, not just the mutant one, which in theory means they're not immune to HIV, as intended.Regardless of that outcome, which may be less impactful than He and other proponents of this technology may have hoped, He achieved superstardom, briefly, even being named one of the most influential people in the world by Time magazine in 2019. But he was also crushed by controversy, stripped of his license to conduct medical research by the Chinese government, sent to prison for three years and fined 3 million yuan, which is more than $400,000, and generally outcast from the global scientific community for ethical violations, mostly because the type of gene-editing he did wasn't a one-off sort of thing, it was what's called germ-line editing, which means those changes won't just impact Lulu and Nana, they'll be passed on to their children, as well, and their children's children, and so on.And the ethical implications of germ-line editing are so much more substantial because while a one-off error would be devastating to the person who suffers it, such an error that is passed on to potentially endless future generations could, conceivably, end humanity.The error doesn't even have to be a botched job, it could be an edit that makes the edited child taller or more intelligent by some measure, or more resistant to a disease, like HIV—but because this is fringy science and we don't fully understand how changing one thing might change other things, the implications for such edits are massive.Giving someone an immunity to HIV would theoretically be a good thing, then, but if that edit then went on the market and became common, we might see a generation of humans that are immune to HIV, but potentially more susceptible to something else, or maybe who live shorter lives, or maybe who create a subsequent generation who themselves are prone to all sorts of issues we couldn't possibly have foreseen, because we made these edits without first mapping all possible implications of making that genetic tweak, and we did so in such a way that those edits would persist throughout the generations.What I'd like to talk about today is another example of a similar technology, but one that's distinct enough, and which carries substantially less long-term risk, that it's being greeted primarily with celebration rather than concern.—In early August of 2024, a gene-editing researcher at the University of Pennsylvania, Dr. Kiran Musunuru, was asked if there was anything he could do to help a baby that was being treated at the Children's Hospital of Philadelphia for CPS1 deficiency, which manifests as an inability to get rid of the ammonia that builds up in one's body as a byproduct of protein metabolism.We all generate a small amount of ammonia just as a function of living, and this deficiency kept the baby from processing and discarding that ammonia in the usual fashion. As a result, ammonia was building up in its blood and crossing into its brain.The usual method of dealing with this deficiency is severely restricting the suffer's protein intake so that less ammonia is generated, but being a baby, that meant it wasn't able to grow; he was getting just enough protein to survive and was in the 7th percentile for body weight.So a doctor at the Children's Hospital wanted to see if there was anything this gene-editing researcher could do to help this baby, who was at risk of severe brain damage or death because of this condition he was born with.Gene-editing is still a very new technology, and CRISPR and associated technologies are even newer, still often resulting in inaccurate edits, many of which eventually go away, but that also means the intended edit sometimes goes away over time, too—the body's processes eventually replacing the edited code with the original.That said, these researchers, working with other researchers at institutions around the world, though mostly in the US, were able to rush a usually very cumbersome and time-consuming process that would typically take nearly a decade, and came up with and tested a gene-editing approach to target the specific mutation that was causing this baby's problems, and they did it in record time: the original email asking if Dr Musunuru might be able to help arrived in August of 2024, and in late-February of 2025, the baby received his first infusion of the substance that would make the proper edits to his genes; they divided the full, intended treatment into three doses, the first being very small, because they didn't know how the baby would respond to it, and they wanted to be very, very cautious.There were positive signs within the first few weeks, so 22 days later, they administered the second dose, and the third followed after that.Now the research and medical worlds are waiting to see if the treatment sticks; the baby is already up to the 40th percentile in terms of weight for his age, is able to eat a lot more protein and is taking far less medication to help him deal with ammonia buildup, but there's a chance that he may still need a liver transplant, that there might be unforeseen consequences due to that intended edit, or other, accidental edits made by the treatment, or, again, that the edits won't stick, as has been the case in some previous trials.Already this is being heralded as a big success, though, as the treatment seems to be at least partially successful, hasn't triggered any serious, negative consequences, and has stuck around for a while—so even if further treatments are needed to keep the gene edited, there's a chance this could lead to better and better gene-editing treatments in the future, or that such treatments could replace some medications, or be used for conditions that don't have reliable medications in the first place.This is also the first known case of a human of any age being given a custom gene-editing treatment (made especially for them, rather than being made to broadly serve any patient with a given ailment or condition), and in some circles that's considered to be the future of this field, as individually tailored gene-treatments could help folks deal with chronic illnesses and genetic conditions (like cystic fibrosis, Huntington's disease, muscular dystrophy, and sickle cell), but also possibly help fight cancers and similar issues.More immediately, if this treatment is shown to be long-term efficacious for this first, baby patient, it could be applied to other patients who suffer the same deficiency, which afflicts an estimated 1 in 1.3 million people, globally. It's not common then—both parents have to have a mutant copy of a specific gene for their child to have this condition—but that's another reason this type of treatment is considered to be promising: many conditions aren't widespread enough to justify investment in pharmaceuticals or other medical interventions that would help them, so custom-tailored gene-editing could be used, instead, on a case-by-case basis.This is especially true if the speed at which a customized treatment can be developed is sped-up even further, though there are concerns about the future of this field and researchers' ability to up its efficiency as, at least in the US, the current administration's gutting of federal research bodies and funding looks likely to hit this space hard, and previous, similar victories that involved dramatically truncating otherwise ponderous developmental processes—like the historically rapid development of early COVID-19 vaccines—are not looked at favorably by a larger portion of the US electorate, which could mean those in charge of allocating resources and clearing the way for such research might instead pull even more funding and put more roadblocks in place, hobbling those future efforts, rather than the opposite.There are plenty of other researchers and institutions working on similar things around the world, of course, but this particular wing of that larger field may have higher hurdles to leap to get anything done in the coming years, if current trends continue.Again, though, however that larger context evolves, we're still in the early days of this, and there's a chance that this approach will turn out to be non-ideal for all sorts of reasons.The concept of tailored gene-editing therapies is an appealing one, though, as it could replace many existing pharmaceutical, surgical, and similar approaches to dealing with chronic, inherited conditions in particular, and because it could in theory at least allow us to address such issues rapidly, and without needing to mess around with the germ-line, because mutations could be assessed and addressed on a person-by-person basis, those edits staying within their bodies and not being passed on to their offspring, rather than attempting to make genetic customizations for future generations based on the imperfect knowledge and know-how of today's science, and the biased standards and priorities of today's cultural context.Show Noteshttps://www.nejm.org/doi/full/10.1056/NEJMoa2504747https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatmenthttps://www.wired.com/story/a-baby-received-a-custom-crispr-treatment-in-record-time/https://www.wsj.com/tech/biotech/crispr-gene-editing-therapy-philadelphia-infant-8fc3a2c5https://www.washingtonpost.com/science/2025/05/15/crispr-gene-editing-breakthrough/https://www.npr.org/sections/shots-health-news/2025/05/15/nx-s1-5389620/gene-editing-treatment-crispr-inheritedhttps://interestingengineering.com/health/first-personalized-crispr-gene-therapyhttps://www.nature.com/articles/d41586-025-01496-zhttps://www.nytimes.com/2025/05/15/health/gene-editing-personalized-rare-disorders.htmlhttps://www.nytimes.com/2025/05/31/world/asia/us-science-cuts.htmlhttps://www.livescience.com/health/genetics/us-baby-receives-first-ever-customized-crispr-treatment-for-genetic-diseasehttps://en.wikipedia.org/wiki/He_Jiankui_affairhttps://en.wikipedia.org/wiki/CCR5https://en.wikipedia.org/wiki/Berlin_Patienthttps://en.wikipedia.org/wiki/CRISPR_gene_editinghttps://en.wikipedia.org/wiki/CRISPRhttps://pmc.ncbi.nlm.nih.gov/articles/PMC6813942/ This is a public episode. 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Episode 16 -  Insights on HIV Cure by Stem Cell Transplant with Dr Ravindra Gupta Recorded Live at CROI 2024 on March 3, 2024 In this episode of Going anti-Viral, Dr Michael Saag hosts Dr Ravindra Gupta. Dr Gupta is the infectious diseases expert who led the team that treated Adam Castillejo, also known as ‘The London Patient,' the second person known to have been cured of HIV. The discussion, recorded on March 3, 2024, at the Conference on Retroviruses and Opportunistic Infections (CROI), focused on the intricate process of finding a suitable stem cell donor, the immunologic and virologic considerations around the transplant process, and the collaborative medical team effort involved.  00:00 Introduction 00:30 The London Patient 03:05 Finding the CCR5∆32 Stem Cell Match 04:21 Clinical Challenges on the Transplant Journey 06:58 Post-Transplant Monitoring and Milestones 15:53 Reflecting on the Journey 18:51 Closing Thoughts and Acknowledgments__________________________________________________Produced by IAS-USA, Going anti–Viral is a podcast for clinicians involved in research and care in HIV, its complications, and other viral infections. This podcast is intended as a technical source of information for specialists in this field, but anyone listening will enjoy learning more about the state of modern medicine around viral infections. Going anti-Viral's host is Dr Michael Saag, a physician, prominent HIV researcher at the University of Alabama at Birmingham, and volunteer IAS–USA board member. In most episodes, Dr Saag interviews an expert in infectious diseases or emerging pandemics about their area of specialty and current developments in the field. Other episodes are drawn from the IAS–USA vast catalogue of panel discussions, Dialogues, and other audio from various meetings and conferences. Email podcast@iasusa.org to send feedback, show suggestions, or questions to be answered on a later episode.Follow Going anti-Viral on: Apple Podcasts YouTube InstagramTikTok...

In this episode of Going anti-Viral, host Dr Michael Saag interviews Adam Castillejo, known as the London patient, who is the second person to have been cured of HIV infection. The discussion, recorded on March 3, 2024, at The Conference on Retroviruses and Opportunistic Infections (CROI), touches on Adam's initial HIV diagnosis in London during the early 2000s, the societal stigma and personal impact of the diagnosis, and his dual battle with HIV and cancer. Adam shares the complex journey of his treatment, including the failure of initial interventions and the ultimate success of a bone marrow transplant from a donor with a CCR5 delta 32 mutation, leading to his cure of HIV and cancer. The conversation delves into the technical aspects of bone marrow transplant, the emotional and physical challenges Adam faced during recovery, and the continued stigma he experiences even post-cure. The episode reflects on the broader implications of Adam's story for HIV research and societal perceptions of the disease.00:00 Introduction01:10 Adam's Early Struggle with HIV Diagnosis02:46 Confronting Stigma and Finding Support05:26 The Battle Against Cancer and Mental Health Challenges08:35 The Turning Point: Bone Marrow Transplant15:14 The Journey of Recovery17:29 Life After the Cure22:37 Concluding Thoughts__________________________________________________Produced by IAS-USA, Going anti–Viral is a podcast for clinicians involved in research and care in HIV, its complications, and other viral infections. This podcast is intended as a technical source of information for specialists in this field, but anyone listening will enjoy learning more about the state of modern medicine around viral infections. Going anti-Viral's host is Dr Michael Saag, a physician, prominent HIV researcher at the University of Alabama at Birmingham, and volunteer IAS–USA board member. In most episodes, Dr Saag interviews an expert in infectious diseases or emerging pandemics about their area of specialty and current developments in the field. Other episodes are drawn from the IAS–USA vast catalogue of panel discussions, Dialogues, and other audio from various meetings and conferences. Email podcast@iasusa.org to send feedback, show suggestions, or questions to be answered on a later episode.Follow Going anti-Viral on: Apple Podcasts YouTube InstagramTikTok...

BUFFALO, NY- October 4, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 18, entitled, “Biomedical generative pre-trained based transformer language model for age-related disease target discovery.” Target discovery is crucial for the development of innovative therapeutics and diagnostics. However, current approaches often face limitations in efficiency, specificity, and scalability, necessitating the exploration of novel strategies for identifying and validating disease-relevant targets. Advances in natural language processing have provided new avenues for predicting potential therapeutic targets for various diseases. In their new study, researchers Diana Zagirova, Stefan Pushkov, Geoffrey Ho Duen Leung, Bonnie Hei Man Liu, Anatoly Urban, Denis Sidorenko, Aleksandr Kalashnikov, Ekaterina Kozlova, Vladimir Naumov, Frank W. Pun, Ivan V. Ozerov, Alex Aliper, and Alex Zhavoronkov from Insilico Medicine present a novel approach for predicting therapeutic targets using a large language model (LLM). “We trained a domain-specific BioGPT model on a large corpus of biomedical literature consisting of grant text and developed a pipeline for generating target prediction.” This study demonstrates that pre-training of the LLM model with task-specific texts improves its performance. Applying the developed pipeline, the researchers retrieved prospective aging and age-related disease targets and showed that these proteins are in correspondence with the database data. Moreover, they propose CCR5 and PTH as potential novel dual-purpose anti-aging and disease targets which were not previously identified as age-related but were highly ranked in their approach. “Overall, our work highlights the high potential of transformer models in novel target prediction and provides a roadmap for future integration of AI approaches for addressing the intricate challenges presented in the biomedical field.” DOI - https://doi.org/10.18632/aging.205055 Corresponding author - Alex Zhavoronkov - alex@insilico.com Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205055 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, transformers, deep learning, therapeutic target discovery, aging biomarkers, human aging About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

