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In this episode, Peter sits down with Dr. Kathryn (Katie) Gray, a physician-scientist, high-risk obstetrician, and maternal-fetal medicine specialist at the University of Washington School of Medicine. Katie begins by explaining the remarkable physiologic changes that occur during pregnancy and how the cardiovascular, metabolic, and hormonal systems adapt to support both mother and developing fetus. From there, the conversation turns to some of the most important complications that can arise. Katie explains how gestational diabetes is screened for and treated, and what a diagnosis may mean for the long-term health of both mother and child. She then walks through the biology of preeclampsia, including who is at risk and how the condition is managed. She also discusses HELLP syndrome and postpartum depression. Peter and Katie explore the realities of labor and delivery, including breech presentation, the role of midwives, and the trade-offs between vaginal and cesarean delivery. The conversation also covers stillbirth and the growing role of cell-free DNA in prenatal genetic screening. Other topics include prenatal nutrition and folate, breastfeeding, and exercise during pregnancy. Throughout the episode, Peter and Katie return to a larger question: What can pregnancy reveal about a woman's long-term health? They discuss how complications during pregnancy can provide important clues about future health risks. Finally, Katie highlights some of the major questions that remain unanswered in maternal health and why greater investment in research is needed to improve outcomes for mothers and their children.

Disclaimer: The views expressed on this podcast are solely those of Dr. Kathryn Gray and do not represent the University of Washington or any of its affiliated units. Dr. Gray speaks solely in a personal capacity, and nothing here should be construed as an official position or endorsement from the University of Washington.

We discuss:

• What drew Katie to obstetrics and gynecology, and fundamental questions in the field that remain unanswered [3:15];
• Pregnancy as a cardiovascular and metabolic stress test; the first symptoms and early changes [6:30];
• Early hormonal changes, prenatal nutrition, and neural tube defects [16:00];
• Fetal development and the physiology of gestational diabetes [23:45];
• Diagnosing and treating gestational diabetes [30:00];
• Preeclampsia: diagnosis, biology, acute risk, and how it's managed [37:00];
• HELLP syndrome, what genetic studies reveal about preeclampsia, and the antihypertensive medications used to treat it [49:00];
• What pregnancy reveals about long-term cardiometabolic health [54:45];
• Cesarean delivery, breech presentation, and stillbirth [1:01:15];
• The onset of labor, cervical dilation, and membrane rupture [1:14:15];
• Vaginal delivery and breastfeeding: benefits versus myths [1:23:15];
• Exercise during pregnancy, sleep position in the third trimester, and postpartum depression [1:27:00];
• Prenatal genetic screening: the growing role of cell-free DNA and the gap between what is technologically possible and what gets deployed in the clinic [1:33:00];
• Midwifery and the realities of childbirth [1:39:00];
• Maternal health in the United States and the need for research investment [1:48:30]; and
• More.

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Lloyd B. Klickstein is a physician-scientist who has spent more than 20 years at the intersection of drug discovery, healthy aging, and preventive medicine. Drawing on his experience in academic medicine, translational research, and biotechnology, Lloyd walks through the full arc of modern drug development. He explains how scientists identify an unmet medical need and decide which diseases and therapeutic targets are worth pursuing. From there, he takes us through the process of engineering a drug, testing it in animals, and navigating clinical trials and regulatory approval. Using bimagrumab as a case study, Lloyd explains the rationale for targeting myostatin and activin signaling to increase muscle mass and strength and describes how the antibody was engineered and screened. He then walks through what was learned from early clinical trials. Unexpected effects on fat mass and type 2 diabetes helped reshape bimagrumab's development as a potential treatment for obesity, including its use in combination with semaglutide. Along the way, Peter and Lloyd explore the differences among drug modalities, including biologics and small-molecule therapeutics. They discuss the roles of patents and capital allocation in drug development, along with the requirements for IND submission and GMP manufacturing. They also examine why developing a new drug takes so long and costs so much, and why identifying failures early is critical. At the end of the episode, the conversation turns to mTOR inhibition and geroprotection, as well as Lloyd's current work on a novel pharmacologic approach to cancer prevention. This episode provides a rare behind-the-scenes look at how new medicines are actually created and the scientific, regulatory, and economic decisions that determine which ideas ultimately make it to patients.

We discuss:

• Lloyd's path from academic medicine to translational drug development [3:15];
• Drug modalities, patents, and the economics of innovation [11:30];
• Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls [23:00];
• The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed) [36:45];
• Engineering and screening the bimagrumab antibody, and the cost of developing a new drug [43:45];
• From candidate antibodies to animal proof of concept (impressive muscle hypertrophy) [54:15];
• Toxicology, capital allocation, and the path to an IND [1:02:45];
• IND requirements, GMP manufacturing, and gray market peptides [1:14:45];
• First in-human study design, patient selection, and protection of healthy volunteers [1:22:00];
• Phase 1 dosing, pharmacodynamics, and global trial strategy [1:33:45];
• Phase 2 lessons on muscle mass, function, and nutrition [1:43:30];
• Bimagrumab's effects on fat mass and type 2 diabetes [1:50:45];
• The BELIEVE trial of bimagrumab plus semaglutide [1:59:30];
• Selective mTORC1 inhibition and the challenge of testing geroprotection [2:11:45];
• A new pharmacologic approach to cancer prevention [2:15:45]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter takes a deep dive into thyroid health and explains why diagnosing and managing thyroid dysfunction is unusually complex. He begins with the basic biology of the thyroid gland and three commonly measured hormones—free T4, free T3, and TSH. He explains how T4 is converted to the active hormone T3 and the important functions T3 performs throughout the body. He also explains what reverse T3 is and when it may be useful to measure it. Peter then breaks down thyroid blood tests and their limitations and provides a practical framework for evaluating suspected thyroid dysfunction. He explains why symptoms alone are insufficient for diagnosis and reviews the criteria for diagnosing hypothyroidism, along with conditions that can mimic it. He also explores how hypothyroidism can be both underdiagnosed and overtreated and how to navigate subclinical hypothyroidism. Peter discusses treatment with T4 and T3, including why some patients continue to experience symptoms despite standard T4 replacement. He also explains how thyroid medications should be taken to optimize absorption. Additional topics include Hashimoto's disease, thyroid considerations during pregnancy, hyperthyroidism, the risks of excess iodine, and supplements marketed to support thyroid function. Finally, Peter offers guidance for patients who continue to feel unwell despite apparently normal thyroid tests.

If you're not a subscriber and are listening on a podcast player, you'll only be able to hear a preview of the AMA. If you're a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #89 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Why thyroid management is unusually complex and what the thyroid does [2:00];
• Why symptoms are insufficient for diagnosis and the risks of underdiagnosis and overtreatment [9:00];
• Regulation of the thyroid axis and conversion of T4 to T3 [13:30];
• Reverse T3 and the metabolic effects of T3 [20:00];
• Thyroid blood tests, assay limitations, and who should be tested [22:45];
• Causes and mimics of hypothyroidism and the criteria for diagnosis [29:00];
• Navigating subclinical hypothyroidism [34:30];
• Treating hypothyroidism with T4 and T3 [37:00];
• Hashimoto's disease, pregnancy, and associated autoimmune risks [42:45];
• Proper timing and administration of thyroid medication [43:45];
• Causes, symptoms, diagnosis, and treatment of hyperthyroidism [45:15];
• Iodine excess, the risks of thyroid-support supplements, and evidence for dietary interventions [53:45];
• A practical framework for evaluating and treating patients who suspect thyroid dysfunction [59:30]; and
• More.

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