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An on-off switch for gene editing
Eva Frederick | Whitehead Institute
April 9, 2021

Now, in a paper published online in Cell on April 9, researchers describe a new gene editing technology called CRISPRoff that allows researchers to control gene expression with high specificity while leaving the sequence of the DNA unchanged. Designed by Whitehead Institute Member Jonathan Weissman, University of California San Francisco assistant professor Luke Gilbert, Weissman lab postdoc James Nuñez and collaborators, the method is stable enough to be inherited through hundreds of cell divisions, and is also fully reversible.

“The big story here is we now have a simple tool that can silence the vast majority of genes,” says Weissman, who is also a professor of biology at MIT and an investigator with the Howard Hughes Medical Institute. “We can do this for multiple genes at the same time without any DNA damage, with great deal of homogeneity, and in a way that can be reversed. It’s a great tool for controlling gene expression.”

The project was partially funded by a 2017 grant from the Defense Advanced Research Projects Agency to create a reversible gene editor. “Fast forward four years [from the initial grant], and CRISPRoff finally works as envisioned in a science fiction way,” says co-senior author Gilbert. “It’s exciting to see it work so well in practice.”

Genetic engineering 2.0

The classic CRISPR-Cas9 system uses a DNA-cutting protein called Cas9 found in bacterial immune systems. The system can be targeted to specific genes in human cells using a single guide RNA, where the Cas9 proteins create tiny breaks in the DNA strand. Then the cell’s existing repair machinery patches up the holes.

Because these methods alter the underlying DNA sequence, they are permanent. Plus, their reliance on “in-house” cellular repair mechanisms means it is hard to limit the outcome to a single desired change. “As beautiful as CRISPR-Cas9 is, it hands off the repair to natural cellular processes, which are complex and multifaceted,” Weissman says. “It’s very hard to control the outcomes.”

That’s where the researchers saw an opportunity for a different kind of gene editor — one that didn’t alter the DNA sequences themselves, but changed the way they were read in the cell.

This sort of modification is what scientists call “epigenetic” — genes may be silenced or activated based on chemical changes to the DNA strand. Problems with a cell’s epigenetics are responsible for many human diseases such as Fragile X syndrome and various cancers, and can be passed down through generations.

Epigenetic gene silencing often works through methylation — the addition of chemical tags to to certain places in the DNA strand — which causes the DNA to become inaccessible to RNA polymerase, the enzyme which reads the genetic information in the DNA sequence into messenger RNA transcripts, which can ultimately be the blueprints for proteins.

Weissman and collaborators had previously created two other epigenetic editors called CRISPRi and CRISPRa — but both of these came with a caveat. In order for them to work in cells, the cells had to be continually expressing artificial proteins to maintain the changes.

“With this new CRISPRoff technology, you can [express a protein briefly] to write a program that’s remembered and carried out indefinitely by the cell,” says Gilbert. “It changes the game so now you’re basically writing a change that is passed down through cell divisions — in some ways we can learn to create a version 2.0 of CRISPR-Cas9 that is safer and just as effective, and can do all these other things as well.”

Building the switch

To build an epigenetic editor that could mimic natural DNA methylation, the researchers created a tiny protein machine that, guided by small RNAs, can tack methyl groups onto specific spots on the strand. These methylated genes are then “silenced,” or turned off, hence the name CRISPRoff.

Because the method does not alter the sequence of the DNA strand, the researchers can reverse the silencing effect using enzymes that remove methyl groups, a method they called CRISPRon.

As they tested CRISPRoff in different conditions, the researchers discovered a few interesting features of the new system. For one thing, they could target the method to the vast majority of genes in the human genome — and it worked not just for the genes themselves, but also for other regions of DNA that control gene expression but do not code for proteins. “That was a huge shock even for us, because we thought it was only going to be applicable for a subset of genes,” says first author Nuñez.

Also, surprisingly to the researchers, CRISPRoff was even able to silence genes that did not have large methylated regions called CpG islands, which had previously been thought necessary to any DNA methylation mechanism.

“What was thought before this work was that the 30 percent of genes that do not have a CpG island were not controlled by DNA methylation,” Gilbert says. “But our work clearly shows that you don’t require a CpG island to turn genes off by methylation. That, to me, was a major surprise.”

CRISPRoff in research and therapy

To investigate the potential of CRISPRoff for practical applications, the scientists tested the method in induced pluripotent stem cells. These are cells that can turn into countless cell types in the body depending on the cocktail of molecules they are exposed to, and thus are powerful models for studying the development and function of particular cell types.

The researchers chose a gene to silence in the stem cells, and then induced them to turn into nerve cells called neurons. When they looked for the same gene in the neurons, they discovered that it had remained silenced in 90 percent of the cells, revealing that cells retain a memory of epigenetic modifications made by the CRISPRoff system even as they change cell type.

They also selected one gene to use as an example of how CRISPRoff might be applied to therapeutics: the gene that codes for Tau protein, which is implicated in Alzheimer’s disease. After testing the method in neurons, they were able to show that using CRISPRoff could be used to turn Tau expression down, although not entirely off.  “What we showed is that this is a viable strategy for silencing Tau and preventing that protein from being expressed,” Weissman says. “The question is, then, how do you deliver this to an adult? And would it really be enough to impact Alzheimer’s? Those are big open questions, especially the latter.”

Even if CRISPRoff does not lead to Alzheimer’s therapies, there are many other conditions it could potentially be applied to. And while delivery to specific tissues remains a challenge for gene editing technologies such as CRISPRoff, “we showed that you can deliver it transiently as a DNA or as an RNA, the same technology that’s the basis of the Moderna and BioNTech coronavirus vaccine,” Weissman says.

Weissman, Gilbert, and collaborators are enthusiastic about the potential of CRISPRoff for research as well.  “Since we now can sort of silence any part of the genome that we want, it’s a great tool for exploring the function of the genome,” Weissman says.

Plus, having a reliable system to alter a cell’s epigenetics could help researchers learn the mechanisms by which epigenetic modifications are passed down through cell divisions. “I think our tool really allows us to begin to study the mechanism of heritability, especially epigenetic heritability, which is a huge question in the biomedical sciences,” Nuñez says.