On Faster, Please! — The Podcast, I've interviewed guests on exciting new technologies like artificial intelligence, fusion energy, and reusable rockets. But today's episode explores another Next Big Thing: biotechnology. To discuss recent advances in CRISPR gene editing and their applications for medicine, I'm sitting down with Kevin Davies.Kevin is executive editor of The CRISPR Journal and author of the excellent 2020 book, Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing.In This Episode* CRISPR advances over the past decade (1:13)* What CRISPR therapies will come next? (8:46)* Non-medical applications of gene editing (13:11)* Bioweapons and the ethics of CRISPR (18:43)* Longevity and genetic enhancements (25:48)Faster, Please! is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Below is an edited transcript of our conversationCRISPR advances over the past decadeWhen people talk about AI, for instance, they might be talking about different versions or applications of AI—machine learning being one. So when we talk about CRISPR, are we just talking about one technique, the one they figured out back in 2012? Are there different ones? Are there improvements? So it's really a different technique. So how has that progressed?You're right. CRISPR has become shorthand for genome editing. But the version of CRISPR that was recognized with the Nobel Prize three years ago in 2020 to Jennifer Doudna and Emmanuelle Charpentier was for one, we can call it the traditional form of CRISPR. And if I refer to it again, I'll call it CRISPR-Cas9. Cas9 is the shorthand name for the enzyme that actually does the cutting of the DNA. But we are seeing extraordinary progress in developing new and even more precise and more nuanced forms of genome editing. They still kind of have a CRISPR backbone. They still utilize some of the same molecular components as the Nobel Prize–winning form of CRISPR. But in particular, I'm thinking of techniques called base editing and prime editing, both of which have commercial, publicly funded biotech companies pushing these technologies into the clinic. And I think over the next five to 10 years, increasingly what we refer to as “CRISPR genome editing” will be in the form of these sort of CRISPR 2.0 technologies, because they give us a much broader portfolio of DNA substitutions and changes and edits, and give the investigators and the clinicians much more precision and much more subtlety and hopefully even more safety and more guarantees of clinical efficiency.Right. That's what I was going to ask. One advantage is the precision, because you don't want to do it wrong. You don't want mutations. Do no harm first. A big advantage is maybe limiting some of the potential downsides.In the ideal gene-editing scenario, you would have a patient with, say, a genetic disease that you can pinpoint to a single letter of the genetic code. And we want to fix that. We want to zero in on that one letter—A, C, T, or G is the four-letter alphabet of DNA, as I hope most of your listeners know—and we want to revert that back to whatever most normal, healthy people have in their genetic code at that specific position. CRISPR-Cas9, which won the Nobel Prize, is not the technology to do that sort of single base edit. It can do many other things, and the success in the clinic is unquestionable already in just a few years. But base editing and, in particular, prime editing are the two furthest developed technologies that allow investigators to pinpoint exactly where in the genome we want to make the edit. And then without completely cutting or slicing the double helix of DNA, we can lay up the section of DNA that we want to replace and go in and just perform chemistry on that one specific letter of DNA. Now, this hasn't been proven in the clinic just yet. But the early signs are very, very promising that this is going to be the breakthrough genome-editing technology over the next 10 to 20 years.Is CRISPR in the wild yet, or are we still in the lab?No, we're in the clinic. We are in human patients. There are at least 200 patients who have already been in or are currently enrolled in clinical trials. And so far, the early results—there are a few caveats and exceptions—but so far the overwhelming mood of the field is one of bullish enthusiasm. I don't want to complete this interview without singling out this one particular story, which is the clinical trial that has been sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals for sickle cell disease. These are primarily African-American patients in this country because the sickle cell mutation arose in Africa some 7,000 years ago.We're talking about a pretty big share of the African-American population.This is about 100,000 patients just in America, in the US alone. And it's been a neglected disease for all kinds of reasons, probably beyond the scope of our discussion. But the early results in the first few dozen patients who have been enrolled in this clinical trial called the exa-cel clinical trial, they've all been cured. Pretty much all cured, meaning no more blood transfusions, no more pain crises, no more emergency hospitalizations. It is a pretty miraculous story. This therapy is now in the hands of the FDA and is speeding towards—barring some unforeseen complication or the FDA setting the bar so high that they need the investigators to go back and do some further checks—this should be approved before the end of this year.There's a catch, though. This will be a therapy that, in principle, will become—once approved by the FDA and the EMA in Europe, of course—will become available to any sickle cell patient. The catch will, of course, be the cost or the price that the companies set, because they're going to look for a return on their investment. It's a fascinating discussion and there's no easy answer. The companies need to reward their shareholders, their investors, their employees, their staff, and of course build a war chest to invest in the next wave, the next generation of CRISPR therapies. But the result of that means that probably we're going to be looking at a price tag of, I mean, I'm seeing figures like $1.9 million per patient. So how do you balance that? Is a lifetime cure for sickle cell disease worth $2, maybe $3 million? Will this patient population be able to afford that? In many cases, the answer to that will be simply, no. Do you have to remortgage your house and go bankrupt because you had a genetic quirk at birth? I don't know quite how we get around this.Different countries will have different answers with different health systems. Do you have a sense of what that debate is going to be like in Washington, DC?It's already happening in other contexts. Other gene therapies have been approved over the last few years, and they come with eye-watering price tags. The highest therapy price that I've seen now is $3.5 million. Yes, there are discounts and waiver programs and all this sort of stuff. But it's still a little obscene. Now, when those companies come to negotiate, say, with the UK National Health Service, they'll probably come to an agreement that is much lower, because the Brits are not going to say that they're going to be able to afford that for their significant sickle cell population.Is it your best guess that this will be a treatment the government pays for?What's interesting and what may potentially shift the calculus here is that this particular therapy is the disease affects primarily African-Americans in the United States. That may change the political calculus, and it may indeed change the corporate calculus in the boardrooms of Vertex and CRISPR Therapeutics, who may not want the backlash that they're going to get when they say, “Oh, by the way, guys, it's $2 million or you're out of luck.”There are companies that are studying using CRISPR to potentially correct the mutations that cause genetic forms of blindness, genetic forms of liver disease.What CRISPR therapies will come next?And after this CRISPR treatment for sickle cell disease is available, what therapies will come next?Probably a bunch of diseases that most people, unless they are unfortunate enough to have it in their family, won't have heard of. There are companies that are studying using CRISPR to potentially correct the mutations that cause genetic forms of blindness, genetic forms of liver disease. It turns out the liver is an organ that is very amenable to taking up medicines that we can inject in the blood. The other big clinical success story has come from another company in the Boston area called Intellia Therapeutics. Also publicly traded. They've developed CRISPR therapies that you can inject literally into the body, rather than taking cells out and doing it in the lab and then putting those cells back in, as in the case of sickle cell.I'm not sure that was actually even clear: that you can do it more than one way.Yes.And obviously it sounds like it would be better if they could just inject you.Exactly. That's why people are really excited about this, because this now opens up the doors for treating a host of diseases. And I think over the next few years we will see a growing number of diseases, and it won't just be these rare sort of genetic diseases with often unpronounceable names. It may be things like heart disease. There's another company—they're all in Boston, it seems—Verve Therapeutics, which is taking one of these more recent gene-editing technologies that we talked about a minute ago, base editing, and saying that there's a gene that they're going to target that has been clearly linked with cholesterol levels. And if we can squash production of this gene, we can tap down cholesterol levels. That will be useful, in the first instance, for patients with genetic forms of high cholesterol. Fair enough. But if it works in them, then the plan is to roll this out for potentially thousands if not millions of adults in this country who maybe don't feel that they have a clearly defined genetic form of high cholesterol, but this method may still be an alternative that they will consider versus taking Atorvastatin for the rest of your life, for example.Where are the CRISPR cancer treatments?They're also making progress, too. Those are in clinical trials. A little more complicated. Of course, cancer is a whole slew of different diseases, so it's a little hard to say, “Yeah, we're making progress here, less so there.” But I think one of the most heartwarming stories—this is an n of one, so it's an anecdotal story—but there was a teenager in the UK treated at one of the premier London medical schools who had a base editing form of CAR T therapy. A lot of people have heard of CAR T therapy for various cancers. And she is now in remission. So again, early days, but we're seeing very positive signs in these early clinical tests.It sounds like we went from a period where it was all in the lab and that we might be in a period over the next five years where it sounds like a wave of potential treatments.I think so, yeah.And for as much as we've seen articles about “The Age of AI,” it really sounds like this could be the age of biotechnology and the age of CRISPR…I think CRISPR, as with most new technologies, you get these sort of hype cycles, right? Two and a half years ago, CRISPR, all the stocks were at peak valuations. And I went on a podcast to say, why are the CRISPR stocks so high? I wasn't really sure, but I was enjoying it at the time. And then, of course, we entered the pandemic. And the biotech sector, perversely, ironically, has really been hit hard by the economy and certainly by the market valuations. So all of the CRISPR gene-editing companies—and there are probably at least eight or 10 now that are publicly traded and many more poised to join them—their valuations are a fraction of what they were a couple of years ago. But I suspect as these first FDA approvals and more scientific peer review papers, of course, but more news of the clinical success to back up and extend what has already been clearly proven as a breakthrough technology in the lab with the Nobel Prize—doesn't get much better than that, does it?—then I think we're going to start to see that biotech sector soar once again.Certainly, there are a lot of computational aspects to CRISPR in terms of designing the particular stretches of nucleic acid that you're going to use to target a specific gene. And AI can help you in that quest to make those ever more precise.Non-medical applications of gene editingThere are also non-medical applications. Can you just give me a little state of play on how that's looking?I think one of the—when CRISPR…And agriculture.Feeding the planet, you could say.That's certainly a big application.It's a human health application—arguably the biggest application.I think one of the fun ones is the work of George Church at Harvard Medical School, who's been on 60 Minutes and Stephen Colbert and many other primetime shows, talking about his work using CRISPR to potentially resurrect the woolly mammoth, which sort of sounds like, “That's Jurassic Park on steroids. That's crazy.” But his view is that, no, if we had herds—if that's the technical term—of woolly mammoths—roaming Siberia and the frozen tundra, they'll keep the ground, the surface packed down and stop the gigatons of methane from leaching out into the atmosphere. We have just seen a week, I've been reading on social media, of the hottest temperatures in the world since records began. And that's nothing compared to what we're potentially going to see if all these greenhouse gases that are just under the surface in places like Siberia further leach into the atmosphere. So that's the sort of environmental cause that Church is on. I think many people think this is a rather foolish notion, but he's launched a company to get this off the ground called Colossal Biosciences, and they're raising a lot of money, it appears. I'm curious to see how it goes. I wish him well.Also, speaking of climate change, making crops more resilient to the heat. That's another I've heard…One of the journals I'm involved in, called GEN Biotechnology, just published a paper in which investigators in Korea have used CRISPR to modify a particular gene in the tomato genome to make it a higher source of vitamin D. And that may not seem to be the most urgent need, but the point is, we can now engineer the DNA of all kinds of plants and crops, many of which are under threat, whether it's from drought or other types of climate change or pests, bacteria, parasites, viruses, fungi, you name it. And in my book Editing Humanity, which came out a couple of years ago, there was a whole chapter listing a whole variety of threats to our favorite glass of orange juice in the morning. That's not going to exist. If we want that all-natural Florida orange juice, we're not going to have that option. We've either got to embrace what technology will allow us to do to make these orange crops more resistant to the existential threat that they're facing, or we're going to have to go drink something else.I started out talking about AI and machine learning. Does that play a role in CRISPR, either helping the precision of the technology or in some way refining the technology?Yeah, hopefully you'll invite me back in a year and I'll be able to give you a more concrete answer. I think the short answer is, yes. Certainly, there are a lot of computational aspects to CRISPR in terms of designing the particular stretches of nucleic acid that you're going to use to target a specific gene. And AI can help you in that quest to make those ever more precise. When you do the targeting in a CRISPR experiment, the one thing you don't want to have happen is for the little stretch of DNA that you've synthesized to go after the gene in question, you don't want that to accidentally latch onto or identify another stretch of DNA that just by statistical chance has the same stretch of 20 As, Cs, Ts, and Gs. AI can help give us more confidence that we're only honing in on the specific gene that we want to edit, and we're not potentially going to see some unforeseen, off-target editing event.Do you think when we look back at this technology in 10 years, not only will we see a wider portfolio of potential treatments, but we'll look at the actual technique and think, “Boy, back in 2012, it was a butchery compared to what we're doing; we were using meat cleavers, and now we're using lasers”?I think, yeah. That's a slightly harsh analogy. With this original form of CRISPR, published in 2012, Nobel Prize in 2020, one of the potential caveats or downsides of the technology is that it involves a complete snip of the double helix, the two strands of DNA, in order to make the edit. Base editing and prime editing don't involve that double-stranded severance. It's just a nick of one strand or the other. So it's a much more genetically friendly form of gene editing, as well as other aspects of the chemistry. We look forward to seeing how base and prime editing perform in the clinic. Maybe they'll run into some unforeseen hurdles and people will say, “You know what? There was nothing wrong with CRISPR. Let's keep using the originally developed system.” But I'm pretty bullish on what base and prime editing can do based on all of the early results have been published in the last few years on mice and monkeys. And now we're on the brink of going into the clinic.One medical scenario that they laid out would be, what if two people with a deadly recessive disease like sickle cell disease, or perhaps a form of cystic fibrosis, wanted to have a healthy biological child?Bioweapons and the ethics of CRISPRThis podcast is usually very optimistic. So we're going to leave all the negative stuff for this part of the podcast. We're going to rush through all the downsides very quickly.First question: Especially after the pandemic, a lot more conversation about bioweapons. Is this an issue that's discussed in this community, about using this technology to create a particularly lethal or virulent or targeted biological weapon?Not much. If a rogue actor or nation wanted to develop some sort of incredibly virulent bioweapon, there's a whole wealth of genetic techniques, and they could probably do it without involving CRISPR. CRISPR is, in a way, sort of the corollary of another field called synthetic biology or synthetic genomics that you may have talked about on your show. We've got now the facility, not just to edit DNA, but to synthesize custom bits of DNA with so much ease and affordability compared to five or 10 years ago. And we've just seen a global pandemic. When I get that question, I've had it before, I say, “Yeah, did we just not live through a global pandemic? Do we really need to be engineering organisms?” Whether you buy the lab leak hypothesis or the bioengineering hypothesis, or it was just a natural transfer from some other organism, nature can do a pretty good job of hurting human beings. I don't know that we need to really worry too much about bioweapons at this point.In 2018, there was a big controversy over a Chinese researcher who created some genome-edited babies. Yeah. Is there more to know about that story? Has that become a hotter topic of discussion as CRISPR has advanced?The Chinese scientist, He Jiankui, who performed those pretty abominable experiments was jailed for the better part of three years. He got early release in China and slowly but surely he's being rehabilitated. He's literally now moved his operation from Shenzhen to Beijing. He's got his own lab again, and he's doing genome editing experiments again. I saw again on social media recently, he's got a petition of muscular dystrophy families petitioning Jack Ma, the well-known Chinese billionaire, to fund his operation to devise a new gene editing therapy for patients with Duchenne muscular dystrophy and other forms of muscular dystrophy. I wouldn't want He Jiankui let within a thousand miles of my kids, because I just wouldn't trust him. And he's now more recently put out a manifesto stating he thinks we should start editing embryos again. So I don't know quite what is going on.It seems the Chinese threw the book at him. Three years is not a trivial prison sentence. He was fined about half a million dollars. But somebody in the government there seems to be okay with him back at the bench, back in the lab, and dabbling in CRISPR. And I don't know that he's been asked, does he have any regrets over the editing of Lulu and Nana. There was a third child born a few months later as well. All he will say is, “We moved too fast.” That is the only caveat that he has allowed himself to express publicly.We know nothing more about the children. They're close to five years old now. There's one particular gene that was being edited was pretty messed up. But we know it's not an essential gene in our bodies, because there are many people walking around who don't have a functional copy of this CCR5 receptor gene, and they're HIV resistant. That was the premise for He Jiankui's experiment. But he has said, “No, they are off limits. The authorities are not going to reveal their identities. We are monitoring them, and we will take care of them if anything goes wrong.” But I think a lot of people in the West would really like to help, to study them, to offer any medical assistance. Obviously, we have to respect their privacy. The twin girls and the third child who was born a bit later, maybe they're being protected for their own good. How would you like it if you grew up through childhood and into your teenage years, to walk around knowing that you were this human experiment? That may be a very difficult thing to live with. So more to come on that.There's no legitimate discussion about changing that in the West or anywhere else?Obviously, in the wake of what He Jiankui did, there were numerous blue ribbon panels, including one just organized by the National Academy of Sciences, just a stone's throw from where we're talking today. And I thought that report was very good. It did two things. This was published a couple of years ago. Two important things came out of it. One is this all-star group of geneticists and other scientists said, “We don't think that human embryo editing should be banned completely. There may be scenarios down the road where we actually would want to reserve this technology because nothing else would help bring about a particular medical outcome that we would like.” And the one medical scenario that they laid out would be, what if two people with a deadly recessive disease like sickle cell disease, or perhaps a form of cystic fibrosis, wanted to have a healthy biological child?There are clinics around the country and around the world now doing something called pre-implantation genetic diagnosis. If you have a family history of a genetic disease, you can encourage the couple to do IVF. We form an embryo or bunch of embryos in the test tube or on the Petri dish. And then we can do a little biopsy of each embryo, take a quick sneak peek at the DNA, look to see if it's got the bad gene or perhaps the healthy gene, and then sort of tag the embryos and only implant the embryos that we think are healthy. This is happening around the country as we speak for hundreds, if not thousands, of different genetic diseases. But it won't work if mom and dad have a recessive, meaning two copies of a bad gene, because there's no healthy gene that you can select in any of those embryos. It would be very rare, but in those scenarios, maybe embryo editing is a way we would want to go. But I don't see a big clamor for this right now. And the early results have been published using CRISPR on embryos in the wake of He Jiankui did have said, “It's a messy technique. It is not safe to use. We don't fully understand how DNA editing and DNA repair works in the human embryo, so we really need to do a whole lot more basic science, as we did in the original incarnation of CRISPR, before we even dare to revisit editing human embryos.” Longevity is interesting because, of course, in the last 18 months there's a company in Silicon Valley called Altos, funded by Yuri Milner, employing now two dozen of the top aging researchers who've been lured away from academia into this transnational company to find hopefully cures or insights into how to postpone aging. Longevity and genetic enhancementsAnother area is using these treatments not to fix things, but to enhance people, whether it's for intelligence or some other trait. A lot of money pouring into longevity treatments from Silicon Valley. Do we know more about the potential of CRISPR for either extending lifespans or selecting for certain desirable traits in people?This sort of scenario is never going to go away. When it comes up, if I hear someone say, “Could we use CRISPR or any gene editing technology to boost intelligence or mathematical ability or music musical ability, or anything that we might want…”Or speed in the hundred meters.“…or speed in the hundred meters, to enhance our perfect newborn?” I would say, what gene are you going to enhance? Intelligence—are you kidding me? Half of the 10,000 genes are expressed in the human brain. You want to start meddling with those? You wouldn't have a prayer of having a positive outcome. I think we can pretty much rule that out. Longevity is interesting because, of course, in the last 18 months there's a company in Silicon Valley called Altos, funded by Yuri Milner, employing now two dozen of the top aging researchers who've been lured away from academia into this transnational company to find hopefully cures or insights into how to postpone aging. That's going to be a long, multi-decade quest to go from that to potentially, “Oh, let's edit a little embryo, our newborn son or daughter so they have the gift of 120 years on this decaying, overheating planet…” Yes, there's a lot to wade through on that.And you have another book coming out. Can you give us a preview of that?I'm writing a book called Curved Air, which is about the story of sickle cell disease. It was first described in a paper from physicians in Chicago in 1910 who were studying the curious anemia of a dental student who walked into their hospital one day. That gentleman, Walter Noel, is now buried back in his homeland, the island of Grenada. But in the 1940s, it was described and characterized as the first molecular disease. We know more about sickle cell disease than almost any other genetic disease. And yet, as we touched on earlier, patients with this who have not had the wealth, the money, the influence, they've been discriminated against in many walks of life, including the medical arena.We're still seeing terribly, tragically, videos and stories and reports of sickle cell patients who are being turned away from hospital rooms, emergency rooms, because the medical establishment just looks at a person of color in absolute agony with one of these pain crises and just assumed, “Oh, they want another opioid hit. Sickle cell? What is that?” There's a lot of fascinating science. There's all this hope in the gene editing and now in the clinic. And there's all this socioeconomic and other history. So I'm going to try to weave all this together in a format that hopefully everyone will enjoy reading.Hopefully a book with a happy ending. Not every book about a disease has a wonderful…I think a positive note to end on is the first American patient treated in this CRISPR clinical trial for sickle cell disease four years ago,Victoria Gray, has become something of a poster child now. She's been featured on National Public Radio on awhole series of interviews and just took her first overseas flight earlier this year to London to speak at a CRISPR gene editing conference. She gave a lovely 15-minute personal talk, shaking with nerves, about her personal voyage, her faith in God, and what's brought her here now, pain-free, traveling the world, and got a standing ovation. You don't see many standing ovations at medical conferences or genetics conferences. And if ever anybody deserved it, somebody like Victoria Gray did. Early days, but a very positive journey that we're on. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit fasterplease.substack.com/subscribe

