STEM-Talk

Today we have Dr. Dominic D’Agostino, who over the past 10 years has been a frequent guest on STEM-Talk. Today Dom joins us to give us an update on his recent research into ketogenic metabolic therapies, ketone supplements as well as hyperbaric oxygen therapy for traumatic brain injuries. Dom and his lab at the University of South Florida have published more than 20 papers since his last appearance on STEM-Talk in 2023. Dom is an Associate Professor in the Department of Molecular Pharmacology and Physiology at South Florida’s Morsani College of Medicine. Dom has a background in neuroscience, molecular pharmacology, nutrition and physiology. In addition to developing and testing metabolic-based therapies, Dom’s lab also investigates seizure disorders, brain cancer, neurodegenerative diseases and rare genetic-metabolic disorders. Show notes: [00:03:28] Dawn welcomes Dom back to the show and explaining that he has been quite busy since his last appearance, authoring or co-authoring more than 20 papers. Over the past several years, Dom has been helping to advance the science and application of ketogenic metabolic therapy (KMT) with colleagues at Moffitt Cancer Center, particularly focusing on using KMT to enhance immune-based therapies for certain types of cancers. Dawn asks Dom about this collaboration. [00:05:04] Dawn explains that ketogenic metabolic therapy is a dietary approach that focuses on a high-fat/low-carb diet to reduce glucose availability for cancer cells, potentially slowing their growth and improving treatment outcomes. It has been explored as a complimentary treatment for a variety of cancers including gliomas by shifting the metabolism of tumor cells away from glucose. Dawn asks Dom to explain what is involved in KMT. [00:06:58] Dawn clarifies that KMT requires less than 20-25 grams of carbohydrates per day, and that ketosis is a metabolic state in which the body switches from glucose metabolism to metabolizing fats in the form of ketones. Dawn goes on to explain that cancer cells typically consume glucose at a higher rate than normal cells. However, cancer cells are also very adaptable, and Dawn asks Dom to talk about this feature of cancer cells. [00:09:14] Ken explains that KMT has shown the most promise in treating high-grade gliomas, or brain cancers, such as glioblastoma, which is the most aggressive primary brain tumor in adults. Ken explains that Dom was part of a massive review titled “Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma,” which proposed guidelines for the management of glioblastoma based on an understanding of cancer as a metabolic disease, particularly involving mitochondria. Ken asks Dom to talk about this review. [00:11:21] From a patient advocacy perspective, Ken notes that the review recommends that there should be an aggressive education campaign that can arm patients with knowledge about KMT and other novel therapies. Ken asks Dom to talk about that recommendation. [00:13:15] Ken asks about the process of cutting the review from upwards of 200 pages down to around 50 pages with 49 authors. [00:15:04] Dawn mentions that Dom was part of another paper in 2024 titled “Targeting the mitochondrial stem cell connection in cancer treatment – a hybrid orthomolecular protocol.” Dawn explains that this paper looked at the mitochondrial stem cell connection theory (MSCC), which argues that cancer originates from chronic oxidative phosphorylation insufficiency in stem cells. This insufficiency leads to the formation of cancer stem cells and abnormal energy metabolism ultimately resulting in malignancy. There were 16 research centers and organizations involved in this paper which introduced a hybrid orthomolecular protocol to target the mitochondrial stem-cell connection. Dawn asks Dom to give an overview of MSCC. [00:18:26] Dawn explains that in this paper Dom and his co-authors propose a protocol that would enhance oxidative phosphorylation and inhibit the primary fuels of cancer, glucose and glutamine. This would target both cancer stem cells and metastasis. Dawn asks Dom to explain why this concept is attracting so much interest as a potential therapeutic approach for cancer. [00:20:48] Dawn asks if Dom could discuss the orthomolecular protocol, which is an approach that focuses on preventing and treating diseases by correcting nutritional balances in the body. [00:24:41] Ken asks if the proposed dietary intervention in the orthomolecular approach is different from a standard or typical ketogenic diet. [00:26:48] Ken shifts the discussion to talk about ketone supplements, explaining that Dom recently published a paper titled “Divergent hepatic outcomes of chronic ketone supplementation.” Ken goes on to explain that ketone salts preserve liver health, while some ketone esters and precursors appear to drive inflammation and steatosis. There is a lot of interest in ketone supplementation because they substantially elevate circulating ketones without having to restrict carbohydrates as strictly. The problem, as Ken explains, is that the long-term hepatic safety of ketone supplements remains unclear. In the aforementioned paper, Dom’s rodent study evaluated the formulation-dependent impact of chronic ketone supplementation on liver histopathology, inflammatory signaling and systemic biomarkers. Ken asks Dom to discuss this paper and its findings and to give an overview of the various ketone supplements currently available. [00:30:49] Dawn asks Dom to dive into the methods and findings of the rodent study. [00:34:36] Ken asks Dom what his confidence is in the rodent model used in this study, and what are the next step for further research. [00:37:47] Regarding the two different doses given to rats in the study, Ken asks Dom how these doses correlate to doses in humans [00:40:23] Ken mentions that Ben Bikman, who was our guest on episode 143, published a study in February which Dom helped co-author. It examined the effects of ketone supplements on liver function. Ken asks Dom to discuss this study. [00:44:38] Dawn pivots to ask about a joint paper that Dom did with Andrew Koutnik, who was our guest on episode 185, on carbohydrates and physical performance titled “Carbohydrate ingestion on exercise metabolism and physical performance.” Dawn asks Dom to talk about this paper, which showed that a small amount of carbohydrates is sufficient to fuel athletic performance, and how additional carbohydrate intake showed diminishing returns. [00:49:18] Ken follows up on the finding that endurance athletes who rely on carb loading can tend toward pre-diabetes. [00:51:39] Ken asks Dom about the University of South Florida trial that Dom is an advisor for on traumatic brain injury and hyperbaric oxygen therapy. [00:54:41] Dawn mentions that Dom recently had an editorial in Frontiers that gave an overview of the emerging applications of hyperbaric/hyperbaric-oxygen therapy in the treatment of different neurological disorders. Dawn asks Dom what the key points in that editorial were. [00:59:06] Dawn explains that Dom recently gave a lecture at IHMC (available to view on IHMC’s YouTube page), on traumatic brain injury and the populations at greatest risk in that context. Dawn asks Dom to give an overview of how an injury to the brain can result in neurometabolic crisis. [01:02:53] Ken asks Dom, excluding occupation demographics, what demographic is most at risk for traumatic brain injury (TBI) and why. [01:04:45] Ken mentions that it is understandable the risk that young people face with TBI due to the activities that young people engage in. Older people, however, have increased risk of TBI from falling as well as an additional age-related biological component that young people are not subject to. Ken asks Dom to elaborate on this. [01:07:12] Dawn mentions that several years ago, Dom and his wife bought some acreage in the countryside and started farming and asks Dom how the farm life is going. [01:07:57] Dawn closes the interview asking how Dom’s wife is doing.

