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How can patients and their families become more integral in the clinical research process? How can patient-led research become more accepted in the scientific community? How are inspiring groups forging new, collaborative paths for science and medicine, and reshaping how medical research is conducted?  We will tackle those questions and much more in this episode with Amy Dockser Marcus, a Pulitzer Prize-winning journalist and author of the recently published book, “We the Scientists: How a daring team of parents and doctors forged a new path for medicine.” Amy is a veteran reporter at the Wall Street Journal and won her Pulitzer Prize for Beat Reporting in 2005 for her series of stories about cancer survivors and the social, economic, and health challenges they faced living with the disease. She has covered science and health at the Journal for years, and she also earned a Masters of Bioethics from Harvard Medical School.  -------------------------------------------------------- Episode Transcript: 00;00;00;00 - 00;00;24;19  How can patients and their families become the centers of research? What is open science and who are citizen scientists? We'll explore those questions and more on this episode of Research and Action in the lead in. Hello and welcome back to Research and Action, brought to you by Oracle Life Sciences. I'm your host, Mike Stiles, and our guest is Amy.     00;00;24;19 - 00;00;48;22  Dr. Marcus That's right, that Amy Marcus, the Pulitzer Prize winning journalist, reporter at the Wall Street Journal, a Pulitzer Prize, was won for her series of stories in 2005 about cancer survivors and the social and financial challenges of living with cancer. Her beat, as you would imagine, has long been science and health. And she holds a master's of bioethics from Harvard Medical School, and she's an author.     00;00;48;22 - 00;01;04;26  Her book is We The Scientists How a Daring Team of Parents and Doctors Forged a New Path for Medicine. So this should be interesting as we talk about collaborative, open science and the rise of citizen scientists and patient led research. So thanks for being with us, Amy.     00;01;05;01 - 00;01;06;22  I'm happy to speak with you today.     00;01;06;22 - 00;01;26;29  Great to have you. In your new book, you take readers through some really, frankly, heart wrenching experiences that patients and their families have gone through with a rare and devastating disease called Niemann-pick. Hopefully I'm pronouncing that correctly. Tell us about the book and that disease and what fascinated you about this story.     00;01;27;14 - 00;02;01;21  The origin of the book really is a personal story, which is my mother got diagnosed with a rare type of cancer. And when I tried to do research on her behalf, I started to learn how challenging it is to develop drugs for rare diseases. After she passed away, I took some time off from the Journal. I had a research grant from the Robert Wood Johnson Foundation and I started traveling around the country looking to see if there were new models that might accelerate drug discovery.     00;02;01;29 - 00;02;25;21  And during the course of that research, I was introduced to a group of parents whose children have this rare and fatal genetic disorder, NIEMANN-PICK type C disease. It's a cholesterol metabolism disorder, so the cholesterol doesn't get out of the lysosome and that compartment in the cell and it starts to build up and it causes all kinds of problems.     00;02;25;21 - 00;02;52;12  And the children eventually lose the ability to walk and to talk and to feed themselves. But the parents that I met wanted to do something novel. They had found a group of scientists and researchers and clinicians and even some policymakers in the government that wanted to work together as partners and to see if they could accelerate the search for a cure or an effective therapy for an epic disease.     00;02;52;19 - 00;02;58;11  And they let me follow along during the course of that partnership for over ten years.     00;02;58;24 - 00;03;05;24  That's amazing that you got that kind of insight. And what did you learn over the course of that ten years?     00;03;06;22 - 00;03;34;15  Well, I was really interested in how they saw the production of science in a different way. They all wanted to try to save or extend the children's lives The disagreements lay in. How do you go about prioritizing drugs? What amount of risk is a patient or a patient's family willing to take compared to the level of risk that a doctor or scientist wants the patients to take?     00;03;34;15 - 00;03;54;14  These sorts of tensions arose, I think, in part because they were modeling a new method of where the patients expertise was considered as valuable or even at the center of this of this project. And that's not usually how it is.     00;03;54;14 - 00;04;09;09  But that's rare, right? I mean, in our in the culture of our health care system, it's not really common that the patients input or the patients families input is invited at all.     00;04;09;19 - 00;04;34;11  Yeah, I think that that you're right about that. I mean, the traditional way of setting things up is that the scientists devise the hypotheses and they then construct trials in conjunction with clinicians and sometimes with pharmaceutical companies, of course. But in this particular collaboration that I was describing, the drug was not in the hands of a pharmaceutical company.     00;04;34;11 - 00;04;59;06  It was widely available. And so the partnership was truly about, you know, going to be conducted at the NIH. And therefore it gave the parent and the families, I think, more leeway to do this experimental idea. What if we all recognized each other's expertise? What if we all saw each other as equal partners? What if we got to weigh in?     00;04;59;13 - 00;05;20;24  Not in once. You've already set up the clinical trial, but at the very, very outset, when you're simply going through the scientific literature to come up with potential compounds, when you're thinking about what might work, when you're trying to prioritize what to do first, second and third, all of those things where patients don't always have a voice. But in this case they really did.     00;05;21;07 - 00;05;43;16  You know, we just had Hilary Hannah Ho on the show. She's secretary general of the Research Data Alliance, and we talked about open science and open data and how important all that is to getting the scientific breakthroughs that will actually help people and get to those breakthroughs faster. But open science can kind of be polarizing. There's some confusion around what exactly it means.     00;05;43;23 - 00;05;48;14  How would you define or describe open science and citizen scientists?     00;05;48;27 - 00;06;34;22  Yeah, I think that's a really good point, that there isn't one sort of accepted name and that there are many names and people use different phrases when they're thinking about different things. For me, I used the term patient LED research and I often use the term citizen science. And what I meant by that was, again, what we've been talking about from the outset, which is a recognition that the patient, the patient experience should be at the center of everything, a recognition that the patient and the families are experts, that they have the ability not only to be beneficiaries of scientific knowledge, but also creators of scientific knowledge.     00;06;34;27 - 00;06;46;15  And to me, that shift the idea that you can be a creator of scientific knowledge is the fundamental one that needs to happen if we're going to really reach the goals that I think we all want to reach.     00;06;46;29 - 00;07;11;10  So here's something we highlighted in your book. Quoting here Science is inherently a social enterprise. Yet too often scientists operate behind closed doors, removed from the very people they intend to help. That's struck me as kind of a mike drop statement with a lot of truth to it. But did the pandemic change anything? Was the work still removed from those patients on ventilators and ICU?     00;07;11;20 - 00;07;52;04  So I do make a point in the book to draw some parallels between the various patient led research movement experiences that I describe and the COVID 19 pandemic, and in particular the group of patients that call themselves long COVID patients, where they're suffering symptoms for many, many months. I argue that COVID allowed us in real time to to recognize that anyone can be an expert and that now that is something that it was easier to see during the pandemic because there was a novel virus, there weren't established experts yet.     00;07;52;14 - 00;08;25;28  And so while doctors and scientists and the government were scrambling to try to help patients, I think they also saw themselves for the first time as part of this effort to understand the disease. Together, there wasn't already an understanding of COVID 19. And so what I say in the book is that we can draw from from that experience and sort of take that part of it forward where we say patients should be at the center of things.     00;08;26;06 - 00;09;07;01  Patients are experts. Patients are able to identify things that many scientists or doctors didn't have time to recognize because they were they had to focus on trying to save lives and, you know, working in a vacuum at that point. So there also was a sense of urgency. Like one of the things that I was struck by during the pandemic as a as a science reporter was that scientists were able to put their papers online right away on these websites before it had gone through the full peer review process because it was recognized is so essential to get this information out there as quickly as possible.     00;09;07;09 - 00;09;29;16  And everyone understood that maybe there were going to be some mistakes. It wasn't fully vetted, but it was out there. Not only was it publicly available to the doctors and scientists who are also studying it, it was publicly available to patients and people who are simply interested. And long COVID patients organized themselves, did research on themselves, and they also published their papers on these websites.     