Barbara Imperiali

Education

  • PhD, 1983, MIT
  • BSc, 1979, Medicinal Chemistry, University College London

Research Summary

We study diverse aspects of protein structure and function and employ multidisciplinary approaches to address fundamental problems at the interface of chemistry and biology. We are fascinated by the amazing complexity and myriad functions of glycoconjugates in human health and disease. Still more enthralling are the intricate membrane-associated pathways that lead to the cellular biogenesis of these important macromolecules. Our group applies approaches and technologies from a wide range of synergistic fields including chemical biology (for inhibitor and probe development), biochemistry and biophysics (for analyses within and beyond native and model membranes), and cellular, molecular and microbiology to unravel these pathways. Ultimately we seek to decipher the molecular logic of glycoconjugate biosynthesis and to identify processes to target in the study of infectious disease.

Awards

  • National Academy of Sciences, Member, 2010
  • Fellow of the Royal Society of Chemistry (FRSC) 2006
  • American Chemical Society – Breslow Award for Achievement in Biomimetic Chemistry 2006
  • Protein Society – Kaiser Award, 2006
  • Margaret MacVicar Faculty Fellow, 2003-2013
  • American Academy of Arts and Sciences, Fellow, 2001
Thomas U. Schwartz

Education

  • PhD, 2000, Free University of Berlin
  • MS, 1996, Biochemistry, Free University of Berlin
  • BS, 1993, Biochemistry, Free University of Berlin

Research Summary

Our primary goal is to understand how signals and molecules are transmitted between the nucleus and cytoplasm across the nuclear envelope. We work to decipher the mechanism and structure of the machinery that executes these cellular processes.

Rebecca Lamason

Education

  • PhD, 2011, The Johns Hopkins University School of Medicine
  • BS, 2002, Molecular Biology and Biotechnology, Millersville University

Research Summary

In the Lamason lab, we investigate how intracellular bacterial pathogens hijack host cell processes to promote infection. In particular, we study how Rickettsia parkeri and Listeria monocytogenes move through our tissues via a process called cell-to-cell spread. We utilize cellular, molecular, genetic, biochemical and biophysical approaches to elucidate the mechanisms of spread in order to reveal key aspects of pathogenesis and host cell biology.

Awards

  • NIH Pathway to Independence Award, 2015
Joseph (Joey) Davis

Education

  • PhD, 2010, MIT
  • BA,  2003, Computer Science, University of California, Berkeley
  • BS, 2003, Biological Engineering, University of California, Berkeley

Research Summary

The Davis lab is working to uncover how cells construct and degrade complex molecular machines rapidly and efficiently. We apply a variety of biochemical, biophysical, and structural approaches including quantitative mass spectrometry and single particle cryo-electron microscopy to understand the detailed molecular mechanisms of these processes. Ongoing projects in the lab are focused on autophagy, an essential eukaryotic protein and organelle degradation pathway, and assembly of the ribosome, which is essential in all cells.

Awards

  • Sloan Research Fellowship, Alfred P. Sloan Foundation, 2021
  • National Institute on Aging R00 Fellowship, 2017
  • National Institute on Aging K99 Fellowship, 2015
Christopher Burge

Education

  • PhD, 1997, Stanford University
  • BS, 1990, Biological Sciences, Stanford University

Research Summary

We aim to understand the code for RNA splicing: how the precise locations of introns and splice sites are identified in primary transcripts and how its specificity changes in different cell types. Toward this end, we are mapping the RNA-binding affinity spectra of dozens of human RNA-binding proteins and integrating this information with in vivo binding and activity data.  We are also studying the functions of 3’ untranslated regions, including their roles in mRNA localization and microRNA regulation. The lab uses a combination of computational and experimental approaches to address these questions.

Awards

  • Schering-Plough Research Institute Award (ASBMB), 2007
  • Overton Prize for Computational Biology (ISCB), 2001
Stephen Bell

Education 

  • PhD, 1990, University of California, Berkeley
  • BS, 1985, Integrated Science Program and Biochemistry, Molecular Biology and Cell Biology, Northwestern University

Research Summary

We focus on the events that occur at the starting points of chromosome duplication. These DNA sequences — called “origins of replication” — are found at multiple sites on each eukaryotic chromosome and direct the assembly of replisomes, which replicate the DNA on both sides of the origin. We study this assembly process to understand how chromosomes are replicated, and how these events are regulated during the cell cycle to ensure genome maintenance.