It’s time for another episode of Ask Me Anything. Dawn and Ken answer listener questions that range from generative AI to whether grip strength is a biomarker for longevity and the potential of ketamine as a treatment for depression. Dawn also gives a brief overview of work she is doing with the deep-sea technology company Deep. As a special treat at the end of today’s episode, Dawn plays a recording of the commencement speech that Ken recently gave at the University of West Florida. As the saying goes, you don’t want to miss it. Show notes: [00:02:18] Ken starts off the episode with a listener question about whether Dawn and Ken read print books or digital, the reason being that a listener recently came across an article that claimed digital screens are rewiring our brains. [00:05:32] A listener asks about a paper titled “Grip Strength An Indispensable Biomarker for Older Adults” which claims that the ability to hang from a bar for 60 seconds for men, and 30 seconds for women, indicates that a person is likely to live longer. The paper claims that a decline in grip strength is associated with adverse health consequences, and the listener asks Ken what advice he has for developing and maintaining grip strength. [00:10:20] A listener asks a question inspired by our recent interview with Dr. Frank Butler. The listener asks if Ken has heard about the FDA approved depression therapy, esketamine, which is a derivative of ketamine and is a long-standing therapy for depression. [00:12:37] A listener asks Ken about a 2023 paper in the journal Age and Aging titled “Higher Dietary Protein Intake is Associated with Sarcopenia in Older British Twins” [00:16:13] A listener asks Ken about “Whisper,” which is a transcription product from OpenAI. The listener explains that OpenAI disclaims that Whisper should not be used in high-risk domains. However, according to a story by the Associated Press titled “Researchers Say an AI Powered Transcription Tool Used in Hospitals Invents Things No One Ever Said,” medical centers have already begun to use the tool to transcribe physician consultations. The listener explains that, according to the article, the use of Whisper in these contexts has led to numerous ‘hallucinations’ from the AI tool and the listener asks Ken what his thoughts are on how tools like Whisper should be integrated into various industries. [00:20:21] A listener asks for Ken’s thoughts on a series of articles by Kevin Roose in The New York Times claiming that there is no reason to learn how to code and program because very soon AI will take over all coding. Mr. Roose also asserts that the time is soon approaching when we need to have discussions on what rights to grant sentient AI. [00:21:57] A listener asks Ken if he concurs with a report from the National Academy of Medicine titled “Generative Artificial Intelligence in Health and Medicine – Opportunities and Responsibilities for Transformative Innovation,” which notes that large language models (LLMs) hold huge promise for patient care and healthcare system workflows, as well as risks. The listener asks if Ken agrees with the report’s claims that two areas in which we could see near term applications of LLMs are patient education and synthesis of information of electronic medical records. [00:23:35] As a follow up question, Ken is asked about the aforementioned report’s discussion of the “digital twin” concept. A digital twin is a computational representation of a patient or disease that could be used to speed up virtual experiments or subgroup analysis of investigational agents that carry risk for real patients. [00:26:26] A listener asks for Ken’s thoughts on a paper published in the journal of Nutrition Health and Aging titled “Effects of Vitamin D3 Omega 3 Fatty Acids and a Simple Home Exercise Program on Change in Physical Activity Among Generally Healthy and Active Older Adults.” The paper claims that among generally healthy, active and vitamin D3 replete individuals 73 and older, that Vitamin D supplementation had a detrimental effect on physical function and activity. [00:28:32] A listener asks Ken and Dawn what their take is on the term “settled science” and if it is ever appropriate to call some science “settled.” [00:30:06] A listener asks both Ken and Dawn whether they have a favorite healthy snack. [00:31:31] A listener asks Ken about his blood flow restriction training and what devices he uses for these workouts. [00:32:29] A listener asks about a new sub-sea technology company called Deep, which Dawn works with. [00:34:21] Dawn wraps up the episode mentioning that a little birdie told her that Ken recently gave a good commencement address to the graduating class of 2025 at the University of West Florida. Dawn then plays the audio from Ken’s speech. Links: Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio

Today we have Dr. Michael A. Schmidt, the founder, CEO, and Chief Scientific Officer of Sovaris Aerospace, a company focused on assessments and solutions applied to humans in space and extreme environments on Earth. Michael is also a professor of aerospace medicine at the University of Central Florida College of Medicine, one of the few programs in the U.S. that offers a medical residency in aerospace medicine. Michael is known for his work pioneering the field of precision medicine. He uses molecular analytics, coupled with physiologic and behavioral assessments, to facilitate human performance and resilience on Earth as well as in the extreme environment of space. His work covers a spectrum from NASA, the NFL, the NBA, U.S. Olympic teams, Nike, SpaceX, Axiom Space, NASCAR, Special Operations, the Naval Submarine Medical Research Lab, the Mayo Clinic, and others. We had a long and fascinating conversation with Michael and decided to break the interview into two parts. This episode focuses on Michael’s background and the cognitive and physical challenges astronauts experience in spaceflight. We also dive into the many ways that precision medicine is facilitating human performance and resilience here on Earth. In part two of our conversation, Michael talks about his work with NASA and SpaceX on the challenges of civilian spaceflight and the future of Mars exploration, including the construction of permanent colonies on the Moon and Mars. You won’t want to miss that conversation. Show notes: [00:03:59] Dawn opens our interview mentioning that Michael grew up in Minnesota in a small farming community, asking if it’s true that he sometimes had to do chores in 20- to 30-degree weather. [00:06:50] Dawn asks if it is true that Michael fell in love with science at a young age, even building telescopes at the age of 11. [00:08:00] Dawn asks Michael what it was that led him to become so fascinated with space specifically. [00:08:58] Dawn asks if Michael ever thought about becoming