Michael B. Yaffe

Education

  • PhD, 1987, Case Western Reserve University; MD, 1989, Case Western Reserve University
  • BS, 1981, Chemistry with Concentration in Solid-State and Polymer Physics, Cornell University

Research Summary

Our goal is to understand how signaling pathways are integrated at the molecular and systems levels to control cellular responses. We have two main focuses: First, we study signaling pathways and networks that control cell cycle progression and DNA damage responses in cancer and cancer therapy. Second, we examine the cross-talk between inflammation, cytokine signaling and cancer. Much of our work focuses on how modular protein domains and kinases work together to build molecular signaling circuits, and how this information can be used to design synergistic drug combinations for the personalized treatment of human disease.

Awards

  • MacVicar Faculty Fellow, 2021
  • Fellow, Association of American Physicians, 2021
  • Teaching with Digital Technology Award, 2018
Omer H. Yilmaz

Education

  • PhD, 2008, University of Michigan; MD, 2008, University of Michigan Medical School
  • BS, 1999, Biochemistry and Physics, University of Michigan

Research Summary

The adult intestine is maintained by stem cells that require a cellular neighborhood, or niche, consisting in part of Paneth cells. Our laboratory will investigate the molecular mechanisms of how intestinal stem cells and their Paneth cell niche respond to diverse diets to coordinate intestinal regeneration with organismal physiology and its impact on the formation and growth of intestinal cancers.  By better understanding how intestinal stem cells adapt to diverse diets, we hope to identify and develop new strategies that prevent and reduce the growth of cancers involving the intestinal tract that includes the small intestine, colon, and rectum.

Awards

  • AAAS Martin and Rose Wachtel Cancer Research Award, 2018
  • Pew-Stewart Trust Scholar, 2016-2020
  • Sidney Kimmel Scholar, 2016-2020
  • V Foundation Scholar, 2014-2017
  • Harold M. Weintraub Award, 2007
Richard A. Young

Education

  • PhD, 1979, Yale University
  • BS, 1975, Biological Sciences, Indiana University

Research Summary

We use experimental and computational technologies to determine how signaling pathways, transcription factors, chromatin regulators and small RNAs regulate gene expression in healthy and diseased cells. Our interests range from the basic molecular mechanisms behind gene control to drug development for cancer and other diseases caused by gene misregulation.

Awards

  • National Academy of Medicine, Member, 2019
  • National Academy of Sciences, Member, 2012
Eliezer Calo

Education

  • PhD, 2011, MIT
  • BS, 2006, Chemistry, University of Puerto Rico-Río Piedras

Research Summary

We focus on the molecular entities controlling and coordinating RNA metabolism — that is, the compendium of processes that involve RNA, including protein synthesis, processing, modifications, export, translation and degradation. Our goal is to understand how different aspects of RNA metabolism are controlled to generate structure and function during development, as well as how mutations in components of the RNA metabolic program lead to congenital disorders and cancer.

David Housman

Education

  • PhD, 1971, Brandeis University
  • BS, 1966, Biology, Brandeis University

Research Summary

We use genetic approaches to identify the molecular basis of human disease pathology. More specifically, we develop strategies to combat three major disease areas: cancer, trinucleotide repeat disorders like Huntington’s disease, and cardiovascular disease.

Awards

  • National Academy of Medicine, Member, 1997
  • National Academy of Sciences, Member, 1994
Tyler Jacks

Education

  • PhD, 1988, University of California, San Francisco
  • SB, 1983, Biology, Harvard University

Research Summary

Dr. Jacks’ research has focused on developing new methods for the construction and characterization of genetically engineered mouse models or GEMMs of human cancer, and recently has moved into the burgeoning area of tumor immunology to understand the interactions between the immune system and cancer.  His group has produced GEMMs with constitutive and conditional mutations in several tumor suppressor genes, oncogenes, and genes involved in oxidative stress, DNA repair and epigenetic control of gene expression. These GEMMS have been used to examine the mechanism of tumor initiation and progression, to uncover the molecular, genetic and biochemical relationship to the human diseases, as tools to study response and resistance to chemotherapy, and to explore methods in molecular imaging and early detection of cancer.

Awards

  • AACR Princess Takamatsu Memorial Lectureship, 2020
  • Massachusetts Institute of Technology, James R Killian Jr Faculty Achievement Award, 2015
  • Sergio Lombroso Award in Cancer Research, 2015
  • American Academy of Arts and Sciences, Fellow, 2012
  • National Academy of Sciences, Member, 2009
  • Institute of Medicine of the National Academies, Member, 2009
  • Paul Marks Prize for Cancer Research, 2005
  • Howard Hughes Medical Institute, HHMI Investigator, 1994
Phillip A. Sharp

Education

  • PhD, 1969, University of Illinois, Urbana-Champaign
  • BA, 1966, Chemistry and Math, Union College

Research Summary

We investigate small, non-coding RNAs called microRNAs (miRNAs), which regulate over half of the genes in mammalian cells at the stages of translation and mRNA stability. We are also interested in the processes underlying transcription from the anti-sense strand (so-called “divergent” transcription), as well as the relationship between elongation of transcription, RNA splicing, and chromatin modifications.

Awards

  • AACR Award for Lifetime Achievement in Cancer Research, 2020
  • AACR Distinguished Award for Extraordinary Scientific Innovation and Exceptional Leadership in Cancer Research and Biomedical Science, 2018
  • Royal Society of London, Foreign Fellow, 2011
  • National Science Foundation, National Medal of Science, 2004
  • The Nobel Foundation, Nobel Prize in Physiology or Medicine, 1993
  • National Academy of Medicine, Member, 1991
  • American Association for the Advancement of Science, Fellow, 1987
  • American Academy of Arts and Sciences, Fellow, 1987
  • National Academy of Sciences, Member, 1983
Stefani Spranger

Education

  • PhD, 2011, Ludwig-Maximilian University Munich/Helmholtz-Zentrum Munich
  • MSc, Biology, 2008, Ludwig-Maximilian University Munich/Helmholtz-Zentrum Munich
  • BSc, Biology, 2005, Ludwig-Maximilian University Munich/Helmholtz-Zentrum Munich

Research Summary

We examine the interaction between cancer and immune cells. Using tumor mouse models designed to mimic tumor progression in humans, we investigate the co-evolution of the anti-tumor immune response and cancer. Understanding the interplay between tumor cells and immune cells will help develop and improve effective cancer immunotherapies.

Awards

  • Forbeck Fellow, 2015
Jianzhu Chen

Education

  • PhD, 1990, Stanford University
  • BS, 1982, Biology, Wuhan University

Research Summary 

We seek to understand the immune system and its application in cancer immunotherapy and vaccine development. We study the molecular and cellular mechanisms behind immunological and disease processes, leveraging the vast array of genomic data, humanized mice and clinical samples.

Awards

  • American Association for the Advancement of Science, Fellow, 2012
New player in cellular signaling

Researchers have identified a key nutrient sensor in the mTOR pathway that links nutrient availability to cell growth.

Nicole Giese Rura | Whitehead Institute
November 9, 2017

To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.

The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.

Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.

Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.

“There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”

Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.

“People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”

The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.

“It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”

This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.