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Koch Institute celebrates inaugural winners of the Angelika Amon Young Scientist Award

Graduate students Alejandro Aguilera Castrejón and Melanie de Almeida honored for their passion for fundamental biology and discovery science.

Bendta Schroeder | Koch Institute
December 13, 2022

On Nov. 17, the Koch Institute for Integrative Cancer Research hosted the inaugural winners of the Angelika Amon Young Scientist Award, Alejandro Aguilera Castrejón and Melanie de Almeida.

The award was established at the Koch Institute by family and friends of MIT faculty member Angelika Amon, a professor of biology and a member of the Koch Institute who died in 2020 following a two-and-a-half-year battle with ovarian cancer. The award is given annually to two graduate students in the life sciences or biomedical research from institutions outside the United States who embody Amon’s infectious enthusiasm for discovery science.

Winners are invited to the Koch Institute for an award ceremony and presentations to the MIT community, friends and family of the winners, and Amon Lab alumni. Attendees joined online from countries around the world, including Argentina, Austria, Denmark, France, Israel, Italy, Mexico, and the United Kingdom.

Amon was born in Vienna, Austria, and studied genetics at the University of Vienna as an undergraduate student and at the Research Institute of Molecular Pathology (IMP). Amon arrived in the United States in 1994 as a postdoc at the Whitehead Institute for Biomedical Research, and joined the MIT faculty in 1999. Widely recognized for her profound contributions to our understanding of the fundamental biology of cell division and proliferation, as well as the causes of chromosome mis-segregation and its consequences for human diseases such as cancer, Amon was equally well-known for her mentorship and advocacy for her students, postdocs, and colleagues.

“Angelika was a dedicated mentor, guide, advocate, and friend to many scientists,” said MIT Koch Institute Director Matthew Vander Heiden at the award ceremony. “She trained countless undergraduate and graduate students, postdoctoral researchers, and technicians, sharing with them her lifelong passion for fundamental biology and discovery science. The ripple effect of Angelika’s inspiration and counsel is profound.”

De Almeida, who recently completed her PhD in the lab of Johannes Zuber at IMP, presented on the development of a time-controlled CRISPR-based system for screening for the effects of gene knockouts. While using the system to knock out genes essential to regulating MYC, a protein often dysregulated in cancer, de Almeida and a fellow grad student stumbled across a poorly understood gene, AKIRIN2, which they discovered to control the import of enzymes that break down unnecessary or damaged proteins into the nucleus of mammalian cells.

When de Almeida started studying AKIRN2, she felt that doing science was “like solving a riddle, where you really need to ask the right questions to get closer to the solution. The best part about science is when you come to the end of a long experiment to find out whether your hypothesis is actually true.”

Aguilera Castrejón, currently a doctoral student in the lab of Jacob Hanna at the Weizmann Institute of Science in Rehovot, Israel, delivered a talk on his work developing in vitro systems for the culture of mammalian embryos outside the maternal uterus and then using these systems to gain insights into mammalian embryogenesis. Aguilera Castrejón’s platform allows post-implantation mouse embryos to develop outside the uterus for up to 6 days, and can also be used to culture stem cell-derived embryo models.

A first-generation graduate student from a working-class family in Mexico City, Aguilera Castrejón hopes that the Amon Award will help him “promote developmental biology in Mexico and other underdeveloped countries, and importantly, will show others that leading-edge science is not only for those born in wealthy or educated families, or in rich countries, but that science is for everyone who is passionate about discovery.”

After their presentations, Aguilera Castrejón and De Almeida were given their awards by Amon’s family, husband Johannes Weis and daughters Theresa and Clara.

“Today I could see some of the same love and passion for science that I saw in Angelika, and that just what we wanted to capture,” said Weis. “In future years, we will try to keep that spirit alive with this award.”

Three MIT seniors win 2024 Schwarzman Scholarships

Sara V. Fernandez, Amanda Hu, and Brigette Wang will spend the 2023-24 academic year at Tsinghua University in China studying global affairs.

Julia Mongo | Office of Distinguished Fellowships
December 7, 2022

Three MIT seniors — Sara V. Fernandez, Amanda Hu, and Brigette Wang — have been named 2024 Schwarzman Scholars and will join the program’s eighth cohort, consisting of 151 scholars from 36 countries. The students were selected from a pool of over 3,000 applicants.

Schwarzman Scholars pursue a master’s degree in global affairs at Tsinghua University in Beijing. The fellowship program aims to develop leadership skills and deepen understanding of China’s changing role in the world. Candidates are chosen through a rigorous application process designed to identify leadership potential, intellect, and strength of character. In the finalist stage, select candidates are invited to interview with panels composed of CEOs, government officials, nonprofit executives, and others.

MIT’s Schwarzman Scholar applicants receive guidance and mentorship from the distinguished fellowships team in Career Advising and Professional Development and the Presidential Committee on Distinguished Fellowships. “Sara, Brigette, and Amanda have demonstrated strong leadership abilities at MIT in their research and extracurricular activities,” says Kim Benard, associate dean of distinguished fellowships. “We are proud that they will represent MIT in China as Schwarzman Scholars, as this will provide them further opportunities to hone their leadership so that they may tackle the world’s problems.”