an astronaut. [00:10:09] Ken asks if it is true that Michael was a big reader as a child. [00:11:21] Dawn asks Michael to talk about his childhood athletic interests. [00:11:55] Dawn asks how it was that a high school quarterback from a small town in Minnesota ended up at university in the United Kingdom. [00:13:38] Ken asks Michael what years he worked at NASA Ames Research Center. [00:14:51] Ken mentions that when Michael was at NASA Ames, he did work collecting molecular and physiologic assessments of humans using NASA’s 20-G centrifuge. Ken asks Michael to talk about the centrifuge and how he used it in his studies of hypergravity. [00:17:49] Ken comments on the fact that pieces of equipment like NASA’s 20-G centrifuge are a precious scientific resource, and when they cease functioning, unfortunately, they are unlikely to be replaced. [00:19:40] Ken and Michael discuss the fact that microgravity, despite being one of the most pressing effects on astronaut health, is the one of the least addressed problems in human spaceflight. [00:21:48] Ken explains that Michael is the founder, CEO and Chief Scientific Officer of a company called Sovaris Aerospace, which is focused on assessments and solutions applied to humans in space and extreme environments on Earth. Ken asks Michael where the idea came from to found this company. [00:24:35] Dawn explains that since the human genome was first sequenced, there has been an acceleration of genome-based technologies that have made it possible to consider a person’s genetic makeup, both in healthcare and optimizing performance. Dawn asks Michael to talk about the work he does applying genomics to human spaceflight. [00:28:52] Dawn asks about Michael’s direction of the molecular profiling and precision medicine efforts for the Golden State Warriors during their record-breaking 73-9 season [00:32:57] Dawn mentions that Michael published a review in the journal Metabolomics in 2013 that looked at the use of omics-based analyses and their potential to enhance astronaut safety and performance. Dawn goes on to say that omics allows us to identify differences in humans responsible for different responses to extreme conditions. Dawn asks Michael to talk about this review and what he learned in terms of the risk profile of individual astronauts and how personalized medicine could mitigate some of the risks. [00:42:01] Ken circles back to the heterogeneity of responses to exercise in space, a phenomenon that is seen on Earth as well. Ken notes that while large populations of astronauts don’t yet exist to be studied, large populations and their response to exercise can be studied on Earth, such as Marcas Bamman’s current NIH-funded multicenter exercise study with aging populations here at IHMC. Here Michael talks about his work creating “digital twins” of astronauts to model exposure to extreme environments on personalized digital models of astronauts. [00:46:04] Ken mentions that the difference between digital twin models in engineering and digital twins used in biomedicine is that engineered systems are nearly fully understood and can therefore be modeled with great accuracy and completeness, while there is much more unknown in biological systems. [00:48:15] Ken asks Michael, given all the confounds and environmental stressors in spaceflight, how confident can we be that omics analyses performed on Earth will provide useful insights about performance in space. [00:54:13] Dawn pivots to discuss Michael’s work as president of the Human Research Program for Civilian Space Flight, the purpose of which is to address the widespread needs that civilians will face as space travelers. [01:01:03] Ken shifts gears to ask Michael to talk about the specific cognitive and physical challenges that humans will face in long duration spaceflight, such as a flight to Mars. [01:10:05] Ken mentions that APOE4/4 positive patients see increased risk of cognitive decline from therapeutic radiation on Earth. Ken notes that while therapeutic radiation is different from the radiation experienced by astronauts, this still poses worrying prospects for APOE4/4 positive astronauts. [01:11:28] Ken and Michael discuss the importance of developing both biological and engineering countermeasures to hazardous exposure to astronauts in space. Links: Michael Schmidt bio Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio    

Today we have planetary scientist Dr. Pascal Lee and STEM-Talk host Dr. Ken Ford in a wide-ranging conversation about NASA’s ambitions to return humans to the Moon as a stepping stone to sending astronauts to Mars. Pascal is making his third appearance on STEM-Talk. Much of his research focuses on asteroids, impact craters, and the future human exploration of Mars. Pascal and Ken have a lively discussion about the growing momentum for space exploration. Pascal is a researcher at the SETI Institute, a not-for-profit NASA program focused on searching for extraterrestrial intelligence in an effort to understand and explain the origin and nature of life in the universe. He also is the co-founder and chairman of the Mars Institute, and director of the Haughton-Mars Project at NASA Ames Research Center. Last year, Pascal received significant news coverage for his discovery of a giant volcano along with a possible sheet of buried glacier ice in the eastern part of Mars’ Tharsis volcanic province. This was the first geological find of this magnitude since the other major volcanos on Mars were discovered back in the 1970s. Show notes: [00:03:06] Ken welcomes Pascal back to STEM-Talk and starts our interview by mentioning the developments in space exploration over the past few years, including civilian space missions, NASA’s Artemis program which aims to send humans back to the moon, and commitments to a manned mission to Mars. Given Pascal’s career in advancement of space exploration, Ken asks if Pascal is excited by these recent developments. [00:04:43] Ken explains that for a couple of decades Pascal has spent his summers visiting Devon Island in the Canadian arctic archipelago, which is the largest uninhabited land on Earth. When Pascal was last on STEM-Talk, his annual trip to Devon Island was cancelled due to COVID-19. Devon Island has unique geological characteristics that are in some ways similar to those on Mars. Since 2001, Devon Isalnd has been the home of the Haughton Mars Project (HMP). Ken asks Pascal to talk about the advances in this project since his last appearance on STEM-Talk. [00:07:59] Ken mentions that while much conversation has been centered on a human trip to Mars, a mission to return humans to the Moon and establish a permanent base is a more immediately feasible goal in the short term. Ken asks Pascal to talk about the importance and significance of such a mission. [00:12:06] On the topic of a Moon base, Ken