Lloyd Klickstein is the Chief Science Officer at resTORbio, a biopharmaceutical company that develops medications to target the biology of aging. In this episode, Lloyd discusses his company’s clinical application of rapamycin and its derivatives. He also elucidates details of his 2014 paper—a paper that greatly influenced Peter’s perspective of rapamycin in the context of longevity. Peter and Lloyd go on to discuss the dose-dependent effect of rapamycin on immune function and compare rapamycin, fasting, and caloric restriction.
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We discuss:
- His background and decision to leave academia for translational medicine [6:15];
- Translational medicine—bridging the gap between basic science and clinical medicine [10:30];
- What prompted Lloyd to focus on mTOR inhibition? [18:00];
- Defining mTOR, TORC1, and TORC2, and the consequences of inhibiting them with rapamycin [21:30];
- Dose-dependent impact of rapamycin on immune function, mTOR inhibition, and toxicity [42:15];
- Lloyd’s 2014 experiment—mTOR inhibition improves immune function in the elderly [53:00];
- Insights into autophagy, antigen presentation, and the pleiotropic benefits of a rapalog, and how it compares to fasting [1:13:00];
- Lloyd’s 2018 experiment—TORC1 inhibition enhances immune function and reduces infections in the elderly [1:18:45];
- Creation of resTORbio, subsequent studies, and takeaways about dosing, TORC2 inhibition, and tissue selectivity [1:29:00];
- Comparing the longevity effect of rapamycin, fasting, and caloric restriction [1:40:00];
- Excitement around RTB101—resTORbio’s mTOR inhibiting molecule [1:47:00];
- Identifying rapalogs selective for TORC1 [1:56:15];
- Treating depression with ketamine, an activator of mTOR [2:00:00];
- Epigenetic clocks, rapalogs, and metformin [2:03:30]; and
- More.
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His background and decision to leave academia for translational medicine [6:15]
- Science and medicine is the family business
- He did the combined MD, PhD track at Harvard
When did you decide you wanted to focus on immunology, rheumatology?
- “Like many things in life it was about the people, not the science that led me into immunology, rheumatology and where I am.”
- He credits his time in a laboratory at Brigham and Women’s Hospital and meeting such wonderful people that ultimately his decision was to stay there and work and learn with them
- He earned his M.D., Ph.D, in 1989
- He then completed postgraduate clinical training in Internal Medicine, Rheumatology & Immunology at Brigham & Women’s Hospital (BWH) in Boston stayed there until 2006
- In 2006, he left academia to join Tim Wright‘s department at Novartis Institutes
Basis for leaving academia?
“For me it’s important to do both science and medicine, and it’s harder and harder and harder to do that now in an academic environment.”
- Within the academic environment, you have many obligations to research, finding grants, and teaching student — “It’s sort of amazing to me that some folks can actually straddle that.”
- Translational medicine, which was a new concept at the turn of the millenia, “was perfect for somebody like me”
Translational medicine—bridging the gap between basic science and clinical medicine [10:30]
Basic science
-One example of basic science that led to a Nobel Prize is the study of restriction enzymes
- This came from studying obscure bacteria and how they limit their infection by viruses which got to the concept of restriction enzymes—which was required for the development of modern molecular biology
-Another example is CRISPR technology
- It is another critical element of the bacterial immune system—It’s simple, elegant, and powerful
- It came from studying bacterial biology and it became exciting when somebody translated the biochemistry in the bacteria to see if it would it work in humans (which it did)
- See work from Jennifer Doudna
–The takeaway: Basic science isn’t necessarily in pursuit of anything beyond knowledge, and it doesn’t come with this need to have a clinical application with respect to the species of interest
Clinical medicine
- Medicine is the science and practice of establishing the diagnosis, prognosis, treatment, and prevention of disease [wikipedia.org]
- Investigating things like: Does taking this medication lower your risk of a stroke? Does taking this vaccine lower your risk of getting the flu?
Translational medicine
- There’s a big gap between basic science and clinical medicine—and translational medicine bridges that gap …
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Lloyd Klickstein M.D., Ph.D.
Dr. Klickstein is Chief Scientific Officer of resTORbio. Prior to joining resTORbio, Dr. Klickstein was Head of Translational Medicine for the New Indication Discovery Unit (NIDU) and the Exploratory Disease Area (DAx) at Novartis Institutes for Biomedical Research. Under his decade of leadership, NIDU & DAx teams carried multiple projects forward from target identification through clinical proof-of-concept in novel areas of drug development including liver disease, hearing loss and aging, among others. Prior to his 13 years at Novartis, Dr. Klickstein was an academic physician-scientist at Brigham & Women’s Hospital (BWH) in Boston, where he directed an NIH-funded basic research laboratory and maintained an active clinical practice in the Arthritis Center. Dr. Klickstein received his B.S. degree from Tufts University, his M.D. and Ph.D. degrees from Harvard University, completed post-graduate clinical training in Internal Medicine, Rheumatology & Immunology at BWH and a post-doctoral research fellowship at the Center for Blood Research in Boston.
