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Playing chess, not checkers

Neurons dynamically control their myelin patterns.

Picower Institute
January 1, 2021

Harvard and MIT researchers have discovered a new way that the brain responds to stimuli, with different types of neurons using myelin in different ways. By dynamically controlling myelin, the insulating coating around their long axon projections that helps with signal conduction, neurons have more ways to adapt to changes. Published in the journal Science, the study in mice advances scientists’ understanding of how the brain works and opens avenues for exploring new disease mechanisms.

“The brain requires a diversity of mechanisms at its disposal in order to adapt to stimuli. We know that neurons have different properties, and we demonstrated several years ago that neurons have different patterns of myelination. Now, we have found an additional layer of complexity: neurons actively use their myelin in dynamic and different ways,” said co-senior author Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University.

In biology textbooks, the prototypical image of a neuron depicts the axon with a series of equally sized, evenly spaced pieces of myelin. However, the Arlotta lab showed in 2014 that the picture is more complicated: different types of neurons show different patterns of myelination, with varying lengths of myelin or no myelination on some segments. In the current study, the researchers delved deeper into the phenomenon of how myelination patterns might change over time.

A video showing a 3D block of red and green neurons with myelin
Researchers used a live imaging system to capture both neurons (red) and their surrounding myelin (green) at the same time. Credit: Arlotta Laboratory, Harvard University.

To investigate myelin plasticity, the researchers used mouse models where specific neuron types were fluorescently labeled. They changed the animals’ sensory input by closing one eye, then tracked how the brain responded using a custom-built in vivo imaging system in the lab of collaborator and co-senior author Elly Nedivi.

“Our multicolor method enables the simultaneous visualization of both the myelin and the axons it was wrapping. This allowed us to closely track how myelin was changing over time as mice reconfigured the visual cortex as sight became deprived in one eye,” said Nedivi, who is the William R. (1964) & Linda R. Young Professor of Neuroscience at MIT, and a member of The Picower Institute for Learning and Memory and the Departments of Biology and Brain and Cognitive Sciences.

The researchers found that even though they tracked neurons that were next to each other and part of the same network, different cell types had different responses — specifically, inhibitory neurons remodeled their myelin more than excitatory neurons.

“In the inhibitory neurons, we saw a two-times increase in the number of myelin changes. Those changes can be any way you can imagine: they can be myelin segments shortening or elongating, the addition of new myelin, and also the elimination of an entire piece of myelin,” said Sung Min Yang, lead author and postdoctoral fellow in the Arlotta lab.

The unique capacity to change their myelin opens up possibilities for the neurons, Yang said: “It turns out that neurons do not move myelin around in a consistent way, as in a game of checkers where every game piece has the same move. Instead, the brain is playing chess, where different neurons — or pieces — can move in different ways. This gives the brain more choice in how to use myelin, which is a limited resource.”

The researchers also found that neurons did not necessarily have to produce new myelin, but could reuse and reshape what they already had in order to respond.

“We have discovered a fundamental property of the brain that opens the window to conceptualizing how the organ maximizes its power and optimizes its function. The dynamic distribution of myelin is yet another level of mechanism that the brain uses to diversify its response to a given stimulus — the endless combinations can enable a more complex, even surprising outcome,” Arlotta said.

Based on the findings, the researchers can now investigate how myelin plasticity plays a role in other contexts, including disease.

“We hope to be able to investigate myelin pathology in human brain organoid models, which can be generated from patients or engineered to contain specific mutations associated with myelin abnormalities, in order to better understand the disease mechanisms,” Arlotta said.

This research was supported by the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institute of Mental Health, the National Institutes of Health, and the JPB Foundation.

Four MIT scientists honored with 2021 National Academy of Sciences awards

Pablo Jarillo-Herrero, Aviv Regev, Susan Solomon, and Feng Zhang are the recipients of distinguished awards for major contributions to science.

Laura Carter | School of Science
January 25, 2021

Four MIT scientists are among the 20 recipients of the 2021 Academy Honors for major contributions to science, the National Academy of Sciences (NAS) announced at its annual meeting. The individuals are recognized for their “extraordinary scientific achievements in a wide range of fields spanning the physical, biological, social, and medical sciences.”

The awards recognize: Pablo Jarillo-Herrero, for contributions to the fields of nanoscience and nanotechnology through his discovery of correlated insulator behavior and unconventional superconductivity in magic-angle graphene superlattices; Aviv Regev, for using interdisciplinary information or techniques to solve a contemporary challenge; Susan Solomon, for contributions to understanding and communicating the causes of ozone depletion and climate change; and Feng Zhang, for pioneering achievements developing CRISPR tools with the potential to diagnose and treat disease.

Pablo Jarillo-Herrero: Award for Scientific Discovery

Pablo Jarillo-Herrero, a Cecil and Ida Green Professor of Physics, is the recipient of the NAS Award for Scientific Discovery for his pioneering developments in nanoscience and nanotechnology, which is presented to scientists in the fields of astronomy, materials science, or physics. His findings expand nanoscience by demonstrating for the first time that orientation can be used to dramatically control nanomaterial properties and to design new nanomaterials. This work lays the groundwork for developing a whole new family of 2D materials and has had a transformative impact on the field and on condensed-matter physics.

The biannual award recognizes “an accomplishment or discovery in basic research, achieved within the previous five years, that is expected to have a significant impact on one or more of the following fields: astronomy, biochemistry, biophysics, chemistry, materials science, or physics.”

In 2018, his research group discovered that by rotating two layers of graphene relative to each other by a magic angle, the bilayer material can be turned from a metal into an electrical insulator or even a superconductor. This discovery has fostered new theoretical and experimental research, inspiring the interest of technologists in nanoelectronics. The result is a new field in condensed-matter physics that has the potential to result in materials that conduct electricity without resistance at room temperature.

Aviv Regev: James Prize in Science and Technology Integration

Aviv Regev, who is a professor of biology, a core member of the Broad Institute of Harvard and MIT, a member of the Koch Institute, and a Howard Hughes Medical Institute investigator has been selected for the inaugural James Prize in Science and Technology Integration, along with Harvard Medical School Professor Allon Kelin, for “their concurrent development of now widely adopted massively parallel single-cell genomics to interrogate the gene expression profiles that define, at the level of individual cells, the distinct cell types in metazoan tissues, their developmental trajectories, and disease states, which integrated tools from molecular biology, engineering, statistics, and computer science.”