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Sara V. Fernandez will graduate MIT in June 2023 with a BS in materials science and engineering and minors in entrepreneurship and innovation and in Chinese. As a Latinx researcher in the MIT Conformable Decoders lab, Fernandez developed innovative medical devices, yielding high-impact publications. Throughout her time at MIT, she has been committed to international student outreach; diversity, NetBet sportequity, and inclusion initiatives; and peer mentorship, both academically and as a varsity tennis team captain. Fernandez looks forward to enriching her study of Chinese language and culture through the Schwarzman Scholars program, and gaining understanding on how to leverage China’s economies of scale for increasing health care accessibility in Latin America.

Amanda Hu

Amanda Hu is a senior majoring in biology and business management. She is passionate about health care entrepreneurship and financing strategies to drive innovation in medical fields. Hu is a founding member of Encreto Therapeutics, a startup discovering treatments for obesity, and is engaged in women’s health research at Massachusetts General Hospital. She also provides strategic support to AI health care portfolio companies at Aegis Ventures. As a Schwarzman Scholar, Hu hopes to work at the intersection of policy, technology, and business to bridge health care innovations between the United States and China.

Brigette Wang

Brigette Wang is a senior majoring in computation and cognition, with a humanities concentration in political science. Her undergraduate research includes studying the effects of the antidepressant ketamine on dendritic spines and evaluating operative outcomes of superior semicircular canal dehiscence, a rare hearing disorder. Wang is a student-athlete on the varsity women’s soccer team and the president of her sorority, where she has advocated for increased accessibility and inclusion in Greek life. She is passionate about health equity and, through Schwarzman Scholars, hopes to gain the global insight necessary to push health policy reform worldwide.

School of Science appoints 10 faculty to named professorships

Those selected for these positions receive additional support to pursue their research and develop their careers.

School of Science
December 5, 2022

The School of Science has announced that 10 of its faculty members have been appointed to named professorships. The faculty members selected for these positions receive additional support to pursue their research and develop their careers.

Camilla Cattania has been named a Cecil and Ida Green Career Development Professor in the Department of Earth, Atmospheric and Planetary Sciences. Her research uses theoretical and computational methods to better understand how faults slip during and between earthquakes, with a focus on explaining statistical patterns of seismicity arising from the underlying small scale physics. She has developed new models of aftershock triggering, as well as estimates of earthquake recurrence and predictability. Recently she has focused on the complexity in the geometry of faults and its relation to foreshock sequences, which in the long term might help to improve earthquake forecasting.

Olivia Corradin, assistant professor in the Department of Biology and a core member of the Whitehead Institute for Biomedical Research, has been named a Class of 1922 Career Development Professor. Corradin focuses on non-coding DNA variants — changes in DNA sequence that can alter the regulation of gene expression — to gain insight into pathogenesis. With her novel outside-variant approach, Corradin’s lab singled out a type of brain cell involved in multiple sclerosis, increasing total heritability identified by three- to five-fold. She also scrutinizes how genetic and epigenetic variation influence susceptibility to substance abuse disorders.

Tristan Collins is now the Class of 1948 Career Development Assistant Professor of Mathematics. He conducts research at the intersection of geometric analysis, partial differential equations, and algebraic geometry. In joint work with Valentino Tosatti, Collins described the singularity formation of the Ricci flow on Kahler manifolds in terms of algebraic data. In work with Gabor Szekelyhidi, he gave a necessary and sufficient algebraic condition for existence of Ricci-flat metrics, which play an important role in string theory and mathematical physics. This result lead to the discovery of infinitely many new Einstein metrics on the 5-dimensional sphere. With Shing-Tung Yau and Adam Jacob, Collins is currently studying the relationship between categorical stability conditions and existence of solutions to differential equations arising from mirror symmetry.

William Frank has been named a Victor P. Starr Career Development Professor in the Department of Earth, Atmospheric and Planetary Sciences. His research investigates the physical mechanisms that control deformation within the Earth’s crust. By examining fault instability within the Earth, from shallow stick-slip earthquakes to deeper steady creep, he hopes to improve estimates of earthquake hazards. Using a multidisciplinary approach, he combines seismological techniques with geodetic observations to learn more about the evolution of faulting processes in time and space, and how the Earth responds to tectonic, volcanic and anthropogenic forcings.

Jeremy Hahn, assistant professor in the Department of Mathematics, has been named the Rockwell International Career Development Professor. Hahn’s research is in in algebraic topology and homotopy theory with a particular emphasis on structured ring spectra. With collaborators, he has done work in equivariant chromatic homotopy theory, the classification of high dimensional manifolds, and the redshift conjectures in algebraic K-theory.

Erin Kara, assistant professor in the Department of Physics and member of the MIT Kavli Institute for Astrophysics and Space Research, has been named the Class of 1958 Career Development Professor. She is an observational astrophysicist, working to understand the physics behind how black holes grow and affect their environments. She also works to develop new and future space missions. She co-chairs the supermassive black hole working group of the XRISM Observatory, a joint JAXA / NASA X-ray spectroscopy mission to launch in 2023, and is the deputy principle investigator of the AXIS Probe Mission Concept.

Kristin Knouse has been named the Whitehead Career Development Professor. An assistant professor in the Department of Biology and the Koch Institute for Integrative Cancer Research, Knouse aims to understand how tissues sense and respond to damage, with the goal of developing new approaches for regenerative medicine. She focuses on the mammalian liver — which has the unique ability to completely regenerate itself — to ask how organisms react to organ injury, how certain cells retain the ability to grow and divide while others do not, and what genes regulate this process.

