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AudioHelicase logo and Whitehead Member David Sabatini

Structure of the mTORC1 complex, which contains mTOR (left) and Whitehead Member David Sabatini (right).

mTORC1 image: Reprinted from Trends in Biochemical Sciences, Vol. 41/Is. 6, C. Gaubitz, et al., TORC2 Structure and Function, Pages 532-545, Copyright 2016, with permission from Elsevier. Logo: Steven Lee/Whitehead Institute

Sabatini image: Ceal Capistrano/Whitehead Institute

September 12, 2017

Tags: Sabatini LabProtein Function

As a graduate student, Whitehead Member David Sabatini identified mTOR, the keystone molecule in a cellular pathway connecting nutrition, metabolism, and disease. In this episode of AudioHelicase, he discusses how the molecule was first discovered and what his lab is currently working on, including mTOR's role in cancer, diabetes, and aging.


Audio

 

Edited transcript

I’m Lisa Girard, Director of Strategic Communications at Whitehead Institute. And welcome to AudioHelicase, the podcast of Whitehead Institute, unwinding the science and the people behind some of the Institute’s most exciting discoveries.

In this episode, I am talking with Whitehead Member David Sabatini – also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. He is uncovering fundamental connections between aging, metabolism, nutrition, and diseases such as cancer and diabetes.

As a graduate student, Sabatini was curious about how a molecule called rapamycin worked. Isolated from soil bacterium in a sample from the Polynesian island of Easter Island scientists had found that rapamycin possessed a curious array of seemingly unrelated medicinal properties, like curbing cancer and fungal infections, as well as blocking the immune system. Sabatini identified rapamycin’s target, a protein called mTOR, which is short for the mechanistic target of rapamycin. Sabatini and others eventually found out that mTOR lies at the center of a cellular pathway that is involved in sensing and adapting metabolism, physiology, and growth to nutrient levels.

How can one molecule seem to be at the hub of so many processes? I first asked David to tell me a bit more broadly about the work in his lab.

Sabatini: Pretty much all the work in the lab falls under the broad umbrella of the study of growth and metabolism. In particular how metabolites and nutrients impact different physiological processes. And to a large extent, that stems from our early work on the mTOR pathway, which is a protein that I discovered when I was a student and then kept working on when I came to the Whitehead. And our realization that this is a major integrator of nutrition to metabolism and eventually leading us not only to studying that pathway, but to study metabolism per se, and in particular how metabolic processes impact diseases like cancer, or diabetes. How does, for example, fasting and feeding affect stem cells in the gut. Or how does it affect the aging process.

Girard: David’s work on mTOR goes back to his graduate student days. David tells us how he started working on it and why it is so compelling.

Sabatini: So when I was a graduate student at Hopkins with Sol Snyder, I became interested in this molecule rapamycin, which at the time was actually not that well studied. But there was a significant mostly clinical and preclinical body of work—largely abstracts—showing that it did interesting things, like immunosuppression, anticancer effects, antifungal effects, and yet we didn’t know how it worked. And so I set about trying to figure that out, and that eventually led to the discovery of the protein mTOR.

What we started to figure out, and by we, I mean the larger community, is that this protein is really at the center of many, many, key processes. And in fact, you could almost argue that it is one of the most tied-in signaling networks there is. And the reason likely for that is that this pathway, that we now call the mTOR pathway, is a pathway that is really involved in sensing the environment, largely the nutrient state of the environment and then tying it to physiology. But, clearly in our evolutionary history, most animals, even now some fraction of the human population, knowing whether you’re fed or fasted, and in particular, what nutrients you have, which ones you don’t, it’s not hard to imagine how this would impact all of your physiology. In fact, you can connect any physiological system to whether the animal is in a fed or fasted state. So if you’re one of the pathways that makes that connection, then almost by definition, you’re going to be connected to most physiological processes.

Girard: One aspect of mTOR biology soon caught the attention of the general public-its effect on aging.

Sabatini: What kind of drove it from the biomedical research space into the public world, is the connections of mTOR to aging. Rapamycin is the small molecule that is best validated to have a pro-longevity effect in multiple different organisms. And the evidence there is both pharmacological using rapamycin but also genetic by perturbing the mTOR pathway in a variety of ways.

And so this has led to a lot of interest in people who want to extend their lifespan, improve their quality of life, and potentially thinking about how to modulate this system.