The prize recognizes individuals “who are able to adopt or adapt information or techniques from outside their fields” to “solve a major contemporary challenge not addressable from a single disciplinary perspective.”

Regev is credited with forging new ways to unite the disciplines of biology, computational science, and engineering as a pioneer in the field of single-cell biology, including developing some of its core experimental and analysis tools, and their application to discover cell types, states, programs, environmental responses, development, tissue locations, and regulatory circuits, and deploying these to assemble cellular atlases of the human body that illuminate mechanisms of disease with remarkable fidelity.

Susan Solomon: Award for Chemistry in Service to Society

Susan Solomon, the Lee and Geraldine Martin Professor of Environmental Studies in the Department of Earth, Atmospheric and Planetary Sciences who holds a secondary appointment in the Department of Chemistry, is the recipient of the Award for Chemistry in Service to Society for “influential and incisive application of atmospheric chemistry to understand our most critical environmental issues — ozone layer depletion and climate change — and for her effective communication of environmental science to leaders to facilitate policy changes.”

The award is given biannually for “contributions to chemistry, either in fundamental science or its application, that clearly satisfy a societal need.”

Solomon is globally recognized as a leader in atmospheric science, notably for her insights in explaining the cause of the Antarctic ozone “hole.” She and her colleagues have made important contributions to understanding chemistry-climate coupling, including pioneering research on the irreversibility of global warming linked to anthropogenic carbon dioxide emissions, and on the influence of the ozone hole on the climate of the southern hemisphere.

Her work has had an enormous effect on policy and society, including the transition away from ozone-depleting substances and to environmentally benign chemicals. The work set the stage for the Paris Agreement on climate, and she continues to educate policymakers, the public, and the next generation of scientists.

Feng Zhang: Richard Lounsbery Award

Feng Zhang, who is the James and Patricia Poitras Professor of Neuroscience at MIT, an investigator at the McGovern Institute for Brain Research and the Howard Hughes Medical Institute, a professor of brain and cognitive sciences and biological engineering at MIT, and a core member of the Broad Institute of MIT and Harvard, is the recipient of the Richard Lounsbery Award for pioneering CRISPR-mediated genome editing.

The award recognizes “extraordinary scientific achievement in biology and medicine” as well as stimulating research and encouraging reciprocal scientific exchanges between the United States and France.

Zhang continues to lead the field through the discovery of novel CRISPR systems and their development as molecular tools with the potential to diagnose and treat disease, such as disorders affecting the nervous system. His contributions in genome engineering, as well as his earlier work developing optogenetics, are enabling a deeper understanding of behavioral neural circuits and advances in gene therapy for treating disease.

In addition, Zhang has championed the open sharing of the technologies he has developed through extensive resource sharing. The tools from his lab are being used by thousands of scientists around the world to accelerate research in nearly every field of the life sciences. Even as biomedical researchers around the world adopt Zhang’s discoveries and his tools enter the clinic to treat genetic diseases, he continues to innovate and develop new technologies to advance science.

The National Academy of Sciences is a private, nonprofit society of distinguished scholars, established in 1863 by the U.S. Congress. The NAS is charged with providing independent, objective advice to the nation on matters related to science and technology as well as encouraging education and research, recognize outstanding contributions to knowledge, and increasing public understanding in matters of science, engineering, and medicine. Winners received their awards, which include a monetary prize, during a virtual ceremony at the 158th NAS Annual Meeting.

This story is a modified compilation from several National Academy of Sciences press releases.

Snake sex chromosomes say less about sex and more about survival
Eva Frederick | Whitehead Institute
January 21, 2021

Sex-specific chromosomes are a dangerous place to be, if you’re a gene. Because these chromosomes — Y chromosomes, in humans — do not have a matching chromosome with which to exchange genetic information, they are prone to losing non-essential genes left and right in a process called genetic decay.

Now, a new study from research scientist Daniel Winston Bellott in the lab of Whitehead Institute Member David Page broadens our understanding of what makes a gene able to survive on a sex-specific chromosome by looking at one especially slithery branch of the evolutionary tree: snakes.

Comparing surviving genes on snake sex-specific chromosomes to those that are lost to the ravages of time can teach scientists about the evolutionary pressures that shaped sex chromosomes as we know them today. “You might think, ‘These are sex chromosomes, so the surviving genes should have something to do with sex, right?’” Bellott said. “But they don’t.”

Instead, many of these genes are essential to the survival of the animal, and take part in key developmental processes. “It turns out that these survivor genes on sex-specific chromosomes may play a very big role in governing how all of the genes across all the chromosomes are read, interpreted and expressed,” said Page, who is also a professor of biology at Massachusetts Institute of Technology (MIT) and an Investigator of the Howard Hughes Medical Institute. “Winston’s study is absolutely foundational to our understanding of what the sex chromosomes are, how the two sexes come to be, and how health and disease traits play out similarly or differently in males and females.”

What is a sex chromosome, anyway? 

Over the course of evolution, all sex chromosomes start out as regular, matching chromosomes called autosomes. Then, somewhere along the line, a mutation happens, and one of the chromosomes gains a “switch,” that, when present, causes an embryo to to develop as a specific sex. “It’s actually really easy to make a sex chromosome,” said Bellott. “In most cases, you only need to change one or two genes and you’ve started the sex chromosome system.”

This process has happened numerous times during the course of evolution. It makes sense; sexual reproduction is an efficient way to ensure genetic diversity. But the whole thing is a bit mysterious; are, for example, certain chromosomes predisposed to become sex chromosomes?

That’s where Bellott thought snakes could be especially helpful. “Snakes have a relatively old system of sex chromosomes, where you have a lot of time for the chromosomes to diverge,” Bellott said. “Time has swept away all the genes that aren’t important, and you can see what kind of genes are left.”

Their sex chromosome system also evolved from different autosomes, some 100 million years after humans’, and thus would provide a useful vantage point from which to consider our own genomes.

To learn more about the evolution of these chromosomes, Bellott and Page first gathered a list of “ancestral genes,” which were likely on the chromosome from which the snake sex chromosomes evolved. New sequencing data for several species of animals distantly related to snakes meant that they had a more complete list of these genes — 1,648 to be exact.

Bellott began painstakingly sifting through the genes that remained on the sex-specific chromosomes of three species of snake: the pygmy rattlesnake, mountain garter snake, and the five-pacer viper. He eventually identified 103 ancestral genes that had survived as long as 90 million years of evolution on the snakes’ sex chromosomes. With this list in hand, Bellott could then ask what these surviving genes had in common that set them apart from the hundreds of genes that were swept off the snakes’ sex chromosomes by genetic decay.