Three people. Ever. That's how many have been cured of HIV. We visited one of them to learn about the extraordinarily rare (and risky) treatment — and to find out if it can, even indirectly, lead to a true cure for 40 million more.

Confirman 3er Caso de paciente con VIH que logra curarse tras trasplante de células madre Para hablar de este tema nos acompañó el Dr. Miguel Morales, Médico Infectólogo. Presidente del Taller Venezolano VIH. Un estudio publicado a principios de año en la Revista Nature Medicine informó que un tercer enfermo de VIH ha logrado curarse tras un trasplante de células madre. Aseguró que en su organismo ya no queda ni rastro del virus del sida. Antes del caso de este «paciente de Düsseldorf» (oeste de Alemania), dos otros enfermos del VIH habían logrado curarse. El primero de ellos en Berlín en 2009 y el segundo en Londres en 2019. Según el consorcio internacional Icistem, este tercer paciente había recibido un trasplante de células madre como parte del tratamiento de una leucemia. Tras esa operación, pudo interrumpir el tratamiento que seguía contra el VIH. En los análisis que le hicieron, no encontraron ni rastro de las partículas virales ni de las reservas virales. Tampoco hubo rastro de la respuesta inmunitaria contra el virus. Los tres enfermos que lograron curarse definitivamente del sida tienen el mismo punto en común: los tres padecían un cáncer de sangre y por ese motivo fueron tratados con un trasplante de células madre, que renovó en profundidad su sistema inmunitario. En los tres casos, su donante presentaba una mutación extraña en el gen CCR5. Este es un cambio genético que impide la entrada del VIH en las células. Como menos del 1% de la población suele beneficiarse de la mutación genética protectora del VIH, pocos donantes de células madre la disponen. Aunque estos casos dan esperanza a los científicos para encontrar una cura del sida, un trasplante de células madre es un tratamiento arriesgado. Además, no se adapta a la situación de la mayoría de enfermos del VIH.

În cadrul ediției de pe 16 mai 2023 a emisiunii #știința360 de pe Radio România Cultural, Dr. Marius Geantă, Președintele Centrului pentru Inovație în Medicină, a comentat ultimele noutăți ale domeniului medical. O terapie de editare genică ce are două ținte, virusul HIV și co-receptorul CCR5 (care permite virusului să pătrundă în celulele umane) ar putea elimina infecția. Cercetarea a fost realizată în cadrul Temple University și University of Nebraska Medical Center. Este pentru prima dată când combinarea editării genice cu țintă dublă și a medicației antiretrovirale determină eliminarea HIV la animalele de laborator. Abordarea terapeutică s-a bazat pe tehnologia de editare genică CRISPR pentru HIV-1, alături de o terapie antiretrovirală care poate menține valori scăzute ale replicării HIV pentru perioade lungi de timp, numită LASER (long-acting slow-effective release). S-a observat că prin folosirea terapiei LASER se poate eradica infecția la animalele de laborator, însă există cazuri în care infecția poate conduce la recăderi, atunci când virusul cantonat în rezervoare redobândește capacitatea de replicare. Conform autorilor, acest mecanism seamănă cu ceea ce se întâmplă la oameni, dacă întrerup tratamentul antiretroviral. HIV își integrează materialul genetic în genomul celulei umane și poate rămâne în organism perioade lungi de timp. Pentru a preveni recăderile, s-a utilizat tehnologia CRISPR care poate inactiva componenta CCR5 și excizează fragmentele de ADN HIV-1 din celulele infectate. Vindecarea infecției HIV a fost raportată până acum în 3 cazuri, pentru care s-au aplicat tratamente bazat pe transplant de celule stem hematopoietice allogen, care conțineau mutații în gena CCR5. Având în vedere rezultatele obținute la acești pacienți s-a emis ipoteza că pentru eliminarea infecției HIV, țintirea CCR5 este esențială, obiectiv care poate fi îndeplinit cu ajutorul CRISPR. Mai multe detalii despre subiectele discutate: ▶ https://raportuldegarda.ro/stiri-covid-romania/ ▶ Esențial în sănătate publică - https://raportuldegarda.ro/esential-sanatate-publica-hiv-crispr-terapie-antiretrovirala/ ▶ Evaluarea riscului de boală cardiovasculară la femei trebuie să țină cont și de determinanții sociali ai sănătății, alături de factorii biologici specifici - https://raportuldegarda.ro/recomandare-aha-risc-boala-cardiovasculara-determinanti-sanatate-femei/ ▶ Disponibilitatea testelor genetice la costuri reduse nu garantează participarea persoanelor eligibile la programele screening - https://raportuldegarda.ro/teste-genetice-costuri-reduse-participare-neincredere/ ▶ Personalizarea terapiei antihipertensive, reducere dublă a tensiunii arteriale vs. creșterea dozei după standardul actual - https://raportuldegarda.ro/studiu-personalizarea-terapiei-antihipertensive-reducere-dubla-a-tensiunii-arteriale-vs-cresterea-dozei-dupa-standardul-actual/

Was your psoriasis caused by the Black Death? Learn more than you might have wanted to know about the Black Death and delve into the data on the immunologic/autoimmune ramifications of wiping out nearly half of Europe. ·       Intro 0:11 ·       In this episode 1:09 ·       The Black Death 1:24 ·       The History of IV Immunoglobulin episode 2:07 ·       How the Black Death happened 4:07 ·       How many people died from the Black Death? 6:49 ·       Record keeping 6:53 ·       The modern immune system, the Black Death and HIV 8:43 ·       What is CCR5? 8:55 ·       Current data on autoimmune diseases 10:35 ·       ERAP2 15:55 ·       How yersinia pestis kills you 21:04 ·       The inflammasome 22:03 ·       The Inflammasome for Dunces episode 22:09 ·       Mediterranean fever and mouse model 24:49 ·       Takeaways 30:20 ·       Summary 30:59 Disclosures: Brown reports no relevant financial disclosures. We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Wheelis M. Emerg Infect Dis. 2002;doi:10.3201/eid0809.100536. Ratner D, et al. PLoS Pathog. 2016;doi:10.1371/journal.ppat.1006035. Park YH, et al. Nat Immunol. 2020;doi:10.1038/s41590-020-0705-6. Patin E. Nat Immunol. 2020;doi:10.1038/s41590-020-0724-3. Galvani AP, et al. Proc Natl Acad Sci USA. 2003;doi:10.1073/pnas.2435085100.

Dr. Ben Doranz co-founded Integral Molecular in 2001. He has led all aspects of the company's growth since its inception, bringing 5 different technologies from research to market and growing the company into a profitable commercial entity. He is an inventor on over 10 of the company's patents, the principal investigator on over 30 NIH grants, and an author on over 100 publications, including articles published in Cell, Science, and Nature. Dr. Doranz is an established life science entrepreneur, previously responsible for directing the biotechnology program at the Port of Technology business incubator in Philadelphia and helping create startups at the Center for Technology Transfer at the University of Pennsylvania. He earned a Ph.D. in Cell and Molecular Biology at the University of Pennsylvania, where he led the discovery of the coreceptor CCR5 for HIV. He holds an MBA from the Wharton School of Business, where he co-founded the Penn Biotech Group and won the Wharton business plan competition, and a B.A. from Cornell University.

Dr. Jana Dickter, MD (https://www.cityofhope.org/jana-dickter) is associate clinical professor in the department of medicine, division of infectious diseases, at City of Hope Comprehensive Cancer Center. She is board-certified in internal medicine, infectious diseases, and the American Academy of HIV Medicine. Dr. Dickter earned her undergraduate degree in cognitive sciences from the University of California, San Diego. She went on to receive her medical doctorate from Rush Medical College in Chicago. After an internal medicine residency at University of Pittsburgh Medical Center, Dr. Dickter began her fellowship at UCLA's Affiliated Program in Infectious Diseases. In her clinical work, she has focused on the management of infections in the immunosuppressed. At City of Hope, she is an on-site HIV specialist and has an interest treating people who are living with HIV and cancer. She was the principal investigator involved in presenting the case of The City of Hope patient: prolonged HIV-1 remission without antiretrovirals after allogeneic hematopoietic stem cell transplantation of CCR5-delta-32 mutation donor cells for acute myelogenous leukemia. She also serves as the HIV physician for the first-in-human trial to evaluate the feasibility, safety and engraftment of zinc finger nuclease genome edited CCR5 modified CD34+ hematopoietic stem/progenitor cells in HIV-1 infected patients. Additionally, Dr. Dickter has been involved in clinical trials for evaluating certain medications for difficult-to treat infections in immunosuppressed patients. She is also involved in antimicrobial stewardship, infection control, and has published papers on aspects of patient management with antimicrobial agents. These papers have dealt with nosocomial infections, cost assessment of antimicrobial use, and unusual case reports, all intended to teach practitioners who manage these difficult to treat patients. 

Amazing work figuring out how to stop the virus from getting into the host cells. Kudos to those drug discoverers. Today we look at a group of drugs that are entry inhibitors. Increase your knowledge on this.....

TWiN explains the observation that in mice, the HIV-1 co-receptor CCR5 closes the temporal window for linking different memories. Hosts: Vincent Racaniello, Jason Shepherd, Timothy Cheung, and Vivianne Morrison Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Links for this episode CCR5 and memory linking (Nature) Timestamps by Jolene. Thanks! Music is by Ronald Jenkees Send your neuroscience questions and comments to twin@microbe.tv

Dr Kat Arney takes a deep dive into our genetic make-up and tells the story of four pieces of human DNA: the fat gene, the Huntington gene, the CCR5 gene associated with HIV resistance, and PAX6, the eyeball gene.

This week Let's Talk Micro is talking virology, specifically about the Human Immunodeficiency Virus (HIV). This episode features an interview with Dr. Hsu, a stem cell specialist from the Weill Medical College at Cornell University in New York. She discusses an article about a patient that has been possibly cured from HIV after a stem cell transplant with cord blood cells. What is the CCR5 gene? What is its relationship to HIV? Tune in to find out about this interesting article.Link to article: https://news.weill.cornell.edu/news/2022/02/patient-possibly-cured-of-hiv-infection-by-special-stem-cell-transplant

In this episode, Daniel R. Kuritzkes, MD, and David A. Wohl, MD, discuss new HIV data from CROI 2022, including:Prevention strategiesLA therapiesSecond-line therapiesThe VISEND study comparing dolutegravir-based antiretroviral therapy (ART) vs protease inhibitor–based ART for second-line therapyThe NADIA study comparing dolutegravir with darunavir/ritonavir and tenofovir disoproxil fumarate with zidovudine for second-line therapyComorbidities and cureACTG A5324 (InMIND) study of ART intensification for cognitive impairment in people with HIVIMPAACT P1107 case of patient with loss of HIV-1–specific antibody response and viral detection following CCR5∆32/∆32 cord/haploidentical transplantDaniel R. Kuritzkes, MDChief, Division of Infectious DiseasesBrigham and Women's HospitalHarriet Ryan Albee Professor of MedicineHarvard Medical SchoolBoston, MassachusettsDavid A. Wohl, MDProfessor of MedicineSchool of MedicineSite Leader, Global Infectious Diseases Clinical Trials UnitUniversity of North Carolina at Chapel HillContent based on a CME program supported by educational grants from Gilead Sciences, Inc.; Janssen Therapeutics, Division of Janssen Products, LP; Merck Sharp & Dohme Corp; and ViiV Healthcare.Follow along with an expanded slideset at:https://bit.ly/3CItz0ZLink to full program:https://bit.ly/3tSpdAx

Anthropologist and author Eben Kirksey discusses his interest in somatic and hereditary human genome editing, particularly the impact on patients and practitioners, the history of CCR5 gene editing, and recalls his exceptional reporting in China in the wake of the CRISPR babies scandal, all of which is included in his riveting book “The Mutant Project” (2020).

Episode 373. Investigating myself. Topic: CCR5. How does HIV immunity work? Do I have deletions in my CCR5 gene? How can I find this out?Twitter: @3minutelessonEmail: 3minutelesson@gmail.comNew episode every Monday, Wednesday, and Friday!Methodology notes:I searched the hg38 BAM file at chr3:46373450-46373488 (samtools view) for the deletion of GTCAGTATCAATTCTGGAAGAATTTCCAGACA. Reads contained the full sequence. I included a search for sequences with concatenated flanking nucleotides (indicating the deletion) but did not find any. I also searched unmapped reads. This strongly indicated that I am homozygous for the intact CCR5.  

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.