School of Science announces 2021 Infinite Mile awards

Thirteen staff members recognized for dedication to School of Science and to MIT.

School of Science
April 9, 2021

The MIT School of Science has recognized 13 staff members with the 2021 Infinite Mile Award.

Staff are nominated for Infinite Mile Awards, presented annually since their creation in 2001, by their peers for going above and beyond in their roles and making MIT a better place. Their support for the School of Science, and the Institute community as a whole, has been invaluable, especially as we pass the one-year mark of work-from-home and social distancing due to the Covid-19 pandemic.

The following are the 2021 School of Science Infinite Mile winners.

  • Rebecca Chamberlain, administrative officer in the Department of Biology, was nominated by Professor Stephen Bell because Chamberlain “makes things easier for everyone in the department and this has never been more true than in this trying year. Even as she has taken on so much more, she has continued to maintain a friendly, patient, and unflappable attitude that makes her all the more remarkable.”
  • Janice Chang, academic administrator in the Department of Biology, was nominated by MIT Human Resources administrator Helene Kelsey because Chang is “truly exceptional, strives for perfection, and her skills and work ethic are recognized throughout the department. Janice has embraced the associated challenges with wisdom, a common-sense approach, dedication, goodwill, and a willingness to devote endless additional hours to the tasks at hand.”
  • Emma Dunn, undergraduate programs assistant in the Department of Physics, was nominated by Academic Administrator Catherine Modica because, when campus closed, “it was Emma who came up with all the ideas we used to try to reach out to our students, […] tracking their arrivals at home to make sure they were safe, and creating and sending shipments of care packages to every undergraduate major to remind them that we were […] thinking about them and standing ready to help.”
  • Jennifer Fentress, communications officer in the Department of Earth, Atmospheric and Planetary Sciences, was nominated by professor of physics and department head Robert van der Hilst; associate professor of physics David McGee; and staff colleagues Julia Keller, Megan Jordan, Angela Ellis, Maggie Cedarstrom, Brandon Milardo, and Scott Wade because Fentress “has helped advance the work of the school and MIT more broadly. At every opportunity, she ensures that the voices of EAPS research scientists are well-represented.”
  • Laura Frawley, a lecturer in the Department of Brain and Cognitive Sciences, was nominated by Professor Michale Fee and staff colleagues Kate White and Kimberli DeMayo because Frawley “has dedicated so much time and effort into learning all the new tools and resources available to help faculty convert to remote learning. […] All in all, Laura has been a savior this year!”
  • Brittany Greenough, an events planning assistant in the Picower Institute for Learning and Memory, was nominated by Picower Institute director and professor of brain and cognitive sciences Li-Huei Tsai and Administrative Officer William Lawson because, “[i]n this new, virtual environment, Brittany has taken it upon herself to be the resident expert with transitioning events to online formats.”
  • Chhayfou Hong, a financial assistant in the Laboratory for Nuclear Science, was nominated by professors of physics Jesse Thaler, Mike Williams, Joseph Formaggio, and Philip Harris because “without Chai’s herculean efforts here, the IAIFI [NSF AI Institute for Artificial Intelligence and Fundamental Interactions] would not exist, and MIT would have missed out on housing one of the inaugural NSF AI institutes — and on $20 million in revenue over the next five years.”
  • Beverly La Marr, a test engineer in the MIT Kavli Institute for Astrophysics and Space Research, was nominated by Kavli Institute director and professor of physics Robert Simcoe and principal research scientists Marshall Bautz, Ronald Remillard, and Gregory Prigozhin because La Marr “has played an essential part in MKI’s success in space with flagships, mid-sized, and small missions; and in fact, at this moment, three missions bearing her intellectual ‘fingerprints’ are all producing exciting scientific data from space. Her contributions to her colleagues are no less significant.”
  • Brian Pretti, a facilities and operations administrator in the Department of Chemistry, was nominated by professor and department head Troy Van Voorhis and administrative officer Richard Wilk because Pretti “is someone who goes far above and beyond his usual call of duty. He is also a joy to work with, no matter the stress or difficulty of the situation. Brian exemplifies all of the qualities of someone who truly cares about the quality of his work and those individuals he supports. He has demonstrated an incredible commitment to the Department, and it is a better place because of him.”
  • Alison Salie, senior fiscal officer in the Department of Biology, was nominated by professor and department head Alan Grossman because Salie “is a top-notch employee, well-respected across the department and Institute, and valued for her knowledge and expertise, common-sense approach, willingness to provide support and guidance at every turn, persistence, and never-ending goal to keep work flowing smoothly with limited administrative burden on faculty.”
  • Amanda Trainor, a technical associate in the Department of Chemistry, was nominated by colleagues John Dolhun, Brian Pretti, Scott Ide, John Grimes, and graduate student Axel Vera because her “work on all aspects of various lab functions has been outstanding, from finishing her assigned responsibilities, to taking on unassigned work that needed to be done, [and] demonstrating a strong commitment to the well-being of the MIT community by going countless extra miles.”
  • Joshua Wolfe, a technical instructor in the Department of Physics, was nominated by postdoc Alex Shvonski and lecturer Michelle Tomasik because Wolfe “goes above and beyond his prescribed duties because he cares holistically about creating an effective learning environment in our classes.”
  • Macall Zimmerman, senior financial officer in the Department of Chemistry, was nominated by professor and department head Troy Van Voorhis and staff colleagues Richard Wilk and Tyler Brezler because Zimmerman “is someone who goes far above and beyond her usual call of duty. She is an excellent leader, manager, and mentor. She demonstrates an exceptional commitment to every aspect of her work and the staff whom she mentors. Our department is a better place with her in it.”

The 2021 Infinite Mile Award winners receive a monetary award. An in-person celebration will be held in their honor, as well as the 2021 Infinite Expansion Award winners, at a later date with their families, friends, and nominators.

Matthew Vander Heiden named director of the Koch Institute

MIT biology professor and pioneering researcher of cancer cell metabolism will succeed longtime director Tyler Jacks.

Anne Trafton | MIT News Office
April 1, 2021

Matthew Vander Heiden, an MIT professor of biology and a pioneer in the field of cancer cell metabolism, has been named the next director of MIT’s Koch Institute for Integrative Cancer Research, effective April 1.

