22 January, 2020
Their discovery of mTOR (mammalian target of rapamycin) is of singular relevance in basic science. “The molecular mechanisms that regulate the growth of organisms and coordinate it with the availability of nutrients were unknown until two decades ago,” the committee points out at the start of its citation. Yet a number of clinical implications are already with us: rapamycin, the drug acting on this molecular target, is administered for an array of conditions, including cancer, diabetes and ageing-related diseases in general.
Not only that, the trailblazing work of Hall and Sabatini – nominated by David Page, Professor of Biology and Director of the Whitehead Institute at MIT – offers clues as to how controlled fasting or “caloric restriction” is able to prolong lifespan, a phenomenon observed in numerous studies since the past century, and demonstrated in mice in the last ten years.
“The function of the mTOR protein is to control cell growth,” explained Michael Hall yesterday after hearing of the award. “In simple terms,” adds Hall, a Professor of Biochemistry in the Biozentrum Center for Molecular Life Sciences at the University of Basel, Switzerland, “mTOR is what makes us grow when we eat.”
“Cell growth is important not only after the fertilization of an egg, giving rise to a full organism, but also in other contexts, such as muscles getting bigger after exercise,” he continues. “Any situation where there is cell growth is controlled by mTOR in response to the availability of nutrients, also in disease contexts like cancer, where cells that are not supposed to grow are growing.”
Sabatini, Professor of Biology at the Massachusetts Institute of Technology, borrows a metaphor from electricity to explain how the mechanism operates: “mTOR is a switch that turns on in the presence of nutrients, so the body can build material [grow], and when there are no nutrients available it breaks the material down.” The on/off of the mTOR switch controls a cascade of hundreds of molecular signals – some of them still unknown to science – and it is this we are referring to when we talk about the mTOR molecular pathway.
The work of the two scientists, who arrived at their findings independently, is the sum of several complementary parts. Hall discovered the target of rapamycin (TOR) protein in yeast cells in 1991 during his time as a senior investigator; Sabatini isolated it in mammals while still a doctoral student, in 1994, and gave it the name mTOR.
Sabatini said yesterday that he “could never have imagined” the implications of this first discovery, made when he was still thinking of devoting himself to clinical medicine. With his PhD thesis, he had set out to explore the therapeutic applications of rapamycin, a natural anti-fungal agent found in the 1970s during an expedition to Easter Island that had proved to have immunosuppressive properties and was used to prevent organ rejection in transplant patients.
After the molecule was isolated in yeast and mice, both researchers began the task of unraveling its multiple organismal functions. Hall would start by showing that TOR represented a paradigm shift in biology. Until then, the general understanding was that the growth of the cell was not an actively regulated physiological process, meaning it was possible to talk about cell division but not cell growth. His group demonstrated that in fact these are two separate, though related processes.
A mechanism implicated in 60% of cancers
Subsequent research has largely focused on mTOR’s role in a series of pathologies. As the committee points, “disruption of the mTOR signaling pathway is linked to numerous diseases, from cancer to neurodevelopmental disorders, and many clinical approaches have been designed to target mTOR or other molecules in the pathway.”
In Hall’s words, “mTOR has a central role in the cell, so central that when it doesn’t work properly it can lead to many different diseases. Cancer is an obvious one, because it is a disease of inappropriate cell growth. And it was known early on that rapamycin had anti-cancer activity, so it has been developed as an anti-cancer drug and is used in the clinic. But what has also emerged in the last 10 or 15 years is that mTOR has a role in many other diseases including diabetes, as well as disorders like obesity.”
Rapamycin is already employed as an immunosuppressant to prevent rejection of transplanted organs, as an anti-cancer agent and in cardiovascular diseases; for example, as a coating for coronary stents to stop new blockages forming in the bloodstream. “It is rare that a drug is used in three major therapeutic areas,” Hall points out, “but that just underscores the central role of mTOR.” Asked about its future potential, he replies that “the most important thing is that what we know about the pathway’s basic biology is exploited to cure disease. I think that is what we’re all shooting for.”
Sabatini takes up the story: “people estimate that 60% of cancers have some mechanism for turning on the mTOR pathway.” And interest is also growing around its role in neurological disorders like epilepsy and ageing-related diseases. “There is evidence that inhibition of the mTOR pathway could also ameliorate the symptoms of conditions like Alzheimer’s or Parkinson’s.” In reality, he adds, “we are just scratching the surface” of possible mTOR applications.
Caloric restriction and longevity
The mTOR pathway and its link with ageing, or rather its prevention or mitigation, is currently among the most active areas of research in this field. And Hall and Sabatini’s findings have provided key insights into how dietary or caloric restriction can promote longevity.
Says Hall, “the molecular basis of this phenomenon was not understood, it was a complete mystery. Then we discovered that mTOR is a nutrient sensor, and if you inhibit it with rapamycin – in animals – it is equivalent to eating less: you ‘trick’ the cells, so they respond as if there were fewer nutrients and prolong their lifespan. This has created a lot of excitement, because of its potential to delay ageing.”
In fact, healthy people are already dosing themselves with rapamycin having read that it extends lifespan in mice. Something both laureates advise against: “I wouldn’t do that,” Hall hastens to say. “I would want it to be studied more carefully before thinking about any kind of anti-ageing therapy on the strength of animal studies.”
However both see promise in the use of mTOR inhibitors to prevent the diseases of age. For Sabatini, “we’re not there yet and we need to do a lot more research, but I think there is a good chance we may be able to exploit this pathway to combat ageing-related diseases.”
“I don’t know if it will help us live to be 120, but I think it will have beneficial effects on different physiological systems,” he concludes, “and I am practically sure that it will ameliorate aspects of ageing-related diseases.”