Você conhece Lulu e Nana? Elas são as duas primeiras pessoas a nascerem após serem editadas pela técnica de CRISPR-Cas-9. Sim, no mundo atual já existem pessoas vivas modificadas geneticamente! O gene "editado" foi o CCR5 que está ligado à suscetibilidade ao HIV. Neste episódio prof. Marquinhos e prof. Geison conversam um pouco sobre a técnica de edição genética, que vai revolucionar o mundo em que vivemos. As potencialidades dela são infinitas. Fala-se em cura do câncer, da AIDS, da possibilidade de vida eterna. Mas existem muitas implicações éticas e certamente você precisa se informar sobre ela para ter lugar de fala na sociedade, que debaterá este assunto no futuro. Então Vem Cienciar conosco!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.14.382739v1?rss=1 Authors: Ali Hassan, A., Ibrahim, M. E. Abstract: Chemokines are small transmembrane proteins with immune surveillance and immune cell recruitment functions. the expression of CCR5 gene affects virus production and viral load(1). The CCR5 gene contains two introns, three exons, and two promoters, and it is necessary as a co-receptor for the entry of the macrophage-tropic HIV strains. Mutations in the coding region of CCR5 affect the protein structure, which will affect production, chemokine binding, transport, signaling and expression of the CCR5 receptor. SNPs within CCR5 gene were retrieved from ensemble database. Coding SNPs were analyzed using SNPnexus. Coding non-synonymous SNPs in CCR5 binding domains with Viral gp120 were analyzed using SIFT, PolyPhen and I-mutant tools. Project HOPE then used to modelled the 3D structure of the protein resulting from these SNPs. Non-coding SNPs that affects miRNAs in 3' rejoin were analyzing using PolymiRTS. SNPs that affect transcription factor binding were analyzed using regulomeDB. (178) non-synonyms missense SNPs were found to have deleterious and damaging effect on the structure and function of the protein. In CCR5 binding domains with Viral gp120: 3 SNPs rs145061115, rs199824195 and rs201797884 were found to affect both structure and function and stability of chemokine protein. The 2 SNPs rs185691679 and rs199722070 has a role in disruption and creation of the target sites in miRNA seeds due to their high conservation score. Mutations in CCR5 gene may explain and represent the molecular basis of the resistance to HIV infection. Copy rights belong to original authors. Visit the link for more info

In the second episode of BioSounds podcast Camila Branco is telling us about her fascinating PhD project on CCR5 receptor. Plus a great interview where Professor Sami El-boustani talks to Chloe Mayere about perception of the brain. Presented by Emilie Trachsel

We've talked about genetic engineering before, but when we hit on Dr. He Jiankui and his genetically modified infants, we may have missed something. After talking with a few people it seemed we needed an update to Episode 4 - Genetic Engineering. Ethical questions involve us all, and understanding where science stands on these issues is more important now than possibly ever before. Join hosts Shanti and Danny as we welcome someone who’s been featured in Popular Mechanic magazine, participated in multiple extreme sports, founded the non-profit organization Crossing Lines, oh and she holds a Doctorate in Cell and Molecular Biology and Biochemistry, Dr. Sonya Iverson. Tune in as we all discuss the ethics and questions surrounding this mysterious testing.ReferencesZhou, M., et. al.; CCR5 is a Suppressor for Cortical Plasticity and Hippocampal Learning and Memory. eLife Neuroscience. 20-Dec-2016. Doi: https://doi.org/10.7554/eLife.20985.001Le Page, M.; CRISPR Babies: More Details on the Experiment that Shocked the World. NewScientist. 28-Nov-2018. https://www.newscientist.com/article/2186911-crispr-babies-more-details-on-the-experiment-that-shocked-the-world/Regalado, A.; China’s CRISPR Twins Might Have Had Their Brains Inadvertently Enhanced. MIT Technology Review. 21-Feb-2019. https://www.technologyreview.com/2019/02/21/137309/the-crispr-twins-had-their-brains-altered/Regalado, A.; China’s CRISPR Babies; Read Exclusive Excerpts from the Unseen Original Research. MIT Technology Review. 03-Dec-2019. https://www.technologyreview.com/2019/12/03/131752/chinas-crispr-babies-read-exclusive-excerpts-he-jiankui-paper/#:~:text=Here%2C%20the%20researchers%20describe%20the,gene%20had%20indeed%20taken%20hold.Philipkoski, K.; Chopsticks for Better Cloning. Wired. 23-May-2005. https://www.wired.com/2005/05/chopsticks-for-better-cloning/Mayell, H.; Genghis Khan a Prolific Lover, DNA Data Implies. National Geographic. 14-Feb-2003. https://www.nationalgeographic.com/news/2003/2/mongolia-genghis-khan-dna/#:~:text=An%20international%20group%20of%20geneticists,16%20million%20descendants%20living%20today.

On this Episode of Purposely Curious we discuss one of the human body’s greatest mistakes, the CCR5 Delta 32 Genetic Mutation. This genetic mutation essentially renders certain people immune to some of the worst diseases in human history. Join us as we delve into this intriguing scientific subject. Grab your lab coats and let’s get nice and cozy as we discuss this topic.

2018年11月底，一則熱門新聞洗捲全球;基因編輯嬰兒事件，正巧CASE說書人也在做《基因編輯大革命》一書(Podcast EP6)，立即找來生物醫學家周成功教授，跨界對談人類學者王道還教授，為觀眾解惑。 #基因編輯嬰兒事件，是中國南方科技大學生物系副教授賀建奎及其團隊於2018年通過基因編輯技術，對一對雙胞胎嬰兒胚胎細胞的CCR5基因進行改造，從而使嬰兒獲得可遺傳的對部分愛滋病的免疫力的爭議性事件。 【與談人】 #周成功 陽明大學生命科學系暨基因體科學研究所兼任教授 #王道還 臺灣大學共同教育中心 兼任助理教授 [中央研究院歷史語言研究所 助理研究員 (退休)] 【主持人】 #周雲 臺灣大學科學教育發展中心特約主持人 【Youtube版本-有詳細的科學注釋與字幕 】 https://youtu.be/j_dkOQr4Ax8 【CASE臺大科教中心facebook粉絲頁 】 https://www.facebook.com/NTUCASE/ 背景音樂:Commute、Home by DeKobe

Today I speak with my good buddy Kevin Hackett. Kevin works in the world of genomics and has a biochemistry and genetics degree from Clemson University. In this episode we talk about gene editing and CRISPR. We start basic, with what genetics are and touch on topics including - how CRISPR works, what sorts of diseases it might be used for and what the future of gene editing looks like. If you're interested at all in this topic but like me, have limited knowledge on it, this podcast should be right up your alley.LINKS:Chinese researcher goes to jail for editing CCR5 five https://abcnews.go.com/International/chinese-scientist-reportedly-gene-edited-babies-sentenced-prison/story?id=67982103What is the SMN1 gene? https://ghr.nlm.nih.gov/gene/SMN1FDA-approved SMN1 gene therapy https://smanewstoday.com/2019/05/24/fda-approves-zolgensma-gene-therapy-newborns-toddlers-with-any-sma-type/Recent use of CRISPR in the news https://www.cbsnews.com/news/crispr-used-inside-a-humans-body-for-the-first-time-scientists-say-today-2020-03-05/theEWpodcast: http://theewpodcast.com/

Link: https://slatestarcodex.com/2019/12/18/acc-should-gene-editing-technologies-be-used-in-humans/   [This is an entry to the 2019 Adversarial Collaboration Contest by Nita J and Patrick N.] Introduction In October 2018, the world’s first genetically edited babies were born, twin girls given the pseudonyms Lulu and Nana; Chinese scientist He Jiankui used CRISPR technology to edit the CCR5 gene in human embryos with the aim of conferring resistance to HIV. In response to the international furor, China began redrafting its civil code to include regulations that would hold scientists accountable for any adverse outcomes that occur as the result of genetic manipulation in human populations. Now, reproductive biologists at Weill Cornell Medicine in New York City are conducting their own experiment designed to target BRCA2, a gene associated with breast cancer, in sperm cells. While sometimes considered controversial, gene editing has been used as a last resort to cure some diseases. For example, a precursor of CRISPR was successfully used to cure leukemia in two young girls when all other treatment options had failed. Due to its convenience and efficiency, CRISPR offers the potential to fight cancer on an unprecedented level and tackle previously incurable genetic diseases. However, before we start reinventing ourselves and mapping out our genetic futures, maybe we should take a moment to reevaluate the risks and repercussions of gene editing and rethink our goals and motives.

The Stock Day Podcast welcomed CytoDyn (CYDY)(“the Company”), a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. President and CEO of the Company, Dr. Nader Pourhassan, joined Stock Day host Everett Jolly. 

The TWiV pro-vaxxers reveal viruses that infect endangered wild salmon, and how iron in host serum modulates dengue virus acquisition by mosquitoes. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Brianne Barker Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode New viruses that infect endangered wild salmon (eLife) Host serum iron modulates dengue virus acquisition by mosquitoes (Nat Micro) Image credit Letters read on TWiV 569 Timestamps by Jolene. Thanks! Weekly Science Picks Brianne - Retraction of new CCR5/lifespan study Alan - Nomad Press illustrated science books, and illustrator Lex Cornell Dickson - RARE: Creatures of the Photo Ark Vincent - The Odyssey of Eradication by Thomas Abraham Listener Picks Justin - Mass spec pen Mark - What really brought down the Boeing 737 Max? Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

The TWiV pro-vaxxers reveal viruses that infect endangered wild salmon, and how iron in host serum modulates dengue virus acquisition by mosquitoes. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Brianne Barker Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode New viruses that infect endangered wild salmon (eLife) Host serum iron modulates dengue virus acquisition by mosquitoes (Nat Micro) Image credit Letters read on TWiV 569 Timestamps by Jolene. Thanks! Weekly Science Picks Brianne - Retraction of new CCR5/lifespan study Alan - Nomad Press illustrated science books, and illustrator Lex Cornell Dickson - RARE: Creatures of the Photo Ark Vincent - The Odyssey of Eradication by Thomas Abraham Listener Picks Justin - Mass spec pen Mark - What really brought down the Boeing 737 Max? Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Due to recent technological advances, scientists have revolutionized our understanding of human evolutionary history. What appeared to be a relatively simple story of divergence from ancient hominids is instead a tangled mess involving repeated cycles of divergence and hybridization between evolving human species. Today my guest is Jason Wilder, who researches human evolutionary genetics and genomics. We discuss the genetics of malaria resistance and parallel evolution, CCR5 deficiency and resistance to HIV infection, gene editing and the creation of designer babies, gene editing to treat disease, and introgression between modern humans and archaic forms, including Neanderthals and Denisovans. Jason received his B.A. in biology at Williams College and his Ph.D. in Ecology and Evolutionary Biology at Princeton University. He then worked at the University of Arizona and Williams before joining the faculty at Northern Arizona University, where he is a professor of genetics and the Interim Dean of the College of the Environment, Forestry and Natural Sciences.

The Stock Day Podcast welcomed CytoDyn Inc. (CYDY)(“the Company”), a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. President and CEO, Dr. Nader Pourhassan, joined Stock Day host Everett Jolly. 

Lulu y Nana son las primeras personas nacidas con edición genética. El motivo ha sido evitar la expresión de CCR5, un receptor relacionado con la infección por VIH. Este experimento ha suscitado el levantamiento en armas de todo tipo de científicos y bioeticistas que consideramos nada ético un experimento que pone en jaque la autonomía del individuo.

In November 2018 news broke via YouTube that He Jiankui, then a professor at Southern University of Science and Technology in Shenzhen, China had created the world’s first gene-edited babies from two embryos. The edited gene was CCR5 delta 32 - a gene that conferred protection against HIV. Alongside the public, most of the scientific community were horrified. There was a spate of correspondence, not just on the ethics, but also on the science. One prominent paper was by Rasmus Nielsen and Xinzhu Wei’s of the University of California, Berkeley. They published a study in June 2019 in Nature Medicine that found an increased mortality rate in people with an HIV-preventing gene variant. It was another stick used to beat Jiankiu – had he put a gene in these babies that was not just not helpful, but actually harmful? However it now turns out that the study by Nielsen and Wei has a major flaw. In a series of tweets, Nielsen was notified of an error in the UK Biobank data and his analysis. Sean Harrison at the University of Bristol tried and failed to replicate the result using the UK Biobank data. He posted his findings on Twitter and communicated with Nielsen and Wei who have now requested a retraction. UCL's Helen O'Neill is intimately acquainted with the story and she chats to Adam Rutherford about the role of social media in the scientific process of this saga. The Herculaneum Library is perhaps the most remarkable collection of texts from the Roman era. Discovered two centuries ago in the villa of Julius Caesar’s father in law, many of the papyrus scrolls bear the writings of the house philosopher, Philodemus. Others are thought to be the works of the philosophers and poets he admired. However, the big drawback is that the villa was buried in the eruption that engulfed Pompeii, and the heat from the volcanic ash turned them all to charcoal. To make life even more difficult, the ink the scribes used was also made of carbon – think black on black. However, now a team from the University of Kentucky are hoping to decipher the texts using X-rays, and have just scanned two complete scrolls, and some fragments at the Diamond Synchrotron in near Oxford. When renowned author Bill Bryson decided to apply his unique eye for anecdote and trivia to the human body he thought he's start at the head and work down. But as he reveals to Adam, it's a lot more complicated and interconnected than that. His book "The Body - A Guide for Occupants" is an indispensable guide to the inner workings of ourselves. Producer: Fiona Roberts

28 Kasım 2018’de bilim dünyasından gelen bir haber şok etkisi yarattı: Çin'de Jiankui He isimli bir araştırmacı, genleri değiştirilmiş bebekler doğurduklarını ilan etti! Seslendiren: Ekin Baran Sunar

The Stock Day Podcast welcomed CytoDyn (CYDY)(“the Company”), a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. President and CEO, Dr. Nader Pourhassan, joined Stock Day host Everett Jolly. 

In this podcast, S. Thomas Carmichael, MD, PhD, discusses the roles of CREB, CCR5, and tonic GABA signaling in memory formation during stroke recovery, as well as other advances in regenerative medicine from the upcoming ANA 2019 annual meeting. More at: www.consultant360.com/neurology.

The Stock Day Podcast welcomed CytoDyn (CYDY)(“the Company”), a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CEO and President, Nader Pourhassan, Ph.D., joined Stock Day host Everett Jolly. 

美国加州大学伯克利分校的科学家们在Nature Medicine 在线发表了一篇研究论文，这项研究使用英国生物银行的409693个人的基因分型和死亡登记信息来探索CCR5-Δ32突变的适应性影响，发现对于CCR5-∆32等位基因纯合的个体，全因死亡率增加21％。

Emlyn tells Emma about the marine biologist, writer, and environmentalist, Rachel Carson, and Emma tells Emlyn about a heck of a lot of boss ladies! PLEASE FILL OUT THE SURVEY: https://docs.google.com/forms/d/e/1FAIpQLScwuYfCujp_voMx1I37E4MB1Tk_UbncK6z8Khn4DC683fV-3A/viewform?usp=sf_link   Sources Main Story - Rachel Carson Wikipedia: https://en.wikipedia.org/wiki/Rachel_Carson Women's History: https://www.womenshistory.org/education-resources/biographies/rachel-carson American Chemical Society: https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/rachel-carson-silent-spring.html Fire Ants Video: https://commons.wikimedia.org/wiki/File:16-p-1402-2_Fire_Ants_on_Trial.webm Women who werk Jess Wade was awarded the Most Excellent Order of the British Empire! https://www.imperial.ac.uk/news/191453/imperial-academics-awarded-honours-queen/ Xinzhu Wei and Rasmus Nielsen find that mutations in the CCR5 gene that make some people resistant to HIV may also reduce longevity. https://www.nature.com/articles/s41591-019-0459-6 Olga Troyanskaya and a team of researchers develop a machine learning model that identified mutations in non-coding regions of the genome that are associated with autism. https://www.simonsfoundation.org/2019/05/27/autism-noncoding-mutations/ Music “Work” by Rihanna “Mary Anning” by Artichoke   Cover Image Alfred Eisenstaedt/The LIFE Picture Collection/Getty Images

Esta semana os traemos un programa más largo de lo habitual, pero muy cargado de noticias. Hablaremos de moléculas subatómicas, de streamming de videojuegos, de galaxias y materia oscura, y os haremos un estupendo resumen del evento para desarrolladores de Apple, la WWDC, entre otras. ¡Esperamos que os guste! Noticias Chrome dirá adiós a los bloqueadores de anuncios tal y como los hemos conocido: Google se reafirma en su postura – https://www.genbeta.com/navegadores/chrome-dira-adios-a-bloqueadores-anuncios-tal-como-hemos-conocido-google-se-reafirma-su-posturaGoogle Stadia ya está aquí: este es el catálogo, la disponibilidad y el precio de la plataforma que busca una revolución gamer – https://www.genbeta.com/actualidad/google-stadia-esta-aqui-este-catalogo-disponibilidad-precio-plataforma-que-busca-revolucion-gamerLa mutación CCR5-Δ32/Δ32 protege contra el SIDA pero podría reducir la esperanza de vida – https://francis.naukas.com/2019/06/08/la-mutacion-ccr5-%ce%b432-%ce%b432-protege-contra-el-sida-pero-podria-reducir-la-esperanza-de-vida/LHCb apunta a que el supuesto pentaquark Pc(4450) es un estado ligado barión-mesón – https://francis.naukas.com/2019/06/08/lhcb-apunta-a-que-el-supuesto-pentaquark-pc4450-es-un-estado-ligado-barion-meson/ALMA obtiene la primera imagen del disco de acreción del agujero negro supermasivo Sagitario A* – https://francis.naukas.com/2019/06/06/alma-obtiene-la-primera-imagen-del-disco-de-acrecion-del-agujero-negro-supermasivo-sagitario-a/La supuesta galaxia sin materia oscura tiene más de un 75% de materia oscura – https://francis.naukas.com/2018/07/01/la-supuesta-galaxia-sin-materia-oscura-tiene-mas-de-un-75-de-materia-oscura/Las megaconstelaciones de satélites: adiós al cielo nocturno de nuestros antepasados – https://danielmarin.naukas.com/2019/05/29/las-megaconstelaciones-de-satelites-adios-al-cielo-nocturno-de-nuestros-antepasados/El módulo PPE: un primer paso hacia la estación lunar Gateway – https://danielmarin.naukas.com/2019/06/02/el-modulo-ppe-un-primer-paso-hacia-la-estacion-lunar-gateway/Toyota da más detalles de su ambiciosa gama global de coches eléctricos, formada por 10 modelos diferentes – https://forococheselectricos.com/2019/06/toyota-da-mas-detalles-de-su-ambiciosa-gama-global-de-coches-electricos-formada-por-6-modelos-diferentes.html Música del episodio Avercage – Enflammer – https://www.jamendo.com/track/1465147/enflammerMESSAGE FROM SYLVIA – Heart of War – https://www.jamendo.com/track/1394654/heart-of-war Podéis encontrarnos en Twitter y en Facebook!