Brent Minchew, assistant professor in the Department of Earth, Atmospheric and Planetary Sciences, has been named the Class of 1948 Career Development Professor. Minchew is a geophysicist working to understand the interactions between climate, the cryosphere, and the solid Earth. He uses a combination of geodetic observations — primarily interferometric synthetic aperture radar — and physical models to study dynamical systems and their various responses to environmental forcing. The bulk of Minchew’s research focuses on the dynamics of extant glaciers, with an emphasis on the mechanics of glacier beds, ice-ocean interactions, and ice rheology.

Taylor Perron is now the Cecil and Ida Green Professor of Earth, Atmospheric and Planetary Sciences at MIT. Perron studies how landscapes form and evolve, both on Earth and on other planets. His approach combines theory and numerical modeling, field and remote sensing observations, analysis of data from planetary missions, and laboratory experiments. His group’s research is organized around three themes: explaining prominent landscape patterns such as branching river networks; using natural experiments to study how climate shapes landscapes; and examining planetary landforms to learn about the evolution of other worlds.

Richard Teague has been named a Kerr-McGee Career Development Professor in the Department of Earth, Atmospheric and Planetary Sciences. He is an observational astronomer studying planetary formation through initial conditions and protoplanetary disks, as well as early planetary life and the formation of their atmospheres. He uses observations from telescopes such as the European Southern Observatory’s Very Large Telescope (VLT) and the Atacama Large (sub-)Millimeter Array (ALMA) to detect and characterize planets during their formation, inventory the materials being used to build planetary systems, and map the physical netbet sports betting appand chemical structures needed for formation.

Scientists unveil the functional landscape of essential genes

Researchers harness new pooled, image-based screening method to probe the functions of over 5,000 essential genes in human cells.

Nicole Davis | Whitehead Institute
November 21, 2022

A team of scientists at the Whitehead Institute for Biomedical Research and the Broad Institute of MIT and Harvard has systematically evaluated the functions of over 5,000 essential human genes using a novel, pooled, imaged-based screening method. Their analysis harnesses CRISPR-Cas9 to knock out gene activity and forms a first-of-its-kind resource for understanding and visualizing gene function in a wide range of cellular processes with both spatial and temporal resolution. The team’s findings span over 31 million individual cells and include quantitative data on hundreds of different parameters that enable predictions about how genes work and operate together. The new study appears in the Nov. 7 online issue of the journal Cell.

“For my entire career, I’ve wanted to see what happens in cells when the function of an essential gene is eliminated,” says MIT Professor Iain Cheeseman, who is a senior author of the study and a member of Whitehead Institute. “Now, we can do that, not just for one gene but for every single gene that matters for a human cell dividing in a dish, and it’s enormously powerful. The resource we’ve created will benefit not just our own lab, but labs around the world.”

Systematically disrupting the function of essential genes is not a new concept, but conventional methods have been limited by various factors, including cost, feasibility, and the ability to fully eliminate the activity of essential genes. Cheeseman, who is the Herman and Margaret Sokol Professor of Biology at MIT, and his colleagues collaborated with MIT Associate Professor Paul Blainey and his team at the Broad Institute to define and realize this ambitious joint goal. The Broad Institute researchers have pioneered a new genetic screening technology that marries two approaches — large-scale, pooled, genetic screens using CRISPR-Cas9 and imaging of cells to reveal both quantitative and qualitative differences. Moreover, the method is inexpensive compared to other methods and is practiced using commercially available equipment.

“We are proud to show the incredible resolution of cellular processes that are accessible with low-cost imaging assays in partnership with Iain’s lab at the Whitehead Institute,” says Blainey, a senior author of the study, an associate professor in the Department of Biological Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research at MIT, and a core institute member at the Broad Institute. “And it’s clear that this is just the tip of the iceberg for our approach. The ability to relate genetic perturbations based on even more detailed phenotypic readouts is imperative, and now accessible, for many areas of research going forward.”

Cheeseman adds, “The ability to do pooled cell biological screening just fundamentally changes the game. You have two cells sitting next to each other and so your ability to make statistically significant calculations about whether they are the same or not is just so much higher, and you can discern very small differences.”

Cheeseman, Blainey, lead authors Luke Funk and Kuan-Chung Su, and their colleagues evaluated the functions of 5,072 essential genes in a human cell line. They analyzed four markers across the cells in their screen — DNA; the DNA damage response, a key cellular pathway that detects and responds to damaged DNA; and two important structural proteins, actin and tubulin. In addition to their primary screen, the scientists also conducted a smaller, follow-up screen focused on some 200 genes involved in cell division (also called “mitosis”). The genes were identified in their initial screen as playing a clear role in mitosis but had not been previously associated with the process. These data, which are made available via a companion website, provide a resource for other scientists to investigate the functions of genes they are interested in.

“There’s a huge amount of information that we collected on these cells. For example, for the cells’ nucleus, it is not just how brightly stained it is, but how large is it, how round is it, are the edges smooth or bumpy?” says Cheeseman. “A computer really can extract a wealth of spatial information.”

Flowing from this rich, multi-dimensional data, the scientists’ work provides a kind of cell biological “fingerprint” for each gene analyzed in the screen. Using sophisticated computational clustering strategies, the researchers can compare these fingerprints to each other and construct potential regulatory relationships among genes. Because the team’s data confirms multiple relationships that are already known, it can be used to confidently make predictions about genes whose functions and/or interactions with other genes are unknown.