Vander Heiden will succeed Tyler Jacks, who has served as director for more than 19 years, first for the MIT Center for Cancer Research and then for its successor, the Koch Institute.

“Matt Vander Heiden has been a part of the Koch Institute almost from the beginning,” says MIT President L. Rafael Reif. “He knows firsthand that incredible discoveries emerge when scientists and engineers come together, in one space, to collaborate and learn from each other. We are thrilled that he will be carrying forward the institute’s groundbreaking work at the frontiers of cancer research.”

The MIT Center for Cancer Research (CCR) was founded by Nobel laureate Salvador Luria in 1974, shortly after the federal government declared a “war on cancer,” with the mission of unravelling the molecular basis of cancer. Working alongside colleagues such as Associate Director Jacqueline Lees, Jacks oversaw the evolution of the CCR into the Koch Institute in 2007, as well as the construction of the institute’s new home in Building 76, completed in 2010.

“I’m very grateful for all of the wonderful things that Tyler’s leadership has led to, because I think this really positions us to build on all of those successes and move forward to do more amazing things over the next decade,” Vander Heiden says.

Vander Heiden, who became a member of the Koch Institute in 2010 and has served as an associate director since 2017, is “an excellent choice for the Koch’s next director,” Jacks says. “Matt knows the landscape of cancer research deeply. He is very well-positioned to guide our existing programs and to develop new ones that take advantage of the unique strengths at the Koch and at MIT more broadly, at the intersection of science and engineering for cancer. I am looking forward to watching him lead the Institute’s exciting next chapter.”

Over the past several decades, cancer researchers have made significant strides in their understanding of the genetic underpinnings of the disease. They’ve also identified molecular signatures that distinguish different types of tumors, leading to the development of targeted treatments for specific types of cancer.

Vander Heiden says that he sees great opportunity in the field of cancer research for making new fundamental discoveries regarding the disease, and also for translating existing knowledge into better treatments. He expects that one key area of focus in the coming years will be applying the power of machine learning and artificial intelligence to understanding cancer.

“With the MIT Schwarzman College of Computing coming online, there’s tremendous opportunity in using the rapid advances in machine learning and computer science for health care,” Vander Heiden says. “I think that’s something MIT absolutely should be a leader on, especially as it applies to cancer.”

“Matt Vander Heiden will be a wonderful director,” says Phillip Sharp, an MIT Institute Professor and a member of the Koch Institute, who chaired the search committee for the new director. “His innovative research on cancer metabolism, service as associate director, and ability to ‘think like an engineer’ has earned him deep admiration from colleagues.”

Vander Heiden, who grew up in Wisconsin, earned his bachelor’s degree, MD, and PhD from the University of Chicago. While a graduate student, he became interested in studying the abnormal metabolism seen in cancer cells, which was first discovered nearly 100 years ago by the German chemist Otto Warburg. Instead of breaking down sugar using aerobic respiration, as healthy mammalian cells do, cancer cells switch to an alternative metabolic pathway called fermentation, which is less efficient.

As a postdoc in 2008, Vander Heiden and his colleagues at Harvard Medical School made the discovery that cancer cells shift their metabolism to fermentation by activating an enzyme called PKM2. While at Harvard, Vander Heiden also worked on a paper that contributed to the eventual development of drugs that target cancer cells with a mutation in the IDH gene. These drugs, the first modern FDA-approved cancer drugs that target metabolism, shut off an alternative pathway used by cancer cells with the IDH mutation.

In 2010, Vander Heiden became one of the first new faculty members hired after the creation of the Koch Institute. The Koch Institute was formed with the mission of bringing scientists and engineers together to work on cancer problems, an experimental approach that has had great success, Vander Heiden says.

“When I look at the Koch Institute today, I don’t think of my colleagues as being scientists or engineers. I just view them as people who are asking interesting questions in cancer, trying to solve translational problems, and trying to solve basic problems,” he says. “We have broken down all these barriers, these traditional silos of fields, and I think that uniquely positions us to answer the big questions about cancer going forward.”

While serving as director, Vander Heiden plans to continue his own research program on the role of cell metabolism in the development and progression of cancer. He also plans to continue his work as a medical oncologist at Dana-Farber Cancer Institute, where he treats prostate cancer patients.

“Having a personal link to the clinic helps keep me grounded in the realities of how patients experience cancer, and hopefully that will help me be a better steward of the Koch Institute and help us have even more impact with the work that we’re doing,” he says.

Spying on enzymes while they perform chemical reactions could help treat gut ailments
Raleigh McElvery
March 26, 2021

Humans breathe oxygen, but many microbes deep within in our gut don’t have access to this precious resource. Instead, they breathe sulfur compounds, releasing hydrogen sulfide in the process. This colorless gas is best-known for its rotten stench, but inside the human colon it has been linked to a thinner mucus barrier, and ailments such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and colorectal cancer. In order to develop potential treatments, researchers are probing how microbes create hydrogen sulfide and which molecules they use.

To help further these efforts, Catherine Drennan’s lab and Heather Kulik’s lab at MIT collaborated with Emily Balskus’ lab at Harvard University to investigate the structure and mechanism of an enzyme that’s critical for hydrogen sulfide production: isethionate sulfite-lyase (IslA). The team examined IslA while it was bound to a metabolite that’s readily available in the gut — and revealed how the bacterium Bilophila wadsworthia uses this interaction to help generate the hydrogen sulfide precursor called sulfite. The researchers then compared IslA’s binding behavior to other enzymes in the same family, in order to better understand how these enzymes have evolved to perform challenging chemistry on a wide variety of molecules. Their findings were published on Mar. 26 in the journal Cell Chemical Biology.

“Although abundant, sulfide-producing bacteria are not well understood,” says Drennan, a professor of biology and chemistry and a Howard Hughes Medical Institute investigator. “By characterizing the enzymes in these bacteria that are responsible for sulfur metabolism, we can develop therapeutic strategies to limit production of hydrogen sulfide that can lead to disease.”

Although researchers have been studying bacterial sulfur respiration for decades, IslA was only recently identified. This enzyme breaks the bond between a carbon atom and a sulfur atom in a compound called isethionate, which is a prevalent metabolite in the human body. In doing so, IslA releases the sulfite that bacteria such as B. wadsworthia use to produce hydrogen sulfide.

IslA is a member of a large family of enzymes, known as glycyl radical enzyme (GREs). Scientists can learn a lot from examining the way GREs bind to other molecules, according to Christopher Dawson PhD ’20, the study’s co-first author.

GREs contain a binding site (or “active site”) where they latch onto their respective substrates to perform chemical reactions. “Understanding GREs better will aid in drug design efforts to combat the deleterious effects of some of these enzymes,” Dawson says. “It will also help to engineer enzymes that perform diverse, challenging reactions to expand the toolkit for chemical synthesis.”

To this end, Dawson wanted to compare IslA’s active site — where it binds to isethionate to break the C-S bond — to other enzymes in the GRE family. He used X-ray crystallography to visualize this interaction at the level of individual atoms. The GREs he examined shared similar “barrel-like” structures in their active sites, but used these core features in different ways, depending on the substrates they bound. For instance, isethionate bound higher in IslA’s active site compared to the way other GREs bind their respective substrates. While this aberrant binding behavior is quite unique — even among GREs — another group had found something similar when they elucidated IslA’s structure in a different bacterium. And, the Drennan lab suspects this pattern could be prevalent in other classes of enzymes as well.

Next, Dawson and his colleagues wanted to investigate how IslA goes about cleaving the C-S bond once the enzyme has bound to isethionate. Others had predicted this process would occur via a “migration” reaction. In that scenario, the sulfite leaving group first migrates to another carbon atom and then that C-S bond is cleaved to release it. However, after co-first author Stephania Irwin generated multiple IslA variants, the Kulik lab performed computational analyses, and the researchers completed structural comparisons, the team concluded that migration was not occurring. Instead, IslA appeared to be performing an “elimination” reaction that severed the C-S bond without forming another one via migration.

Now that they know more about IslA — and GREs in general — the researchers hope their insights will aid drug design.

“Understanding how pathogens use enzymes like these to extract sulfite from their hosts and fuel hydrogen sulfide production has very clear therapeutic implications,” Dawson says. “And that’s one of the things I like best about this story.”

Citation
“Molecular Basis of C-S Bond Cleavage in the Glycyl Radical Enzyme Isethionate Sulfite-Lyase”
Cell Chemical Biology, online March 26, 2021,
DOI: 10.1016/j.chembiol.2021.03.001
Christopher D. Dawson, Stephania M. Irwin, Lindsey R. F. Backman, Chip Le, Jennifer X. Wang, Vyshnavi Vennelakanti, Zhongyue Yang, Heather J. Kulik, Catherine L. Drennan, and Emily P. Balskus

Study of synapse strength focuses on ‘active zones’

With new NIH grant, team will learn how neurons build key sites that release neurotransmitters a lot, or a little, to drive nervous system communication

Picower Institute
March 16, 2021

Job descriptions for the thousands of types of neurons in the brain typically include a common function: release chemicals called neurotransmitters to communicate across circuit connections called synapses. In a new study funded by the National Institutes of Health, the lab of MIT Professor Troy Littleton will seek to understand how neurons construct synapses of different strengths, a variety that may be key to the diversity of neural communication.

Littleton, Menicon Professor of Neuroscience in The Picower Institute for Learning and Memory and the Departments of Biology and Brain and Cognitive Sciences at MIT, said the findings could increase scientists’ understanding of how neural circuits develop and change to reflect learning and experience – a phenomenon called plasticity – and might also suggest ways to adjust synaptic strength when it is atypical in disorders such as autism or intellectual disability.

Video from a 2018 Littleton Lab study shows calcium flux (green) indicating the release of glutamate at synapses tagged by the presence of a glutamate receptor (red).

Using neurons that control muscles in the Drosophila fruit fly, the study will focus on “active zones” (AZs), which are tiny neural structures that enable the release of neurotransmitters across each synapse. The flies provide a simple model, Littleton said, that can help elucidate many basic factors affecting AZ strength that are also at play in the neurons of other animals, including mammals.

“Understanding the rules in a simple model like Drosophila that help to define when a synapse is strong or weak allows us to view these principles as fundamental elements of how neurons control synaptic growth and development,” he said. “Depending on which of these factors a neuron modifies or plays around with, it is likely to be able to make synapses stronger or weaker in very different patterns.”

During larval development the neurons build hundreds of AZs. In a 2018 study, Littleton’s lab found that AZs vary widely in their strength: About 10 percent release neurotransmitters as much as 50 times more often than the majority of weaker synapses. The researchers also found that the strongest AZs were typically the ones that had the most time to develop and accumulate their many protein building blocks.

In the new study, which will provide nearly $1.9 million over five years, the team will learn how those active zones get built step by step out of more than a dozen different proteins that arrive at different stages of development. Because some AZs apparently build up bigger and stronger than others, Littleton likens the process to the construction of a variety of houses in a neighborhood—from big four-bedroom homes to little townhomes. The new study, including preliminary work the team has done with the support of the Picower Institute Innovation Fund, will help explain how each kind of structure emerges, in their relative abundance, in the same cell.

In one set of experiments, for instance, his team will study whether the supply of building materials – the various proteins – is a limitation on how many AZs can mature to full strength before development ceases (i.e. maybe they don’t all get enough lumber or nails to fully frame the house in time). The scientists will test that, for instance, with genetic manipulations that change the amount of key proteins produced. By imaging the proteins as they accumulate and by looking in on the same AZs day after day, a technique the lab uses called “intravital imaging,” they can see how changing protein availability changes the construction of AZs in a neuron.

With a house blueprint background a cartoon shows two frames: a few lines and circles arranged over a horizontal bar and then a larger array of lines over the bar with the overall appearance of an erupting fountain or a sprouting plant
A model of active zone construction: Numerous proteins arrive over time during development to ultimately build a structure for releasing neurotransmitters.

In another set of experiments, the team will test whether some AZs are better than others at acquiring the available material supply and putting it to use (i.e. some may have more carpenters than others to make the best use of the available nails and lumber). And to better understand how the construction process might work in longer-lived animals like mammals, where protein materials not only need to be gathered but also maintained and replaced, they will artificially prolong the flies’ larval stage.

In a third set of tests they will examine the case of two types of neurons that each connect to the same fly muscles but exert control in different ways. Though each type works by releasing the same neurotransmitter, called glutamate, “tonic” neurons feature small but constant glutamate release, while the “phasic” cells release stronger, but more occasional, bursts. The study will examine how AZ development differs, for instance, due to differences in gene expression to promote the different function of these otherwise similar cells.

In all, their goal will be to determine how neurons build their different capacities and styles of connection and communication.

In addition to Littleton the research team includes research scientists Yulia Akbergenova and Suresh Jetti, and graduate students Karen Leopold Cunningham and Andrés Crane.

Intrigued by immortality
Eva Frederick | Whitehead Institute
March 16, 2021

New Whitehead Institute director Ruth Lehmann and new Member Yukiko Yamashita study opposite sides of the germ cell life cycle. Yamashita’s work in male germ cells shows how the cells are formed and maintained; Lehmann studies female germ cells to understand their fates. At the Whitehead Institute, they join Member and former director David Page in painting a fuller picture of how these seemingly immortal cell lines pass instructions uninterrupted from generation to generation.

All other cells in the body — neurons, muscle cells, the stem cells that replenish other tissue types — are made anew in each embryo and go away when organisms die. But not the germ cells. “The germ cell passes its DNA to the next generation, then that DNA is used to build up to a new germ cell,” says Yamashita. “That means that germ cells never cease to exist.”

In this way, an unbroken chain of germ cells stretches back to our most distant ancestor. Scientists study this never-ending link for insights into the fundamentals of biology and evolution. Yamashita began studying germ cells as a model to investigate other questions, but as her research progressed, she grew more and more intrigued by the cells’ special properties.

“This is one thing Ruth and I have in common,” Yamashita says. “There are many biologists that study germ cells, but not many are acutely interested or fascinated by this immortality. We want to know, where does it come from?”

Yamashita, also an Investigator of the Howard Hughes Medical Institute, joined Whitehead Institute in September. Work in her laboratory at Whitehead Institute will focus on two areas, using the fruit fly Drosophila melanogaster as a model. First, she will continue her focus from previous projects on the mechanics of asymmetric cell division using male germline stem cells. These cells, like other stem cells in the body, must undergo a series of asymmetric divisions — instead of simply dividing into two identical daughter cells, the cells must create daughters with different cell fates and programming.

“This balance — maintaining the stem cell number while making some differentiating cells — is considered to be a very important process,” she says. “If you end up making too many stem cells, it can become cancerous; but if you commit too much to the differentiation, you lose the stem cell count, and that means you cannot continue sperm production.”

A newer project in her lab centers on the long sequences of nucleotides within organisms’ genomes that don’t code for any genes. They’re often nonsensical, gibberish combinations or long strings of certain bases. This “genomic junk” has long been dismissed as meaningless filler between essential genes, but Yamashita proposes that the junk is essential for the overall structure of the genome. Much like the binding of a book holds together its contents in an organized fashion, the genomic junk may provide a blueprint for how genetic material is held together and eventually read.

Ultimately, it is the germline cells that are responsible for maintaining this DNA framework. Yamashita hypothesizes that slow changes in junk DNA could provide some explanation for why different species are reproductively incompatible.

“If you look at the chimpanzee genome and the human genome, the protein coding regions are, like, 98 percent, 99 percent identical,” she says. “But the junk DNA part is very, very different. We think this divergence might explain what happens when one species splits into two.”

Yamashita’s research team will share lab space with Lehmann’s group. Both researchers use fruit flies for their experiments, but Lehmann’s research focuses on egg cells, not sperm. “Germ cells are special; you don’t need them for survival, but you need them to keep the species going,” she says. “How are they initially specified and set aside? What makes them different, how are they set aside from somatic cells, and how do they maintain their cell fate?”

One project Lehmann is carrying over from her work at New York University’s Skirball Institute of Biomolecular Medicine involves phase transition condensates — small, membraneless granules that bring together the components needed for complex cellular functions. Lehmann studies a specific type of condensate called a germ granule, an aggregation of small RNAs and RNA binding proteins found only in germline cells, which helps determine the cells’ fate.

Lehmann is also investigating the female germline cells’ role in maternal inheritance. After fertilization, the maternal cell imparts not only its nuclear DNA but also components of its cytoplasm, including mitochondria, RNAs, and even bacteria. “This whole idea of cytoplasmic inheritance and the transgenerational continuum of the cytoplasm is something I’m just starting to think about,” she says.

Yamashita and Lehmann share a large open space on the third floor of the Institute, with researchers from each lab integrated throughout. They will also share a fly room and computational room. The researchers hope the communal setup will allow a flow of ideas between their labs. “By sharing this kind of basic space, we are hoping to let our people interact with each other and for discussions to happen,” Yamashita says.

“This is a new concept for Whitehead, and we’ll see how it works,” Lehmann says. “It’s an exciting experiment in lab sociology.”

Linda Griffith and Douglas Lauffenburger honored for contributions to biological engineering education

Professors awarded the National Academy of Engineering's prestigious Bernard M. Gordon Prize for Innovation in Engineering and Technology Education.

School of Engineering
March 11, 2021

The National Academy of Engineering (NAE) has announced that two MIT professors have been jointly awarded the Bernard M. Gordon Prize for Innovation in Engineering and Technology Education, the most prestigious engineering education award in the United States.

Linda G. Griffith, the School of Engineering Professor of Teaching Innovation in the Department of Biological Engineering, and Douglas A. Lauffenburger, the Ford Professor of Biological Engineering, Chemical Engineering and Biology, were recognized for their respective contributions to “the establishment of a new biology-based engineering education, producing a new generation of leaders capable of addressing world problems with innovative biological technologies,” according to an NAE statement.

“We are absolutely delighted that professors Griffith and Lauffenburger received this prestigious prize from the NAE,” says Angela Belcher, head of the Department of Biological Engineering. “Anyone who knows Doug Lauffenburger and Linda Griffith knows that educating and mentoring in engineering, particularly biological engineering, is at the core of who they are.”

Griffith and Lauffenburger spearheaded the establishment of the biological engineering discipline at MIT, which revolves around teaching students how to translate innovations in the molecular life sciences into therapeutics, and a range of non-medical products in agriculture, materials, energy, and nutrition.

“Professor Griffith and Professor Lauffenburger have made incredible contributions to education in biological engineering,” says Anantha P. Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “They have both been fundamental in establishing and shaping the biological engineering curriculum at MIT, and continue to inspire current and former students in this space.”

Griffith championed the biological engineering BS degree program, while Lauffenburger focused his efforts on the graduate level. Students who have participated in the curriculum have gone on to found innovative startups, such as Gingko Bioworks.

“The award is really in recognition of the power of MIT students to create change,” says Griffith. “The creation of a new discipline of engineering was a lot of effort, but it was done in partnership with students who were brave enough to imagine what could be.”

In addition to her achievements in education, Griffith directs the Center for Gynepathology Research and has championed novel approaches in tissue engineering. She is also responsible for establishing the field of physiomimetics.

She holds more than a dozen patents, has over 200 publications, and has chaired multiple scientific conferences, including the annual TED conference-like Open Endoscopy Forum that assembles gynecology scientists, surgeons, and engineers at MIT for a weekend of talks.

Lauffenburger is affiliated with multiple biomedical organizations including the Center for Gynepathology Research, Center for Biomedical Engineering, and Koch Institute for Integrative Cancer Research at MIT. He is a past president of the Biomedical Engineering Society and currently the chair of the College of Fellows of American Institute for Medical and Biological Engineering.

Both Griffith and Lauffenburger hope that their accomplishments at MIT will help propel biological engineering forward on a global level.

“The world needs biology-based technologies to address a broad spectrum of critical challenges that have not been satisfactorily met by physics- and chemistry-based technologies,” says Lauffenburger. “Our aspiration, and expectation, is that what we’ve created here will catalyze adoption of biology-based engineering at many other institutions worldwide in the coming years.”

Established in 2001, the Gordon Prize includes a cash award of $500,000, of which Griffith and Lauffenburger will receive half. The other half will go to support biological engineering education efforts at MIT. Griffith and Lauffenburger will also each receive a gold-plated, sterling silver medal and a hand-scribed certificate.

2021 MacVicar Faculty Fellows named

Professors Guth, Olivetti, Short, and Yaffe are honored for exceptional undergraduate teaching.

Registrar’s Office
March 11, 2021

The Office of the Vice Chancellor and the Registrar’s Office have announced this year’s Margaret MacVicar Faculty Fellows: professor of mathematics Larry Guth, associate professor of materials science and engineering Elsa Olivetti, associate professor of nuclear science and engineering professor Michael Short, and professor of biology and biological engineering Michael Yaffe.

For nearly three decades, the MacVicar Faculty Fellows Program has recognized exemplary and sustained contributions to undergraduate education at MIT. The program was named after Margaret MacVicar, the first dean for undergraduate education and founder of the Undergraduate Research Opportunities Program (UROP). Departments must submit nominations along with recommendation letters from the nominees’ colleagues, students, or alumni. The selection process is highly competitive. Award recipients are appointed to a 10-year term and receive $10,000 per year of discretionary funds. Junior faculty are eligible for an initial three-year term with the possibility of conversion to a 10-year term if tenure is granted.

The 2021 fellows join an elite group of scholars from across the Institute who are committed to curricular innovation, scientific research, and improving the student experience through teaching, mentoring, and advising. Within each of their departments, Guth, Olivetti, Short, and Yaffe have made groundbreaking discoveries, created new subjects, breathed life into longstanding MIT subjects and programs, and gone the extra mile to support and connect with their students.

They will be recognized at a private, virtual gathering on March 12 along with the 2020 fellows — associate professor of materials science and engineering Polina Anikeeva, professor of literature Mary Fuller, associate professor of chemical engineering William Tisdale, and professor of electrical engineering and computer science Jacob White — whose celebration was canceled last spring due to Covid-19.

Larry Guth

A Claude E. Shannon Professor of Mathematics, Larry Guth received his PhD from MIT in 2005 and became a professor in the mathematics department in 2012. He received both the Maryam Mirzakhani Prize in Mathematics and the American Mathematical Society’s Bocher Prize last year.

Guth’s research combines mathematics and mathematical analysis (metric geometry and harmonic analysis specifically), but his special talent lies in his ability to gracefully translate complex information into succinct and digestible terms and communicate these principles to individuals of all levels.

Professor of mathematics Gigliola Staffilani says, “for most of us theoretical mathematicians, our advancement in our research does not make its way into our undergraduate classes. For Larry, it is different. He is capable of distilling the thought process that goes into his most sophisticated papers and present it to his students in an incredibly effective way.”

Junior Dina Atia wrote, “It turned out that Guth’s approach to advising is the same as his approach to integration. Whenever I came to him with a problem that felt huge and complicated, he did the same thing: cut it into small pieces and added them all up.”

Students say his classes are challenging, yet approachable and inclusive. One notes, “He has an incredible ability to place himself in his students’ shoes and make them feel heard.” Another student nominator remarks that Guth’s approach changed her relationship with mathematics as a discipline: “Before coming to MIT, I had decided that mathematics was not for me, and it was through Professor Guth’s instruction I was able to once more realize a passion I thought I had lost.”

Mathematics Research Affiliate Sanjoy Mahajan calls Larry Guth “a wonderful colleague [and a] deep mathematical thinker” and affirms that he “teaches students how to think like a mathematician.”

“There is no one more deserving of such an exceptional award,” concludes Atia. “Throughout my undergraduate career … Professor Guth has been a source of knowledge, passion, and reassurance. He is a model educator and I cannot imagine someone more qualified to be a Margaret MacVicar Faculty Fellow.”

Elsa Olivetti

“It is an overwhelming honor to be selected as a MacVicar Faculty Fellow, particularly in this year when each of us has had to transform both our teaching and our learning in profound and unprecedented ways,” says Elsa Olivetti, the Esther and Harold E. Edgerton Career Development Associate Professor.

Innovation is a key tenet of education at MIT and is a critical part of professor Olivetti’s subjects. Department of Materials Science and Engineering (DMSE) head Jeffrey Grossman remarks of her experimentation in lecturing, curriculum building, mentoring, and more, “[She] is in a class by herself … a brilliant teacher with an uncanny ability to keep the students on the edge of their seats.”

Olivetti received her PhD in materials science and engineering from MIT in 2007 before securing a position of postdoc a few months later. She subsequently worked as a research scientist in the Materials Systems Lab from 2009 to 2013 and began teaching in 2014.

Olivetti’s research addresses environmental issues such as sustainability, recycling-friendly materials, and waste disposition, which have significant real-world implications. After joining Course 3, she was tasked with creating a new subject in the area of industrial ecology and materials from “scratch,” which rolled out with flying colors in 2014.

Elsa Olivetti’s work underscores the importance of caring for undergraduates as a whole, and what most stands out from their testimonials is her positive spirit and compassionate demeanor. “Professor Olivetti’s classroom was one of the most supportive learning environments at MIT,” says Rahul Ramakrishnan, a recent Course 3 alumnus. Another calls her “universally loved by all undergraduates.”

2020 MacVicar Faculty Fellow and DMSE Associate Professor Polina Anikeeva confirms that while Olivetti’s high teaching scores speak to her gift as an educator, “what makes her absolutely unique is the extra mile (more like an extra marathon…) [she] goes to advance undergraduate education and well-being at the level of the department and the Institute.”

Olivetti received the Earll M. Murman Award for Excellence in Undergraduate Advising in 2017, the award for “best DMSE advisor” in 2019, and the Paul Gray Award for Public Service in 2020.

In order to assist students in finding employment, Olivetti established the Course 3 Industry Seminars, pairing undergraduates with individuals working in careers related to 3D printing, environmental consulting, and manufacturing. Olivetti also champions the issues of diversity, equity, and inclusion and incorporates them into her curriculum.

“Her approach is visionary,” says materials science and engineering Associate Professor James LeBeau, “The result of her work serves as the model for materials science and engineering across the country and the world.” Moreover, Olivetti has continued to innovate during the pandemic by spearheading a pilot community on Canvas for faculty to share strategies, recommendations, and best practices for digital and remote learning.

On working with MIT students, she is full of optimism and inspiration: “their humble, creative persistence gives me hope that we actually have a shot to take on the pressing challenges we face today.”

Michael Short

Creative, dedicated, and enthusiastic, Michael Short is an associate professor in nuclear science and engineering (NSE) and, according to his colleagues, “a leader in the field of nuclear materials.”

He received his BS, MS, and PhD from MIT, joined the department in 2005, and became an assistant professor in 2013. He has been recognized with the Joel and Ruth Spira Award, the Junior Bose Award from the School of Engineering, and the Earll M. Murman Award for Excellence in Undergraduate Advising.

Short’s research interests include fouling and its prevention, nondestructive evaluation (NDE), and radiation damage and effects, and he has spent more than a decade in the fields of nuclear materials, microstructural characterization, and alloy development.

A unique element of Short’s classes is his imaginative, hands-on approach. For example, in 22.01 (Ionizing Radiation and Nuclear Engineering), students have the ability to irradiate their toenails in the MIT Nuclear Reactor Laboratory to learn how much arsenic they have in their bloodstream.

Short’s students say that his teaching impacts are nothing “short” of inspirational, musing that he “never sets ‘ceilings’ for the performance of his students” and gives them space to fail. Third-year PhD student Jonathan Paras remarks that Short is “among the very few at the Institute who embody integrity, student-centric focus, and the eccentric hacker spirit that MIT has become known for.”

Michael Short is also deeply committed to curricular innovation and solving complex environmental issues. He is currently working on the problems of climate change and renewable energy through a NEET thread. He also developed the 22-ENG major to provide curricular flexibility, implemented a new prototyping focus to 22.033 (Nuclear Systems Design Project), and substantially revamped 22.01 (Introduction to Nuclear Engineering and Ionizing Radiation).

Much of Short’s work in these two subjects set the stage for wide-ranging improvements to the Course 22 curriculum by “futurizing” undergraduate education through a “context-first” approach that additionally addressed the problem of low enrollment within the major itself.

Associate Provost Richard K. Lester says, “He is a force of nature, and his impact on the NSE undergraduate program has been transformative.”

Among his most impressive accomplishments is his expansion of the department’s UROP program. Professor of nuclear science and engineering Jacopo Buongiorno notes, “[Short] stimulated the faculty to develop and continuously update a rich portfolio of UROP projects and made it easy for students to connect with the faculty through the online UROP system that he created.”

Buongiorno goes on to say that Short’s “energy and creativity, as well as intellectual and emotional connection to UG [undergraduate] students, are second to no one. Simply put … [he] is an unstoppable, inexhaustible machine.”

On being named a 2021 fellow, Short says, “I was absolutely thrilled to be selected, since as an undergrad and grad at MIT I had the distinct pleasure to take courses from a great number of MacVicar Fellows … To be selected to join their ranks … is an enormous honor.”

Michael Yaffe

Michael Yaffe is the David H. Koch Professor of Science, professor of biology and biological engineering, and director of the MIT Center for Precision Cancer Medicine.

After completing his undergraduate degree at Cornell University, he received his MD and PhD from Case Western Reserve University. He has been a member of the Course 7 faculty since 2000 and a member of the biological engineering faculty since its inception.

Yaffe has taught 7.05 (General Biochemistry), an important core subject, since 2001. He also developed 7.10 (Physical Chemistry of Biomolecular Systems), and his work on a 9th edition of “Molecular Cell Biology” has become a primary textbook used by several undergraduate courses.

Yaffe’s research extends across multiple disciplines including materials science, biophysical chemistry, and medicine. He also runs a highly esteemed cell biology and cancer laboratory and serves as physician and trauma surgeon.

“He offered to let me shadow him on his surgeries,” writes one student. “I have not had another professor before or since who was so invested in helping me explore the entirety of my academic interests.” MacVicar Faculty Fellow and professor in the department of biological engineering Linda G. Griffith additionally praises Yaffe’s “unusual ability to straddle the basic science and clinical universes and to translate science into practice.”

Associate professor of biology Matthew Vander Heiden applauds Yaffe’s ability to do it all: “It is difficult to balance … the demands of a research laboratory and teaching responsibilities, but somehow Michael finds a way to take care of some of the sickest patients in Boston … and is among the best educators at any university.”

Michael Yaffe’s teaching style draws on this twin — academic and clinical — expertise, and his classes often include physical props such as Styrofoam balls, colored balloons, and cardboard constructs to help students visualize different structures.

Department head and professor of biology Alan Grossman remarks that Yaffe “mixes rigor and showmanship while presenting cutting-edge findings and science history, all combined into a pedagogy that is captivating and effective. He is an educator in the style of some of MIT’s most magnificent professors who have raised the level of lecturing to an art form.”

In addition to serving as a professor and physician, he is actively involved in MIT’s ROTC program and served in the Middle East as a member of the medical corps of the armed forces reserve. ROTC colleagues called him an “exemplar of the intersection of the military and academia.”

“Yaffe is one of the select few professors at MIT that everyone should get a chance to know,” confirms another student, “as he truly changes the way you understand, view, and approach the world.”

Members of MIT Biology came together with alumni, industry representatives, and supporters to review the department’s challenges and accomplishments.

March 9, 2021
Eyeless roundworms sense color

C. elegans compares the ratio of wavelengths in its environment to avoid dangerous bacteria that secrete colorful toxins.

Raleigh McElvery | Department of Biology
March 4, 2021

Roundworms don’t have eyes or the light-absorbing molecules required to see. Yet, new research shows they can somehow sense color. The study, published on March 5 in the journal Science, suggests worms use this ability to assess the risk of feasting on potentially dangerous bacteria that secrete blue toxins. The researchers pinpointed two genes that contribute to this spectral sensitivity and are conserved across many organisms, including humans.

“It’s amazing to me that a tiny worm — with neither eyes nor the molecular machinery used by eyes to detect colors — can identify and avoid a toxic bacterium based, in part, on its blue color,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute Investigator, and the co-senior author of the study. “One of the joys of being a biologist is the opportunity to discover things about nature that no one has ever imagined before.”

The roundworm in question, Caenorhabditis elegans, is only about a millimeter long. Despite their minute stature and simple nervous system, these nematodes display a complex repertoire of behaviors. They can smell, taste, sense touch, react to temperature, and even escape or change their feeding patterns in response to bright, blue light. Although researchers once thought that these worms bury themselves deep in soil, it’s becoming increasingly clear that C. elegans prefers compost heaps above ground that offer some sun exposure. As a result, roundworms may have a need for light- and color-sensing capabilities after all.

The decomposing organic matter where C. elegans resides offers an array of scrumptious microbes, including bacteria like Pseudomonas aeruginosa, which secretes a distinctive blue toxin. Previous studies showed that worms in the lab feed on a lawn of P. aeruginosa for a few hours and then begin avoiding their food — perhaps because the bacteria continue to divide and excrete more of the colorful poison. Dipon Ghosh, Horvitz lab postdoc and the study’s first author, wondered whether the worms were using the distinctive color to determine if their meal was too toxic to consume.

Over the course of his experiments, Ghosh noticed that his worms were more likely to flee the colorful bacterial lawn if it was bathed in white light from a nearby LED bulb. This finding was curious on its own, but Ghosh wanted know if the blue toxin played a role as well.

To test this theory, he first exchanged the blue toxin for a harmless dye of the same color, and then for a clear, colorless toxin. On its own, neither substitute was sufficient to spur avoidance. Only together did they prompt a response — suggesting the worms were assessing both the toxic nature and the color of the P. aeruginosa secretions simultaneously. Once again, this behavioral pattern only emerged in the presence of the LED’s white light.

Intrigued, Ghosh wanted to examine what it was about the blue color that triggered avoidance. This time, he used two colored LED lights, one blue and one amber, to tint the ambient light. In doing so, he could control the ratio of wavelengths without changing the total energy delivered to the worms. The beam had previously contained the entire visible spectrum, but mixing the amber and blue bulbs allowed Ghosh to tweak the relative amounts of short-wavelength blue light and long-wavelength amber light. Surprisingly, the worms only fled the bacterial lawn when their environment was bathed in light with specific blue:amber ratios.

“We were able to definitively show that worms aren’t sensing the world in grayscale and simply evaluating the levels of brightness and darkness,” Ghosh says. “They’re actually comparing ratios of wavelengths and using that information to make decisions — which was thoroughly unexpected.”

It wasn’t until Ghosh ran his experiments again, this time using various types of wild C. elegans, that he realized the popular laboratory strain he’d been using was actually less color-sensitive compared to its close relatives. After analyzing the genomes of these worms, he was able to identify two genes in particular (called jkk-1 and lec-3) that contributed to these variations in color-dependent foraging.

Although the two genes play many important functions in a variety of organisms, including humans, they are both involved in molecular pathways that help cells respond to stress caused by damaging ultraviolet light.

“We’ve discovered that the color of light in the worm’s environment can influence how the worm navigates the world,” Ghosh says. “But our work suggests that many genes, in addition to the two we’ve already identified, can affect color sensitivity, and we’re now exploring how.”

The notion that worms can sense color is “astounding” and showcases nature’s innovation, according to Leslie Vosshall, Robin Chemers Neustein Professor and Howard Hughes Medical Institute Investigator at The Rockefeller University, who was not involved in the study. “These worms are sliding around in a dim muck with colorful, toxic bacteria. It would be helpful to see and avoid them, so the worms somehow evolved a completely new way to see.”

Vosshall is curious about which cells in C. elegans help discriminate light, as well as the specific roles that the jkk-1 and lec-3 genes play in mediating light perception. “This paper, like all important papers, raises many additional questions,” she says.

Ghosh suspects the lab’s findings could generalize to other critters besides roundworms. If nothing else, it’s clear that light-sensitivity does not always require vision — or eyes. C. elegans are seeing the light, and now so are the biologists.

This research was funded by the Howard Hughes Medical Institute and National Institute of General Medical Sciences.