What makes a survivor? 

To Bellott’s surprise, the genes that remained on the snakes’ sex-specific chromosome had nothing to do with sex determination; neither were they expressed more often in sex-specific tissues, or more often in one sex than the other.

Instead, Bellott and Page’s research identified three key properties that led to a gene’s survival on snake sex-specific chromosomes. First, the gene must be dosage sensitive. In other words, the snake’s body depends on its cells to produce an exact amount of that gene’s protein product. Any more, or any less, and the snake experiences illness or death. Second, a surviving gene is likely broadly expressed in different tissues across the body, not localized to one specific organ or area. And third, surviving genes are subject to strong purifying, or negative, selection. Simply put, this means that if something goes wrong with one of these genes, the snake has a slim chance of survival or producing offspring.

When Bellott dove deeper into the genes’ function, he discovered that for many of them the equivalent gene in humans played a role in key developmental processes such as the formation of the face. When these genes were mutated in humans, their faces — and other essential parts of the body — would not develop properly. “What Winston is seeing here is that the genes that were preserved on the sex specific chromosomes in snakes are disproportionately involved in birth defects in people,” Page said. “We think that nature is selecting for the survival of [sex chromosome] genes whose dosage in certain parts of embryonic development is especially critical.”

In time, Bellott said, this may allow scientists to predict genes whose role in developmental disorders is yet to be discovered.  “In some sense, you get to the place where you’re starting to work the experiment backwards in your mind, and say, ‘Let’s take the set of genes that are on sex specific chromosomes in snakes and birds, but that have not yet been implicated in birth defects in humans,’” Page said. “They might be prime candidates to be responsible for heretofore unexplained birth defects.”

From snakes to humans

Next, the researchers sought to broaden their scope. They compared ancestral genes across the three species of snakes and 38 species of birds and mammals with a larger pool of genes that made it to the present day. Many of the surviving genes on bird and mammal chromosomes had different functions than those on snake chromosomes, but again, most had little to do with sex determination.

“Adding the snakes in with the birds and the mammals gave Winston enough data points to be able to see further and to see more precisely, and now for the first time, he was able to confirm something that we had been suspecting for a long time but really didn’t have sufficient data to pin down,” Page said. “And that is that the chromosomes that became sex chromosomes were not sort of inclined to function in sex differences. Before they got picked out of the crowd, they weren’t specialized towards differentiating between the sexes in much of any way.”

Then, as genes were lost over time, evolutionary pressures ensured that the same sort of genes survived. This idea that sex chromosomes — besides their key developmental switch — have little do do with sex determination challenges the common notion of what a sex chromosome actually is.

“I hope people will pick up on this idea that the chromosomes that became sex chromosomes weren’t in any way preordained,” Page said. “They were just ordinary chromosomes out for a walk in the park, and something happened.”

In the future, Bellott and Page plan to further broaden their scope to include other animals, toward the ultimate goal of understanding our own sex chromosomes. “We take these results, and we turn them into a lens through which we look at sex differences in health and disease in our own species,” Page said. “This research really refines our ideas about what it means to be a gene on the human X or Y chromosome, and how we should think about those genes that survive.”

Notes

Bellott, D.W. and Page, D.C. “Dosage-sensitive functions in embryonic development drove the survival of genes on sex-specific chromosomes in snakes, birds, and mammals.” Genome Research, Jan. 21, 2021. DOI: 10.1101/gr.268516.120.

Catching cancer in the act
Eva Frederick | Whitehead Institute
January 21, 2021

When cancer is confined to one spot in the body, doctors can often treat it with surgery or other therapies. Much of the mortality associated with cancer, however, is due to its tendency to metastasize, sending out seeds of itself that may take root throughout the body. The exact moment of metastasis is fleeting, lost in the millions of divisions that take place in a tumor. “These events are typically impossible to monitor in real time,” said Whitehead Institute Member Jonathan Weissman.

Now, researchers led by Weissman, who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute, have turned a CRISPR tool into a way to do just that. In a paper published January 21 in Science, Weissman’s lab, in collaboration with Nir Yosef, a computer scientist at the University of California, Berkeley, and Trever Bivona, a cancer biologist at the University of California, San Francisco (UCSF), treats cancer cells the way evolutionary biologists might look at species, mapping out an intricately detailed family tree. By examining the branches, they can track the cell’s lineage to find when a single tumor cell went rogue, spreading its progeny to the rest of the body.

“With this method, you can ask questions like, ‘How frequently is this tumor metastasizing? Where did the metastases come from? Where do they go?’” Weissman said. “By being able to follow the history of the tumor in vivo, you reveal differences in the biology of the tumor that were otherwise invisible.”

Scratch paper cells

Scientists have tracked the lineages of cancer cells in the past by comparing shared mutations and other variations in their DNA blueprints. These methods, however, depend to a certain extent on there being enough naturally occurring mutations or other markers to accurately show relationships between cells. That’s where Weissman and co-first authors Jeffrey Quinn, then a postdoctoral researcher in Weissman’s lab, and Matthew Jones, a graduate student in Weissman’s lab, saw an opportunity to use CRISPR technology — specifically, a method developed by Weissman Lab member Michelle Chan to track embryo development — to facilitate tracking. Instead of simply hoping that a cancer lineage contained enough lineage-specific markers to track, the researchers decided to use Chan’s method to add in markers themselves. “Basically, the idea is to engineer a cell that has a genomic scratchpad of DNA, that then can be ‘written’ on using CRISPR,” Weissman said. This ‘writing’ in the genome is done in such a way that it becomes heritable, meaning a cell’s grand-offspring would have the ‘writing’ of its parent cells and grandparent cells recorded in its genome.