There are a multitude of notable discoveries to emerge from the researchers’ screening data, including a surprising one related to ion channels. Two genes, AQP7 and ATP1A1, were identified for their roles in mitosis, specifically the proper segregation of chromosomes. These genes encode membrane-bound proteins that transport ions into and out of the cell. “In all the years I’ve been working on mitosis, I never imagined ion channels were involved,” says Cheeseman.

He adds, “We’re really just scratching the surface of what can be unearthed from our data. We hope many others will not only benefit from — but also build upon — this resource.”

This work was supported by grants from the U.S. National Institutes of Health as well as support from the Gordon and Betty Moore Foundation, a National Defense Science and Engineering Graduate Fellowship, and a Natural Sciences and Engineering Research Council Fellowship.

Honoring Salvador Luria, longtime MIT professor and founding director of the MIT Center for Cancer Research

Koch Institute event celebrates the new MIT Press biography “Salvador Luria: An Immigrant Biologist in Cold War America.”

Kate Silverman Wilson | MIT Press
November 18, 2022

On Oct. 26, the Koch Institute for Integrative Cancer Research at MIT and the MIT Press Bookstore and the co-hosted a special event launching the new biography “Salvador Luria: An Immigrant Biologist in Cold War America,” by Rena Selya. The book explores the life of longtime MIT professor Salvador Luria (1912–1991), whose passion for science was equaled by his commitment to political engagement in Cold War America.

Luria was born in Italy, where the Fascists came to power when he was 10. He left Italy for France due to the antisemitic Race Laws of 1938, and then fled as a Jewish refugee from Nazi Europe, making his way to the United States. Once an American citizen, Luria became a grassroots activist on behalf of civil rights, labor representation, nuclear disarmament, and American military disengagement from the Vietnam and Gulf wars. Luria joined the MIT faculty in 1960 and was later the founding director of the MIT Center for Cancer Research (CCR), which is now the Koch Institute. Throughout his life he remained as passionate about his engagement with political issues as about his science, and continued to fight for peace and freedom until his death.

As inaugural director of the CCR, Luria secured status and funding as a National Cancer Institute basic cancer center to embark on what were then the vast unknowns of cancer biology, oversaw the physical transformation of a former chocolate factory into a research facility, recruited brilliant young scientists to form its founding faculty, and helped foster a culture of scientific rigor, innovation, and excellence that ultimately helped set the standard for the field.

MIT Institute Professor Philip Sharp and Daniel K. Ludwig Professor for Cancer Research Richard Hynes, both founding faculty at the CCR, participated in the special event. Speaking of the center’s earliest days, Hynes explained, “There was an awful lot of cooperation, which was key in the success of this institution. I credit that to Salva and David [Baltimore] in particular. And it’s continued. Because when you grow up in that sort of environment you learn to repeat it.” The discussion was moderated by Deborah Douglas, director of collections and curator, science and technology at the MIT Museum.

Blacklisted from federal funding review panels but awarded a Nobel Prize for his research on bacteriophages, Luria was as much an activist as a scientist. In this first full-length NetBet live casinobiography of Luria, Selya draws on extensive archival research; interviews with Luria’s family, colleagues, and students; and FBI documents obtained through the Freedom of Information Act to create a compelling portrait of a man committed to both science and society.

The event was fittingly held in the Salvador E. Luria Auditorium at the Koch Institute. Quoting Zella Hurwitz Luria, Luria’s wife, Selya said, “‘Let us celebrate Salva’s life, his humanity, his struggle for understanding life and its biophysical basis, his sense of deep and personal fulfillment at having helped to build what he believed to be the best biology department in the country, his driving need to see justice done, his struggle for a peaceful, democratic world, his real interest in knowing people unlike himself and his love of his family, friends and, coworkers.’ More than 30 years later, it is an honor and pleasure for me to do just that here in the Salvador E. Luria Auditorium.”

New faculty join the School of Science in 2022

Seven professors join the departments of Biology; Chemistry; Earth, Atmospheric and Planetary Sciences; Mathematics; and Physics.

School of Science
November 17, 2022

This fall, the MIT School of Science welcomes seven new faculty to the departments of Biology; Chemistry; Earth, Atmospheric and Planetary Studies (EAPS); Mathematics; and Physics.

Wanying Kang researches large-scale atmospheric and oceanic dynamics, and their effects on the climate of Earth and other planetary bodies. She hopes to bridge multiple geoscience fields by applying tools from climate science on Earth to planetary science questions. Currently, Kang is looking into the atmospheric circulation on superhot lava worlds and the ocean circulation on icy moons, given the potential to observe them in more detail in the near future.

Kang earned an undergraduate degree in physics from Peking University and a PhD in applied math from Harvard University. She first joined the Department of Earth, Atmospheric and Planetary Sciences as a distinguished postdoc through the Houghton-Lorenz Fellowship. Now, Kang has been appointed an assistant professor in climate science in EAPS.

Sarah Millholland explores the demographics and diversity of extrasolar planetary systems. Using orbital dynamics and theory, she investigates how gravitational interactions like tides, resonances, and spin dynamics influence the formation and evolution of planetary systems and shape observable exoplanet properties.