explains that NASA’s Artemis project aims to send humans to the south pole of the Moon. Pascal has written a paper on that topic titled “An Off-Polar Site Option for the NASA Artemis Space Camp.” Ken asks Pascal what he sees as the primary weakness in the south pole location. [00:20:25] Ken agrees with Pascal’s perspective on sending humans to the lunar south pole, and the two discuss the problems with focusing human space exploration on romantic ideas such as “living off the land.” [00:22:24] Ken follows up on the previous questions by mentioning that in Pascal’s aforementioned paper, he suggests setting up a lunar base at the floor of the Clavius crater. Ken asks Pascal to talk about Clavius and why it is a potentially good permanent location for a moon base. [00:27:56] Ken asks Pascal how confident he and the community at large is in the Sophia finding of water. [00:29:00] Ken notes that contemporary interest in human space exploration appears tied to current geopolitical issues, much like the first space race between the US and USSR. Today, interest in space travel is closely linked with relations between the US and China. Ken asks Pascal to discuss this and how he believes the US should view this current situation. [00:35:43] Ken asks Pascal what he knows about the China’s current plans for a lunar mission. [00:34:36] Ken talks about a meeting at IHMC that addressed power-beaming to the lunar surface. [00:39:01] Ken notes that there is a lot of talk these days about not not only traveling to Mars, but also colonizing Mars. Ken asks Pascal where he believes this sentiment is coming from and what are some of the challenges associated with colonizing Mars. [00:46:48] Ken notes that last year Elon Musk made an announcement to his SpaceX employees that he expects 1 million people to be living on Mars in the next 20 years. Ken asks Pascal what his thoughts are on this. [00:53:28] Ken asks Pascal to talk about a paper he published discussing a previously unrecognized volcano on Mars. Given that it was generally accepted for decades that all the volcanos had been accounted for, Ken asks Pascal to talk about the story of his recent discovery. [01:02:44] Ken pivots to a discussion of the Moons of Mars, specifically Phobos, asking Pascal to talk about the nature of this Moon. [01:07:42] Ken mentions that docking on Phobos and then going from Phobos to Mars would likely be a safer strategy for early Mars missions than landing directly on Mars from Earth. [01:12:30] Ken starts a discussion about Perseverance, as well as the new Japanese mission that may bring back Mars rocks from Phobos. Ken asks Pascal about Perseverance’s collection Mars’ of rock samples that NASA plans for a mission to bring those Mars rocks to Earth. Ken asks it is worth the cost of a mission to collect these samples and what we might learn if we are successful in getting these samples to Earth. [01:17:09] Ken wraps up our interview asking Pascal what year it was that he started working at NASA Ames, which turns out to be the same year Ken started working at NASA Ames. Links: Pascal Lee bio Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page

Today we have Dr. Karl Herrup, a neurobiologist known for his investigations into the roles that DNA damage and noncoding genetic variants have in Alzheimer’s disease. Joining Ken today to interview Karl is Dr. Tommy Wood, a visiting scientist here at IHMC. Tommy also is an associate professor of pediatrics and neuroscience at the University of Washington, where he focuses on brain health across lifespan. He has been our guest several times on STEM-Talk and we will have links to those interviews in our show notes for today’s episode. After more than a century of research, the underlying cause of Alzheimer’s remains a mystery. For the past few decades, the leading theory has been the amyloid cascade hypothesis, which proposes that abnormal amyloid plaques in the brain are the central cause of the disease. Today we talk to Karl about his lab and research as well as his view that the amyloid cascade hypothesis is not only flawed, but also could be holding back research for a cure of Alzheimer’s. A professor of neurobiology and an investigator in the Alzheimer’s Disease Research Center at the University of Pittsburgh School of Medicine, Herrup is the author of How Not to Study a Disease: The Story of Alzheimer’s. Show notes: [00:03:50] Tommy asks Karl what he was like as a kid to open the interview. [00:04:36] Tommy asks Karl about his educational environment growing up. [00:05:10] Ken mentions that Karl went to Brandies University originally with the intent of becoming a physician and asks Karl what happened to change his mind. [00:06:14] Ken asks Karl if it is true that his father was disappointed with Karl’s decision to abandon medical school in favor of genetics. [00:07:02] Tommy mentions that Karl began researching genetics in the late 1960s when researchers were just beginning to unravel the secrets of DNA. Tommy asks Karl to discuss why this was such an exciting time to study genetics. [00:08:38] Tommy asks Karl what prompted him to pursue a PhD in neuroscience. [00:11:34] Continuing on the theme of happy accidents, Ken asks if it was also an accident that led to Karl moving to Switzerland for a second post-doc. [00:12:36] Ken asks Karl to expound on his experience taking an overseas post-doc, which was not a common practice in the 1970s. [00:14:11] Ken mentions that Karl has seemed to benefit in his life from the combination of preparation and the willingness to explore opportunities that present themselves. [00:15:00] Tommy mentions that when Karl arrived back in the US from Switzerland, he accepted a faculty position at Yale and asks him to discuss this experience. [00:17:06] Tommy mentions that after Yale, Karl had several faculty appointments, including a seven-year stint in Hong Kong, and asks Karl to talk about that experience. [00:21:36] Tommy asks Karl why, in 2019, he moved back to his hometown to become a professor of neurobiology at the University of Pittsburgh and co-investigator at the university’s Alzheimer’s research center. [00:24:45] Ken asks Karl to talk about his lab at the University of Pittsburgh, which focuses on the biology of neurodegeneration. [00:26:32] Ken asks Karl if there was anything specific that caused him to shift his focus at this stage in his career so heavily towards Alzheimer’s research. [00:28:21] Tommy comments on Karl’s hypothesis of the aging brain, noting that it would make sense for the same processes involved in the developing brain to relate to what we see in the aging brain, as these processes are continuous throughout the lifespan. [00:29:54] Tommy pivots to talk about Karl’s book, entitled “How Not to Study a Disease: The Story of Alzheimer’s” for which Karl interviewed a number