00;09;29;16 - 00;09;43;22  I think those types of models where patient researchers can be contributors and can benefit from the information to fuel their own research, I think that should move forward and is it shouldn't be just a relic of the COVID 19 pandemic.     00;09;44;07 - 00;10;05;03  But what isn't there a risk of chaos a little bit? Because we're always told, hey, whatever condition you have, don't go Googling it on the Internet. You'll just go down a rabbit hole and, you know, worry about all these conditions that you may or may not have. So what is the risk of, like you said, mistakes and wrong information being published?     00;10;05;13 - 00;10;27;11  Well, even the traditional peer review process in science publishes papers that turn out to have mistakes in them. Papers are retracted all the time. And there is a well-known phenomenon that peer reviewed papers sometimes the results can't be replicated. I mean, that's the problem for science. I don't think that's a problem just for having patient researchers get involved.     00;10;27;28 - 00;10;54;27  I also think that the advice not to Google something is both old fashioned at this point and probably unrealistic given that almost all of us are connected in some way through the Internet. My sort of idea, rather, is that let's use the Internet and other methods to become better partners. Let's share good quality information online that people have access to.     00;10;55;06 - 00;11;20;20  Let's form partnerships where we can collaborate, where among experts, the people that I was talking to and interviewing and spending time with the parents, they weren't saying, Hey, we're trying to go it alone. We know everything. No, the opposite. What they were saying is we have very relevant and valuable information. We are experts because we live with this disease and we know what level of risk we're willing to tolerate.     00;11;20;20 - 00;11;43;28  And we do our own research. But we need partners who can also help us fill the gaps where we don't have knowledge. We want to collaborate with scientists, we want to collaborate with clinicians treating our children. We want to collaborate with government scientists who have access to data and and robots and things that we're not going to have in lab equipment that we don't have access to.     00;11;44;06 - 00;12;02;19  So no one's saying, go down a rabbit hole by yourself. What people are arguing is let's find ways to pool information, and by pooling everyone's information, we can sort through more quickly what's good, what we think is good, but might turn out not to be good later. And what can benefit all of us.     00;12;03;04 - 00;12;20;02  Yeah, and from a technology standpoint, gathering that data and organizing it and working with it is becoming more possible than ever. COVID should have scared our health system out of its mind. Did it? And is that leading to any systemic changes in science and health?     00;12;20;15 - 00;12;46;19  Well, I'd like to focus on what my book was focusing on, which is can a group of patient activists and scientists and clinicians and government policymakers working together make changes to the system? And I think the answer is yes. You can make changes to the system. The patient researchers that I was talking to and the families I was talking to, they built on activist patient work that had gone before.     00;12;46;19 - 00;13;10;06  And there have been responses in the past. HIV activists were able to influence the FDA to pass the accelerated approval rule that now allows drugs to be approved more quickly. And I think that, you know, compassionate use program that FDA has the patients in my family, the patients in my book and the families benefited from that as well.     00;13;10;17 - 00;13;48;01  So there have been changes along the way. But I think what my book is arguing for, and I think this message came out of the COVID 19 pandemic as well, is that even with all the changes that have been made in the past, the patient experience is still not at the heart of the system. And I think that's the message that all of these families are saying put the patient experience at the heart of things, and then you will see that the system, when you configure the system around the patient centric experience, you'll see that it will work in a different way and an I think, a better way.     00;13;48;02 - 00;13;50;02  But we need to run that experiment.     00;13;50;17 - 00;14;12;20  So we mentioned the concept of citizen scientists. That's what we've been talking about. These are people that pursue what they pursue, driven by mostly love and urgency for their kids, which is just a whole different level of motivation than most researchers have. I think you have a few stories about, you know, people like Chris and Hugh Hempel and and some others that went through this experience.     00;14;13;02 - 00;14;34;21  I want to make a point here that I think also is really important for people to understand who are listening to this. The parents in my book and you know, you cited Chris and Hugh, they were definitely among the pioneers who did this. And there was Phil and Andrea Morella, and there were also Darrel and Mark Poppea who are who are part of this, too.     00;14;34;21 - 00;14;57;29  And many, many other parents. I mean, the Parseghian Research Foundation and the National Niemann-pick Disease Foundation, all family driven. The people who are doing this. Yes, they are driven by their love of their children. They are driven by a sense of urgency. But they're not going to the FDA and saying, Hey, please pass and approve a drug because we love our children.     00;14;58;05 - 00;15;24;05  Please pass and approve a drug based on our emotion. No, not at all. They want to give effective drugs to their children. What they are saying is we are creating scientific knowledge and we think that that should be part of this approval process, that should be part of the drug development process. I just want to give some examples that I cite in the book where the parents were creators of scientific knowledge.     00;15;24;24 - 00;16;07;11  You had parents who read the scientific literature, published scientific literature, called up. The scientists interviewed the scientists came up with hypotheses themselves that they proposed to scientists, contributed to the two scientific experiments, coauthored papers that were published in the peer reviewed scientific literature. You know, went to the NIH regularly to have meetings where they helped contribute to assessing and prioritizing which compounds should go first in terms of advancing them into clinical trials, contributed their thoughts on the risk benefit analysis in devising the clinical trials.     00;16;07;22 - 00;16;34;28  One of the parents went to an FDA sponsored workshop for how to file an orphan drug designation, which is part of the approval process and the long process to getting approval for rare disease drugs. And went to the workshop, participated in the workshop, presented scientific data to the regulators, met with the regulators, and earned an orphan drug designation for one of the compound Cyclodextrin that got moved forward.     00;16;35;07 - 00;16;46;24  So yeah, they have a sense of urgency and yes, they love their children and want to save their lives, but they're producing real scientific knowledge and I really hope that that people take that message away from reading the book.     00;16;47;10 - 00;17;08;15  So those are great examples of exactly what citizen scientists do that sets them apart from just patients who are not doing that level of research, that depth of research. You talk about Chris Austin and the book, and I'm going to read another quick excerpt here, The Promise of Genetics to Deliver new interventions, new drugs and new treatments for patients is not going to happen.     00;17;08;15 - 00;17;27;28  Chris told his boss, unless there's some way to get through the valley of death. Francis gave Chris a green light to pursue his vision. So the boss in that excerpt is former National Institutes of Health director Francis Collins. What is the Valley of Death and Chris's role in citizen led research?     00;17;28;06 - 00;17;54;21  Great. No, that's a great question. So Chris Austin is a Harvard Medical School trained neurologist, also with a background in genetics who worked at pharmaceutical companies as well, and then found his way to the niche where he worked for Dr. Collins and became also a director of one of the institutes at NIH called Ed Katz, the National Center for Advancing Translational Science.     00;17;55;06 - 00;18;23;29  And one of the sort of green lights he got from Dr. Collins was to set up a lab that would have robots that were sort of at the same type of robots that pharmaceutical companies have that would work around the clock and could rapidly screen drugs to try to find compounds that might work for diseases. And what Chris Austin's idea was is that let's screen these vast libraries.     00;18;24;04 - 00;18;50;06  Let's find some drugs that might be promising, and let's also find patient partners. Let's find scientist partners, and let's then try to take all this data and move it forward together. One of the hypotheses that Chris Austin said he had as a scientist was can drug development go faster if patients and families are part of that process from the very beginning?     00;18;50;18 - 00;19;17;02  And one of the things that Chris Austin was trying to get around is this valley of death, which is this, you know, where compounds kind of go to die. You have a great idea as a scientist. But how do you get that idea from the bench to the clinic and to a patient's bedside? And the Valley of Death is just all the various obstacles that end up making it hard to develop a drug.     00;19;17;13 - 00;19;39;21  Some of it can be scientific. You know, you test it in a in a mouse or an animal, you test it in the lab and it turns out to be toxic for the cells or the amount of drug that you need to give to a person is so high it's not realistic or a drug company decides they want they don't want to put any money into it anymore or it gets or a drug company gets bought and they don't want to pursue it anymore.     