Millholland obtained bachelor’s degrees in physics and applied mathematics from the University of Saint Thomas in 2015. She spent her first year of graduate school at the University of California at Santa Cruz before transferring to Yale University, earning her PhD in astronomy from Yale in 2020. She then moved to Princeton University, where she was a NASA Sagan Postdoctoral Fellow from 2020-22. Millholland joins MIT as an assistant professor in the Department of Physics and a member of the Kavli Institute for Astrophysics and Space Research.

Sam Peng PhD ’14 aims to develop novel probes and microscopy techniques to visualize the dynamics of individual molecules in living cells, which will improve the understanding of molecular mechanisms underlying human diseases. Peng’s group will focus on studying molecular dynamics, protein-protein interactions, and cellular heterogeneity involved in neurobiology and cancer biology. Their long-term goal is to translate these mechanistic insights into drug discovery.

Peng received his bachelor’s degree in chemistry from the University of California at Berkeley, and his PhD from MIT in physical chemistry. Most recently, he completed postdoctoral research at Stanford University. He returns to MIT as an assistant professor in the Department of Chemistry and a core member of the Broad Institute of MIT and Harvard.

Julien Tailleur is a physicist focusing on the emerging properties of active materials, which encompass systems made of large assemblies of units able to exert propelling forces on their environment. From molecular motors to cells and animal groups, active systems are found at all scales in nature. Most recently, Tailleur combined the development of theoretical frameworks to describe active systems with their applications to the study of microbiological systems.

Tailleur completed his undergraduate studies in mathematics at Université Pierre et Marie Curie (UPMC) and in physics at Université d’Orsay. He earned his PhD in physics in 2007 from UPMC. After becoming an Engineering and Physical Sciences Research Council postdoc at the University of Edinburgh, Tailleur joined French National Centre for Scientific Research (CNRS) and Université Paris Diderot in 2011, then becoming a CNRS Director of Research in 2018. Tailleur joins the Department of Physics as an associate professor.

Richard Teague works to understand the earliest stages of planetary systems, specifically, where, when, and how they can form. A major component of his research is the development of new techniques to detect examples of planets while they are still embedded in their parental protoplanetary disks, a period of the planet’s growth phase which is currently hidden from view. Teague is also leading the exoALMA collaboration, searching for the youngest exoplanets with one of the largest telescopes in the world, the Atacama Large (sub-) Milimeter Array (ALMA).

Teague earned a master’s degree from the University of Edinburgh and a PhD from the Max-Planck-Institute for Astronomy. Previously, he was a Submillimeter Array fellow at the Harvard-Smithsonian Center for Astrophysics and a postdoc at the University of Michigan and the Max-Planck-Institute for Astronomy. Teague joins MIT as an assistant professor in the Department of Earth, Atmospheric and Planetary Sciences.

Research interests of Martin Wainwright PhD ’02 include high-dimensional statistics, statistical machine learning, information theory, and optimization theory. One focus is algorithms and Markov random fields, a class of probabilistic model based on graphs used to capture dependencies in multivariate data: for example, image models, data compression, and computational biology. He also studies the effect of decentralization and communication constraints in statistical inference problems. A final area of interest is methodology and theory for high-dimensional inference problems.

Wainwright received a bachelor’s degree in mathematics from University of Waterloo followed by a PhD in electrical engineering and computer science (EECS) from MIT. Most recently, he was the Chancellor’s Professor at the University of California at Berkeley with a joint appointment between the departments of Statistics and EECS. Wainwright returns to MIT as a professor of mathematics and electrical engineering and computer science.

Immune cells communicate across scales in time and space, forming circuits that control their destructive capacity. Harikesh Wong employs a variety of quantitative approaches, including advanced fluorescence microscopy and computational modeling, to study these circuits within intact tissue environments. Ultimately, he seeks to understand how imbalanced immune cell communication — due to genetic or environmental variation — results in detrimental outcomes, including chronic infection, autoimmunity, and the formation of tumors.

Wong received a bachelor’s degree from McMaster University followed by a PhD in cell biology from the University of Toronto. Next, he pursued a postdoc at the National Institutes of Health in immunology and systems biology. Wong joins MIT as an assistant professor in the Department of Biology and a core member of the Ragon Institute of MGH, MIT and Harvard.

Genome-wide screens could reveal the liver’s secrets

A new technique for studying liver cells within an organism could shed light on the genes required for regeneration.

Anne Trafton | MIT News Office
November 15, 2022

The liver’s ability to regenerate itself is legendary. Even if more than 70 percent of the organ is removed, the remaining tissue can regrow an entire new liver.

Kristin Knouse, an MIT assistant professor of biology, wants to find out how the liver is able to achieve this kind of regeneration, in hopes of learning how to induce other organs to do the same thing. To that end, her lab has developed a new way to perform genome-wide studies of the liver in mice, using the gene-editing system CRISPR.

With this new technique, researchers can study how each of the genes in the mouse genome affects a particular disease or behavior. In a paper describing the technique, the researchers uncovered several genes important for liver cell survival and proliferation that had not been seen before in studies of cells grown in a lab dish.

“If we really want to understand mammalian physiology netbet sports bettingand disease, we should study these processes in the living organism wherever possible, as that’s where we can investigate the biology in its most native context,” says Knouse, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

Knouse is the senior author of the new paper, which appears today in Cell Genomics. Heather Keys, director of the Functional Genomics Platform at the Whitehead Institute, is a co-author on the study.