Some people have a genetic mutation in a gene called CCR5 that seems to bestow immunity to a form of HIV. This is the mutation which controversial Chinese scientist Jianqui He tried to bestow upon two baby girls last year when he edited the genes in embryos and then implanted them in a mother. A paper in the journal Nature Medicine this week uses data from the UK Biobank to look at the long term health patterns associated with this gene variant. It suggests that whilst the HIV-1 immunity may be considered a positive, having two copies of the gene also comes with a cost. It seems that it may also lower our immunity to other diseases and shows in the database as a 21% increase in mortality overall. Author Rasmus Nielsen talks about how important this gene is to evolutionary biologists trying to find signs of natural selection in humans. Adam discusses the ethical implications of the research with Dr Helen O’Neill. The Surrey Earthquake Swarm Over the last year several small earthquakes have been detected in one part of Surrey. Many have surmised that these may be caused by oil drilling taking place nearby, but it might be simpler than that. So the British Geological Survey has been monitoring the region. Roland Pease joined Imperial College seismologist Steven Hicks out in the countryside inspecting his detectors to find out more. Mama’s Last Hug Frans de Waal, one of the world’s leading primatologists talks to Adam about his latest book, and the difficulties we as human observers have with studying emotion in animals. Prof de Waal coins a neologism ‘anthropodenialism’ to describe the belief that emotions in animals are incommensurable with human experience. He thinks most mammals, and certainly primates, experience pretty much the same emotions as we do, for similar reasons. Feelings, however, are a different matter. Producer: Alex Mansfield

A missing chunk of DNA, 32 base pairs long and smack in the middle of the CCR5 gene, might be the most studied mutation in human history. The spontaneous deletion, which arose thousands of years ago, has a striking relationship with one of the worst human diseases: HIV/AIDS. People who inherit this mutation from both of their parents are naturally immune. The only two people to have ever been cured both received bone marrow transplants from people who carry the Δ32 mutation.

Si chiama Ccr5. È il nome del gene modificato con la tecnica crispr nelle due gemelle nate in Cina alcuni mesi fa

近日，在美国西雅图举行的逆转录病毒和机会性感染会议上宣布了第三个疑似艾滋病治愈的病例。荷兰乌得勒支大学医学中心的Annemarie Wensing参与了该病例的研究，她表示：通过对这位“杜塞尔多夫患者”的肠道和淋巴结进行的活组织检查显示，其在停用抗病毒药物3个月后，未表现出HIV感染迹象。这也许是继“柏林病人”、“伦敦病人”之后全球第三例艾滋病治愈的病例。值得一提的是：他们除了感染HIV病毒外，都是肿瘤患者，均接受了骨髓干细胞移植，而且供者都携带CCR5的基因突变。

2018 föddes för första gången enligt uppgift genförändrade barn. Nu börjar bilden klarna om vad som gjorts. Vi återutsänder ett program från 2018 om etiska aspekter på att genförändra människor. En kinesisk forskare har hävdat att han skapat världens första genförändrade bebisar. Kritiken har varit stark. Tekniken som använts, CRISPR/Cas 9, är inte alls mogen för steget, enligt forskare. Forskaren He Jiankui har varit tjänstledig från det universitet där han arbetar, och universitet genomför nu en utredning av vad som hänt eftersom genförändringar av den här typen är olagliga i Kina. Tanken med experimentet är att skapa individer som har motståndskraft mot HIV, genom att en mutation på genen CCR5 ger ett visst skydd mot viruset. I programmet hörs: Magnus Lundgren, cell- och molekylärbiolog med bakgrund i CRISPR-forskning vid Uppsala universitet, Gunilla Karlsson Hedestam, professor i vaccinimmunologi vid Karolinska institutet, Nils-Eric Sahlin, professor i medicinsk etik vid Lunds universitet. Camilla Widebeck, programledare camilla.widebeck@sverigesradio.se Peter Normark, producent peter.normark@sverigesradio.se

At the end of November 2018, Chinese scientist He Jiankui announced that he had genetically modified human embryos which were then brought to term. The resulting twin sisters appear to be healthy. But this experiment was not greeted with enthusiasm by the scientific community. The critique attacks every aspect of the experiment: the treatment’s medical necessity, the reasoning behind the treatment approach, the way it was conducted, the ethical implications, and it also wasn’t legal. Listen to the Full Conversation on Patreon! He Jiankui was aware that he was doing something the public and the scientific community would not agree with. In order to dampen the fall, He announced his experiments in a series of YouTube videos in which he also attempts an ethical justification. He addressed the public in this way before the scientific community could comment, to frame the following discussion in his favor. Possibly also to force Chinese authorities to act cautiously with the eyes of the world resting on He Jiankui. After an appearance at a conference in Hong Kong, He Jiankui went missing, and it still seems to be unclear where he is. Some news outlets reported the Dr. He was put under house arrest. In this episode, Bart Geurten (@BartGeurten) and I (Dennis Eckmeier, @DennisEckmeier) have a conversation about what we understand about what happened. (Recorded Dec 16th, 2018) What Happened? He Jiankui is a geneticist who works on genetic alteration of human embryos. In some countries, scientists can get permission to experiment on human embryos when the embryos are just a few cells big. Such embryos, however, may not be allowed to develop into full human beings. The goal of such experiments is, for example, to establish safer methods for gene therapies. The embryos are created through in-vitro-fertilization, an established practice for couples who are having trouble having healthy babies. Eggs and sperms are brought together outside the woman’s body, and the growing embryos can be tested for possible gene defects. Healthy embryos can then be implanted in the becoming mother’s womb. But He implanted genetically modified embryos in the womb of a woman, which the scientific community has many problems with. The two embryos have become babies and were born several months before the announcement. What exactly did He Jiankui try to achieve? He Jiankui wants to protect children of HIV infected parents from infection, AIDS, and social discrimination that comes with HIV infection. The medical community, however, does not agree that gene modification would be an appropriate method to accomplish this. There are numerous ways to protect yourself from infection with HIV by following simple rules of caution. He chose couples where the father is HIV positive, while the mother is not. To protect the mother, such couples can use in vitro fertilization, if they want a child. In the process of IVF, the HIV is removed. Was the treatment well designed? So there was no medical necessity for this treatment. But let’s say there would have been. To genetically protect the children from HIV, He Jiankui attempted to change a gene (CCR5) to a specific variant (delta32) that is believed to play a role in HIV resilience. But the scientific community agrees that they don’t know enough about the gene’s function. Genes code for proteins, and the same protein may play different roles in different bodily functions. Besides it’s implication in HIV resilience, the delta32 variant of CCR5 seems to be just as likely to increase vulnerability to influenza and the West Nile virus. There seems to be one study that even claims it might play a role in increasing cognitive ability. If the experiment worked, He may have introduced human enhancement which he himself says would be unethical. Or he may have put the girls at an increased risk to die from the flu. This means that this was a highly risky experiment and He may ...

“Genome editing had to happen sometime,” says our guest Kiran Musunuru, MD, PhD, MPH, internationally recognized Crispr expert and Laura's colleague on the American Society of Human Genetics’ task force on human germline genome editing. Kiran was one of the first to see He Jiankui’s paper on the birth of twin girls after the in vitro editing of their CCR5 gene, courtesy of the Associated Press. We discuss what comes next, as the dust settles on one of the most important science news stories of 2018.

Episode 17 of the Joe and Mike vs. the Future podcast. In this podcast, we discussed the news that the first genetically engineered humans were born in China. More specifically, CRISPR was used to remove the CCR5 gene in the embryos in order to reduce their chance of contracting HIV. We discuss the technological, methodological, and ethical issues behind this work.  Correction: Huntington’s disease requires only one copy of the defective gene, not two as we stated in the podcast.  If anyone wants to contact us with feedback, comments, or to let us know any errors we may have made, please send us an email at joeandmikepodcast@gmail.com. 

En kinesisk forskare har hävdat att han skapat världens första genförändrade bebisar. Kritiken har varit stark. Tekniken som använts, CRISPR/Cas 9, är inte alls mogen för steget, enligt forskare. De första genförändrade människorna, ett par tvillingflickor, har troligen skapats i Kina med hjälp av genkniven CRISPR/Cas 9. Detta enligt ännu obekräftade uppgifter. Forskaren He Jiankui har varit tjänstledig från det universitet där han arbetar, och universitet genomför nu en utredning av vad som hänt eftersom genförändringar av den här typen är olagliga i Kina. Tanken med experimentet är att skapa individer som har motståndskraft mot HIV, genom att en mutation på genen CCR5 ger ett visst skydd mot viruset. I programmet hörs: Magnus Lundgren, cell- och molekylärbiolog med bakgrund i CRISPR-forskning vid Uppsala universitet, Gunilla Karlsson Hedestam, professor i vaccinimmunologi vid Karolinska institutet, Nils-Eric Sahlin, professor i medicinsk etik vid Lunds universitet. Camilla Widebeck, programledare camilla.widebeck@sverigesradio.se Peter Normark, producent peter.normark@sverigesradio.se

This is Special English. I am Sam Duckett in Beijing. Here is the news. China is open to space cooperation with all nations including the United States. The heavyweight of China's space program, China's first astronaut Yang Liwei, made the remark recently on the occasion of the anniversary of China's first satellite launch 46 years ago. Yang said China does not rule out cooperating with any country, including the United States. The senior astronaut said payload has been reserved in the Chinese space station for international projects and foreign astronauts. The space station is due to enter service around 2022. China marked its first Space Day, which was newly designated by the government to commemorate China's first satellite launch on April 24, 1970. Upon request, China will also train astronauts for other countries, and jointly train astronauts with the European space station. Yang said the future of space exploration lies in international cooperation, and it's true for China as well as for the United States. Citing security reasons, the United States Congress passed a law in 2011 to prohibit NASA from hosting Chinese visitors at its facilities or working with researchers affiliated to any Chinese government entity or enterprise. The ban remains in effect. The US-dominated International Space Station, which unsurprisingly blocks China, is scheduled to end its service in 2024. China's space station will be the only operational one in outer space, at least for a while. This is Special English. Five domestic airlines have agreed to tackle air rage by blacklisting passengers who misbehave. The five airlines, including Air China and China Southern, are the country&`&s major carriers. They will collectively keep records of those who are not behaved. Improper behaviors include attacking on check-in counters, forcibly occupying airplanes and fighting on board an airplane. Passenger records will be shared throughout the country's civil aviation and tourism industries. Those who are blacklisted will face penalties including being denied special seats, ticket discounts, or even service. However, an official from the Civil Aviation University of China said airlines do not have the right to limit passengers&`& travel rights. The official said that although air passenger blacklists have been adopted overseas, there is no legal provision for them in China, adding that this may lead to disputes. Others say that the provisions for the blacklist should be decided by a third party rather than just the airlines. It is the first time that a blacklist has covered most of the domestic civil aviation industry. The five airlines and their subsidiaries handle more than 80 percent of China&`&s air traffic. The decision comes after the China Air Transport Association adopted a new management policy to record uncivilized behavior by air passengers. You are listening to Special English. I am Sam Duckett in Beijing. The authorities are trying to restore public confidence in vaccines after a nationwide scandal struck fear into the hearts of parents. China banned drug wholesalers from selling vaccines, according to a decision publicized on the nation&`&s Vaccination Day, which fell on April 25th. The decision requires B-class, or non-compulsory, vaccines to be distributed in the same way as A-class, which are covered by the national compulsory immunization program. It also requires disease control departments, hospitals and clinics to keep records of purchases and received inventory. According to the decision, China will establish a system to track vaccines. Enterprises and user agencies must record circulation and use, so all vaccines can be tracked across their life cycle. The public were shocked and appalled in March when the news that improperly stored vaccines worth millions of dollars were sold nationwide. More than 300 officials implicated in cases concerning the event will be penalized. In the eastern city of Ningbo, the number of vaccinated children decreased by around one fourth from March 18 to 31. Local authorities are trying to quell public unease. This is Special English. Individuals and organizations that conduct medically inessential prenatal sex discernment or sex-selective abortions will be fined up to 30,000 yuan, roughly 4,600 U.S. dollars. Under a revised regulation taking effect recently, besides a fine, the government will confiscate the income from such screenings and abortions, which are illegal in China. Those who introduce expectant parents to take up illegal prenatal sex discernment and selective abortion will also face the same punishment. The regulation has been jointly issued by the National Health and Family Planning Commission, the State Administration for Industry and Commerce and the China Food and Drug Administration. The revision to the law aims to tackle China&`&s high gender imbalance, a direct result of pre-birth sex discernment and sex-selective abortions driven by cultural preference for boys. The birth sex ratio stood at almost 114 in 2015, much higher than a normal ratio between 103 and 107, though it has decreased from 121 in 2004. In China, legitimate reasons for a hospital conducting a sex-selective abortion include serious genetic disease or deadly threat to the mother's health. It requires at least three senior doctors with a genetics background and clinical experience to decide whether prenatal sex discernment is necessary. If an abortion is necessary, the hospital must report the case to the local health department. You are listening to Special English. I&`&m Sam Duckett in Beijing. The State Council has published its major health care reform tasks for the year, with a general practitioner pilot program, and reduced reliance on drug revenue for health centers. This year, 200 cities will trial GP practices, making the service available to 15 percent of urban citizens and 30 percent of key groups. According to the statement from the State Council, China's Cabinet, GPs will open their practices to residents, providing them with basic, consistent medical services. The plan is part of a tiered health system being rolled out across the country. To improve local-level medical institutions, the government will allow physicians in public hospitals to practice or establish their own practices. Another health reform task this year will be the establishment of a pricing mechanism for medicine to reduce the cost born by patients. Patients will be given the choice of buying drugs from hospitals or retail pharmacies. The public hospital reform will be further advanced, as 100 more cities will carry out pilot public hospital reform this year. According to the pilot reform, revenues of public hospitals will not rely on drugs but medical service charges. This is Special English. Chinese scientists are working on new projects inspired by the documented case of a man who was cured of AIDS. They hope eventually find a way to ensure that humans are born with immunity to the condition. Nine years ago, a 41-year-old man, who has since been dubbed the "Berlin patient", was close to death and in the advanced stages of both AIDS and leukemia. Doctors gave him a stem cell transplant from an HIV-resistant donor, and miraculously cured both conditions. The event made him arguably the first person ever to be cured of AIDS. The remarkable case shed light on CCR5, a receptor in humans that helps HIV enter cells. The bone-marrow transplant had changed the Berlin patient&`&s gene to a mutation called CCR5-delta32, which blocks HIV. With new gene technology now available, Chinese scientists have recently moved forward with attempts to modify the CCR5 gene in embryos, advancing their drive to ensure humans are born already immune to HIV. In the latest case, researchers from the Third Affiliated Hospital of Guangzhou Medical University used a gene editing technique to attempt to replace the CCR5 gene in 26 human embryos. The researchers tried to give the embryos the HIV-resistant mutation. Four embryos were successfully edited, while the other 22 cases failed to produce the desired results. You&`&re listening to Special English. I&`&m Sam Duckett in Beijing. You can access the program by logging on to newsplusradio.cn. You can also find us on our Apple Podcast. If you have any comments or suggestions, please let us know by e-mailing us at mansuyingyu@cri.com.cn. That&`&s mansuyingyu@cri.com.cn. Now the news continues. Chinese science fiction writer Hao Jingfang was shortlisted for the Hugo Award for her book "Folding Beijing". According to Tsinghua University, where she is pursuing her doctorate, the news was posted on the official website of the World Science Fiction Convention. "Folding Beijing", one of five candidates, is listed under the "Best Novelette" category. Hao said on her Sina Weibo microblog that she is so excited to be shortlisted. The story was first published in a new electronic magazine. She didn&`&t expect to have this result. Hao graduated from the department of physics at Tsinghua University in 2006. The story follows the protagonist, Lao Dao, as he tries to navigate the complicated class barriers of a futuristic Beijing in order to send his daughter to school. She said she used to live in suburban Beijing. Near her apartment building there were noisy alleys, small restaurants and an open-air market. The experience inspired her to write the story. Hao said she regretted that the second volume of "The Three-Body Problem" by Liu Cixin, who won the 2015 Hugo Award for Best Novel, was not shortlisted. Established in 1953, the Hugo Awards are given annually to the best works of science fiction or fantasy and are seen as the "highest honor bestowed in science fiction and fantasy writing. Fifth-three-year old Liu was the first writer in Asia to win the honor. This is Special English. A university in northwest China's Qinghai Province plans to offer international students Master&`&s degrees in traditional Tibetan medicine. Tibetan Medical College of Qinghai University has said that it planned to recruit five foreign postgraduates this autumn. The Master&`&s program will last three years, with students taught in both English and Tibetan. Established in 1987, the college is one of the two higher educational institutes in China which train traditional Tibetan medicine practitioners. The other is in Tibet. The college's honorary president said the school had exchange programs with universities in the United States, Russia, South Korea and Japan since 2007. So far, almost 100 overseas students have come for short-term training in Tibetan medicine. Traditional Tibetan medicine was also listed as optional course at University of Virginia medical school last July. The president said the core of development of Tibetan medicine lies in training. Helping it go global will be beneficial to more people. Tibetan medicine is at least 2,300 years old. It has absorbed the influences of traditional Chinese, Indian and Arab medicines and is mainly practiced in Tibet and the Himalayan region. Tibetan medicine uses herbs, minerals and sometimes insects and animal parts. It was put on the list of China's national intangible cultural heritage in 2006. You're listening to Special English. I&`&m Sam Duckett in Beijing. Disney's "The Jungle Book" continued to lead the box office in its second week after release. （全文见周六微信。）