Where did you come from, where did you go? 
To create these special “scratchpad” cells, Weissman engineered human cancer cells with added genes: one for the bacterial protein Cas9 — the famed “molecular scissors” used in CRISPR genome editing methods — others for glowing proteins for microscopy, and a few sequences that would serve as targets for the CRISPR technology. They then implanted thousands of the modified human cancer cells into mice, mimicking a lung tumor (a model developed by collaborator Bivona).  Mice with human lung tumors often exhibit aggressive metastases, so the researchers reasoned they would provide a good model for tracking cancer progression in real time. As the cells began to divide, Cas9 made small cuts at these target sites. When the cell repaired the cuts, it patched in or deleted a few random nucleotides, leading to a unique repair sequence called an indel. This cutting and repairing happened randomly in nearly every generation, creating a map of cell divisions that Weissman and the team could then track using special computer models that they created by working with Yosef, a computer scientist.
Revealing the invisible
Tracking cells this way yielded some interesting results. For one thing, individual tumor cells were much different from each other than the researchers expected. The cells the researchers used were from an established human lung cancer cell line called A549. “You’d think they would be relatively homogeneous,” Weissman said. “But in fact, we saw dramatic differences in the propensity of different tumors to metastasize — even in the same mouse. Some had a very small number of metastatic events, and others were really rapidly jumping around.”To find out where this heterogeneity was coming from, the team implanted two clones of the same cell in different mice. As the cells proliferated, the researchers found that their descendents metastasized at a remarkably similar rate. This was not the case with the offspring of different cells from the same cell line — the original cells had apparently evolved different metastatic potentials as the cell line was maintained over many generations. The scientists next wondered what genes were responsible for this variability between cancer cells from the same cell line. So they began to look for genes that were expressed differently between nonmetastatic, weakly metastatic and highly metastatic tumors. Many genes stood out, some of which were previously known to be associated with metastasis — although it was not clear whether they were driving the metastasis or simply a side effect of it. One of them, the gene that codes for the protein Keratin 17, is much more strongly expressed in low metastatic tumors than in highly metastatic tumors. “When we knocked down or overexpressed Keratin 17, we showed that this gene was actually controlling the tumors’ invasiveness,” Weissman said. Being able to identify metastasis-associated genes this way could help researchers answer questions about how tumors evolve and adapt. “It’s an entirely new way to look at the behavior and evolution of a tumor,” Weissman said. “We think it can be applied to many different problems in cancer biology.”
Where did you come from, where did you go? 
Weissman’s CRISPR method also allowed the researchers to track with more detail where metastasizing cells went in the body, and when. For example, the progeny of one implanted cancer cell underwent metastasis five separate times, spreading each time from the left lung to other tissues such as the right lung and liver. Other cells made a jump to a different area, and then metastasized again from there. These movements can be mapped neatly in phylogenetic trees (see image), where each color represents a different location in the body. A very colorful tree shows a highly metastatic phenotype, where a cell’s descendents jumped many times between different tissues. A tree that is primarily one color represents a less metastatic cell. Mapping tumor progression in this way allowed Weissman and his team to make a few interesting observations about the mechanics of metastasis. For example, some clones seeded in a textbook way, traveling from the left lung, where they started, to distinct areas of the body. Others seeded more erratically, moving first to other tissues before metastasizing again from there.One such tissue, the mediastinal lymph tissue which sits between the lungs, appears to be a hub of sorts, said co-first author Jeffrey Quinn. “It serves as a waystation that connects the cancer cells to all of this fertile ground that they can then go and colonize,” he said. Therapeutically, the discovery of metastasis “hubs” like this could be extremely useful. “If you focus cancer therapies on those places, you could then slow down metastasis or prevent it in the first place,” Weissman said.In the future, Weissman hopes to move beyond simply observing the cells and begin to predict their behavior. “It’s like with Newtonian mechanics — if you know the velocity and position and all the forces acting on a ball, you can figure out where the ball is going to go at any time in the future,” Weissman said. “We’re hoping to do the same thing with cells. We want to construct essentially a function of what is driving differentiation of a tumor, and then be able to measure where they are at any given time, and predict where they’re going to be in the future.”The researchers are optimistic that being able to track the family trees of individual cells in real time will prove useful in other settings as well. “I think that it’s going to unlock a whole new dimension to what we think about as a measurable quantity in biology,” said co-first author Matthew Jones. “That’s what’s really cool about this field in general is that we’re redefining what’s invisible and what is visible.”

Notes

Jeffrey J. Quinn, Matthew G. Jones, Ross A. Okimoto, Shigeki Nanjo, Michelle M. Chan, Nir Yosef, Trever G. Bivona, Jonathan S. Weissman. “Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts.” Science, Jan. 21, 2021.

Understanding antibodies to avoid pandemics

Structural biologist Pamela Björkman shared insights into pandemic viruses as part of the Department of Biology’s IAP seminar series.

Saima Sidik | Department of Biology
January 19, 2021

Last month, the world welcomed the rollout of vaccines that may finally curb the Covid-19 pandemic. Pamela Björkman, the David Baltimore Professor of Biology and Bioengineering at Caltech, wants to understand how antibodies like the ones elicited by these vaccines target the SARS-CoV-2 virus that causes Covid-19. She hopes this understanding will guide treatment strategies and help design vaccines against future pandemics. She shared her lab’s work during the MIT Department of Biology’s Independent Activities Period (IAP) seminar series, Immunity from Principles to Practice, on Jan. 12.

“Pamela is an amazing scientist, a strong advocate for women in science, and has a stellar history of studying the structural biology of virus-antibody interactions,” says Whitehead Institute for Biomedical Research Member Pulin Li, the Eugene Bell Career Development Professor of Tissue Engineering and one of the organizers of this year’s lecture series.

Immunology research often progresses from the lab bench to the clinic quickly, as was the case with Covid-19 vaccines, says Latham Family Career Development Professor of Biology and Whitehead Institute Member Sebastian Lourido, who organized the lecture series with Li. He and Li chose to focus this year’s seminar series on immunity because this field highlights the tie between basic molecular biology, which is a cornerstone of the Department of Biology, and practical applications.

“Pamela’s work is an excellent example of how fundamental discoveries can be intimately tied to real-world applications,” Lourido says.

Björkman’s lab has a long history of studying antibodies, which are protective proteins that the body generates in response to invading pathogens. Björkman focuses on neutralizing antibodies, which bind and jam up the molecular machines that let viruses reproduce in human cells. Last fall, the U.S. Food and Drug Administration (FDA) authorized a combination of two neutralizing antibodies, produced by the pharmaceutical company Regeneron, for emergency use in people with mild to moderate Covid-19. This remains one of the few treatments available for the disease.

Together with Michel Nussenzweig’s lab at The Rockefeller University, Börkman’s lab identified four categories of neutralizing antibodies that prevent a protein that decorates SARS-CoV-2’s surface, called the spike protein, from binding to a human protein called ACE2. Spike acts like the virus’s key, with ACE2 being the lock it has to open to enter human cells. Some of the antibodies that Björkman’s lab characterized bind to the tip of spike so that it can’t fit into ACE2, like sticking a wad of chewing gum on top of the virus’s key. Others block spike proteins from interacting with ACE2 by preventing them from altering their orientations. Understanding the variety of ways that neutralizing antibodies work will let scientists figure out how to combine them into maximally effective treatments.