Extracellular context

As a graduate student at MIT, Knouse used regenerating liver tissue as a model to study an aspect of cell division called chromosome segregation. During this study, she observed that cells dividing in the liver did not behave the same way as liver cells dividing in a lab dish.

“What I internalized from that research was the extent to which something as intrinsic to the cell as cell division, something we have long assumed to be independent of anything beyond the cell, is clearly influenced by the extracellular environment,” she says. “When we study cells in culture, we lose the impact of that extracellular context.”

However, many types of studies, including genome-wide screens that use technologies such as CRISPR, are more difficult to deploy at the scale of an entire organism. The CRISPR gene-editing system consists of an enzyme called Cas9 that cuts DNA in a given location, directed by a strand of RNA called a guide RNA. This allows researchers to knock out one gene per cell, in a huge population of cells.

While this approach can reveal genes and proteins involved in specific cellular processes, it has proven difficult to deliver CRISPR components efficiently to enough cells in the body to make it useful for animal studies. In some studies, researchers have used CRISPR to knock out about 100 genes of interest, which is useful if they know which genes they want to study, but this limited approach doesn’t reveal new genes linked to a particular function or disease.

A few research groups have used CRISPR to do genome-wide screens in the brain and in skin cells, but these studies required large numbers of mice to uncover significant hits.

“For us, and I think many other researchers, the limited experimental tractability of mouse models has long hindered our capacity to dive into questions of mammalian physiology and disease in an unbiased and comprehensive manner,” Knouse says. “That’s what I really wanted to change, to bring the experimental tractability that was once restricted to cell culture into the organism, so that we are no longer limited in our ability to explore fundamental principles of physiology and disease in their native context.”

To get guide RNA strands into hepatocytes, the predominant cell type in the liver, Knouse decided to use lentivirus, an engineered nonpathogenic virus that is commonly used to insert genetic material into the genome of cells. She injected the guide RNAs into newborn mice, such that once the guide RNA was integrated into the genome, it would be passed on to future generations of liver cells as the mice grew. After months of effort in the lab, she was able to get guide RNAs consistently expressed in tens of millions of hepatocytes, which is enough to do a genome-wide screen in just a single animal.

Cellular fitness

To test the system, the researchers decided to look for genes that influence hepatocyte fitness — the ability of hepatocytes to survive and proliferate. To do that, they delivered a library of more than 70,000 guide RNAs, targeting more than 13,000 genes, and then determined the effect of each knockout on cell fitness.

The mice used for the study were engineered so that Cas9 can be turned on at any point in their lifetime. Using a group of four mice — two male and two female — the researchers turned on expression of Cas9 when the mice were five days old. Three weeks later, the researchers screened their liver cells and measured how much of each guide RNA was present. If a particular guide RNA is abundant, that means the gene it targets can be knocked out without fatally damaging the cells. If a guide RNA doesn’t show up in the screen, it means that knocking out that gene was fatal to the cells.

This screen yielded hundreds of genes linked to hepatocyte fitness, and the results were very consistent across the four mice. The researchers also compared the genes they identified to genes that have been linked to human liver disease. They found that genes mutated in neonatal liver failure syndromes also caused hepatocyte death in their screen.

The screen also revealed critical fitness genes that had not been identified in studies of liver cells grown in a lab dish. Many of these genes are involved in interactions with immune cells or with molecules in the extracellular matrix that surrounds cells. These pathways likely did not turn up in screens done in cultured cells because they involve cellular interactions with their external environment, Knouse says.

By comparing the results from the male and female mice, the researchers also identified several genes that had sex-specific effects on fitness, which would not have been possible to pick up by studying cells alone.

Renew and regenerate

Knouse now plans to use this system to identify genes that are critical for liver regeneration.

“Many tissues such as the heart are unable to regenerate because they lack stem cells and the differentiated cells are unable to divide. However, the liver is also a highly differentiated tissue that lacks stem cells, yet it retains this amazing capacity to regenerate itself after injury,” she says. “Importantly, the genome of the liver cells is no different from the genome of the heart cells. All of these cells have the same instruction manual in their nucleus, but the liver cells are clearly reading different sentences in this manual in order to regenerate. What we don’t know is, what are those sentences? What are those genes? If we can identify those genes, perhaps someday we can instruct the heart to regenerate.”

This new screening technique could also be used to study conditions such as fatty liver disease and cirrhosis. Knouse’s lab is also working on expanding this approach to organs other than the liver.

“We need to find ways to get guide RNAs into other tissues at high efficiency,” she says. “In overcoming that technical barrier, then we can establish the same experimental tractability that we now have in the liver in the heart or other issues.”

The research was funded by the National Institutes of Health NIH Director’s Early Independence Award, the Koch Institute Support (core) Grant from the National Cancer Institute, and the Scott Cook and Signe Ostby Fund.

Nanosensors target enzymes to monitor and study cancer

By analyzing enzyme activity at the organism, tissue, and cellular scales, new sensors could provide new tools to clinicians and cancer researchers.

Bendta Schroeder | Erika Reinfeld | Koch Institute
November 2, 2022

Cancer is characterized by a number of key biological processes known as the “hallmarks of cancer,” which remodel cells and their immediate environment so that tumors can form, grow, and thrive. Many of these changes are mediated by specific genes and proteins, working in tandem with other cellular processes, but the specifics vary from cancer type to cancer type, and even from patient to patient.

Sensitive tools for measuring protein or gene expression, even on the single cell level, have helped researchers understand the different cell types present in a tumor’s microenvironment and how this composition changes after treatments. However, these assays don’t necessarily show which proteins are active or relevant to tumor progression, or allow clinicians to noninvasively monitor the progress of the disease or its response to treatment. A protein could be present in a cancer cell as a bystander, for example, but not an active participant in its cellular transformations. Enzymes, which catalyze biochemical reactions inside cells, may give a clearer picture of which genes or proteins to target at a particular time.

In work recently published in Nature Communications, researchers from the MIT Koch Institute for Integrative Cancer Research have developed a set of enzyme-targeting nanoscale tools to monitor cancer progression and treatment response in real time, map enzyme activity to precise locations within a tumor, and isolate relevant cell populations for analysis.

“We hope that this new suite of tools can be useful in the clinic and the lab alike,” says Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and netbet sports betting appTechnology, professor of electrical engineering the computer science, and senior author of the study. “With further development, the nanosensors could be used by clinicians to tailor treatments to a patient’s specific cancer, and to monitor cancer progression and treatment response, while researchers could use them to better understand the molecular biology of cancer and develop new tools to diagnose, track, and treat the disease.”

Bhatia is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. The study, conducted in collaboration with the laboratory of Tyler Jacks, was led by Ava Amini (Soleimany) ’16, a former graduate student from the Bhatia laboratory; and postdoc Jesse Kirkpatrick, also from the Bhatia lab.

Tracking tumors in real time

For several years, the Bhatia laboratory has been developing noninvasive urine tests for the detection of cancer, including colon, ovarian, and lung cancer. The tests rely on nanoparticles that interact with tumor proteins called proteases. Proteases are a type of enzyme that act as molecular scissors to cleave proteins and break them down into smaller components. Proteases help cancer cells escape from tumors by cutting through the extracellular network of proteins that holds cells in place.

The nanoparticles are coated with peptides (short protein fragments) that target cancer-linked proteases. When the nanoparticles arrive at the tumor site, the peptides are cut and release biomarkers that can be detected in the urine.

In the current study, the researchers tested whether they could use this technology not just to detect cancer, but to track the development of cancer and its response to treatments accurately and sensitively over time. The team created a panel of 14 nanoparticles designed to target proteases overexpressed in non-small cell lung cancer induced in a mouse model. These nanoparticles had been adapted to release barcoded peptides when they encounter dysregulated enzymes in the tumor microenvironment.

Each nanosensor was able to track different patterns of protease activity, which changed dramatically as the tumor progressed. After treatment with a lung cancer-targeting drug, the researchers were able to find signs tumor regression quickly, within just three days of administering treatment.

Cell maps and populations

While the existing nanosensor technique could be used to track tumor progression and treatment response in general, by itself, it could not shed any light on the specific cellular process at work.

“Like many of the tools available to assess molecular markers for cancer, our urine reporter treats the body like a black box,” says Kirkpatrick. “While we get some information about the state of the disease, we wanted to know more about the cells or proteins that are causing the disease to behave in a particular way.”

Having identified nanosensors of interest, researchers mapped where in the tumor microenvironment the enzymes acting on these sensors were active. They adapted their nanoprobes to leave behind fluorescent tags when they are cleaved from the nanosensor, assigning different tags to different proteases. After applying the nanoprobes to samples of lung tissue, they looked for patterns in how the tags were distributed.

One tag resulted in a curious spindle-like pattern that turned out to belong to the tumor vasculature. Researchers pinpointed the protease activity to specific types of cells: endothelial cells, which line blood vessels, and pericytes, which regulate vascular function and are actively recruited in angiogenesis — one of the archetypal hallmarks of cancer cell growth. Angiogenesis allows tumor cells to recruit existing blood vessels and stimulate new ones to form, in order to obtain the nutrients needed for tumor formation and progression.

Using their nanoprobes to label and sort cells based on their enzymatic activity, the team identified populations of cells associated with vasculature that displayed heightened expression of genes related to angiogenesis. The researchers also found evidence of signaling between pericytes and the endothelial cells that together comprise angiogenic blood vessels in vascular tissue.

Hallmark observations

In future work, the team seeks to identify the specific protease active in pericytes and dissect its role in angiogenesis. With this knowledge, they hope to develop formulations of therapies that can be delivered to patients to disrupt the recruitment and formation of blood vessels associated with tumor growth.

Ultimately, however, the team envisions panels of nanoprobes targeting several important features of cancer simultaneously and noninvasively in patients. Other hallmarks of cancer include proliferative signaling, the evasion of growth suppressors, genome instability, resistance to cell death, deregulated metabolism, and activation of invasion and metastasis. Because cancer alters protease activity across all of these processes, the team’s nanoprobes could be designed to target these different processes, with the aim of providing a comprehensive picture of tumor activity driving the disease. The approach could be used by researchers looking to investigate key biological phenomena in cancer models, as well as by clinicians seeking to monitor cancer progression noninvasively and select treatments for their patients.

The study was supported, in part, by the Virginia and D.K. Ludwig Fund for Cancer Research, the Koch Institute Frontier Research Program through a gift from Upstage Lung Cancer, the Koch Institute’s Marble Center for Cancer Nanomedicine, and Johnson & Johnson.

A career in biochemistry unfolds

In an MIT summer research program, Rita Anoh learned about molecular machines and the value of collaborations.

Sarah Costello | School of Science
November 1, 2022

Rita Anoh’s first exposure to college-level research was not something she recognized as a path she could follow. While in high school, the daughter of Anoh’s Advanced Placement biology teacher presented a poster to her class about what she was working on in graduate school. “At the time, actually, it did not click to me what she was presenting,” Anoh laughs. “Because I didn’t know that you could do research as such, I just didn’t put it together.”

Instead, Anoh traces the start of her journey to science back to her childhood in Ghana, where she enjoyed spending summers assisting in a health clinic run by her grandmother, a nurse. Anoh especially loved the problem-solving and teamwork involved. “Every time, people would leave like, ‘Problem solved!’ or ‘Oh, my problem is not solved, but I know where to go next.’”

Anoh’s enthusiasm for finding solutions to complex problems shifted from medicine to research when she arrived as an undergraduate at Mount Saint Mary’s University (The Mount) in Maryland, and later as a participant in the 2022 Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio).

As a first-year majoring in biology at The Mount, Anoh applied to a summer research program with the encouragement of Patrick Lombardi, assistant professor of chemistry. She earned an internship to work in his lab exploring how DNA damage in cells is detected and repaired. Then, the summer following her sophomore year, she participated in the Caltech WAVE Fellows program in the lab of Douglas Rees, the Roscoe Gilkey Dickinson Professor of Chemistry, focusing on the structures and mechanisms of complex metalloproteins and integral membrane proteins. Anoh was also awarded a Barry M. Goldwater Scholarship for students intending to pursue research careers in natural science, mathematics, and engineering. “I was the first sophomore to receive at my school, so that was very exciting,” adds Anoh.

“It’s been a blast”

Eager to continue building her science skills and experience a new city, Anoh quickly accepted an offer to join the BSG-MSRP-Bio program at MIT this past summer.

Anoh spent 10 weeks in the lab of assistant professor of biology Joey Davis, whose lab works to uncover how cells construct and degrade complex molecular machines rapidly and efficiently. Anoh also worked with Robert Sauer, the Salvador E. Luria Professor of Biology at MIT, who studies the relationship between protein structure, function, sequence, and folding.

“It’s been a blast,” says Anoh.

Specifically, her project centered on a complex in the cell that helps oversee proteolysis, or the breakdown of proteins into peptides, or strings netbet sports betting appof amino acids, and further into amino acids for recycling by the cell. Called ClpXP, this molecular machine is made up of two substructures: ClpX and ClpP. First, ClpX identifies and unfolds peptide sequences in the protein substrate to be broken down; then ClpP breaks the unfolded peptides down into smaller fragments.

In her research, Anoh looked at the degradation of a protein RseA by ClpXP bound to another piece of molecular machinery called SspB. This “adapter protein” delivers the targeted protein to ClpXP to begin breaking it down. By degrading RseA, ClpXP plays an essential role in the signaling pathway in bacteria allowing the bacterial cell to respond to stress. Along with her mentor, she examined samples under a cryo‐electron microscope (Cryo-EM) at MIT.nano and collected data to determine its 3D map, shedding light on how ClpXP with the help of SspB breaks down proteins within a cell.

In addition to her gain of technical and research skills, one of Anoh’s takeaways from her summer at MIT was “how collaborative and dynamic science is in general,” she says, especially with mentors such as Alireza Ghanbarpour, a joint postdoc in the Davis and Sauer labs.

“During her time at our lab, she became friends with everyone,” says Ghanbarpour, who mentored Anoh and another undergraduate student whom Anoh befriended. “Rita developed a great relationship with her and, on many occasions, helped her with her project.”

Anoh attended group meetings, lab retreats, and conferences. In MSRP seminars, she heard from MIT researchers about their own experiences solving problems using advice from fellow scientists.

“I talk to my peers about what we’re all doing, and how different people at the same lab work together, or how different labs work together,” Anoh says. “I’ve learned different ways to achieve the same goal.”

Ghanbarpour also assisted Anoh in deepening her understanding of the material beyond the bench. Passionate about structural biology and biochemistry, he provided explanations and connected Anoh with materials to expand her knowledge of relevant researchers and concepts. “I was learning not just stuff in the lab but actually the meaning of what I was doing, so that was pretty cool,” she says.

Now in her senior year back at The Mount, Anoh intends to keep an open mind. An open mind, after all, is why she acted on her professor’s suggestion when she was a first-year student to apply to the program that set her on her current path to a research career. Without a doubt, though, Anoh says she plans to pursue a PhD in biochemistry and mentor young researchers like herself along the way.

Introducing the Amon Award Winners
MIT Koch Institute
October 25, 2022

Cheers to the inaugural winners of the Koch Institute’s Angelika Amon Young Scientist Award, Alejandro Aguilera and Melanie de Almeida. The new award recognizes graduate students in the life sciences or biomedical research from institutions outside the U.S. who embody Dr. Amon’s infectious enthusiasm for discovery science.

Aguilera, a student at the Weizmann Institute of Science in Israel, has developed a platform for studying mammalian embryogenesis. De Almeida, who recently completed her doctoral work at the Research Institute of Molecular Pathology in Austria, develops CRISPR screens to explore cancer vulnerabilities and gene regulatory networks.

Aguilera and de Almeida will visit the Koch Institute in November to deliver scientific presentations to the MIT community and Amon Lab alumni.