What happens when you allow human materials to become property? More specifically, how does granting monopoly rights over genetic material affect the potential for innovation and research on treatments of disease related to those genes? In his new book, The Genealogy of a Gene: Patents, HIV/AIDS, and Race (MIT Press, 2015), Myles W. Jackson (NYU) considers this question by examining the history of the sequencing and patenting of the CCR5 gene, which was found to have an important role in HIV/AIDS viral infection. In doing so, Jackson chronicles the challenges to the granting of property rights over materials that occur naturally, and the legal and policy arguments both for and against allowing patents on these materials. But the book is more than just an examination of the instability of patent law. On the contrary, Jackson provides an interdisciplinary examination of the history of CCR5, which analyzes the role of race, culture, medicine and other fields, to examine of the wider impact of science and science policy on society. Just listen. Learn more about your ad choices. Visit megaphone.fm/adchoices

What happens when you allow human materials to become property? More specifically, how does granting monopoly rights over genetic material affect the potential for innovation and research on treatments of disease related to those genes? In his new book, The Genealogy of a Gene: Patents, HIV/AIDS, and Race (MIT Press, 2015), Myles W. Jackson (NYU) considers this question by examining the history of the sequencing and patenting of the CCR5 gene, which was found to have an important role in HIV/AIDS viral infection. In doing so, Jackson chronicles the challenges to the granting of property rights over materials that occur naturally, and the legal and policy arguments both for and against allowing patents on these materials. But the book is more than just an examination of the instability of patent law. On the contrary, Jackson provides an interdisciplinary examination of the history of CCR5, which analyzes the role of race, culture, medicine and other fields, to examine of the wider impact of science and science policy on society. Just listen. Learn more about your ad choices. Visit megaphone.fm/adchoices

What happens when you allow human materials to become property? More specifically, how does granting monopoly rights over genetic material affect the potential for innovation and research on treatments of disease related to those genes? In his new book, The Genealogy of a Gene: Patents, HIV/AIDS, and Race (MIT Press, 2015), Myles W. Jackson (NYU) considers this question by examining the history of the sequencing and patenting of the CCR5 gene, which was found to have an important role in HIV/AIDS viral infection. In doing so, Jackson chronicles the challenges to the granting of property rights over materials that occur naturally, and the legal and policy arguments both for and against allowing patents on these materials. But the book is more than just an examination of the instability of patent law. On the contrary, Jackson provides an interdisciplinary examination of the history of CCR5, which analyzes the role of race, culture, medicine and other fields, to examine of the wider impact of science and science policy on society. Just listen. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/medicine

What happens when you allow human materials to become property? More specifically, how does granting monopoly rights over genetic material affect the potential for innovation and research on treatments of disease related to those genes? In his new book, The Genealogy of a Gene: Patents, HIV/AIDS, and Race (MIT Press, 2015), Myles W. Jackson (NYU) considers this question by examining the history of the sequencing and patenting of the CCR5 gene, which was found to have an important role in HIV/AIDS viral infection. In doing so, Jackson chronicles the challenges to the granting of property rights over materials that occur naturally, and the legal and policy arguments both for and against allowing patents on these materials. But the book is more than just an examination of the instability of patent law. On the contrary, Jackson provides an interdisciplinary examination of the history of CCR5, which analyzes the role of race, culture, medicine and other fields, to examine of the wider impact of science and science policy on society. Just listen. Learn more about your ad choices. Visit megaphone.fm/adchoices

What happens when you allow human materials to become property? More specifically, how does granting monopoly rights over genetic material affect the potential for innovation and research on treatments of disease related to those genes? In his new book, The Genealogy of a Gene: Patents, HIV/AIDS, and Race (MIT Press, 2015), Myles W. Jackson (NYU) considers this question by examining the history of the sequencing and patenting of the CCR5 gene, which was found to have an important role in HIV/AIDS viral infection. In doing so, Jackson chronicles the challenges to the granting of property rights over materials that occur naturally, and the legal and policy arguments both for and against allowing patents on these materials. But the book is more than just an examination of the instability of patent law. On the contrary, Jackson provides an interdisciplinary examination of the history of CCR5, which analyzes the role of race, culture, medicine and other fields, to examine of the wider impact of science and science policy on society. Just listen. Learn more about your ad choices. Visit megaphone.fm/adchoices

We've gathered this evening to consider 1959's The Bat, starring Agnes Moorehead and Vincent Price.

We've gathered this evening to consider 1959's The Bat, starring Agnes Moorehead and Vincent Price.

We've gathered this evening to consider 1959’s The Bat, starring Agnes Moorehead and Vincent Price.

We've gathered this evening to consider 1959's The Bat, starring Agnes Moorehead and Vincent Price.

Interstitial lung diseases (ILD) are severe chronic lung diseases characterized by an increased deposition of extracellular matrix in the lung interstitial space, leading to a thickening of the alveolar walls and impairment of the gas exchange. One of the most common entities in this category is idiopathic pulmonary fibrosis (IPF) with a mean survival time of 2 to 3 years from diagnosis. Until now, there is no curative therapy available and the symptomatic anti- inflammatory treatment and oxygen supplementation cannot prevent the development of the end stage pulmonary fibrosis. The chemokine receptor CCR2 is important for leukocyte recruitment to inflamed tissues through interaction with CCL2 (MCP-1). The blockade of the CCR2/CCL2 pathway attenuated the development of pulmonary fibrosis in mouse models. However, CCR2+ T-lymphocytes acquired regulatory functions in experimental arthritis during the course of disease. Therefore, it is unknown whether CCR2+ T cells are involved in the pathogenesis of IPF or, on the contrary, represent an unsuccessful effort of the immune system to limit the disease. Observations in paediatric patients with different forms of ILDs suggested a role for CCR2+ T cells in pulmonary fibrosis. To characterize these T cells, flow cytometric studies were performed using the bleomycin mouse model of pulmonary fibrosis. The kinetic of CCR2+ T cells in BALF, lung tissue, and spleen following intratracheal administration of bleomycin (BLM) was assessed at time points between day 3 and day 21. To determine, if the constellation of naïve, central memory and effector memory T cells changes after BLM treatment, and to which of these subtypes CCR2+ T cells belong to, the cells were additionally stained for CD62L and CD44. For further characterization of CCR2+ T cells, chemokine receptor co-expression with CCR2 was investigated at the time point of the maximal presence of CCR2+ T cells. Total T cell numbers increased in BAL and lung tissue but not in spleen. Percentages of CD62LlowCD44hi effector memory T cells increased in lung tissue in the early phase of BLM induced fibrosis, while the CD62LhiCD44low naïve T cell population decreased. The percentage of CCR2+ T cells increased following BLM treatment with a maximum on day 12. The majority of CCR2+CD4+ T cells showed a Tem phenotype. CCR3, CCR4, CCR6, CXCR4, and CXCR5 expressing cells increased within the pulmonary CD4+ T cell population following bleomycin treatment. Among CD8+ T cells from treated mice, CCR5, CCR6, and CXCR5 positive cells were increased. CCR7 was highly co-expressed with CCR2 in saline and bleomycin treated mice, whereas co-expression of CCR3, CCR4, CCR6 and CXCR5 increased significantly in treated mice. The results indicate an activation of pulmonary T cell populations following bleomycin treatment. CCR2+CD4+ T cells probably take part on this T cell response as they exhibit an effector memory phenotype and increase following BLM treatment. In contrast, the stable percentages of the different T cell subtypes in spleens gave no hint for a systemic T cell reaction. The pattern of chemokine receptor expression argues against a Th1 polarization and towards a Th2, Th17 or TFH polarization of CCR2+ T cells.

There's never been a more optimistic time for finding the cure for AIDS.AIDS, or acquired immune deficiency syndrome, is the final stage of the HIV disease that causes damage to your immune system. When you have AIDS, your body's cellular immunity is severely decreased, which lowers your resistance to infection.You may think that HIV/AIDS is no longer a huge epidemic and that not that many people are suffering from this disease. However, according to the AIDS website, more than 1.1 million people in the U.S. are living with the HIV infection, and 1 in 6 people are unaware of their infection.In the past few years, there have been several breaks in research that hold a promising hope that the cure for AIDS can and will be found. Why does amfAR believe a cure for HIV/AIDS is feasible by the year 2020?Remember the Berlin patient? His real name is Timothy Brown, and he was thought to be the first and only person to be cured of HIV. He was diagnosed in 1995 and aggressively controlled the virus for several years by using anti-retroviral therapy. In 2007, things took a turn for the worse when Brown was diagnosed with acute myeloid leukemia and had a stem cell transplant. Brown's chemotherapy failed but his doctors went with an unrelated donor who screened positive for homozygous mutation, CCR5∆32. Four years after that transplant, Brown is free from cancer as well as HIV.A cure for HIV is possible, and for the first time there is an understanding of the scientific barriers of finding a cure and what researchers need to do to overcome these barriers.Now, when you hear the word "cure," you may think that the HIV/AIDS is no longer found in that patient's body. However, at amfAR, cure means a different thing: if you've been diagnosed with HIV/AIDS, were taking anti-retroviral therapy, and now no longer need it or any other medication, you are considered cured. You are living a long and healthy life and not transmitting HIV to anyone else.What is the countdown to a cure?Vice president and director of research at amfAR, Rowena Johnston, joins Melanie Cole, MS, to discuss why she believes a cure for AIDS can be reached by 2020 and the steps that are needed to reach that goal.

There's never been a more optimistic time for finding the cure for AIDS.AIDS, or acquired immune deficiency syndrome, is the final stage of the HIV disease that causes damage to your immune system. When you have AIDS, your body's cellular immunity is severely decreased, which lowers your resistance to infection.You may think that HIV/AIDS is no longer a huge epidemic and that not that many people are suffering from this disease. However, according to the AIDS website, more than 1.1 million people in the U.S. are living with the HIV infection, and 1 in 6 people are unaware of their infection.In the past few years, there have been several breaks in research that hold a promising hope that the cure for AIDS can and will be found. Why does amfAR believe a cure for HIV/AIDS is feasible by the year 2020?Remember the Berlin patient? His real name is Timothy Brown, and he was thought to be the first and only person to be cured of HIV. He was diagnosed in 1995 and aggressively controlled the virus for several years by using anti-retroviral therapy. In 2007, things took a turn for the worse when Brown was diagnosed with acute myeloid leukemia and had a stem cell transplant. Brown's chemotherapy failed but his doctors went with an unrelated donor who screened positive for homozygous mutation, CCR5∆32. Four years after that transplant, Brown is free from cancer as well as HIV.A cure for HIV is possible, and for the first time there is an understanding of the scientific barriers of finding a cure and what researchers need to do to overcome these barriers.Now, when you hear the word "cure," you may think that the HIV/AIDS is no longer found in that patient's body. However, at amfAR, cure means a different thing: if you've been diagnosed with HIV/AIDS, were taking anti-retroviral therapy, and now no longer need it or any other medication, you are considered cured. You are living a long and healthy life and not transmitting HIV to anyone else.What is the countdown to a cure?Vice president and director of research at amfAR, Rowena Johnston, joins Melanie Cole, MS, to discuss why she believes a cure for AIDS can be reached by 2020 and the steps that are needed to reach that goal.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Kathy Spindler Vincent, Dickson, Alan, and Kathy discuss disruption of the ccr5 gene in lymphocytes of patients infected with HIV-1. Links for this episode Gene editing of ccr5 in AIDS patients (NEJM) HIV gets the zinc finger (TWiV 144) Genome engineering with zinc finger nucleases (Genetics) Photo credit: Watty's Wall Stuff Mice lie, monkeys exaggerate t-shirt design (thanks, Christophe) Letters read on TWiV 278 Weekly Science Picks Alan - Digital scale model of solar systemDickson - Font of knowledgeVincent - Measles outbreaks trends, and NYC measles (one, two)Kathy - Winner, funding basic science to revolutionize medicine Listener Pick of the Week Stephen & Jon - Watty's Wall StuffJohyne - Macro views of snowflakesRicardo & Stephen - Vaccine exemptionsBill - Books by John JanovyMarshall - Animation of DNA replicationSteve - Debunking influenza vaccine myths Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv

Vincent, Michael, and Elio discuss the HIV co-receptor CCR5 as a receptor for S. aureus leukotoxin ED, and the vineyard yeast microbiome.

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1{*}1303, KIR and PARD3B. Copyright (C) 2012 S. Karger AG, Basel

Background: The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24(+)Vβ11(+) NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore, IL-4 and IFN-γ secreting NKT cells were quantified within the single CKR(+) subsets. Results: Cord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3+ and CCR5+ cord blood NKT cells (Th1-related) were present at lower percentages. Within CD4negCD8neg (DN) NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-γ secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3+, CCR4+, CCR5+, CCR6+, CCR7+, CCR8+ and CXCR4+ DN subsets in cord blood. This resulted in significantly decreased IFN-γ /IL-4 ratios of CCR3+, CCR6+ and CCR8+ cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR) transcripts in sorted cord blood Vα24Vβ11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells. Conclusions: Despite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non-inherited maternal antigens.