Björkman isn’t satisfied with just designing treatments for this pandemic, however. “Coronavirus experts say this is going to keep happening,” she says. “We need to be prepared next time.”

To this end, Björkman’s lab has put pieces of spike-like proteins from multiple animal coronaviruses onto nanoparticles and injected them into mice. This made the mice generate antibodies against a mix of pathogens that are poised to jump into humans, suggesting that scientists could use this approach to create vaccines before pandemics occur. Importantly, the nanoparticles still work after they’re freeze-dried, meaning that companies could stockpile them, and that they could be shipped at room temperature.

Björkman’s talk was the second in the Immunity from Principles to Practice series, which was kicked off by Gabriel Victora from The Rockefeller University. Victora discussed how antibodies are produced in structures called germinal centers that are found in lymph nodes and the spleen.

Next in the series is Chris Garcia from Stanford University, who will speak on Jan. 19 about his lab’s work on engineering immune signaling molecules to maximize their potential to elicit therapeutic responses. To round out the series, Yasmine Belkaid from the National Institute of Allergy and Infectious Disease will speak on Jan. 26 about interactions between the gut microbiome and the pathogens we ingest. These talks complement a number of career development seminars that were organized by graduate students Fiona Aguilar, Alex Chan, Chris Giuliano, Alice Herneisen, Jimmy Ly, and Aditya Nair.

Biden taps Eric Lander and Maria Zuber for senior science posts

Lander to take a leave of absence to assume Cabinet-level post; Zuber to co-chair presidential advisory council.

Steve Bradt | MIT News Office
January 19, 2021

President-elect Joseph Biden has selected two MIT faculty leaders — Broad Institute Director Eric Lander and Vice President for Research Maria Zuber — for top science and technology posts in his administration.

Lander has been named Presidential Science Advisor, a position he will assume soon after Biden’s inauguration on Jan. 20. He has also been nominated as director of the Office of Science and Technology Policy (OSTP), a position that requires Senate confirmation.

Biden intends to elevate the Presidential Science Advisor, for the first time in history, to be a member of his Cabinet.

Zuber has been named co-chair of the President’s Council of Advisors on Science and Technology (PCAST), along with Caltech chemical engineer Frances Arnold, a 2018 winner of the Nobel Prize in chemistry. Zuber and Arnold will be the first women ever to co-chair PCAST.

Lander, Zuber, Arnold, and other appointees will join Biden in Wilmington, Delaware, on Saturday afternoon, where the president-elect will introduce his team of top advisors on science and technology, domains he has declared as crucial to America’s future. Biden has charged this team with recommending strategies and actions to ensure that the nation maximizes the benefits of science and technology for America’s welfare in the 21st century, including addressing health needs, climate change, national security, and economic prosperity.

“From Covid-19 to climate change, cybersecurity to U.S. competitiveness in innovation, the nation faces urgent challenges whose solutions depend on a broad and deep understanding of the frontiers of science and technology. In that context, it is enormously meaningful that science is being raised to a Cabinet-level position for the first time,” MIT President L. Rafael Reif says. “With his piercing intelligence and remarkable record as scientific pioneer, Eric Lander is a superb choice for this new role. And given her leadership of immensely complex NASA missions and her deep engagement with the leading edge of dozens of scientific domains as MIT’s vice president for research, it is difficult to imagine someone more qualified to co-chair PCAST than Maria Zuber. This is a banner day for science, and for the nation.”

Lander will take a leave of absence from MIT, where he is a professor of biology, and the Broad Institute, which he has led since its 2004 founding. The Broad Institute announced today that Todd Golub, currently its chief scientific officer as well as a faculty member at Harvard Medical School and an investigator at the Dana-Farber Cancer Institute, will succeed Lander as director.

Zuber, the E.A. Griswold Professor of Geophysics in MIT’s Department of Earth, Atmospheric, and Planetary Sciences, will continue to serve as the Institute’s vice president for research, a position she has held since 2013.

Separately, Biden announced earlier this week that he will nominate Gary Gensler, professor of the practice of global economics and management at the MIT Sloan School of Management, as chair of the Securities and Exchange Commission.

Eric Lander

Eric S. Lander, 63, has served since 2004 as founding director of the Broad Institute of MIT and Harvard. A geneticist, molecular biologist, and mathematician, he was one of the principal leaders of the international Human Genome Project from 1990 to 2003, and is committed to attracting, teaching, and mentoring a new generation of scientists to fulfill the promise of genomic insights to benefit human health.

From 2009 to 2017, Lander informed federal policy on science and technology as co-chair of PCAST throughout the two terms of President Barack Obama.

“Our country once again stands at a consequential moment with respect to science and technology, and how we respond to the challenges and opportunities ahead will shape our future for the rest of this century,” Lander says. “President-elect Biden understands the central role of science and technology, and I am deeply honored to have been asked to serve.”

Trained as a mathematician, Lander earned a BA in mathematics from Princeton University in 1978. As a Rhodes Scholar from 1978 to 1981, he attended Oxford University, where he earned his doctorate in mathematics. Lander served on the Harvard Business School faculty from 1981 to 1990, teaching courses on managerial economics, decision analysis, and bargaining.

In 1983, his younger brother, Arthur, a developmental neurobiologist, suggested that, with his interest in coding theory, Lander might be interested in how biological systems, including the brain, encode and process information. Lander began to audit courses at Harvard and to moonlight in laboratories around Harvard and MIT, learning about molecular biology and genetics.

In 1986, he was appointed a Whitehead Fellow of the Whitehead Institute for Biomedical Research, where he started his own laboratory. In 1990, Lander was appointed as a tenured professor in MIT’s Department of Biology and as a member of the Whitehead Institute.

Lander’s honors and awards include the MacArthur Fellowship, the Breakthrough Prize in Life Sciences, the Albany Prize in Medicine and Biological Research, the Gairdner Foundation International Award of Canada, and MIT’s Killian Faculty Achievement Award. He was elected as a member of the U.S. National Academy of Sciences in 1997 and of the U.S. Institute of Medicine in 1999.

Maria Zuber

The daughter of a Pennsylvania state trooper and the granddaughter of coal miners, Maria T. Zuber, 62, has been a member of the MIT faculty since 1995 and MIT’s vice president for research since 2013. She has served since 2012 on the 24-member National Science Board (NSB), the governing body of the National Science Foundation, serving as NSB chair from 2016 to 2019.