Awards

  • National Academy of Sciences, Member, 2017
  • National Academy of Sciences Award in Molecular Biology, 2009
  • Howard Hughes Medical Institute, HHMI Investigator, 2000
David Bartel

Education

  • PhD, 1993, Harvard University
  • BA, 1982, Biology, Goshen College

Research Summary

We study microRNAs and other small RNAs that specify the destruction and/or translational repression of mRNAs. We also study mRNAs, focusing on their untranslated regions and poly(A) tails, and how these regions recruit and mediate regulatory phenomena.

Awards

  • National Academy of Sciences, Member, 2011
  • Howard Hughes Medical Institute, HHMI Investigator, 2005
  • National Academy of Sciences Award in Molecular Biology, 2005
  • AAAS Newcomb Cleveland Prize, 2002
Gerald R. Fink

Education

  • PhD, 1965, Yale University
  • BA, 1962, Biology, Amherst College

Research Summary

We study the molecules that allow fungi to penetrate tissues and grow in a hostile environment. Using genetics, biochemistry and genomics, we answer questions such as:  What makes Candida albicans such a successful pathogen?  How do fungal pathogens evolve antibiotic resistance? How do they manage to change their genetic composition so rapidly?

The Fink lab is no longer accepting students.

Awards

  • Thomas Hunt Morgan Medal, Genetics Society of America, 2020
  • James R. Killian Jr. Faculty Achievement Award, 2018
  • American Association for the Advancement of Science, Fellow, 2015
  • Gruber International Prize in Genetics, 2010
  • American Philosophical Society, 2003
  • Yeast Genetics and Molecular Biology – Lifetime Achievement Award, 2002
  • George W. Beadle Award, Genetics Society of America, 2001
  • Ellison Medical Foundation, Senior Scholar Award, 2001
  • National Academy of Medicine, 1996
  • Wilbur Lucius Cross Medal, Yale University, 1992
  • Emil Christian Hansen Foundation Award for Microbiology, Denmark, 1986
  • American Academy of Arts and Sciences, Fellow, 1984
  • Yale Science and Engineering Award, 1984
  • National Academy of Sciences, Member, 1981
  • National Academy of Sciences Award in Molecular Biology, 1981
  • John Simon Guggenheim Memorial Foundation, Guggenheim Fellowship, 1974
Catherine Drennan

Education

  • PhD,1995, University of Michigan
  • BS, 1985, Chemistry, Vassar College

Research Summary

We use X-ray crystallography to investigate the structure and function of enzymes that are medically important in environmental remediation. We are particularly interested in metalloprotein biochemistry, and in the role of conformational change in catalysis.

Awards

  • National Academy of Sciences, 2023
  • American Society for Biochemistry and Molecular Biology, Fellow, 2021
  • American Academy of Arts and Sciences, Member, 2020
  • Dorothy Crowfoot Hodgkin Award, Protein Society, 2020
  • Margaret MacVicar Faculty Fellow, 2015-2025
  • Howard Hughes Medical Institute, HHMI Investigator, 2008
  • Howard Hughes Medical Institute, HHMI Professor, 2006
Revealing an imperfect actor in plant biotechnology

Whitehead Institute researchers detect the chemical mistakes of a common herbicide-resistance enzyme, then successfully re-engineer it for enhanced precision.

Nicole Davis | Whitehead Institute
November 29, 2017

A research team led by MIT’s Whitehead Institute for Biomedical Research has harnessed metabolomic technologies to unravel the molecular activities of a key protein that enables plants to withstand a common herbicide.

Their findings reveal how the protein — a kind of catalyst or enzyme first isolated in bacteria and introduced into plants such as corn and soybeans in the 1990s — can sometimes act imprecisely, and how it can be successfully re-engineered to be more precise. The new study, which appears online in the journal Nature Plants, raises the standards for bioengineering in the 21st century.