There’s been an interesting convergence around aging, because for a long time we’ve known that things like caloric restriction have a pro-longevity effect. And now we know that rapamycin has a pro-longevity effect, and now we can connect through mTOR, rapamycin to caloric restriction and dietary restriction, where you manipulate a particular component of the diet rather than simply reduce total calories.

Girard: From mTOR’s position in this sensing hub it is emerging to play a role in a number of diseases. David tells us more.

Sabatini: So we now know that mTOR is implicated in a large number of diseases. The best connection, probably, is still cancer. And there is really two sides to this. All cancer cells have to grow. And so this is the pathway that drives that growth response. And so by definition, a cancer cell almost has to activate this. And so, there are estimates in the literature that 60-80% of cancer-causing mutations will lead to the activation of this system. And so this has led to quite a bit of excitement of using rapamycin as an anticancer agent, where rapamycin and other molecules that inhibit mTOR are starting to have a significant impact are in cancers where it’s really the pathway itself that’s hyperactivated, like either through mTOR or direct regulators, rather than more upstream components that lead to turning on potentially of any downstream processes. So there I think there’s clear evidence and that’s having an impact already.

In the world of diabetes, it’s actually quite interesting because there are multiple things that are going on. So one is that, this pathway, the mTOR pathway, actually is known to be a suppressor of the insulin-signaling pathway. And in many cases, you know, people have insulin resistance, which means that they can secrete insulin, like in Type 2 diabetes, but don’t respond to it very well. And so there again you might imagine that mTOR inhibitors could sensitize to insulin. There are challenges to that because the pancreas seems to require mTOR to actually secrete insulin. And so you have this double-edged sword. So, it’s not clear that mTOR modulators are necessarily going to have a big impact in the world of diabetes, but theoretically they could, particularly if we could have tissue-specific versions of it.

But then there are many other diseases that that are connected. So, for example, many neurodegenerative diseases are associated sort of with the incapacity to turn over misfolded proteins. And there’s been an argument that if you could modulate the degradation of these proteins through autophagy, for example, you might have some beneficial effect. And mTOR is a major regulator of autophagy. So there’s interest in doing that with that pathway.

There’s a connection to muscle mass. As you know, with aging you lose a lot of muscle. There’s evidence in aging that mTOR is activated in the muscle. And that might be driving that process, because you’re not then turning on autophagy and allowing the muscle to rejuvenate itself and to restore dysfunctional proteins that accumulate.

Girard: Rapamycin appears to have all the makings of a magic bullet for treating diseases involving the mTOR pathway. Yet we are not at that point. What are the challenges?

Sabatini: If you look at the literature, rapamycin looks like a wonder drug. It’s pretty much used in everything. In reality though, the fact that it is connected to so many things, while interesting, also is basically the Achilles’ heel because many normal processes will also be affected. So the therapeutic window—that index—is the challenge with manipulating mTOR. And that has led to the hope that we might be able to develop tissue-specific modulators of this system. That’s largely theoretical right now, but I think that there is some hope that that might actually be the case.

Girard: Many of the challenges facing our efforts to manipulate the mTOR pathway are common in our work in other signaling pathways as well—moving from sustenance in a petri dish to real life physiology.

Sabatini: So we have an idealized version of this pathway that has largely evolved out of tissue culture work in relatively few cell lines. But how that pathway is now manipulated in different tissues and modified and made specific, we don’t, we don’t really know.

And to some extent, that’s the big challenge of all signal transduction—is going from easily manipulatable models in vitro to the real in vivo physiology. And to a large extent, the complexity of these pathways is because different tissues are going to use them differentially in response to different signals and to give different outputs. So that’s one of our big challenges, is how to go in vivo and deal with what the redundancy that there is of signaling inputs. How does one tissue care more about some more than others. And the truth is, we don’t know. And it’s actually non-trivial to do because in culture, we can remove an amino acid and say, “This is what happens with this pathway.” We can remove insulin and see what happens.

In vivo, you can’t have an animal that has no leucine, for example, no arginine. You just can’t do that. You have buffering systems that prevent those things from going away. So the study is a lot harder.

Girard: The mTOR pathway is so intriguingly connected to so many processes that are central to our wellbeing. This makes it at the same time incredibly compelling as well as incredibly challenging to piece apart. As the work of Sabatini and others is revealing, understanding such highly integrated systems provides important clues to how our bodies function in health and disease, and we will eagerly follow their progress.

For Whitehead Institute, I’m Lisa Girard. Thanks for listening. You can learn more about Whitehead science on our website at wi.mit.edu.


Produced by Nicole Giese Rura

Original music by Chocolat Billy. CC BY-NC-ND 4.0

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