Zuber’s own research bridges planetary geophysics and the technology of space-based laser and radio systems. She was the first woman to lead a NASA spacecraft mission, serving as principal investigator of the space agency’s Gravity Recovery and Interior Laboratory (GRAIL) mission, an effort launched in 2008 to map the moon’s gravitational field to answer fundamental questions about the moon’s evolution and internal composition. In all, Zuber has held leadership roles associated with scientific experiments or instrumentation on nine NASA missions since 1990.

As MIT’s vice president for research, Zuber is responsible for research administration and policy. She oversees more than a dozen interdisciplinary research centers, including the David H. Koch Institute for Integrative Cancer Research, the Plasma Science and Fusion Center, the Research Laboratory of Electronics, the Institute for Soldier Nanotechnologies, the MIT Energy Initiative (MITEI), and the Haystack Observatory. She is also responsible for MIT’s research integrity and compliance, and plays a central role in research relationships with the federal government.

“Many of the most pressing challenges facing the nation and the world will require breakthroughs in science and technology,” Zuber says. “An essential element of any solution must be rebuilding trust in science, and I’m thrilled to have the opportunity to work with President-elect Biden and his team to drive positive change.”

Zuber holds a BA in astronomy and geology from the University of Pennsylvania, awarded in 1980, and an ScM and PhD in geophysics from Brown University, awarded in 1983 and 1986, respectively. She has received awards and honors including MIT’s Killian Faculty Achievement Award; the American Geophysical Union’s Harry H. Hess Medal; and numerous NASA awards, including the Distinguished Public Service Medal and the Outstanding Public Leadership Medal. She was elected as a member of the National Academy of Sciences in 2004.

Todd Golub

Todd Golub, 57, will become the next director of the Broad Institute. He joined Dana-Farber and Harvard Medical School in 1997, and is currently a professor of pediatrics at Harvard Medical School and the Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber.

Golub served as a leader of the Whitehead Institute/MIT Center for Genome Research, the precursor to the Broad Institute. He has also been an investigator with the Howard Hughes Medical Institute, and has served as chair of numerous scientific advisory boards, including at St. Jude Children’s Research Hospital and the National Cancer Institute’s Board of Scientific Advisors.

Golub is also an entrepreneur, having co-founded several biotechnology companies to develop diagnostic and therapeutic products. He has created and applied genomic tools to understand the basis of disease, and to develop new approaches to drug discovery. He has made fundamental discoveries in the molecular basis of human cancer, and has helped develop new approaches to precision medicine.

“Broad is in a stronger scientific and cultural position today than at any point in our 16-year history,” Golub says. “Moreover, the pandemic has pushed us to think differently about nearly every aspect of how we collaborate and deliver on our scientific mission. We are well-positioned to work with the larger scientific community to confront some of the most urgent challenges in biomedicine: from developing novel diagnostics and therapeutics for infectious diseases and cancer, to understanding the genetic basis of cardiovascular disease and mental illness. I am honored to serve as director of this remarkable institution.”

Members of the Broad Institute’s Board of Directors thanked Lander for his lengthy service and expressed optimism in Golub’s ability to build upon that foundation.

“Todd’s deep knowledge of the Broad Institute community, its science, and its mission to propel the understanding and treatment of disease make him the perfect choice for the Institute’s next director,” says Louis Gerstner, Jr., chair of the Broad Institute Board of Directors. “Todd is well-positioned to lead the Institute and our key scientific collaborations forward, and the board is highly confident he will continue the Broad’s culture of innovation, collegiality, and constant renewal.”

Broad board member Shirley Tilghman, professor of molecular biology and public policy and president emerita of Princeton University, adds: “In its 16 years, the Broad has become one of the most unique institutions in the biomedical ecosystem. Under Eric’s and Todd’s leadership, it has developed powerful new methods and made many contributions to genomic medicine that will benefit human health.”

Why cancer cells waste so much energy

MIT study sheds light on the longstanding question of why cancer cells get their energy from fermentation.

Anne Trafton | MIT News Office
January 19, 2021

In the 1920s, German chemist Otto Warburg discovered that cancer cells don’t metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient.

MIT biologists have now found a possible answer to this longstanding question. In a study appearing in Molecular Cell, they showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

“This has really been a hundred-year-old paradox that many people have tried to explain in different ways,” says Matthew Vander Heiden, an associate professor of biology at MIT and associate director of MIT’s Koch Institute for Integrative Cancer Research. “What we found is that under certain circumstances, cells need to do more of these electron transfer reactions, which require NAD+, in order to make molecules such as DNA.”

Vander Heiden is the senior author of the new study, and the lead authors are former MIT graduate student and postdoc Alba Luengo PhD ’18 and graduate student Zhaoqi Li.

Inefficient metabolism

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don’t have enough oxygen available to perform aerobic respiration.

Since Warburg’s discovery, scientists have put forth many theories for why cancer cells switch to the inefficient fermentation pathway. Warburg originally proposed that cancer cells’ mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

In this study, the MIT team decided to try to come up with a solution by asking what would happen if they suppressed cancer cells’ ability to perform fermentation. To do that, they treated the cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway.

They saw, as others have previously shown, that blocking fermentation slows down cancer cells’ growth. Then, they tried to figure out how to restore the cells’ ability to proliferate, while still blocking fermentation. One approach they tried was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins.

When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn’t perform fermentation. This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows.

“We hypothesized that when you make both NAD+ and ATP together, if you can’t get rid of ATP, it’s going to back up the whole system such that you also cannot make NAD+,” Li says.

Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. “If you step back and look at the pathways, what you realize is that fermentation allows you to generate NAD+ in an uncoupled way,” Luengo says.

Solving the paradox

The researchers tested this idea in other types of rapidly proliferating cells, including immune cells, and found that blocking fermentation but allowing alternative methods of NAD+ production enabled cells to continue rapidly dividing. They also observed the same phenomenon in nonmammalian cells such as yeast, which perform a different type of fermentation that produces ethanol.

“Not all proliferating cells have to do this,” Vander Heiden says. “It’s really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they’re burning, that’s when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed.”

The findings suggest that drugs that force cancer cells to switch back to aerobic respiration instead of fermentation could offer a possible way to treat tumors. Drugs that inhibit NAD+ production could also have a beneficial effect, the researchers say.