“Our work underscores a critical aspect of bioengineering that we are now becoming technically able to address,” says senior author Jing-Ke Weng, a member of the Whitehead Institute and an assistant professor of biology at MIT. “We know that enzymes can behave indiscriminately. Now, we have the scientific capabilities to detect their molecular side effects, and we can leverage those insights to design smarter enzymes with enhanced specificity.”

Plants provide an extraordinary model for scientists to study how metabolism changes over time. Because they cannot escape from predators or search for new food sources when supplies run low, plants must often grapple with an array of environmental insults using what is readily available — their own internal biochemistry.

“Although they appear to be stationary, plants have rapidly evolving metabolic systems,” Weng explains. “Now, we can gain an unprecedented view of these changes because of cutting-edge techniques like metabolomics, allowing us to analyze metabolites and other biochemicals on a broad scale.”

Key players in this evolutionary process, and a major focus of research in Weng’s laboratory, are enzymes. Traditionally, these naturally occurring catalysts have been viewed as mini-machines, taking the proper starting material (or substrate) and flawlessly converting it to the correct product. But Weng and other scientists now recognize that they make mistakes, often by latching on to an unintended substrate.

“This concept, known as enzyme promiscuity, has a variety of implications, both in enzyme evolution and more broadly, in human disease,” Weng says.

It also has implications for bioengineering, as Bastien Christ, a postdoctoral fellow in Weng’s laboratory, and his colleagues recently discovered.

Christ, then a graduate student in Stefan Hörtensteiner’s lab at the University of Zurich in Switzerland, was studying a particular strain of the flowering plant Arabidopsis thaliana as part of a separate project when he made a puzzling observation. He found that two biochemical compounds were present at unusually high levels in the plant’s leaves.

Strangely, these compounds (called acetyl-aminoadipate and acetyl-tryptophan) weren’t present in any of the normal, so-called wild type plants. As he and his colleagues searched for an explanation, they narrowed in on the source: an enzyme, called BAR, that was engineered into the plants as a kind of chemical beacon, enabling scientists to more readily study them.

But BAR is more than just a tool for scientists. It is also one of the most commonly deployed traits in genetically modified crops such as soybeans, corn, and cotton, enabling them to withstand a widely-used herbicide (known as phosphinothricin or glufosinate).

For decades, scientists have known that BAR, originally isolated from bacteria, can render the herbicide inactive by tacking on a short string of chemicals, made of two carbons and one oxygen (also called an acetyl group). As the researchers describe in their Nature Plants paper, BAR has a promiscuous side, and can work on other substrates, too, such as the amino acids tryptophan and aminoadipate (a lysine derivative).

That explains why they can detect the unintended products (acetyl-tryptophan and acetyl-aminoadipate) in crops genetically engineered to carry BAR, such as soybeans and canola.

Their research included detailed studies of the BAR protein, including crystal structures of the protein bound to its substrates. This provided them with a blueprint for how to strategically modify BAR to make it less promiscuous, and favor only the herbicide as a substrate and not the amino acids. Christ and his colleagues created several versions that lack the non-specific activity of the original BAR protein.

“These are natural catalysts, so when we borrow them from an organism and put them into another, they may not necessarily be perfect for our purposes,” Christ says. “Gathering this kind of fundamental knowledge about how enzymes work and how their structure influences function can teach us how to select the best tools for bioengineering.”

There are other important lessons, too. When the BAR trait was first evaluated by the U.S. Food and Drug Administration (FDA) in 1995 for use in canola, and in subsequent years for other crops, metabolomics was largely non-existent as a technology for biomedical research. Therefore, it could not be applied toward the characterization of genetically engineered plants and foods, as part of their regulatory review. Nevertheless, acetyl-aminoadipate and acetyl-tryptophan, which are normally present in humans, have been reviewed by the FDA and are safe for human and animal consumption.

Weng and his colleagues believe their study makes a strong case for considering metabolomics analyses as part of the review process for future genetically engineered crops.

“This is a cautionary tale,” Weng says.

The work was supported by the Swiss National Science Foundation, the EU-funded Plant Fellows program, the Pew Scholar Program in the Biomedical Sciences, and the Searle Scholars Program.