of experts and colleagues, asking each one to define Alzheimer’s disease in their own words. [00:30:51] Tommy reiterates the point that we still do not have a universally accepted definition of Alzheimer’s disease and asks Karl why this is such a critical problem for the field. [00:32:27] Ken asks if Karl has a working definition of Alzheimer’s disease. [00:33:47] Ken explains that Karl begins his book with the story of a woman named Dorothy, who after living a vibrant life and taking good care of herself as she aged, fell victim to Alzheimer’s disease. Ken asks Karl to talk about Dorothy, and why he chose to begin his book with her story. [00:36:58] Tommy asks Karl to define the difference between Alzheimer’s and dementia more broadly. [00:38:00] Tommy explains that while Alzheimer’s is typically characterized as a disease of late life, early onset Alzheimer’s, while rare, is possible, typically very aggressive, and generally runs in families. Tommy asks Karl to explain how we differentiate late and early onset Alzheimer’s. [00:38:58] Ken asks Karl to explain how one differentiates Alzheimer’s from other forms of dementia in a clinical context. [00:41:53] Ken points out that the title of Karl’s book “How Not to Study a Disease” highlights that assumptions about Alzheimer’s disease potentially have misdirected research in some ways. Ken asks Karl to talk about this misdirection and its consequences. [00:43:37] Tommy gives some background on the amyloid cascade hypothesis, explaining that Dr. Alzheimer himself was not entirely convinced that the cases he had been studying were necessarily representative of a single condition. Dr. Alzheimer’s mentor, Dr. Kraepelin, coined the disease in a book that he was writing. Tommy also mentions that Karl has said that this is one of three key events that cemented the amyloid cascade hypothesis as the leading hypothesis of Alzheimer’s disease and asks Karl to discuss more of this history. [00:49:20] Tommy asks Karl to give an overview of the amyloid cascade hypothesis. [00:53:36] Ken explains that Karl sees the amyloid cascade hypothesis as failing three basic tests. Ken goes on to ask Karl to discuss, in depth, the first test, which is the fact that in both humans and mice the addition of amyloid to healthy brains does not trigger an amyloid cascade. [00:56:55] Tommy moves to Karl’s second test of the amyloid cascade hypothesis, the fact that removal of amyloid from the brains of mice and humans does not stop Alzheimer’s disease processes. Given the recent FDA approval of several anti-amyloid drugs, Tommy asks Karl to give his thoughts on the history of anti-amyloid therapies. [01:03:29] Ken explains that the third test of the amyloid cascade hypothesis entails blocking the formation of amyloid from the amyloid precursor protein, which was not only found to not stop Alzheimer’s progression, but in fact makes humans and mice sicker. [01:05:47] Ken takes a moment to clarify that Karl is not arguing that amyloid has no role in Alzheimer’s disease, just that it is not the primary cause of Alzheimer’s. [01:06:21] Ken asks Karl what his response is when people ask what he proposes the cause of Alzheimer’s is if it’s not amyloid. [01:08:45] Tommy asks Karl to elaborate on the idea of the emergent nature of the brain and the potential for this emergence to help explain Alzheimer’s disease. [01:10:54] Ken mentions that the last section of Karl’s book is titled “Where Do We Go From Here” in which he argues that because age is an absolute prerequisite for Alzheimer’s, there is no solution to the problem of dementia that does not rely heavily on an understanding of the process of aging. Ken goes on to explain that much of this was originally posited in Karl’s 2010 paper Reimagining Alzheimer’s disease: An age-based hypothesis. Ken goes on to ask Karl to talk about his view that developing an age-based hypothesis is going to be difficult given that aging is one of the greatest unsolved mysteries in biology. [01:13:19] Ken mentions that aging research gets a very small amount of funding in comparison to the myriad disorders for which aging is the primary risk factor. [01:16:11] Tommy shifts gears to talk about a series of studies that Karl conducted on the benefits of exposure to Japanese gardens on the clinical symptoms of Alzheimer’s disease. In one of these studies, Karl found that the Japanese garden not only relieved physiological stress but also improved qualitative measures such as verbalization and memory retrieval. Tommy asks Karl how he became interested in Japanese gardens, and if the results of his experiments surprised him. [01:20:33] Tommy comments that Karl’s work on the effects of Japanese gardens on the clinical symptoms of Alzheimer’s contributes to a larger body of literature showing the critical importance of the environment in shaping and maintaining cognitive function. Tommy goes on to say that the decline in certain cases of Alzheimer’s can be matched to the increasing levels of institutionalization and the decrease of enriching stimuli in a patient’s environment as their disease progresses. Tommy asks Karl to talk about the importance of social, cognitive, and environmental stimuli for cognitive function. [01:23:34] Ken mentions that Karl has pointed out in the past that non-pharmacological approaches to treating Alzheimer’s have been the most effective tools in our arsenal so far. Given this, Ken asks Karl what he recommends to people for their brain health and cognitive function. [01:25:22] Ken explains that Karl is involved with, or supports, at least two charitable organizations that aim to reshape the face of funding for Alzheimer’s research, namely the Coins for Alzheimer’s Research Trust, and the Clear Thoughts Foundation. Ken asks Karl to talk about his relationship to these organizations and what he hopes will change in the landscape of Alzheimer’s research funding. [01:27:23] Tommy closes our interview asking whether Karl has a Japanese garden of his own in his back yard. Links: About IHMC Karl Herrup bio Ken Ford bio Ken Ford Wikipedia page Tommy Wood bio Tommy Wood STEM-Talk episode 47 Tommy Wood STEM-Talk episode 48 Tommy Wood STEM-Talk episode 110 Tommy Wood STEM-Talk episode 111 Tommy Wood STEM-Talk episode 128