00;19;39;21 - 00;20;02;08  And there's a million things that happen in the Valley of Death. But Chris Austin's vision was if we can involve patients and families as partners, along with scientists and drug developers and government officials from the beginning, maybe we can get things out of the Valley of Death, or maybe we can fail faster and find the successful compounds more quickly.     00;20;02;25 - 00;20;22;23  Yeah, a big takeaway from your book is the need to build bridges between science and citizens. But and we talked touched on this a little bit. You can't sacrifice scientific rigor or safety. So what are the challenges to building these bridges? What's holding that process back, especially when it does come to drug discovery and clinical trials?     00;20;23;09 - 00;20;47;05  So I think that there is a variety of issues that make it challenging to build bridges. For one thing, there's often a tension between, you know, people who are sick or are advocating on behalf of people who are sick, who really want to focus on the here and now. They they really need something to help their loved one right now.     00;20;47;19 - 00;21;22;19  And often, you know, clinical trials are an experiment. And when you enroll in a clinical trial, you're told this is not designed for the benefit of you. This is designed to benefit future patients. And therefore, it's not a treatment and it's not the equivalent of clinical care. And that can be a source of frustration and tension. And often also when research crews are doing research, they weigh the risk benefit assessment of moving drugs forward differently than people who are trying to you know, solve a problem now.     00;21;23;00 - 00;21;48;14  So I think that and that came up in this partnership in my book. It came up in this partnership in my book a lot. And yet I think each side was able to get a sense of what the points were, what the what the tensions were. But again, in my opinion, one of the ways that they overcame this divide was by both sides saying patient centric medicine is the way to go.     00;21;48;15 - 00;22;16;29  Patient centric science is the way to go. There are ways to collect data in a rigorous manner that can both benefit patients now and also not stop you from insights that will lead to benefits in the future. There are ways to come to terms with that. Some people have a higher acceptance of risk than others. I mean, we see movement towards that already right now.     00;22;17;01 - 00;22;23;01  I think that one of the messages of my book is to try to accelerate that even further.     00;22;23;25 - 00;22;37;19  Well, to that point, you say in the book, government and agencies like the FDA and NIH have a vested interest in helping these science and citizen partnerships succeed. Do they understand that? And what role should government be playing to move this forward?     00;22;38;01 - 00;22;57;01  Well, government is not one person. You know, so but I think that the book shows that there are people in the government who were partners with the patients and the families and the scientists and the clinicians. I mean, this whole book is about a partnership. And Chris Austin, although he's no longer in the government, he left the government.     00;22;57;10 - 00;23;28;05  He was in the government at the time, and he was a partner with these people. So I think that the government has shown in the book that, you know, and outside of my book, obviously interest in investing in new ways to do science, interest in investing in new ways to accelerate science, the government is supposed to represent the interests of the people, and the people's interest is in being healthy and in and trying to find solutions for drugs.     00;23;28;14 - 00;23;56;15  So in the book, I do talk about how the patients and the families in my book were able to directly talk to FDA regulators. Some of the parents went to workshops that the FDA was sponsoring. They had conversations with FDA regulators. I think those types of workshops are really novel and they really are fruitful because they allow the families and the patients to really think like scientists and to produce science as they can and should do.     00;23;56;16 - 00;24;21;16  They want to produce science. And I think also one of the messages that Chris Austin gave at representing the NIH was that the NIH is here to be your partner, and we're open to coming up with novel ways of accelerating science. So I think that there's there's openness to doing this, but of course, always more can be done.     00;24;21;17 - 00;24;51;16  I mean, patients have a sense of urgency, and that's the message that they bring to the government all the time. I mean, in the book, I, I describe FDA advisory committee hearings that are held when the FDA isn't sure about the data and they want to have a public hearing about it. And many of the parents and families showed up and gave testimony not just about their thoughts and their opinions, but about the data that they had gathered, the science that they were generating, that they wanted to share with the FDA and be heard.     00;24;52;00 - 00;25;16;13  What role does Rules Framework's guidelines play and what we're talking about here? I think you even your former advisor, was part of a group of scientists that worked on this framework. And the platform for patient led research, I think was spearheaded by that advisor, former advisor and a group of scientists. What's the infrastructure that needs to be put in place for this to work?     00;25;17;08 - 00;25;46;03  So, yes, So the advisor that you were referring to, Effie Diana was my advisor in my bioethics program and she does a lot of pioneering research on patient led research movements. And she and a group of collaborators, scientists and, and social scientists and clinicians and, and policymakers got together and tried to devise what they called a new social contract.     00;25;46;13 - 00;26;14;17  What they argued is, is that patient led research is a novel form of research that doesn't fit into the traditional regulatory standards that have guided, you know, clinical trials and human subjects research up until now. And that's because the traditional methods of regulation are based on the idea that scientists are going to be leading the research and doctors are going to be leading the research.     00;26;14;26 - 00;26;42;04  And that still is the traditional model. And they usually are leading the research. And in those cases, they often have more information and more power than the traditional patient or human subject. So Effie and her collaborators weren't arguing. We're arguing that the traditional rules should be thrown out because obviously patients do need protection and human subject research does need regulatory guidance.     00;26;42;11 - 00;27;17;26  But what she and the others were saying is let's also think about these new ways of doing research and how we can get scientists and clinicians to accept the results. That patient led research arrives at. And one of the ways she and the others said is let's come up with ways that patient researchers can seek ethical guidance. Let's put tools online that they can use so that they can devise experiments in ways that approach the rigor that traditional scientific experience experiments do.     00;27;18;06 - 00;27;52;04  Let's generate research that's of benefit to the people now, but also can be useful in guiding treatments in the future. Let's make a path towards publishing their data in peer reviewed journals. Let's make them part of the peer review process. I mean, you do have journals now that have patient researchers participating in peer review of scientific papers. And you have groups like Pachauri that ask scientists and patients to collaborate together on experiments.     00;27;52;13 - 00;28;24;24  So I think I think what she and the others were getting at is the current contract that we have may still be fine in certain circumstances, but isn't set up to address this new kind of research that's being done. And if we want it to be generalizable, scientific knowledge, which is always the gold standard, then we need to work together to help all of the partners to do better research that meets the standards that we can all except.     00;28;25;09 - 00;28;40;27  When you kind of make the promise of patient led research obvious. But, you know, how many times do we see things with great promise get tied up in knots? Is a paradigm shift likely? And if so, how long of a runway is that going to need?     00;28;41;15 - 00;29;01;11  I mean, I don't know how long it's going to take, but if there is a message in my book, if there is a message from the people that I focused on in my book, I mean, they've been working together for more than ten years. They've made a lot of progress, but they're not where they want to be yet.     00;29;01;20 - 00;29;23;29  So that's a long time. And I think that they want to go faster. I think the message of long COVID patients is we need to go faster. I think the message of HIV activists and breast cancer activists and disability activists is we need to go faster. And I don't think that you need to change a paradigm in a day.     00;29;24;12 - 00;29;53;19  Paradigms, by definition, take time to change, and they involve a lot of debate and discussion, dissension. And that's what happens in a society. People have different, different views. But I think what we're getting at here as a society is that patients need to be at the center of any paradigm that exists and that if everyone works together towards that goal, they may not agree how to get to that.     00;29;53;24 - 00;30;14;21  They may have different ideas on how to ensure that the science is rigorous and works. But if they keep this notion always at the center that the purpose is, is patient centered science, then I do think that you can end up with a paradigm that works better for more people.     