The research was funded by the Ludwig Center for Molecular Oncology, the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Medical Research Council, NHS Blood and Transplant, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, Stand Up 2 Cancer, the Lustgarten Foundation, and the MIT Center for Precision Cancer Medicine.

Through my Viewfinder: savoring the little things
Irene Shih | MindHandHeart
January 13, 2021
window in a house

If the coronavirus pandemic has taught me (and probably many of you) anything, it is that time is of the essence. Funnily enough, when campus and research were shut down, I had too much time that I didn’t know what to do with. In the beginning, I was glad that I could sleep in as much as I wanted but after a month of doing just that, I was so bored of staying indoors. One of the ways to get myself out of the house was the anticipation of witnessing something I would find endearing. I’ve always loved people watching and being observant of random details that most others miss. These little quiet acts, signs that life was happening inside these still, quiet facades, I say to them: I see you, I acknowledge your existence. I spent much of the spring and summer taking long walks around Cambridge, sometimes with a friend but mostly on my own. I feel happy that I managed to capture some of my favorite moments on these walks with my film camera.

My favorite part of photography is that I get to share how I see life, how I am able to note what matters to me. It has never been about creating a pretty image. What I find interesting, sad, beautiful, I take pictures of.

 

girl holding a cake

I made a chocolate dairy-free cake for my awesome labmate who defended her PhD thesis during the pandemic.

food cans on a table

In East Cambridge, free food laid out on a table outside a house.

 

wall with names
a blue house

I enjoyed walking around my neighborhood and seeing signs like these.

window in a house
window in a house
Neuroscientists identify brain circuit that encodes timing of events

Findings suggest this hippocampal circuit helps us to maintain our timeline of memories.

Anne Trafton | MIT News Office
January 12, 2021

When we experience a new event, our brain records a memory of not only what happened, but also the context, including the time and location of the event. A new study from MIT neuroscientists sheds light on how the timing of a memory is encoded in the hippocampus, and suggests that time and space are encoded separately.

In a study of mice, the researchers identified a hippocampal circuit that the animals used to store information about the timing of when they should turn left or right in a maze. When this circuit was blocked, the mice were unable to remember which way they were supposed to turn next. However, disrupting the circuit did not appear to impair their memory of where they were in space.

The findings add to a growing body of evidence suggesting that when we form new memories, different populations of neurons in the brain encode time and place information, the researchers say.

“There is an emerging view that ‘place cells’ and ‘time cells’ organize memories by mapping information onto the hippocampus. This spatial and temporal context serves as a scaffold that allows us to build our own personal timeline of memories,” says Chris MacDonald, a research scientist at MIT’s Picower Institute for Learning and Memory and the lead author of the study.

Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at the Picower Institute, is the senior author of the study, which appears this week in the Proceedings of the National Academy of Sciences.

Time and place

About 50 years ago, neuroscientists discovered that the brain’s hippocampus contains neurons that encode memories of specific locations. These cells, known as place cells, store information that becomes part of the context of a particular memory.

The other critical piece of context for any given memory is the timing. In 2011, MacDonald and the late Howard Eichenbaum, a professor of psychological and brain sciences at Boston University, discovered cells that keep track of time, in a part of the hippocampus called CA1.

In that study, MacDonald, who was then a postdoc at Boston University, found that these cells showed specific timing-related firing patterns when mice were trained to associate two stimuli — an object and an odor — that were presented with a 10-second delay between them. When the delay was extended to 20 seconds, the cells reorganized their firing patterns to last 20 seconds instead of 10.

“It’s almost like they’re forming a new representation of a temporal context, much like a spatial context,” MacDonald says. “The emerging view seems to be that both place and time cells organize memory by mapping experience to a representation of context that is defined by time and space.”

In the new study, the researchers wanted to investigate which other parts of the brain might be feeding CA1 timing information. Some previous studies had suggested that a nearby part of the hippocampus called CA2 might be involved in keeping track of time. CA2 is a very small region of the hippocampus that has not been extensively studied, but it has been shown to have strong connections to CA1.

To study the links between CA2 and CA1, the researchers used an engineered mouse model in which they could use light to control the activity of neurons in the CA2 region. They trained the mice to run a figure-eight maze in which they would earn a reward if they alternated turning left and right each time they ran the maze. Between each trial, they ran on a treadmill for 10 seconds, and during this time, they had to remember which direction they had turned on the previous trial, so they could do the opposite on the upcoming trial.

When the researchers turned off CA2 activity while the mice were on the treadmill, they found that the mice performed very poorly at the task, suggesting that they could no longer remember which direction they had turned in the previous trial.

“When the animals are performing normally, there is a sequence of cells in CA1 that ticks off during this temporal coding phase,” MacDonald says. “When you inhibit the CA2, what you see is the temporal coding in CA1 becomes less precise and more smeared out in time. It becomes destabilized, and that seems to correlate with them also performing poorly on that task.”

Memory circuits

When the researchers used light to inhibit CA2 neurons while the mice were running the maze, they found little effect on the CA1 “place cells” that allow the mice to remember where they are. The findings suggest that spatial and timing information are encoded preferentially by different parts of the hippocampus, MacDonald says.

“One thing that’s exciting about this work is this idea that spatial and temporal information can operate in parallel and might merge or separate at different points in the circuit, depending on what you need to accomplish from a memory standpoint,” he says.

MacDonald is now planning additional studies of time perception, including how we perceive time under different circumstances, and how our perception of time influences our behavior. Another question he hopes to pursue is whether the brain has different mechanisms for keeping track of events that are separated by seconds and events that are separated by much longer periods of time.

“Somehow the information that we store in memory preserves the sequential order of events across very different timescales, and I’m very interested in how it is that we’re able to do that,” he says.

The research was funded by the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, and the JPB Foundation.

Turning microbiome research into a force for health

A diverse group of researchers is working to turn new discoveries about the trillions of microbes in the body into treatments for a range of diseases.

Zach Winn | MIT News Office
January 8, 2021

The microbiome comprises trillions of microorganisms living on and inside each of us. Historically, some researchers have guessed at its role in human health, but in the last decade or so genetic sequencing techniques have illuminated this galaxy of microorganisms enough to study it in detail.

As researchers unravel the complex interplay between our bodies and microbiomes, they are beginning to appreciate the full scope of the field’s potential for treating disease and promoting health.

For instance, the growing list of conditions that correspond with changes in the microbes of our gut includes type 2 diabetes, inflammatory bowel disease, Alzheimer’s disease, and a variety of cancers.

“In almost every disease context that’s been investigated, we’ve found different types of microbial communities, divergent between healthy and sick patients,” says professor of biological engineering Eric Alm. “The promise [of these findings] is that some of those differences are going to be causal, and intervening to change the microbiome is going to help treat some of these diseases.”

Alm’s lab, in conjunction with collaborators at the Broad Institute of MIT and Harvard, did some of the early work characterizing the gut microbiome and showing its relationship to human health. Since then, microbiome research has exploded, pulling in researchers from far-flung fields and setting new discoveries in motion. Startups are now working to develop microbiome-based therapies, and nonprofit organizations have also sprouted up to ensure these basic scientific advances turn into treatments that benefit the maximum number of people.

“The first chapter in this field, and our history, has been validating this modality,” says Mark Smith PhD ’14, a co-founder of OpenBiome, which processes stool donations for hospitals to conduct stool transplants for patients battling gut infection. Smith is also currently CEO of the startup Finch Therapeutics, which is developing microbiome-based treatments. “Until now, it’s been about the promise of the microbiome. Now I feel like we’ve delivered on the first promise. The next step is figuring out how big this gets.”

An interdisciplinary foundation

MIT’s prominent role in microbiome research came, in part, through its leadership in a field that may at first seem unrelated. For decades, MIT has made important contributions to microbial ecology, led by work in the Parsons Laboratory in the Department of Civil and Environmental Engineering and by scientists including Institute Professor Penny Chisholm.

Ecologists who use complex statistical techniques to study the relationships between organisms in different ecosystems are well-equipped to study the behavior of different bacterial strains in the microbiome.

Not that ecologists — or anyone else — initially had much to study involving the human microbiome, which was essentially a black box to researchers well into the 2000s. But the Human Genome Project led to faster, cheaper ways to sequence genes at scale, and a group of researchers including Alm and visiting professor Martin Polz began using those techniques to decode the genomes of environmental bacteria around 2008.

Those techniques were first pointed at the bacteria in the gut microbiome as part of the Human Microbiome Project, which began in 2007 and involved research groups from MIT and the Broad Institute.

Alm first got pulled into microbiome research by the late biological engineering professor David Schauer as part of a research project with Boston Children’s Hospital. It didn’t take much to get up to speed: Alm says the number of papers explicitly referencing the microbiome at the time could be read in an afternoon.

The collaboration, which included Ramnik Xavier, a core institute member of the Broad Institute, led to the first large-scale genome sequencing of the gut microbiome to diagnose inflammatory bowel disease. The research was funded, in part, by the Neil and Anna Rasmussen Family Foundation.

The study offered a glimpse into the microbiome’s diagnostic potential. It also underscored the need to bring together researchers from diverse fields to dig deeper.

Taking an interdisciplinary approach is important because, after next-generation sequencing techniques are applied to the microbiome, a large amount of computational biology and statistical methods are still needed to interpret the resulting data — the microbiome, after all, contains more genes than the human genome. One catalyst for early microbiome collaboration was the Microbiology Graduate PhD Program, which recruited microbiology students to MIT and introduced them to research groups across the Institute.

As microbiology collaborations increased among researchers from different department and labs, Neil Rasmussen, a longtime member of the MIT Corporation and a member of the visiting committees for a number of departments, realized there was still one more component needed to turn microbiome research into a force for human health.

“Neil had the idea to find all the clinical researchers in the [Boston] area studying diseases associated with the microbiome and pair them up with people like [biological engineers, mathematicians, and ecologists] at MIT who might not know anything about inflammatory bowel disease or microbiomes but had the expertise necessary to solve big problems in the field,” Alm says.

In 2014, that insight led the Rasmussen Foundation to support the creation of the Center for Microbiome Informatics and Therapeutics (CMIT), one of the first university-based microbiome research centers in the country.

Tami Lieberman, the Hermann L. F. von Helmholtz Career Development Professor at MIT, whose background is in ecology, says CMIT was a big reason she joined MIT’s faculty in 2018. Lieberman has developed new genomic approaches to study how bacteria mutate in healthy and sick individuals, with a particular focus on the skin microbiome.

Laura Kiessling, a chemist who has been recognized for contributions to our understanding of cell surface interactions, was also quick to joint CMIT. Kiessling, the Novartis Professor of Chemistry, has made discoveries relating to microbial mechanisms that influence immune function. Both Lieberman and Kiessling are also members of the Broad Institute.

Today, CMIT, co-directed by Alm and Xavier, facilitates collaborations between researchers and clinicians from hospitals around the country in addition to supporting research groups in the area. That work has led to hundreds of ongoing clinical trials that promise to further elucidate the microbiome’s connection to a broad range of diseases.

Fulfilling the promise of the microbiome

Researchers don’t yet know what specific strains of bacteria can improve the health of people with microbiome-associated diseases. But they do know that fecal matter transplants, which carry the full spectrum of gut bacteria from a healthy donor, can help patients suffering from certain diseases.

The nonprofit organization OpenBiome, founded by a group from MIT including Smith and Alm, launched in 2012 to help expand access to fecal matter transplants by screening donors for stool collection then processing, storing, and shipping samples to hospitals. Today OpenBiome works with more than 1,000 hospitals, and its success in the early days of the field shows that basic microbiome research, when paired with clinical trials like those happening at CMIT, can quickly lead to new treatments.

“You start with a disease, and if there’s a microbiome association, you can start a small trial to see if fecal transplants can help patients right away,” Alm explains. “If that becomes an effective treatment, while you’re rolling it out you can be doing the genomics to figure out how to make it better. So you can translate therapeutics into patients more quickly than when you’re developing small-molecule drugs.”

Another nonprofit project launched out of MIT, the Global Microbiome Conservancy, is collecting stool samples from people living nonindustrialized lifestyles around the world, whose guts have much different bacterial makeups and thus hold potential for advancing our understanding of host-microbiome interactions.

A number of private companies founded by MIT alumni are also trying to harness individual microbes to create new treatments, including, among others, Finch Therapeutics founded by Mark Smith; Concerto Biosciences, co-founded by Jared Kehe PhD ’20 and Bernardo Cervantes PhD ’20; BiomX, founded by Associate Professor Tim Lu; and Synlogic, founded by Lu and Jim Collins, the Termeer Professor of Medical Engineering and Science at MIT.

“There’s an opportunity to more precisely change a microbiome,” explains CMIT’s Lieberman. “But there’s a lot of basic science to do to figure out how to tweak the microbiome in a targeted way. Once we figure out how to do that, the therapeutic potential of the microbiome is quite limitless.”