Today our guest is Dr. JoAnn Manson, an endocrinologist, epidemiologist, and Principal Investigator of several research studies, including the landmark Women’s Health Initiative. She is a highly cited researcher and was one of the physicians featured in the National Library of Medicine’s exhibition, History of American Women Physicians. Her primary research interests include clinical prevention trials of nutritional and lifestyle factors related to heart disease, diabetes, and cancer and the role of endogenous and exogenous estrogens as determinants of chronic disease. Show notes: [00:02:53] Dawn kicks off the interview by asking JoAnn what it was that drew her to endocrinology. [00:04:33] Ken asks how the things JoAnn witnessed in her early medical practice influenced her interest in disease prevention. [00:05:51] Dawn asks JoAnn to discuss how her mother, who suffered from ovarian cancer, influenced JoAnn’s focus on women’s health. [00:06:40] Dawn asks JoAnn what prompted her interest in clinical research. [00:08:06] Noting the difference between public health and laboratory medical research, Dawn asks JoAnn what the most valuable thing is that she learned from her master’s and Ph.D. work in public health at Harvard. [00:09:10] Ken mentions that while JoAnn and many others are interested in the prevention of disease, our healthcare system does not seem focused on prevention. Ken goes on to asks if this was part of what led JoAnn to work on the Nurses’ Health Study. [00:10:17] Ken asks JoAnn to give an overview of the Nurses’ Health Study for listeners who may not be familiar. [00:11:41] Dawn explains that the Nurses’ Health Study found that women taking hormone therapy had a lower risk of heart disease and a reduction in all-cause mortality. Dawn asks JoAnn to talk about this finding. [00:15:00] Ken asks JoAnn what the impact of the Nurses’ Study has been on public health and women’s health in general. [00:16:29] Dawn asks JoAnn about her experience being a principal investigator in the Women’s Health Initiative starting in 1993. [00:18:17] Ken asks JoAnn to give context regarding how the Women’s Health Initiative (WHI) was designed, how the women were recruited, and what the specific questions were that the study aimed to answer. [00:21:34] Dawn mentions that the three interventions that were evaluated in the WHI were hormone therapy; calcium and vitamin D supplementation; and a low-fat diet. Dawn starts by asking JoAnn about the hormone therapy interventions, and how it was decided which hormone therapies to test. [00:24:25] Dawn asks JoAnn to give some context to the finding from the WHI that women taking the combination of conjugated estrogen and medroxyprogesterone acetate had higher risks of breast cancer and stroke. [00:27:01] Ken asks if the worse outcomes from hormone therapy for older women was due to their advanced age, or the hormone therapy itself. [00:30:25] Ken asks JoAnn to talk about the risk factors for breast cancer that were uncovered by the WHI. [00:35:38] Dawn explains that because of the WHI’s findings, it is more common to use transdermal estradiol, as opposed to the oral form evaluated in the original trial. Dawn asks JoAnn to explain how the different ways these hormone formulations are processed in the body affects the risk benefit ratio. [00:39:04] Dawn asks if these transdermal estradiol treatments might have benefits regarding cognitive decline. [00:43:26] Ken asks JoAnn for her thoughts on the overuse and potential misuse of the term ‘bioidentical hormones.’ Ken goes on to note that the term has seemingly become more related to marketing and further distanced from clinical science. [00:46:48] Dawn asks JoAnn to talk about the role that perimenopausal birth control decisions can play in the management of hot flashes for women in their 40s and 50s. [00:49:14] Ken shifts the conversation to discuss the second pillar of the WHI, calcium and vitamin D supplementation. Ken explains that this pillar of the trial tested to see if this supplementation decreased risk of hip fractures in post-menopausal women. Ken asks JoAnn to discuss these findings. [00:53:13] Dawn asks about the third pillar of the WHI, which looked at whether a low-fat dietary pattern reduced the risk of breast cancer, colorectal cancer, or coronary heart disease. [00:55:31] Dawn asks JoAnn what questions are left for the WHI to explore. [01:00:17] Ken asks about a recent report in the journal Menopause, which looked at the cognitive effects of clinical menopausal symptoms. [01:01:36] Dawn asks JoAnn to expound on what ‘cognitive decline’ is measured as, with respect to sleep loss resulting from menopausal symptoms such as hot flashes and night sweats. [01:02:38] Dawn asks JoAnn about a study she and her colleagues conducted at Brigham showing that a comprehensive multivitamin can delay age related memory decline by an average of two years. [01:06:41] Ken asks about the findings of JoAnn’s 2018 study in The New England Journal of Medicine, which looked at whether vitamin D supplementation resulted in a lower incidence of invasive cancers and cardiovascular events. [01:10:11] Regarding the aforementioned study, Ken explains that a subgroup analysis raised the possibility of differential effects of cancer incidence connected to BMI. Ken asks JoAnn to elaborate on this subgroup analysis. [01:13:41] Ken asks if the aforementioned results would look more pronounced, or different in some way, if the data was analyzed with respect to body composition as opposed to BMI. [01:15:09] Dawn asks JoAnn what she would like to see change about how women’s health is taught and studied with respect to perimenopause, menopause, and post-menopause. [01:16:13] Dawn asks JoAnn what she and her colleagues plan to investigate next, and what answers she thinks we will have for future generations of women as they age that we don’t have now. [01:18:13] Ken wraps up our interview asking JoAnn what she likes to do in her spare time. Links: JoAnn Manson bio Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio    

Today we have Dr. Rudolph E. Tanzi, who is perhaps best known for co-discovering all three familial early-onset Alzheimer’s disease genes. In addition, Rudy’s lab was the first to use human stem cells to create three-dimensional human brain organoids and three-dimensional neural-glial culture models of Alzheimer’s disease, which became known as “Alzheimer’s-in-a-Dish.” These models were the first to recapitulate all three of the key pathological hallmarks of Alzheimer’s disease and have made drug screenings faster and cheaper. Rudy is the director of the Genetics and Aging Research Unit as well as the director of the Henry and Allison McCance Center for Brain Health. Rudy is also co-Director of the Massachusetts General Institute for Neurodegenerative Disease at Massachusetts General Hospital and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Rudy has published more than 700 research papers and is one of the top 50 most cited neuroscientists in the world. He is author of “Decoding Darkness,” and a co-author of two books with Deepak Chopra, “Super Brain” and “The Healing Self.” Show notes: [00:03:18] Ken opens the interview mentioning that Rudy began playing the accordion when he was just seven years old. Ken goes on to ask Rudy about the time his father gave him a Jimmy Smith album and some advice. [00:05:51] Ken mentions that, in