00;30;15;16 - 00;30;27;10  One of the chapters in your book is Cathedral of Science, and in it a professor at Harvard. Had you read the story Cathedral by Raymond Carver. Why did they have you read that? And how does that relate to what we've been talking about?     00;30;28;04 - 00;30;55;26  Yeah, I mean, I say in the book that when we were told to read Cathedral by Raymond Carver, I was really surprised because usually in in my bioethics classes when we talk about stories and narrative bioethics, many of them involve sort of cases drawn from real life and cathedrals, really a quiet story that involves a married couple that seems to be drifting apart.     00;30;56;06 - 00;31;16;24  And the wife invites a friend who happens to be a blind man to come and stay with her and her husband. And the husband's a little bit jealous of the relationship that this person has with his wife and he doesn't really know what to say to him. And the wife goes to sleep and leaves these two men alone watching TV together.     00;31;17;00 - 00;31;38;19  And they start to watch a program about the building of a cathedral. And the narrator says to the blind man, Have you ever seen a cathedral? Do you know how to build a cathedral? And the blind man says, Let's draw one together. And the two of them construct a cathedral together. The man places his hand on the husband's hand, and they draw that cathedral.     00;31;38;27 - 00;32;01;23  And at the end of creating this cathedral, it's the blind man who says, Let's put some people inside, inside the cathedral. What's a cathedral without people? And I thought about this story all the time as I was spending time with the families and the scientists, because so many of the scientists were products of the Cathy trial of science.     00;32;01;23 - 00;32;34;13  They were the products of the best medical schools. They worked at the NIH. They I mean, they they really were, you know, part of this edifice that's been constructed and that has benefited so many people. And one of the things I kept thinking about is how do we put more people in this cathedral? I mean, that's really one of the messages that came through in this partnership that the parents and families and scientists and doctors and government officials were constructing a cathedral without people isn't really what you're looking for.     00;32;34;20 - 00;32;52;05  You're you're looking to use the power of science and research to help people. That's should be the goal of everything. And that's really the message I took from this story, that it touched me in just such a fundamental way. And it wasn't even a story about science.     00;32;53;27 - 00;32;57;18  As literature often does. That inspires us in many different ways.     00;32;57;21 - 00;32;58;20  Absolutely.     00;32;58;27 - 00;33;20;02  What did I miss? I mean, what is it that our listeners should know that you cover in the book that's important for them to know or some way that they can help or participate in this kind of effort? Or is there something that a follow up book might cover, something that you think needs additional exploration?     00;33;20;11 - 00;33;53;25  Well, I mean, I think that the message of the book is that we can all be scientists, right? I mean, it's in the title. We, the scientists, and I chose a title that echoes We the People, because I wanted people to think about the fact that what works best is a partnership. What works best is when we all come together and try to bring our different visions forward and to come up with something that will benefit all of us.     00;33;54;07 - 00;34;15;25  I think, you know, one of the things that I was struck by during during the research, not only for this book, but also when I, you know, covering health and science as a reporter is that all of us really are patients. We're either patients now or we were in the past or we will be in the future, or we love people who are patients.     00;34;16;04 - 00;34;50;28  We're advocates for those people, even if we're a doctor or a scientist, we're often on the other side of the table either trying to advocate for people we love or because we're patients. And so I think we all have a vested interest in creating a system that works well for all of us that remembers that we need treatments and that we that we need science and that all of us are experts in our own lives and that we can do research in a way that can contribute to advancing health and wellness for us all.     00;34;50;29 - 00;34;56;00  So I feel like that's the message that I hope is the takeaway of the book.     00;34;56;12 - 00;35;03;10  Well, I'm pretty sure there are listeners who are interested in the book and getting it or getting in touch with you. How can they do that?     00;35;04;00 - 00;35;26;00  So there are a variety of ways to get in touch with me. My email is publicly available. It's Amy Marcus at WSJ dot com. I'm on Twitter at Amy D Marcus. You can go into the bookstore and get the book, you know, in person, or you can order it online. You can get it from bookshop. You can get it from Powells.     00;35;26;00 - 00;35;32;18  You can get it from Amazon, Barnes and Noble. I mean, they're, you know, any, any, any place online. You can order the book.     00;35;32;26 - 00;36;03;05  Great. We appreciate that. And we want to thank you for being faithful listeners to Oracle Life Sciences, Research and Action. As always, we invite you to subscribe so you don't miss a single episode. And also maybe tell your friends and colleagues about the show as well. And we'll be back next time with more research and action.

For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·Jubilee website·PrevMed's website·PrevMed's YouTube channel·PrevMed's Facebook page·PrevMed's Instagram·PrevMed's LinkedIn·PrevMed's Twitter ·PrevMed's Pinterest

This podcast covers CycloDextrin. It's a new medication that dissolves cholesterol crystals. And it stimulates LXR -related genes. It's actually been shown clearly in lab mouse models to dissolve plaque. It hasn't been used in humans yet. But it has been shown to stop human immune cells from attacking plaque, again by the LXR pathway. For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·PrevMed's website·PrevMed's YouTube channel·PrevMed's Facebook page 

TWiM reveals a potential mucus-busting weapon for patients with cystic fibrosis, and bacteria in the intestinal tract that can oxidize cholesterol, leading to lower levels of the lipid in blood. Subscribe to TWiM (free) on Apple Podcasts, Google Podcasts, Android, RSS, or by email. Become a patron of TWiM. Links for this episode Biofilm eradication with nitric oxide release (ACS Inf Dis) Pseudomonas quorum sensing network (Protein) Cholesterol metabolism by gut bacteria (Cell Host Microbe) Microbes might manage your cholesterol (Harvard Gazette) TWiM Listener survey Send your microbiology questions and comments (email or recorded audio) to twim@microbe.tv

https://www.einstein.yu.edu - Determined to find a treatment for children with the degenerative brain disease Niemann-Pick Type C, Steven Walkley, D.V.M., Ph.D., turned a serendipitous laboratory discovery into a successful national research collaboration with other academic institutions and the National Center for Advancing Translational Sciences' program for rare diseases (Therapeutics for Rare and Neglected Diseases). These efforts led to an NIH Phase 1 clinical trial testing cyclodextrin as a therapy for children with this disease. Dr. Walkley is a professor in the Dominick P. Purpura Department of Neuroscience and director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center at Albert Einstein College of Medicine.

Eine Glomerulonephritis kann durch eine virale Infektion verschlechtert werden, sie kann aber auch erst durch diese entstehen. Die Erkennung der viralen Bestandteile erfolgt über Pathogenerkennungsrezeptoren, wie beispielweise Toll-like Rezeptoren und RIG-like Rezeptoren. Die Hypothese der vorliegenden experimentellen Arbeit war, dass die nierenspezifischen Podozyten Pathogenerkennungsrezeptoren besitzen, die pathogen-assoziierte molekulare Muster erkennen und daraus Zytokine und antivirale Typ-I Interferone produzieren. Hierbei könnten Podozyten zu der Entstehung bzw. Veschlechterung einer virusassoziierten Glomerulonephritis beitragen. Murine Podozyten exprimieren, mit Ausnahme des Toll-like Rezeptors 8, alle bis dato bekannten Toll-like Rezeptoren (TLR-1 bis -11) in verschiedener Ausprägung. Sie exprimieren außerdem die zytosolische Rezeptoren RIG-1, MDA-5, DAI sowie deren Adaptermolekül IPS-1. Die Aktivierung dieser Rezeptoren verursacht die Produktion von Zytokinen und Typ-I Interferonen. Um die intrazelluläre Aufnahme der Nukleinsäuren zu gewährleisten, wurden diese mit kationischen Lipiden komplexiert. Dieser Vorgang wurde durch Cytochalasin D, Chlorpromazin und Methyl-β-Cyclodextrin unterbrochen. Daraufhin ergeben sich die Phagozytose, die Clathrin-abhängige Endozytose und die Caveolae-vermittelte Endozytose als mögliche Transportmechanismen. Das Adaptorprotein MyD88 zeigte bei Podozyten keine Bedeutung für die Nukleinsäureaufnahme in die Zelle zu besitzen. Die Stimulation von Podozyten mit Typ-I Interferonen veranlasste die Produktion von großen Mengen an Interleukin-6 und führte zu einer starken Expression von Pathogenerkennungsrezeptoren sowie proinflammatorischen Zytokinen auf Transkriptionsebene. Eine autokrin-parakrine Aktivierung der Podozyten durch ausgeschüttete Typ-I Interferone konnten wir ausschließen. Weder die Durchlässigkeit für Albumin noch die Viabilität der Zellen wurde durch die Aktivierung von Pathogenerkennungsrezeptoren beeinflusst. Eine Funktionseinschränkung der Podozyten nach Stimulation der TLRs oder RLRs im Sinne eines direkten Einflusses auf die Permeabilität oder die Fußfortsatzzahl fand sich nicht, jedoch zeigten Podozyten eine vermehrte Zytokinproduktion, was zur glomerulären Entzündung bei viraler Glomerulonephritis beitragen könnte.

Cyclodextrin podcast from Chemistry World - the magazine of the Royal Society of Chemistry

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The use of carbohydrates as ligands in coordination chemistry is an important area of research with many potential applications. Few studies have been done on the complexation behaviour of main group metals under aqueous conditions. In this thesis the complexation of carbohydrates in the presence of tin(IV) and lead(IV) central metals in aqueous solution was studied. Tin(IV) was investigated using 119Sn NMR techniques. It could be shown that a mixture of hexahydroxidostannate and the threefold amount of ethanediol forms a mixture of heteroleptic mono- and bis- (ethanediolato)hydroxidostannates and homoleptic tris(ethandiolato)stannate. In contrast to these observations, the threefold amount of beta-cyclodextrin with hexahydroxidostannate(IV) showed a single signal, whose chemical shift indicates a new, hexacoordinate, tin-containing species. When using lithium as a counterion, crystals suitable for X-ray diffraction grew over the course of one week. The results from the structural analysis were consistent with the spectroscopic results and show a supramolecular assembly with threefold rotational symmetry that consists of three components: three beta-cyclodextrin dianions, three tetrahedral tetraaqualithium cations and the tetravalent metal center. Attempts to prepare chelates using lead(IV) as the central metal by adding potential chelators such as oxalate, catecholate, or glycosides to hexahydroxidoplumbat(IV) solutions result in the formation of decomposition products. Surprisingly, beta-cyclodextrin could avoid decomposition and formed single crystals. X-ray analysis of the product showed lead(IV) complexed by three cyclodextrin dianions isotypic to the tin(IV)-cyclodextrin complex. It is the first described carbohydrate-lead(IV) complex. It could be shown, that the functional groups of the oligosaccharide cyclodextrin are able to assemble into a nanoscaled trimer that provides a mononuclear binding site for high valent metal centers. These findings may be helpful to develop other cyclodextrin-metal complexes with metals which show catalytic activity. One possible use for the developed system could be the treatment of heavy-metal-contaminated water.

Wie die im Rahmen dieser Arbeit röntgenographisch charakterisierten Verbindungen 1–3 zeigen, sind mit Blei(II) und Nucleosiden sowohl anionische Bis-diolato-plumbate(II) wie der Adenosin-Komplex K2[Pb(AdoH- 2)2] · 11 H2O (1) als auch koordinations polymere Blei(II)- diolat-Komplexe zugänglich. In den Adenosin- und Cytidin- Diolat(2- )-Komplexen [Pb(AdoH- 2)] · H2O (2) und [Pb(CytH- 2)]2 · 9 H2O (3) werden zwei unterschiedliche Verknüpfungsmuster der Blei(II)-diolat-Einheiten über Pb2O2-Vierringe verwirklicht. Der polymere Aufbau des Adenosinats 2 läßt sich als eindimensionaler Ausschnitt aus der orthorhombischen PbO-Struktur beschreiben; in dem Cytidinosat 3 bildet das Koordinationspolymer dagegen eine ungewöhnliche schraubenartige Struktur aus. Mit Blei(II) und a- oder b-Cyclodextrin als Liganden sind neben mehrkernigen Polyolat- Komplexen auch mehrkernige anionische Polyolato-plumbate(II) zugänglich. In den Kristallen von 5, 6, 9, 11–17 baut das cyclische Oligosaccharid als zwölf- bzw. vierzehnfach deprotonierter Ligand mit Blei(II)-Ionen sandwichartige Zwölf- bzw. Vierzehnkernkomplexe auf. Die zwei Cyclodextrinato-plumbate(II) Ca7[Pb7(b-CDH-14)2] · 53.41 H2O (4) und Na2[Na2Pb10(a-CDH-12)2] · 29.2 H2O (7) zeigen, daß zusammen mit Blei(II) auch andere Ionen mit vergleichbaren Ionenradien in die Doppeltori eingebaut werden können. In Na2[Na2Pb10(a-CDH-12)2] · 29.2 H2O (7) und [Pb12(a-CDH-12)2] · Li2(bdc) · 20 H2O (10) werden die Doppeltori über Alkali-Ionen zu einem dreidimensionalen Netzwerk verknüpft. Im Rahmen dieser Arbeit konnten erstmals Blei(II)-Cyclodextrinat-Einlagerungskomplexe mit verschiedenen aromatischen Gästen strukturell charakterisiert werden. Die Verbindungen 11– 17 sind isotyp zu dem entsprechendem freien Wirt [Pb12(a-CDH-12)2] · 21 H2O (6) bzw. [Pb14(b-CDH-14)2] · 18 H2O (5). Dagegen zeigt das Blei(II)-Cyclodextrinato-plumbat(II) Pb[Pb12(a-CDH-12)2] · (bdc) · 35 H2O (9) ein für Cyclodextrin-Strukturen völlig neuartiges Verknüpfungsmuster: über ein dreizehntes Blei(II)-Atom werden die Doppeltori zu endlosen eindimensionalen Koordinationspolymeren verknüpft. Die Strukturen von 9–14 belegen, daß in Blei(II)-a-CD-Komplexe sowohl anionische Gäste wie Biphenyl-4,4’-dicarboxylat als auch ungeladene, unpolare Gäste wie Benzol oder 1-substituierte bzw. 1,4-disubstituierte Benzol-Derivate eingelagert werden können. In 9 und 10 bildet das eingelagerte Biphenyl-4,4’-dicarboxylat zwei verschiedene Wasserstoffbrückenbindungssyteme zu den O6-Hydroxy-Funktionen des Wirtkomplexes aus. Für Blei(II) und b-CD wurde die Einlagerung unpolarer Gäste wie Benzol, Toluol und Ferrocen beobachtet. Während in den a-CD-Komplexen des Typs [Pb12(a-CDH-12 )2] · Ar (mit Ar = Benzol, Toluol, p-Xylol, Chlorbenzol) 11–14 die eingelagerten Aromaten die erwartete Orientierung orthogonal zur Blei-Ebene zeigen, weisen die Gäste Benzol und Toluol in den b-CD-bis-Aryl-Komplexen [Pb14(b-CDH-14)2] · (Toluol)2 · 22 H2O (15) und [Pb14(b-CDH-14)2] · (Benzol)2 · 24 H2O (16) eine ungewöhnliche Orientierung parallel zur Blei(II)-Ebene auf. In [Pb14(b-CDH-14)2] · (FeCp2) · 23 H2O (17) wurden für den Gast-Komplex Ferrocen zwei symmetrie unabhängige Lagen bestimmt, die unterschiedliche Orientierungen gegenüber der Blei(II)-Ebene einnehmen. Eine der Ferrocen-Lagen ist senkrecht zur Blei-Ebene ausgerichtet, während die andere Ferrocen-Lage im Inneren des Doppeltorus fast parallel zur Blei- Ebene liegt. Das eingelagerte Ferrocen zeigt wie freies Ferrocen ekliptische Konformation. Durch die Ausbildung der sandwichartigen Blei( II)-Cyclodextrin-Komplexe wird in allen vorgestellten Strukturen eine head-to-head-Anordnung der Cyclodextrinringe erzwungen. Die Packung der Doppeltori in den a-CD-Komplexe 10-14 kann als channel-type beschrieben werden. Entlang der b-Achse existieren aufgrund der Stapelung der Doppeltori endlose Kanäle, wobei die entlang [001] gestapelten Schichten gegeneinander verschoben sind. In den b-CD-Komplexen 15-17 tritt ein ähnliches Packungs muster auf, allerdings sind hierbei sowohl die Doppeltori-Stapel als auch die Blei-Ebenen gegeneinander verkippt. Die Packung der Blei( II)-b-CD-Stränge in dem Blei(II)-plumbat 9 entspricht dem herringbone-type. Mit racemischen a-Hydroxycarbonsäuren bilden Zinn( II) und Blei(II) 1:1-Komplexe durch Koordination des Metallzentrums über ein O-Atom der Carboxylatgruppe und das a- Hydroxy-O-Atom unter Bildung von Chelatfünfringen aus. 18–21 besitzen im Kristall ein- oder zweidimensionalen polymeren Aufbau. Während 18 und 20 Koordinationspolymere bilden, werden in [Sn(rac-mal)]2 (19) die Zinn( II)-malat-Dimere über lange Sn–O-Kontakte sowie durch intermolekulare Wasserstoffbrückenbindungen zwischen den Hydroxy-HAtomen und den jeweils nicht an Zinn(II) koordinierenden Carboxylat-O-Atomen zu Doppelsträngen verknüpft. In [Pb(rac-mal)] · 2 H2O (18) und [Sn(rac-lacH- 1)] (20) erfolgt dagegen die Bildung von Koordinations polymeren durch inversionssymmetrische, planare M2O2- Vierringe, dabei koordiniert jede a-Hydroxycarbonsäure an je drei Metall-Zentren. In dem Dihydrat 18 werden die Blei-malat(2-)Stränge über Wasserstoffbrückenbindungen zu entlang [100] verlaufenden Schichten verknüpft. In dem kristallwasserfreien [SnCl(amyg)] (21) bestehen zwischen den O2-Hydroxy-H-Atomen und Carboxylat-O-Atomen intermolekulare Wasserstoffbrückenbindungen; durch lange Sn–Cl-Kontakte werden gewellte Schichten aus Sn2Cl2-Vierringen aufgebaut. Der Cluster Sn6(OMe)3(O)4Cl (22) kann als ein Zwischenprodukt der Hydrolyse von Dimethoxy-Zinn(II) angesehen werden. Er besteht aus einem adamantanartigen Sn6O4-Gerüst sowie dreifach verbrückenden Methoxygruppen. Bei Einbeziehung des freien Elektronenpaars ergibt sich verzerrt trigonal-bipyramidale Koordination am Zinn(II).

In dieser Arbeit werden neue Kohlenhydrat-Komplexe mit Palladium(II) und Kupfer(II) beschrieben. Die Verbindungen mit Palladium(II) werden durch ein- und zweidimensionale NMR-Spektroskopie in Lösung und durch Einkristall-Röntgenstrukturanalyse identifiziert, während Verbindungen von Kupfer(II) durch ihre Redoxstabilität in Lösung und Einkristall- Röntgenstrukturanalysen charakterisiert werden. Besonderes Augenmerk wird in dieser Arbeit auf Metallkomplexe mit reduzierenden Zuckern gelegt, denn hier existierten noch keine strukturell charakterisierten Komplexe mit Kupfer(II) oder Palladium(II). Strenge Regeln für die Koordination von Zuckeralkoholen in Pd-en konnten mit Hilfe der 13C-NMR-Spektroskopie ausgearbeitet werden. Hierbei wurde zum ersten Mal eine Koordination von zwei Pd(en)-Fragmenten in einer Threit-Teilstruktur bei der Verbindung mit dem Zucker-alkohol Xylit 1 röntgenstrukturanalytisch nachgewiesen. Es wurden Lösungen von Palladium(II) mit reduzierenden Zuckern stabilisiert. Dabei wurde die Röntgenstruktur der in Pd-en entstehenden Metall-koordinierten Verbindungen von rac-Mannose 2, D-Arabinose 3, D-Ribose 4, D-Glucose 5 und D-Galactose 6 aufgeklärt. Die Strukturen 3–6 sind die ersten Kristallstrukturen von Metall-Komplexen dieser reduzierenden Zucker. Auch konnte das erste Mal ein Metallkomplex mit einem reduzierenden Zucker in der Pyranose-Form strukturell charakterisiert werden. Die Lösungen dieser Zucker in Pd-en wurden mit Hilfe der zweidimensionalen NMR-Spektroskopie untersucht und der Anteil von den jeweiligen verschiedenen vorhandenen Konfigurationen der Zucker in Lösung bestimmt. Neue [(RNH2)2Pd(OH)2]-Reagenzien wurden synthetisiert, wobei die beiden Amin- Liganden im Gegensatz zum bisher untersuchten [(en)Pd(OH)2] durch keine Alkylbrücke verbunden sind. Ihre Koordination an Polyole wurde mit Hilfe der Röntgenstrukturanalyse charakterisiert, wobei Strukturen von Pd-NH3 mit Erythrit 7 und von Pd-MeNH2 mit Dulcit 8 bestimmt wurden. NMR-spektroskopische Untersuchungen zeigten, dass die Anbindung an Zuckeralkohole analog dem Pd-en erfolgt. Dies ist jedoch nicht mehr der Fall, wenn der Platz für die Anbindung an Kohlenhydrate geringer ist. So konnte gezeigt werden, dass der sterische Anspruch der [(RNH2)2Pd(OH)2]-Reagenzien in der Reihe Pd-en ≈ Pd-NH3 < Pd-MeNH2 < Pd-iPrNH2 deutlich steigt. Während reduzierende Zucker stets an zwei Pd(en)-Fragmente anbinden, binden sie meist nur einmal an Pd(iPrNH2)2-Fragmente an. Dabei erfolgt die Koordination stets über O1 und O2. Dieser steigende Platzbedarf zeigt sich auch in Komplexen mit Cyclodextrinen. Hier konnten erstmals heteroleptische Metall-Komplexe von Cyclodextrinen mit Palladium(II) strukturell charakterisiert werden. Sowohl mit α-Cyclodextrin und Pd-NH3 bzw. Pd-iPrNH2 als auch mit γ-Cyclodextrin und Pd-iPrNH2 (Strukturen 9–11) erhält man Strukturen, bei denen jede zweite Anhydroglucose-Einheit an Palladium anbindet, wobei die nicht-koordinierenden Hydroxy-Gruppen O2-H und O3-H intramolekulare Wasserstoffbrückenbindungen zu den deprotonierten Alkoxy-O-Atomen benachbarter Anhydroglucose-Einheiten ausbilden. 13CNMR- Spektren ergaben hier für Pd-en und Pd-NH3 in Lösung Gemische, die auf Spezies hinweisen, bei denen mehr als jede zweite Anhydroglucose-Einheit an Palladium koordiniert. In Lösungen mit Pd-iPrNH2 wurden lediglich die kristallisierten Spezies gefunden. Beim Versuch, ungewöhnliche Polyol-Strukturen mit Palladium-Zweikernkomplexen zu stabilisieren, wurden die neuen Komplexe Dihydroxy-µ-oxo-[1,3-bis(2’-(dimethylamino)- ethyl)-hexahydropyrimidin]-dipalladium(II), Dihydroxy-µ-oxo-[1,3-bis(2’-(dimethylamino)- ethyl)-imidazolidin]-dipalladium(II), Tetrahydroxy-[N,N´-bis(2-(dimethylamino)ethyl)-α,α´- diamino-p-xylol]-dipalladium(II) und Tetrahydroxy-[N,N´-bis(2-(dimethylamino)ethyl)-α,α´- diamino-m-xylol]-dipalladium(II) hergestellt. Die ersten beiden aufgeführten Komplexe stabilisieren Polyolato-Komplexe mit Palladium(II) in einer Pd2-µ-Triolato(3−)-Koordination, wobei jeweils die Verbindungen mit Dulcit [(C12H28N4)2Pd4(DulcH−6)] ⋅ 2 Cl ⋅ 16 H2O (12) bzw. [(C11H26N4)2Pd4(DulcH−6)] ⋅ 2 Cl ⋅ 16 H2O (14) strukturell charakterisiert wurden. Die langsame Oxidation von Galactose in Lösungen des erstgenannten Komplexes führte zur Kristallisation des Galactonsäure-Komplexes [(C12H28N4)2Pd4(Gal1AH−6)] ⋅ 2 Cl ⋅ 16 H2O (13). 13CNMR- spektroskopische Untersuchungen zeigten, dass Dihydroxy-µ-oxo-[1,3-bis(2’- (dimethylamino)-ethyl)-hexahydropyrimidin]-dipalladium(II) und Dihydroxy-µ-oxo-[1,3- bis(2’-(dimethylamino)-ethyl)-imidazolidin]-dipalladium(II) an reduzierende Zucker an den Atomen O1–O3 in ihrer Pyranose-Form anbinden, und dass hier stets eine Hauptspezies entsteht. Das an das mittlere verbrückende O-Atom gebundene C-Atom zeichnet sich im 13CNMR- Spektrum durch CIS-Werte von über 20 aus. Bei Diolato-Koordination beobachtet man lediglich CIS-Werte von ca. 10. Die hier gebildeten Komplexe sind unzersetzt löslich in Wasser und bei Raumtemperatur mehrere Stunden stabil. Die beiden oben aufgeführten Xylol- Komplexe bewirken eine Bisdiolato-Koordination der Polyole, wie man an den Strukturen der p-Xylol-Verbindung mit Ethylenglykol [(C16H30N4)Pd2(EthgH−2)2] ⋅ 11 H2O (15) und an der Struktur der m-Xylol-Verbindung mit Dulcit [(C16H30N4)2Pd4(Dulc2,3,4,5H−4)2] ⋅ 18 H2O (16) erkennen kann. Daher koordiniert auch nicht ein Polyol-Molekül an die beiden Pd-Atome eines Xylol-Liganden, sondern an Pd-Atome zweier verschiedener Liganden. Mit der Aufklärung der Struktur von Dulcit in Cu-en 17 konnte das noch fehlende Glied in der Reihe homoleptischer und heteroleptischer Komplexe von Kupfer(II) mit Erythrit und Dulcit charakterisiert werden. Hierbei koordinieren ähnlich wie beim Pd-en zwei Cu(en)- Fragmente an das Tetraolat in der Erythrit-Teilstruktur. Erstmals wurden Lösungen von Kupfer(II) und reduzierenden Zuckern so stabilisiert, dass Kristallstrukturen von Koordinationsverbindungen aus diesen Lösungen beschrieben werden konnten. Mit den Amin-Liganden Ethylendiamin und Ammoniak konnten trinukleare Komplexe mit D-Lyxose kristallisiert und ihre Strukturen 18 bzw. 19 beschrieben werden. Dabei wurde der erste Polyol-Komplex aus Schweizers Reagenz beschrieben. Bei allen Kupfer- Komplexen zeigt sich hierbei eine Stabilität von Cu2-µ-Triolato(3−)-Fragmenten. Die Strukturen von zwei Cu7-Clustern wurden mit den reduzierenden Zuckern D-Mannose 20 und DRibose 22 und den Hilfsliganden Ethylendiamin bzw. Hydroxyethyl-ethylendiamin bestimmt, wobei hier die Amin-Hilfsliganden teilweise am anomeren C-Atom N-glycosidisch anbinden. Ein Cu5-Cluster 21 konnte mit Mannose und Cu(OH)2 im stark alkalischen Medium ohne Zugabe eines Amins hergestellt und strukturell charakterisiert werden. Bei all diesen ClusternGibt man N,N´-Bis(2-(dimethylamino)ethyl)-α,α´-diamino-p-xylol zu Suspensionen aus Cu(OH)2 und Xylit, so erhält man Kristalle eines Cu18-Clusters 23, der in seinem Torus zwei Aceton-Moleküle eingelagert hat. Auch hier sind wieder eckenverknüpfte Cu3O3-Sechsecke charakteristisch für die Struktur. Eine unerwartete Reaktion wurde mit demselben Liganden bei Zugabe von D-Ribose gefunden. Hierbei entstand aus dem N-Alkyl-N´,N´- dimethylethylendiamin-Fragment, der D-Ribose bzw. ihren Abbauprodukten und aus Kupfer( II) eine Verbindung 24, die als Amin-Liganden cis-4,5-Dihydroxy-1,3-bis(2’- (dimethylamino)ethyl)-imidazolidin enthält. D-Ribose liegt dabei in der 1C4-Form vor, weil sie so über die O-Atome O1–O3 in der optimalen cis-cis-äquatorial-axial-äquatorial Konfiguration an das Cu2-µ-Triolato(3−)-Fragment koordinieren kann. Der trikationische Kupfer-Zweikernkomplex Diaqua-µ-hydroxy-[3,6-Bis(2’-pyridyl)- pyridazin]-dikupfer(II) ergibt mit Luftsauerstoff durch Reduktion mit einem reduzierenden Zucker eine für Kupfer(II) sehr ungewöhnliche Struktur 25 mit einer µ4-Peroxy-Einheit. Mit dem Liganden 1,4-Bis(2´-aminoethyl)-piperazin erhält man bei Zugabe von Kupfer(II) bei offenem Stehen an der Luft einen für Kupfer ungewöhnlich gebundenen Carbonat-Komplex 26, bei dem der Carbonat-Ligand über zwei O-Atome an das Kupfer bindet und somit ein Vierring entsteht. sind zwei über ein Kupfer-Atom eckenverknüpfte Cu3O3-Sechsecke vorhanden.

In dieser Arbeit werden die ersten röntgenographisch charakterisierten Kristallstrukturen von Mangan(IV)-Polyolato-Komplexen vorgestellt (1–11, 13). Ausgehend von Mangan(II) wird mittels zwei Äquivalenten Kaliumhexacyanoferrat(III) die Oxidationsstufe +IV erreicht. Alle Komplexe entstehen aus wäßriger, stark alkalischer Lösung. Die Kristallisation erfolgt in der Kälte, da Mangan(IV)-Komplexe bei Raumtemperatur innerhalb eines Tages zu Mangan(III) reduziert werden. Mangan(IV) zeigt eine starke Präferenz für Koordinationsoktaeder, welches ein stabiles Struk- turelement darstellt. Das Metallion wird von mindestens zwei 1,2-Diolato- oder 1,3-Diolato- Gruppen chelatartig koordiniert. Mangan(IV) bildet mit D-Glucon- und Lactobionsäure jeweils einen mononuklearen Komplex, KNa3[Mn(D-Glc1AH–4)2] · 7 H2O (1) und KNa2,5[Mn(Lac1AH–3,75)2] · 19,23 H2O (2). D-Glu- conato(4–)-Liganden koordinieren über die Sauerstoff-Donoren der Alkohol-Gruppen an C3, C4 und C6, während Lactobionato(3,5–)-Liganden über die Sauerstoff-Donoren der Alkohol- Gruppen an C2, C3 und C5 an Mangan(IV) binden. Dieses Koordinationsmuster entspricht einer threo-Sequenz, von der die dritte Koordinationsstelle um ein C-Atom weiter entfernt liegt. Lactobionsäure besitzt D-Gluconsäure-Teilstruktur, was sich auch im Bauprinzip wie- derfindet. In 1 liegen die Kalium- und Natrium-Ionen mit den Mangan-Atomen auf unendlich langen Strängen entlang [001]. In 2 entsteht ein dreidimensionales Netzwerk mit dimeren Un- tereinheiten aus kantenverknüpften Oktaedern. Auch mit Dulcitol gelingt es, zwei Komplexe zu kristallisieren, die das Bindungsstellenmus- ter der Lactobionato(3,5–)-Liganden aufweisen: K6[Mn(Dulc2,3,5H–3)2]2 [DulcH–2] · 12 H2O (3) und Ba4[Mn(Dulc2,3,5H–3)2]2 [Fe(CN)6] · 8 H2O (4). Die beiden Dulcitolato-Komplexe unterscheiden sich nicht vom Bindungsmodus her, sondern nur in der Art der eingelagerten Gegenionen. In 3 verknüpfen die Kaliumkationen zwei Komplexanionen aus benachbarten Strängen miteinander, des weiteren koordinieren diese an die bindenden Alkohol-Gruppen der Dulcitolato-Liganden, als auch an die Sauerstoff-Atome des zweifach deprotonierten, nicht- koordinierenden Dulcitol. In 4 beteiligen sich die Bariumkationen sowohl an der Reduktion der effektiven Ladung an Mangan als auch am Aufbau eines dreidimensionalen Netzwerks über die Anbindung an Stickstoffatome des Hexacyanoferrat(II)-Ions. Mangan(IV) und Methyl-β-D-ribopyranosid-2,3,4-ato(3–)-Liganden bilden ebenfalls ein Ko- ordinationsoktaeder, Na4[Mn(Me-β-D-Ribp2,3,4H–3)2]2 · 4 H2O (5). Methyl-β-D-ribopyranosid koordiniert in 1C4-Konformation, in welcher die drei cis-ständigen Hydroxyl-Gruppen als Tri- olatoeinheit auf einer Seite zu liegen kommen. Die Natriumkationen binden an Ligand-O- Atome und ein Wassermolekül. Es entsteht ein dreidimensionales Netzwerk mit dimeren Un- tereinheiten von flächenverknüpften Oktaedern, jedoch fehlt eine Verknüpfung der Stränge entlang [001] wie in 4. Es ist kein Wasserstoffbrückenbindungssystem vorhanden. Pentaerythritol-Liganden bilden mit Mangan(IV) zwei Komplexe, die sich nicht in ihren Bin- dungsmodi, sondern in der Art der eingebauten Gegenionen als auch in der Ladung ihrer Komplexanionen unterscheiden, KLi4[Mn(C5H9O4)(C5H8O4)][Mn(C5H9O4)2] · 21 H2O (6) und Na6[Mn(C5H8O4)2][Mn(C5H9O4)2] · 20 H2O (7). Sowohl in 6 als auch in 7 entstehen mehrere kantenverknüpfte Polyeder, die wiederum einen unendlich langen Strang bilden. Mit α- und β-Cyclodextrin sind bei Verwendung von Lithiumhydroxid als Base zwei Kom- plexe durch Kristallisation zugänglich, Li2[∆-Mn(α-CDH–2)3] · 3 EtOH · 38 H2O (8) und K3Li4[Λ-Mn(β-CDH–3,67)3] · 33 H2O (9). Die Ausbildung von intramolekularen Wasserstoff- brückenbindungen wird durch die eingebauten Gegenkationen erleichtert, wodurch es zu einer Reduktion negativer Ladung um das Zentralmetall kommt. Die Koordinationsstelle wird durch die sperrigen Liganden nach außen abgeschirmt. Eine Anbindung von Lithium- bzw. Kalium-Ionen an die koordinierenden Alkohol-Gruppen ist deshalb nicht möglich. Die La- dungskompensation um das Zentralion geschieht allein durch intramolekulare Wasserstoff- brückenbindungen. Allerdings sind die höhere Ladungsdichte des Lithium-Ions bzw. des Ka- lium-Ions und die passende Größe für die Stabilität des Komplexes entscheidend. Xylitol und D-Threitol koordinieren mit jeweils zwei Liganden an Mangan(IV), die Koordina- tionssphäre wird durch eine di-µ-Oxo-Brücke vervollständigt. Xylitol besitzt D-Threitol- Teilstruktur. Es entstehen die Komplexe Ca8[Mn2(Xylt2,4H–2)4 (µ-O)2]2 [Fe(CN)6]2 · 24 H2O (10) und Ca4[Mn2(rac-Thre2,4H–2)4 (µ-O)2] [Fe(CN)6] · 22 H2O (11). Beiden Komplexen ist die zentrale, dimere Einheit [Mn2O2]4+ gemeinsam, die in Inversionssymmetrie vorliegt. Die Koordinationspolyeder sind untereinander kantenverknüpft. Die Annäherung der Mangan(IV)- Zentren liegt in derselben Größenordnung (in 10 287,4(2) pm, in 11 284,4(6) pm). Sowohl in 10 als auch in 11 finden sich Calcium- und Hexacyanoferrat(II)-Ionen, welche für die Stabili- sierung des Komplexes erforderlich sind. In beiden Fällen entsteht ein dreidimensionales Netzwerk mit dimeren Untereinheiten von kantenverknüpften Polyedern. Die Manganzentren sind jeweils antiferromagnetisch gekoppelt (für 10: J/k = –12,2 K und für 11: J/k = –15,2 K). Cytidin bildet mit Mangan(IV) ein Koordinationsoktaeder, K2[Mn(CytH–2)3]·17H2O (13), in welchem drei Cytidin-Liganden als 1,2-Diolat wirken. Mit meso-D-Glycero-D-gulo-heptitol gelingt lediglich die Kristallisation eines Mangan(III)- Komplexes, K2Ba11[Mn2(HeptH–7)2]2 [Fe(CN)6]4 · 49,8 H2O (12). Der Heptitol-Ligand weist sieben Hydroxyl-Gruppen auf, von denen fünf für die Komplexierung des Mangan(III) betätigt werden, wobei eine Hydroxyl-Gruppe µ2-verbrückend wirkt. Die Annäherung der Man- gan(III)-Zentren beträgt 326,3(2) pm bzw. 328,7(3) pm. Der Komplex zeigt die für Man- gan(III) typische Jahn-Teller-Verzerrung, die in den µ2-Oxo-Brücken zum Ausdruck kommt. Die Manganzentren sind ferromagnetisch gekoppelt (J/k = +1,1 K). Die UV/VIS-Spektren der intensiv roten Mangan(IV)-Polyol-Lösungen zeigen nur wenig cha- rakteristische Absorptionsbanden (Schulter bei ca. 520 nm bzw. 19230 cm–1). 4.2 Untersuchungen zur Sauerstoffabsorption wäßriger Mangan(II)- Polyol-Systeme Für die Untersuchung der Sauerstoffabsorption wäßriger Mangan(II)-Polyol-Systeme entfiel die Wahl auf vier Polyole, D-Gluconsäure, Dulcitol, Xylitol und α-Cyclodextrin. Das Ver- hältnis von Base : Mangan(II) : Ligand betrug 10:1:3,5, im Fall des α-Cyclodextrins 10:1:3. Es wurden zwei Meßreihen bei verschiedenen Temperaturen, 20 °C und 5 °C, durchgeführt. Die Messungen bei 20 °C wurden zudem UV/VIS-spektroskopisch verfolgt. Als relevante Parameter sind die Konzentration der Reaktionsteilnehmer, das gewählte Ver- hältnis von Base : Mangan(II) : Ligand, der pH-Wert, die gewählte Base und die Temperatur anzusehen. Auch dem eingesetzten Liganden muß ein Einfluß zugebilligt werden. Die Untersuchungen zeigen, daß eine sukzessive Erhöhung der Mangan(II)-Konzentration bei konstantem Verhältnis von Base : Mangan(II) : Ligand und bei konstanter Temperatur sowohl das Anwachsen der Basenkonzentration sowie des pH-Wertes als auch einen steigenden Sau- erstoffverbrauch bewirken. Starke Abweichungen vom theoretisch zu erwartenden Sauer- stoffbedarf zeigen sich bei hohen Konzentrationen (0,06 M Mn(II)) der Reaktionsteilnehmer. Dies konnte in beiden Meßreihen festgestellt werden. Die bessere Löslichkeit des Sauerstoffs bei abnehmender Temperatur läßt sich bestätigen, da der Gesamtsauerstoffbedarf bei hohen Konzentrationen der Reaktionsteilnehmer niedriger lag als bei den Messungen bei 20 °C. Die spektroskopischen Daten zeigen, daß die Oxidation zunächst sehr schnell voranschreitet und schließlich immer langsamer wird. Da die Reaktionsgeschwindigkeit von der Oxidationszahl des Zentralatoms abhängt und um so schneller ist, je niedriger die Oxidationszahl des Zentral- atoms und je größer das Zentralatom ist, erfolgt die Bildung von Mangan(IV) demnach (klei- nes Metallion, hohe Oxidationszahl) langsam. Bei einer sequentiellen Oxidation von Man- gan(II) über Mangan(III) zu Mangan(IV) wird ein isosbestischer Punkt bei Verwendung von D- Gluconsäure, Dulcitol und Xylitol durchlaufen. Dieser zeigt an, daß zwei Spezies den glei- chen Extinktionskoeffizienten haben. Bei Messungen mit α-Cyclodextrin ist kein isosbesti- scher Punkt vorhanden. Daher sind wohl thermodynamische Aspekte zu berücksichtigen, die einerseits die Stabilisierung von Mangan(III) begünstigen und andererseits die Stabilisierung von Mangan(IV). Die Auswertung des Sauerstoffverbrauchs im Zusammenhang mit der Rot- verschiebung der Absorptionsbanden deckt eine Diskrepanz auf: Es ist ein Überschuß an Sau- erstoff vorhanden, welcher nicht für die Oxidation von Mangan(II) zu Mangan(IV) genutzt wird. Der Gesamtsauerstoffbedarf setzt sich folglich aus zwei Komponenten zusammen. Ab- hängig von der Einwaage an Mangan(II) dient ein Teil dazu, Mangan(II) zu Mangan(IV) zu oxidieren, der Rest des Sauerstoffverbrauchs läßt auf Ligandoxidationsprozesse schließen. Analyseverfahren wie die HPLC oder/und die Cyclovoltammetrie könnten dieses Ergebnis untermauern. Eine Ausnahme bilden Mangan(II)-α-Cyclodextrin-Systeme: Diese erreichen den theoretisch zu erwartenden Verbrauch nicht. Ob Diskrepanzen in den ermittelten Ergeb- nissen apparativ bedingt sein können, muß geprüft werden. Untersuchungen mit Wasserstoffperoxid und natronalkalischen Gluconat-Lösungen sprechen für den gleichen Sachverhalt. Der theoretisch zu erwartende Verbrauch bei hohen Konzentra- tionen der Reaktionsteilnehmer und bei gleicher Meßtemperatur wird ebenfalls überschritten. Die spektroskopischen Daten zeigen die gleiche Rotverschiebung der Absorptionsbanden. Die Annahme, daß es sich bei der reaktiven Spezies in Lösung um die gleiche handeln könnte, scheint nicht abwegig.