T cells directed against brain antigens are generally held to play a crucial role in the initiation of multiple sclerosis (MS). This was deduced from experimental autoimmune encephalomyelitis (EAE). In this model for MS, T cells reactive for myelin antigens induced a severe paralytic disease upon transfer to healthy syngeneic recipients. Intriguingly, the disease does not start immediately upon transfer of the pathogenic effector T cells. Instead, as earlier studies have shown, the effector T cells attack their target organ only after having migrated in the periphery through secondary lymphoid organs. The aim of the project was to characterize the functional properties of these migrating encephalitogenic T cells during the course of EAE and to identify biological pathways which determine their migratory behaviour and pathogenic potential. To this end, average linkage hierarchical clustering, pathway and gene ontology (GO) analyses of transcriptomes from cultured and ex vivo-isolated myelin basic protein-reactive T cells (TMBP cells) were performed. At the time of transfer, encephalitogenic T cells in vitro are maximally activated, i.e. they exhibit a prominent upregulation of cell cycle genes such as cyclin A2 (CCNA2) and cyclin B2 (CCNB2) among others. In contrast, T cells isolated from spleen 3 days post transfer, downregulated activation markers such as interleukin 2 receptor (IL2R) and interferon γ (IFNγ), and at the same time upregulated migration specific genes such as CC-chemokine receptor 1 (CCR1), CC-chemokine receptor 2 (CCR2) and CC-chemokine receptor 5 (CCR5). Hierarchical cluster analysis revealed that several transcription regulators known for inhibiting cell cycle progression such as krüppel-like factor 4 (KLF4), B-cell translocation gene 2 (BTG2) and transducer of ERBB2, 1 (TOB1) were clustered together with cell cycle and migration genes. Overexpression of KLF4 in T cells not only inhibited G1/S phase progression of the cell cycle but additionally induced upregulation of CCR2 and CCR5. A novel tetraspan membrane protein called epithelial membrane protein (EMP1), was found to be up regulated in ex vivo-isolated effector T cells. Overexpression of EMP1 in encephalitogenic T cells influenced the migratory behaviour of effector T cells both in vitro and in vivo. EMP1 enhanced T cell motility within the extracellular matrix milieu in vitro and promoted T cell migration from the connective tissue to lymph nodes in vivo resulting in an accelerated onset of EAE. In conclusion, gene expression profiling of encephalitogenic T cells revealed interesting genome wide transcriptomic changes and established a correlation between cell cycle progression and cell migration. As a result, in silico analysis put forth several interesting candidate genes that hold promise as potential targets for therapeutic intervention.

Summary and hypothesis Role of pro-inflammatory chemokines in diabetic nephropathy Beyond hemodynamic and metabolic abnormalities associated with diabetes, the role of inflammation in development and progression of diabetic nephropathy is well accepted. Recruitment and activation of macrophages in different renal compartment is considered to be hallmark of all inflammation in diabetic nephropathy. Although recruitment of macrophages to the renal compartment has been extensively studied, the exact mechanisms involved are still to be explored. The chemokine-chemokine receptor interactions are implicated to be mainly responsible for trafficking and infiltration of different monocytes and macrophages. Contribution of macrophages to the development of DN can be addressed in either by inhibiting chemokines or chemokine receptor associated with diabetes. We hypothesized that inhibition of CCL2 may inhibit macrophages infiltrating into different compartments in kidney and inhibition started at earlier stage of disease progression may show more beneficial effects than CCL2 blockade at late stage of DN. To address the involvement of additional chemokine receptors we hypothesized that blocking CCR5 and CCR2 simultaneously might have some additive or synergistic effects. Role of homeostatic chemokines in diabetic nephropathy Homeostatic chemokies are mainly involved in hematopoeisis, immune cell survival and adaptive immune responses. CXCL12 attracted our attention as it is being extensively studied and reported to be responsible for different functions like stem cell survival and homing and trafficking to different compartments. The role of CXCL12 in diabetic nephropathy has not been explored yet. CXCL12 is constitutively expressed by different renal cells. It may contribute to tissue repair and inhibit disease progression by stem cell recruitment or may cause increased tissue fibrosis and aggravate the disease. We hypothesized that CXCL12 plays role in development and progression of diabetic nephropathy. In order to address this question we used CXCL12 blocker in a mouse model of diabetic nephropathy.

Die vorliegende Studie trägt zum besseren Verständnis des breiten klinischen Spektrums und des Fehlens universeller Serum- Marker der infektionsassoziierten Krankheitsaktivität der Lupus- Nephritis und möglicherweise anderer Formen der Immunkomplexnephritis bei. Exogener Kontakt mit TLR 7- Liganden hat die Entwicklung der Lupus- Nephritis bei jungen, gesunden MRL- Wildtyp und MRLlpr/lpr Mäusen nicht getriggert und hatte keinen signifikanten Effekt auf die Krankheitsaktivität bei diesen jungen Mäusen. Bei alten Lupus- Mäusen führte eine ähnliche Exposition jedoch zu einem merklichen Anstieg der Serumspiegel proinflammatorischer Zytokine und von IFNα, sowie zu einer Infiltration der Nierenglomeruli 18 Wochen alter MRLlpr/lpr Mäuse mit Makrophagen und einer (nicht signifikanten) Erhöhung der Autoantikörperspiegel. Diese Daten unterstützen die Theorie, dass dem Toll- like Rezeptor 7 eine Rolle bei den Mechanismen, die das Fortschreiten der autoimmunen Gewebsschädigung in MRLlpr/lpr Mäusen fördern, zukommt. Basierend auf den Ergebnissen der funktionellen Rolle von TLR 7 in Lupus- Mäusen und in Primärzellen, die aus Lupusmäusen isoliert wurden, sahen wir in der TLR 7- Blockade ein mögliches neues Ziel, um die schädlichen Effekte des Signalings über Immunkomplexe und endogene Liganden zu begrenzen. Es zeigte sich, dass die Blockade von TLR 7 und TLR 7 + TLR 9 die Gewebsschäden in Nieren und Lunge signifikant reduzieren konnte. Eine TLR 7 Antagonisierung mit dem Oligodeoxyribonukleotid IRS661 senkte die Menge an Autoantikörpern (insbesondere anti- SM, anti- dsDNA, IgG2a, IgG2b), entzündlichen Zytokine und Chemokinen im Serum, glomerulären Ablagerungen von IgG2a und Komplementfaktor C3c deutlich. Die Hemmung von TLR 7 reduzierte ebenfalls die CC- Chemokin- gesteuerten Makrophagen- und T- Zell- Infiltrate in den Nieren. Dies zeigte sich durch erniedrigte Spiegel von Ccr2, Ccr5, Ccl2 und Ccl5 in den Nieren behandelter Tiere. Diese Ergebnisse unterstützen das Konzept, dass endogene TLR 7- Liganden zur Pathogenese der Autoantikörperproduktion und der autoimmun vermittelten Gewebsschädigung des SLE beitragen. Die TLR 7- Blockade könnte ein neues therapeutisches Konzept beim Lupus erythematodes sein.

The two chemokine receptors CCR2 and CCR5 play important roles in the recruitment and activation of monocytes/macrophages and T-lymphocytes at sites of infection and inflammation. To further examine their function, I cloned the two murine chemokine receptors Ccr2 and Ccr5 from genomic mouse DNA by a PCR-based cloning strategy and functionally expressed them in stably transfected CHO-cells. These cells were used to generate the first monoclonal antibodies against Ccr2 and Ccr5.

Die Eigenschaft von Leukozyten, das Gefäßsystem zu verlassen und in das umliegende Gewebe auszuwandern, ist von essentieller Bedeutung für die Bekämpfung von Infektionen und darüber hinaus entscheidend für die Pathogenese des I/R-Schadens. Die Extravasation von Leukozyten stellt dabei einen kaskadenartig verlaufenden Prozess dar, welcher sich in die Schritte Rolling, Adhärenz, transendotheliale und interstitielle Migration gliedern lässt. Ein geeignetes Versuchsmodell, welches am M. cremaster der Maus in vivo alle Schritte des leukozytären Rekrutierungsprozesses während I/R zu analysieren erlaubt, liegt bisher nicht vor. Während die frühen Schritte des leukozytären Extravasationsprozesses weitgehend aufgeklärt sind, sind die Schritte der transendothelialen und interstitiellen Migration von Leukozyten unzureichend verstanden. In vitro Untersuchungen zeigen, dass das Molekül JAM-A in die Transmigration von Leukozyten involviert ist, jüngste in vivo Studien zeigen jedoch kontroverse Ergebnisse. Ferner gibt es zunehmend Hinweise darauf, dass die Chemokinrezeptoren Ccr1, Ccr2 und Ccr5 an der Extravasation von Leukozyten beteiligt sind. Welche Bedeutung diese Chemokinrezeptoren für die einzelnen Schritte des leukozytären Rekrutierungsprozesses bei Entzündung und I/R besitzen, ist bislang unklar. Die Ziele der vorliegenden Arbeit waren daher i) ein geeignetes Modell zur Untersuchung aller Schritte des leukozytären Rekrutierungsprozesses bei I/R am M. cremaster der Maus zu entwickeln, ii) die Bedeutung des Adhäsionsmoleküls JAM-A für die Transmigration von Leukozyten zu untersuchen und iii) die Rolle der Chemokinrezeptoren Ccr1, Ccr2 und Ccr5 für die einzelnen Schritte des leukozytären Rekrutierungsprozesses bei Entzündung und I/R zu analysieren. In unterschiedlichen Versuchsansätzen wurde mit Hilfe der RLOT-Intravitalmikroskopie am M. cremaster anästhesierter Mäuse die leukozytären Migrationsparameter untersucht. Zur Bestimmung des Phänotyps transmigrierter Leukozyten wurden immunhistochemische Färbungen von Paraffinschnitten durchgeführt. In einer ersten Versuchsreihe wurden die einzelnen Schritte des leukozytären Extravasations-prozesses systematisch in Abhängigkeit von Ischämiedauer und Reperfusionszeit untersucht. Die Ergebnisse zeigen, dass es bereits nach 30 min Ischämie und 120 min Reperfusion gegenüber schein-operierten Kontrolltieren zu einem starken Anstieg von Leukozyten-adhärenz und -transmigration kommt. Eine Verlängerung der Ischämiezeit auf 60 bzw. 90 min konnte keine Steigerung der Effekte erzielen. Diese Befunde waren der Ausgangspunkt für weitergehende Untersuchungen, welche die Mechanismen des leukozytären Rekrutierungs-prozesses näher charakterisieren sollen. In diesem Zusammenhang wurde in einer zweiten Versuchsreihe unter Verwendung von JAM-A-defizienten Mäusen die Bedeutung des Adhäsionsmoleküls JAM-A für die Leukozytenrekrutierung systematisch unter verschiedenen inflammatorischen Bedingungen analysiert. Unsere Daten belegen, dass die transendotheliale Migration von neutrophilen Granulozyten und Monozyten einer Stimulus-spezifischen Regulation durch JAM-A unterliegt. Ferner lassen die Ergebnisse unserer Untersuchungen in eJAM-A-defizienten Tieren darauf schließen, dass endotheliales JAM-A die Transmigration von neutrophilen Granulozyten und Monozyten zwar in der Initialphase entzündlicher Prozesse vermittelt, zu späteren Zeitpunkten jedoch keine Bedeutung mehr zu besitzen scheint. Schließlich deuten unsere Befunde darauf hin, dass leukozytäres JAM-A an den der interstitiellen Leukozytenmigration zugrunde liegenden Mechanismen beteiligt ist. In einer letzten Versuchsreihe wurde die Rolle der Chemokinrezeptoren Ccr1, Ccr2 und Ccr5 für die Rekrutierung von Leukozyten bei Chemokin-induzierter Entzündung und I/R untersucht. Es konnte gezeigt werden, dass diese Chemokinrezeptoren die Extravasation von neutrophilen Granulozyten und Monozyten bei Chemokin-induzierter Entzündung durch Effekte auf Adhärenz und (konsekutive) transendotheliale Migration mediieren und keinen Einfluss auf das interstitielle Migrationsverhalten transmigrierter Leukozyten besitzen. Des Weiteren ist es mittels durchflusszytometrischer Analyse gelungen, die Expression von Ccr2 und Ccr5 auf nativen neutrophilen Granulozyten nachzuweisen. Darüber hinaus konnte erstmals gezeigt werden, dass die Chemokinrezeptoren Ccr1, Ccr2 und Ccr5 zur Rekrutierung von neutrophilen Granulozyten und Monozyten in das postischämische Gewebe durch dynamische bzw. differentielle Regulation von Adhärenz und (konsekutiver) Transmigration beitragen.

The past year has brought so many new drug approvals that even some HIV experts are scratching their heads as they try to figure out how all of these meds work and how they can best be used to treat people with HIV. Today, we're going to look at one of the new classes, or types, of HIV medications. Called CCR5 inhibitors, this drug class attacks HIV in a totally new way. Helping us to understand this new drug class will be Dr. David Hardy, a researcher and clinician who is the director of the Division of Infectious Diseases at Cedars-Sinai Medical Center in Los Angeles. He is also one of the leading researchers looking at Selzentry (maraviroc, Celsentri), the first CCR5 inhibitor to be approved in the United States. He'll give us the lowdown on how this new drug class works and put it into context.

Thu, 17 Jan 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8060/ https://edoc.ub.uni-muenchen.de/8060/1/Becker_Marie-Christine.pdf Becker, Marie-Christine ddc:600, d

The global burden of chronic kidney diseases remains an ongoing medical challenge. Therapies that can halt or reverse advanced renal injury are not yet available. Increasing numbers of patients progress to the end-stage renal failure and require renal replacement therapy, the latter being associated with significant mortality, a lower quality of life, and high costs for national health systems. Thus, new treatment strategies that slow down, halt or even revert progressive renal damage are requested. Chemokines and their receptors are involved in the pathogenesis of renal diseases. They mediate leukocytes and macrophages recruitment and activation during initiation as well as progression of renal inflammation. Infiltrating leukocytes are the major source for proinflammatory and profibrotic cytokines and are therefore critical for mediating fibroblast proliferation, differentiation into myofibroblasts, matrix production, and tubular atrophy. Recent advances in the understanding of the molecular mechanisms that regulate renal leukocyte recruitment suggest chemokines and chemokine receptors as novel targets for specific pharmacological intervention. The aim of the present thesis was to investigate the role of chemokine receptor CCR1 for the progression of chronic kidney diseases, e.g. Alport disease and diabetic nephropathy. Two different animal models were used: Col4A3-deficient mice and type 2 diabetic db/db mice with advanced diabetic nephropathy. We blocked CCR1 in Col4A3-deficient mice with BX417, a small molecule CCR1 antagonist, and BL5923, a novel orally available antagonist with a high specificity for human and murine CCR1 in uninephrectomized type 2 diabetic db/db mice, respectively. Treatment with BX471 (25mg/kg) from weeks 6 to 10 of life improved survival of COL4A3- deficient mice, characterized by glomerulosclerosis and subsequent progressive tubulointerstitial injury, leading to fatal end-stage renal disease (ESRD). Improvement was associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Ccl5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. When CCR1 was blocked with BL5923 (60mg/kg, b.i.d), the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with type 2 diabetes. Similarly, BL5923 orally administered from month 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, Tgf-β1, and collagen I-α1 when compared to untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for CCR1-dependent recruitment of interstitial macrophages for the progression of chronic kidney disease in Alport disease and diabetic nephropathy. These data identify CCR1 as a potential therapeutic target for Alport disease and late stage diabetic nephropathy or other progressive nephropathies associated with interstitial macrophage infiltrates.

Background: Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma. Methods: The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression. Results: Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells. Conclusion: Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology of osteosarcoma, but also contradict aspects of previous reports describing the expression of these receptors in this tumor.

Background: Chemokines immobilized on endothelial cells play a central role in the induced firm adhesion and transendothelial migration of leukocytes. Activation of platelets at sites of vascular injury is considered to support leukocyte adhesion and extravasation. However, activated platelets also secrete soluble glycosaminoglycans that can interfere with immobilization of chemokines. We therefore analyzed the impact of platelet derived glycosaminoglycans on the immobilization of the chemokine CCL5 (RANTES) on human microvascular endothelial cells and their influence on CCL5-CCR5 interactions. Results: We confirm that undiluted serum in contrast to plasma decreases binding of CCL5 to endothelial cells. However, when lower concentrations of serum were used, CCL5-presentation on endothelial cells was markedly enhanced. This enhancement was neutralized if serum was digested with chondroinitase ABC. Using different chondroitinsulfate-subtypes we demonstrate that chondroitinsulfate A mediates the enhanced presentation of CCL5 on endothelial cells, whereas chondroitinsulfate B/C even at low concentrations block CCL5 binding. CCR5 downregulation on CCR5-transfected CHO cells or human monocytes is increased by preincubation of CCL5 with serum or chondroitinsulfate A. Conclusion: We show that chondroitinsulfate A released from platelets increases the binding of chemokines to endothelial cells and supports receptor internalization in a dose dependent manner. These data help to understand the proinflammatory effects of activated platelets.

It's been a year since the United States approved a new HIV medication, and four long years since we witnessed the birth of a whole new class of meds. But on Aug. 6, 2007, the U.S. Food and Drug Administration gave the green light to maraviroc, which will be known by the brand name Selzentry. Maraviroc is the first in a new class of HIV meds known as CCR5 inhibitors. Which HIV-positive people stand to benefit the most from maraviroc? How can you know if maraviroc's a good fit for you? To get the answers to these questions, we spoke with Dr. Joel Gallant, a professor of medicine and epidemiology at the Johns Hopkins University School of Medicine and one of the leading HIV specialists in the United States.

In der vorliegenden Arbeit wurde bronchoalveolären Lavage Flüssigkeit (BALF) von Patienten mit interstitiellen Lungenerkrankungen (23 Patienten) auf Chemokinkonzentrationen und Chemokinrezeptorexressionsmuster der Lymphozyten analysiert und die Ergebnisse mit Patienten, die an chronischer Bronchitis (6 Patienten) oder malignen Erkrankungen (9 Patienten) der Lunge erkrankt waren verglichen. Mittels ELISA wurden die Chemokinkonzentrationen und mittels Durchflusszytometrie der Anteil an Chemokinrezeptor-exprimierenden T-Zellen in der BALF bestimmt. Hierbei wurden die Chemokinkonzentrationen von MCP 1, TARC, MDC und RANTES und die Häufigkeit CCR2+, CCR5+, CCR4+ und CXCR3+ Zellen innerhalb der CD4+ und CD8+ T-Zellpopulationen gemessen. Es konnte gezeigt werden, dass bei interstitiellen Lungenerkrankungen im Vergleich zu den Kontrollgruppen die MCP-1 Konzentration knapp signifikant (p = 0,055) und die CCR2+CD4+T-Zellen signifikant erhöht waren. Im Zusammenhang mit Daten aus Kinder- und Erwachsenenstudien, in denen in der bronchoalveolären Lavageflüssigkeit erhöhte MCP-1 Werte und vermehrt CCR2+ T-Zellen nachgewiesen wurden, legen diese Ergebnisse eine wichtige Rolle der MCP 1/CCR2-Achse in der Pathogenese der interstitiellen Lungenerkrankungen nahe. Ebenso fanden sich bei interstitiellen Lungenerkrankungen signifikant mehr der TH2-assoziierten CCR4+ T-Zellen; bei dem TH1-assoziierten Rezeptor CXCR3+ ergab sich kein Unterschied. Gemeinsam mit ähnlichen Ergebnissen einiger Studien in Mausmodellen und humanen Studien weisen sie auf eine TH2-Polarisierung der T Zellen bei interstitiellen Lungenerkrankungen hin, welche hierbei einen profibrotischen Effekt haben sollen. Gleichzeitig konnten bei interstitiellen Lungenerkrankungen signifikant mehr CCR5+CD4+ und CCR5+CD8+ Zellen als in den Kontrollgruppen nachgewiesen werden. Da auch bei gesunden Menschen CCR5+ T-Zellen nachgewiesen werden konnten, postulieren wir, dass CCR5+ T-Zellen auch unabhängig von der Polarisierung der T-Zellen ein regulärer Bestandteil des bronchoalveolären Raumes im Rahmen einer normalen Immunreaktion sind. Insgesamt hat diese explorative Analyse aufgezeigt, dass sowohl die MCP 1/CCR2-Achse, als auch TH2-polarisierte T-Zellen ein potentielles Angriffsziel in der Behandlung interstitieller Lungenerkrankungen darstellen könnten. Die Ergebnisse sollten den Anstoß für ausführlichere Untersuchungen mit einem wesentlich größeren Patientenkollektiv geben.

Audio Journal of Global Health Issues Maraviroc: New Antiretroviral Drug Shows Efficacy and Safety REFERENCE: Abstract Number: 104aLB, 104bLB, 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles February 25-28, 2007 HOWARD MAYER, Pfizer Global Research, New London CT MARK WAINBERG, McGill University, Montreal In a population of treatment-experienced HIV-infected subjects, maraviroc plus optimised background antiretroviral therapy provided significantly superior virologic control and increases in CD4 cell counts compared with placebo plus optimized background therapy. There were no clinically relevant differences in the safety profiles between the maraviroc and the placebo treatment groups. These drugs do not attack the virus itself but rather block host cells’ CCR5 cell surface cytokine receptors that HIV interacts with to gain entry into the cell.

Background: Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2(+) T cells accumulate in pediatric ILD and are related to disease severity. Methods: Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2(+), CCR4(+), CCR3(+), CCR5(+) and CXCR3(+) T cells were quantified by flow-cytometry. Results: CCR2(+) T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2(+) T cells in bronchoalveolar lavage fluid compared to non-fibrotic children. Conclusion: The results indicate that pulmonary CCR2(+) T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies.

Epidemiologische Daten und Tiermodelle geben Hinweise auf eine verschlechterte Immunabwehr bei Karzinomen des Kopf- und Halsbereiches, wobei die genauen Wirkmechanismen bisher nicht aufgeschlüsselt werden konnten. In Untersuchungen konnte gezeigt werden, dass Karzinome im Kopf- und Halsbereich mit erhöhten Konzentrationen an Prostaglandinen im Serum einhergehen, ein anderer Autor wies eine verminderte Expression des Chemokinrezeptors CCR5 auf Monozyten nach Behandlung mit Prostaglandin nach. In der vorliegenden Arbeit konnte erstmalig aufgezeigt werden, dass es im Rahmen einer Karzinomerkrankung im Hals- und Kopfbereich zu strukturellen und funktionellen Defiziten der Monozytenfunktion kommt. Hierbei finden sich erniedrigte Expressionsraten an CCR5, CCR2 und des Adhäsionsmoleküls CD11b des β-Integrins Mac-1 sowie eine verminderte Adhäsionsfähigkeit der Monozyten an das interzelluläre Adhäsionsmolekül ICAM-1. Weiterhin konnte nachgewiesen werden, dass nach Inkubation der Monozyten in Serum gesunder Spender die verminderte Immunfunktion wieder verbessert wird. Parallel dazu zeigte sich, dass die oben beschriebenen Immundefekte auf Monozyten gesunder Spender durch Inkubation in Serum von Tumorpatienten künstlich herbeigeführt werden können. Dies legt den Schluss nahe, dass im Rahmen einer Karzinomerkrankung Metaboliten im Serum gelöst sind, die eine immunologische Tumorabwehr erschweren. Diese Erkenntnisse sind ein weiterer Schritt zum Verständnis der Tumorimmunologie und könnten dazu hilfreich sein, immunologische Therapieverfahren voranzubringen.

Hintergrund und Fragestellung: Die Konfrontation des Immunsystems mit einem definierten Antigen löst eine spezifische Immunantwort aus. Die daran beteiligten TH-Zellen können anhand der von ihnen sezernierten Zytokine in TH1- und TH2-Zellen sowie in weitere Subtypen differenziert werden. Dabei sind TH1-Zellen durch die Synthese von IFN-g charakterisiert, während TH2-Zellen vorwiegend Interleukin-4 produzieren. Die gezielte Auswanderung von TH-Zellen in inflammatorische Gewebe wird unter anderem durch Chemokinrezeptoren, welche chemotaktische Zytokine (sog. Chemokine) binden, gesteuert. TH1-Zellen exprimieren bevorzugt CXCR3 und CCR5, TH2-Zellen dagegen CCR3 und CCR4. TH-Zellen sind an der Pathogenese von Typ I Allergien entscheidend beteiligt. Für die Entwicklung der hinsichtlich der Ausbildung von Typ I Allergien protektiven TH1-Zellen scheint die Auseinandersetzung des Immunsystems mit mikrobiellen Antigenen in der allerfrühesten Kindheit notwendig zu sein. Ziel der vorliegenden Arbeit war es, in einem Pilotprojekt an einem Normalkollektiv zweijähriger Kinder das Expressionsmuster oben genannter Chemokinrezeptoren auf peripheren TH-Zellen zu analysieren. In einem zweiten Schritt sollte untersucht werden, ob ein positiver Zusammenhang zwischen TH2-assoziierten Chemokinrezeptoren und der Familienanamnese hinsichtlich atopischer Erkrankungen, der klinischen Diagnose einer atopischen Dermatitis und anderen in der Allergiediagnostik eingesetzten Parametern besteht, oder sich ein negativer Zusammenhang zwischen den TH1-assoziierten Chemokinrezeptoren und oben genannten Parametern zeigen lässt. Darüber hinaus sollte überprüft werden, ob zwischen der Endotoxinexposition, als Proxy für die mikrobielle Exposition in den ersten Lebensmonaten, und dem Expressionsmuster der Chemokinrezeptoren ein Zusammenhang nachgewiesen werden kann. Ergebnisse:Die Chemokinrezeptoren CCR4, CCR5 sowie CXCR3 waren bei allen Probanden nachweisbar. CCR3 konnte bei acht von 37, IFN-g bei 33 von 42 untersuchten Probanden nachgewiesen werden. IL-4 war nicht nachweisbar. Es bestand ein positiver Trend in der Korrelation zwischen der mRNA-Expression von IFN-g und den Chemokinrezeptoren CCR5 (r=0,571) sowie CXCR3 (r=0,386). Ebenso zeigte sich ein positiver Trend in der Korrelation zwischen CCR5 und CXCR3 (r=0,273). Diese Zusammenhänge waren nicht statistisch signifikant. Dagegen korrelierte die CCR5 mRNA-Expression hochsignifikant (p=0,001) sowie die CCR4 mRNA-Expression grenzwertig signifikant (p=0,046) mit dem Endotoxingehalt in der Muttermatratze der Probanden. Schlussfolgerungen: ·In unstimulierten peripheren T-Helferzellen zweijähriger Kinder ist die Quantifizierung der Chemokinzeptoren CCR4, CCR5 sowie CXCR3 mit Hilfe der real-time RT-PCR möglich. IFN-g ist in der überwiegenden Anzahl der untersuchten Probanden nachweisbar, CCR3 nur bei wenigen, IL-4 bei keinem der Probanden. ·Die mRNA-Expression TH1-/TH2-assoziierter Chemokinrezeptoren in unstimulierten, peripheren T-Helferzellen ist für die Differenzierung von Kindern mit von Kindern ohne atopische Dermatitis nicht hilfreich. ·Dagegen scheint die mRNA-Expression von CCR5 als möglichem Marker einer TH1-Antwort mit dem Symptomenkomplex wheezing zu korrelieren. Dieser Befund muss in Studien mit großen Fallzahlen überprüft werden. Wheezing ist am häufigsten mit viralen Infektionen vergesellschaftet. Die weitere Nachuntersuchung der Kinder im Schulalter wird zeigen, bei welchen Kindern sich dennoch Asthma manifestiert. ·Die perinatale Endotoxin-Exposition ist mit einer erhöhten CCR5 mRNA-Expression peripherer TH-Zellen assoziiert. ·Damit deuten die Befunde auf eine Verwertbarkeit der CCR5 mRNA-Expression als TH1-Marker in unstimulierten peripheren TH-Zellen hin.

Background: Lymphocytes are recruited to sites of inflammation by chemokines. Accordingly, a number of chemokine receptors are differentially expressed on effector T cells. We hypothesized that selected T cells accumulate in inflammatory lung diseases involving different pulmonary compartments. To test this hypothesis the frequencies of chemokine receptor expressing T cells were compared in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) of children with chronic bronchitis and interstitial lung diseases. Methods: BAL was performed in 70 children. According to clinical, macroscopic and cytological findings 37 children were selected for the study and classified as chronic bronchitis (CB, n=17, m=7, mean age 6.6 yrs.) or interstitial lung diseases (ILD, n=20, m=13, mean age 7.0 yrs.). Patients (n=33) with other diagnoses or without cells in BALF were excluded. CD4+ and CD8+ T cells were analyzed in PB (n=30) and BALF (n=37) by flow cytometry. The percentages of CCR5+and CXCR3+ cells were determined within each T cell subset. Results are expressed as medians. For statistical analyses non-parametric tests (Wilcoxon, Mann-Whitney U) were applied. Results: In peripheral blood, the percentage of CXCR3+ T cells (16.4%, range: 0-35.2%) was higher than the percentage of CCR5+ T cells (3.9%, range: 0-19.1%; p

Thu, 5 Jun 2003 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/1060/ https://edoc.ub.uni-muenchen.de/1060/1/Pfirstinger_Jochen.pdf Pfirstinger, Jochen

Memory T cells display phenotypic heterogeneity. Surface antigens previously regarded as exclusive markers of naive T cells, such as L-selectin ( CD62L), can also be detected on some memory T cells. Moreover, a fraction of CD45RO(+) ( positive for the short human isoform of CD45) memory T cells reverts to the CD45RA(+) ( positive for the long human isoform of CD45) phenotype. We analyzed patients with biopsy-proven localized Wegener's granulomatosis (WG) (n = 5), generalized WG (n = 16) and age- and sex-matched healthy controls ( n = 13) to further characterize memory T cells in WG. The cell-surface expression of CD45RO, CD45RA, CD62L, CCR3, CCR5 and CXCR3 was determined on blood-derived T cells by four-color flow cytometric analysis. The fractions of CCR5(+) and CCR3(+) cells within the CD4(+) CD45RO(+) and CD8(+) CD45RO(+) memory T cell populations were significantly expanded in localized and generalized WG. The mean percentage of Th1-type CCR5 expression was higher in localized WG. Upregulated CCR5 and CCR3 expression could also be detected on a fraction of CD45RA(+) T cells. CD62L expression was seen on approximately half of the memory T cell populations expressing chemokine receptors. This study demonstrates for the first time that expression of the inducible inflammatory chemokine receptors CCR5 and CCR3 on CD45RO(+) memory T cells, as well as on CD45RA(+) T cells ('revertants'), contributes to phenotypic heterogeneity in an autoimmune disease, namely WG. Upregulated CCR5 and CCR3 expression suggests that the cells belong to the effector memory T cell population. CCR5 and CCR3 expression on CD4(+) and CD8(+) memory T cells indicates a potential to respond to chemotactic gradients and might be important in T cell migration contributing to granuloma formation and vasculitis in WG.

To investigate mechanisms of cell-mediated injury in renal inflammatory disease it is critical to determine the surface phenotype of infiltrating renal leukocyte subsets. However, the cell-specific expression of many leukocyte receptors is difficult to characterize in vivo. Here, we report a protocol based on flow cytometry that allows simultaneous characterization of surface receptor expression on different subsets of infiltrating renal leukocytes. The described technique combines an adapted method to prepare single cell suspensions from whole kidneys with subsequent four-color flow cytometry. We recently applied this technique to determine the differential expression of murine chemokine receptors CCR2 and CCR5 on infiltrating renal leukocyte subsets. In this article, we summarize our current findings on the validity of the method as compared with immunohistology and in situ hybridization in two murine models of nonimmune ( obstructive nephropathy) and immune-mediated ( lupus nephritis) inflammatory renal disease. Flow cytometry analysis revealed an accumulation of CCR5-, but not CCR2-positive lymphocytes in inflamed kidneys, compared to the peripheral blood. Particularly renal CD8(+) cells expressed CCR5 (79% in obstructed kidneys, 90% in lupus nephritis). In both models, infiltrating renal macrophages were positive for CCR2 and CCR5. These data corresponded to immunohistological and in situ hybridization results. They demonstrate that flow cytometric analysis of single cell suspensions prepared from inflamed kidneys is a rapid and reliable technique to characterize and quantify surface receptor expression on infiltrating renal leukocyte subsets.