addition to Rudy’s musical talents, he was also interested in science growing up. Ken asks about Rudy’s participation in the Westinghouse Science Talent Search and what that experience was like. [00:07:09] Ken asks Rudy about growing up in Cranston, Road Island. [00:08:39] Rudy talks about how he ended up at the University of Rochester after high school. [00:09:51] Ken mentions that both Rudy’s grandfather and father passed away at the age of 45. Ken asks Rudy if this played a role in his pursuit of a career in genetics research. [00:10:57] Rudy explains how he chose Harvard Medical School for his Ph.D. [00:12:47] Ken pivots to ask Rudy about his time working with Jim Gusella in the early 80’s at Mass General, where they were the first to ever find a disease gene. Family studies at the time had shown that the Huntington’s disease gene was linked to a polymorphic DNA marker. Rudy talks about this discovery and how the chromosomal localization of the Huntington’s disease gene was the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder. [00:16:07] Ken asks Rudy about his work in 1987, when he discovered the first Alzheimer’s gene, recombinant DNA technology, which causes the production of amyloid. Ken goes on to explain that mutations in the APP gene can cause a rare form of early onset Alzheimer’s. Rudy talks about the paper that came out in “Science” that detailed this discovery. [00:18:38] Rudy discusses his personal philosophy and approach to research. [00:19:43] Ken mentions that in Rudy’s book, Decoding Darkness, he writes that few nightmares on Earth can compare to Alzheimer’s disease. Ken asks Rudy to talk more about this book. [00:21:50] Ken explains that in the same way our physical capabilities will suffer some form of decline with age, it is also expected that we have some decline in memory and cognitive ability as we age as well. However, Ken goes on to say that when people begin to experience age-related memory lapses, it can lead to a lot of anxiety about their genetic predisposition to Alzheimer’s. Ken asks Rudy to talk about the lifestyle factors that play into whether someone predisposed to develop Alzheimer’s can stave off or avoid disease development. [00:26:09] Ken explains that aging appears to intensify when people stop challenging themselves with new things. Given this, Ken asks Rudy what his thoughts are on challenging our brains as they age to protect our cognitive abilities. [00:29:08] Ken asks Rudy about the principal advances in Alzheimer’s research that have occurred over the past few decades. He also asks Rudy for his thoughts on the biggest and most important mysteries that remain regarding Alzheimer’s. [00:34:48] Ken brings up one of Rudy’s papers, published in 2014, which they successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Ken goes on to mention that this paper had a huge impact in the field of research, and even landed Rudy a spot on Time Magazine’s 100 most influential people list. [00:38:57] Ken mentions that in 2019, Rudy published another influential paper, which investigated the crosstalk between microglial receptor genes CD33 and TREM2. Ken explains that these two genes have been associated with an increased risk of Alzheimer’s disease, and that Rudy has referred to them as yin and yang to each other. Ken asks Rudy to elaborated on this concept. [00:43:00] Ken pivots to discuss Rudy’s paper that was published last year and which the press somewhat misleadingly reported on. Ken explains that physical exercise has been shown to reduce amyloid beta in various Alzheimer’s models, but it is imperfectly associated with amyloid burden in humans. Ken goes on to explain that Rudy’s paper demonstrated, for the first time, a cellular and molecular mechanism by which exercise induced irisin attenuates amyloid beta pathology. [00:46:27] Ken mentions that Rudy is currently writing a new book and mentions that some of Rudy’s previous books have been co-authored with Deepak Chopra. Ken asks how Rudy and Deepak came to work together. [00:51:24] Ken asks, given the complex nature of Alzheimer’s and the many components that contribute to the pathology, if there is a way to organize all we know about Alzheimer’s in a straight-forward way. [00:58:19] Ken asks if there are any particularly promising FDA approved drugs or nutraceuticals for stopping the production of amyloid. [01:00:16] Ken asks if Rudy gets questions regarding which drugs and supplements screened have shown the most promise. [01:03:33] Ken closes the interview by asking how he manages to be such a prolific scientist. Rudy has published more 700 papers while also having a lifetime of playing music with rock bands, working with sports teams and publishing New York Times best sellers. Links: Rudy Tanzi bio Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page  

Few people know as much about inflammation and neuroscience as Dr. Kevin Tracey does. In this episode of STEM-Talk, we learn much from Tracey, who was the first to identify the inflammatory reflex, a physiological mechanism that regulates the body’s immune response to injury and invasion. He is a neurosurgeon, a pioneer in bioelectrical medicine and president and CEO of the Feinstein Institutes for Medical Research in Manhasset, N.Y. The conversation in this episode covers a career spent working on “producing tomorrow’s cures today” in the treatment of inflammatory diseases, including: How the death of his mother from a brain tumor when Tracey was 5 years old ultimately influenced his scientific journey. How the death of a young patient of his from sepsis further fueled his path, leading him to the insight that “good science begins with hard questions,” as Tracey shared in a TedTalk. The molecular mechanisms of inflammation and the use of vagus nerve stimulation to treat it. His 1987 discovery of tumor necrosis factor (TNF), which contributed to a new class of drugs for inflammatory and autoimmune diseases. Another discovery that allowed him and his colleagues to merge neuroscience and immunology. His work on “The Inflammatory Reflex”, which emphasized the basic neural pathway that reflexively monitors and adjusts the inflammatory response. A sketch he drew while having lunch, which laid out how treating inflammatory diseases using a bioelectronic device might be possible. What advances in bioelectronic medicine he envisions in the next decade, and much more. [00:03:04] Dawn asks Kevin to tell the story of how he developed an interest in science that evolved into him becoming a neurosurgeon. [00:04:56] Dawn mentions that Kevin was a curious youth and asks if it is true that after getting his first car, Kevin removed the entire engine because he wanted to better understand how to do a valve job. [00:06:33] Ken mentions that after Kevin graduated from high school, he enrolled in Boston College where he earned a bachelor’s degree in chemistry. Ken explains that Kevin went to Boston University Medical School for his M.D. and asks Kevin about the transition. [00:08:41] Ken asks if it is true that during Kevin’s first year at medical school his classmates had better luck finding him on the golf course than in the classroom. [00:10:42] Dawn asks Kevin about his transition from medical school to the neurological surgery training program at New York Hospital, home of the Cornell University Medical College. [00:13:11] Dawn pivots to talk about sepsis, which kills more than 350,000 people annually. She asks Kevin to discuss his tragic story of treating a patient with sepsis as a young neurosurgeon and how that changed the trajectory of his career. [00:16:38] Ken explains that since the aforementioned incident, Kevin has focused on determining why septic shock occurs. Ken refers to a Ted Talk of Kevin’s in which he says, “good science begins with hard questions.” Ken asks Kevin to elaborate on this point. [00:20:49] Dawn mentions that Kevin often describes himself as a brain surgeon who is fascinated by inflammation. Dawn asks Kevin how he responds when people ask him what inflammation is. [00:22:29] Ken follows up by explaining that in 1987 Kevin made progress investigating inflammation with his discovery of tumor necrosis factor (TNF), which contributed to a new class of drugs for inflammatory and autoimmune diseases. Ken asks Kevin to discuss this discovery. [00:25:56] Dawn mentions that in the late ‘90s, Kevin made another discovery that allowed him and his colleagues to merge neuroscience and immunology. Before getting into that discovery, Dawn asks Kevin to explain how humans have simple reflex circuits that harmonize the activity of our organs. She also asks him to talk about Charles Sherrington’s Nobel Prize-winning research, which laid the groundwork for contemporary neuroscience by showing how reflex circuits are the building blocks of our nervous system. [00:29:50] Ken asks Kevin to elaborate on what monoclonal antibodies are, what disorders they can be used to treat, and what their potential benefits and downsides are. [00:33:10] Dawn asks Kevin to talk about the discovery he made in the late 1990s, while studying the possibility of blocking TNF during a cerebral infarction or stroke by injecting a molecule that he and his colleagues developed directly into the brain. [00:35:59] Ken mentions that after this discovery, Kevin started looking into well-established methods in neuroscience, such as those that link specific areas of the brain to specific cognitive functions and asks Kevin to discuss this research. [00:39:45] Dawn explains that the insight that discrete brain regions control specific behaviors led Kevin to postulate that cutting the circuits connecting the brain and organs could reveal the identity of specific areas that control TNF. Dawn asks Kevin to walk through how he investigated this hypothesis. [00:44:22] Ken asks Kevin to give an overview of the functions of the vagus nerve. [00:46:00] Ken mentions that our show notes will provide a link to a short video that maps out the vagus nerve in detail. Ken goes on to mention that after Kevin looked into the relationship between TNF and the vagus nerve, he theorized that the TNF off signal from the vagus nerve completes a nerve circuit between the brain and the immune system. This finding had broad implications, and Ken asks Kevin to elaborate on them. [00:50:57] Dawn mentions that Kevin wrote an article in 2002 for the journal Nature titled “The Inflammatory Reflex”, which emphasized the basic neural pathway that research had identified which reflexively monitors and adjusts the inflammatory response. Dawn goes on to mention that Kevin coined the term “inflammatory reflex” to describe how the nervous system monitors and controls the circuit to prevent the immune system from becoming overactive or underactive. Additionally, Kevin proposed in this article that it might be possible to activate neural anti-inflammatory mechanisms using small molecules to initiate signals in the central nervous system. Dawn asks Kevin to give an overview of the key insights into the inflammatory reflex he discussed in that article. [00:54:15] Ken comments on the monumental importance of this paper to the field of neuro-immunology, and the treatment of inflammatory diseases, and asks Kevin what the response to this paper was. [00:57:30] Dawn explains that Kevin has proposed that a dysregulated inflammatory reflex can lead to toxicity, tissue damage, and the presence of cytokines. It also can lead to miscommunication among cytokines leading to potential complications with autoimmune diseases. Dawn asks Kevin to talk about the process of testing this theory. [01:00:54] Dawn asks Kevin about a sketch he drew while having lunch, which laid out how treating inflammatory diseases using a bioelectronic device might be possible. [01:05:18] Ken pivots to talking about an influential 2016 paper that Kevin wrote on how the stimulation of the vagus nerve targeted the inflammatory reflex. [01:08:23] Ken asks if there are any adverse effects suspected or identified for stimulating the vagus nerve in humans. [01:12:02] Ken mentions that in writing about the vagus nerve Kevin has often talked about how the vagus nerve can get “out of tune.” Ken asks Kevin to explain how this occurs and what it means. [01:14:41] Dawn mentions a study that Kevin spearheaded, which found that the dorsal motor nucleus is an important brain stem locus controlling anti-inflammatory signals and the inflammatory reflex. Dawn asks Kevin to discuss this study and how it was the first to demonstrate that neurons in the brain stem nuclei control the production of TNF. [01:17:51] Dawn asks about a study Kevin and his colleagues conducted that looked at the use of an implanted vagus nerve stimulator in a small group of patients with Crohn’s disease. [01:20:55] Ken asks Kevin what advances in bioelectronic medicine he envisions in the next decade. [01:23:23] Ken mentions that the pharmaceutical industry is likely keeping a close eye on the development of bioelectronic medicine. [01:24:25] Dawn mentions that Kevin is the president and CEO of the Feinstein Institute for Medical Research at Northwell Health, which has 50 research labs, and more than 5,000 researchers and staff on board. Dawn asks Kevin to talk about this research center and the range of work that goes on there. [01:27:29] After mentioning that Kevin holds 120 U.S. patents, Ken asks Kevin about his ongoing tinkering and development of inventions. [01:30:22] Dawn asks Kevin, with all the work he has on his plate, if he still finds time to golf. Links: Kevin Tracey bio Feinstein Institutes for Medical Research Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio