Discovery of how cancer drugs find their targets could lead to a new toolset for drug development
Whitehead Institute
June 17, 2020

In the watery inside of a cell, complex processes take place in tiny functional compartments called organelles. Energy-producing mitochondria are organelles, as is the frilly golgi apparatus, which helps to transport cellular materials. Both of these compartments are bound by thin membranes.

But in the past few years, research at Whitehead Institute and elsewhere has shown that there are other cellular organelles held together without a membrane. These organelles, called condensates, are tiny droplets which keep certain proteins close together amidst the chaos of the cell, allowing complex functions to take place within. “We know of about 20 types of condensate in the cell so far,” says Isaac Klein, a postdoc in Richard Young’s lab at Whitehead Institute and oncologist at the Dana-Farber Cancer Institute.

Now, in a paper published in Science on June 19, Klein and Ann Boija, another postdoc in Young’s lab, show the mechanism by which small molecules, including cancer drugs, are concentrated in these cellular droplets — a finding that could have implications for the development of new cancer therapeutics. If researchers could tailor a chemical to seek out and concentrate in one kind of droplet in particular, it might have a positive effect on the delivery efficiency of the drug. “We thought, maybe that’s an avenue by which we can improve cancer treatments and discover new ones,” says Klein.

“This [research] is part of a revolutionary new way of looking at the organization within cells,” says Phillip Sharp, a professor at the Massachusetts Institute of Technology’s Koch Institute for Integrative Cancer Research and a co-author on the study. “Cells are not little pools of soup, all mixed together. They are actually highly organized, compartmentalized units, and that organization is important in their function and in their diseases. We’ve just started to understand that, and this new paper is a really important step, using that insight, to understand how to potentially treat diseases differently.”

CONDENSATES AND DRUG DELIVERY

To explore how different properties of condensates inside the cell’s nucleus affected the delivery of cancer drugs, Boija and Klein selected a few example condensates to study. These included splicing speckles, which store cellular materials needed for RNA splicing, nucleoli, where ribosomes are formed, and a new kind of droplet Young’s lab discovered in 2018 called a transcriptional condensate. These new condensates bring together all the different proteins needed to successfully transcribe a gene.

The researchers created their own suite of four different fluorescently-labeled condensates by adding glowing tags to marker proteins specific to each kind of droplet. For example, transcriptional condensates are marked by the droplet-forming protein MED1, splicing speckles by a protein called SRSF2, and nucleoli by FIB1 and NPM1.

Now that they could tell individual droplets apart by their cellular purpose, the team, along with the help of Nathanael Gray, a chemical biologist at Harvard University and the Dana-Farber Cancer Institute, created fluorescent versions of clinically important drugs. The tested drugs included cisplatin and mitoxantrone, two anti-tumor medicines commonly used in chemotherapy. These therapeutics were the perfect test subjects, because they both target proteins that lie within nuclear condensates.

The researchers added the cancer drugs to a mixture containing various droplets (and only droplets, none of the actual drug targets), and found that the drugs sorted themselves into specific condensates. Mitoxantrone concentrated in condensates marked by MED1, FIB1 and NPM1, selectively avoiding the others. Cisplatin, too, showed a particular affinity for droplets held together by MED1.

“The big discovery with these in vitro studies is that a drug can concentrate within transcriptional condensate independent of its target,” Boija says. “We used to think that drugs come to the right place because their targets are there, but in our in vitro system, the target is not there. That’s really informative — it shows the drug is actually being concentrated in a different way than we thought.”

To understand why some drugs were drawn into transcriptional condensates, they screened a panel of chemically-modified dyes and found that the important part of many drugs — the part that led them to concentrate in transcriptional condensates  —  is the molecules’ aromatic ring structure. Aromatic rings are stable, ring-shaped groupings of carbon atoms. The aromatic ring in some drugs are thought to stack with rings in MED1’s amino acids, leading the drug to concentrate in transcriptional condensates.

Being able to tailor a drug to enter a certain condensate is a powerful tool for drug developers. “We found that if we add an aromatic group to a molecule, it becomes concentrated within the transcriptional condensate,” Boija says. “It’s that type of interaction that is important when we design new drugs to enter transcriptional condensates — and maybe we can improve existing drugs by modifying their structure. This will be very exciting to look into.”

WHERE DRUGS CONCENTRATE AFFECTS HOW WELL THEY FIGHT CANCER

In order for this tool to be practically useful in drug development, the researchers had to make sure that concentration in specific droplets would actually impact the drugs’ performance. Boija and Klein decided to test this using cisplatin, which is drawn to transcriptional condensates by MED1 and works to fight cancer by adding clunky platinum molecules to DNA strands. This damages tumor cells’ genetic material. When the researchers administered cisplatin to a mixture of different condensates, both in the test tube and in cells, the drug preferentially altered DNA that lay within transcriptional condensates.

This could explain why cisplatin and other platinum drugs are effective against so many diverse cancers, says Young, who is also a professor of biology at MIT; cancer-causing genes often carry regions of DNA called super enhancers, which are extremely active in transcription, leading to very large transcriptional condensates. “We now think the reason that drugs like cisplatin can work well in patients with diverse cancers is because they’re becoming selectively concentrated at the cancer-causing genes, where these large transcriptional condensates occur,” he said. “The effect is to have the drug home in on the gene that’s causing each cancer to be so deadly.”

A DRUG RESISTANCE MYSTERY, SOLVED

The new insights in condensate behavior also provided some answers to another question in cancer research: why people become immune to the breast cancer drug tamoxifen.Tamoxifen works by attaching itself to estrogen receptors in the cancer cells, preventing them from getting the hormones they need to grow and eventually slowing or stopping the formation of new cancer cells altogether. The drug is one of the most effective treatments for the disease, reducing recurrence rates for ER+ breast cancers by around 50%.

Unfortunately, many patients quickly develop a resistance to tamoxifen — sometimes as soon as a few months after they start taking it. This happens in a variety of ways — for example, sometimes the cancer cells will mutate to be able to kick the tamoxifen out of the cells, or simply produce fewer estrogen receptors for the drug to bind. One form of resistance was associated with an overproduction of the protein MED1, but scientists didn’t know why.

With their newfound knowledge of how a drug’s activity is affected by where it concentrates, Boija and Klein had a hypothesis: the extra MED1 might increase the size of the droplets, effectively diluting the concentration of tamoxifen and making it more difficult for the drug to bind its targets. When they tested this in the laboratory, the team found that more MED1 did indeed cause larger droplets, leading to lower concentrations of tamoxifen.

A NEW TOOLSET FOR DRUG DESIGNERS

The ability to better understand the behavior of drugs in cancer cells — how they concentrate, and why the cancer could become resistant to them — may provide drug developers with a new arsenal of tools to craft efficient therapeutics. “This study suggests that we should be exploring whether we can design or isolate drugs that are concentrated in a given condensate, and to understand how existing drugs are concentrated in the cell,” says Phil Sharp. “I think this is really important for drug development — and I think [figuring it out] is going to be fun.”

Biology community organizes day-long program to address diversity and inclusion

In honor of #ShutDownSTEM, students, faculty, and staff facilitated virtual discussions to understand and combat anti-Black racism in academia.

June 18, 2020

On June 10, as part of the #ShutDownSTEM, #ShutDownAcademia, and #Strike4BlackLives national initiative, members of the Department of Biology took the day to engage in open conversations about racial bias, diversity, and inclusion.

The #ShutDownSTEM.MITbio program, organized by trainees, postdocs, and staff, included 13 virtual sessions on topics ranging from allyship and white privilege to antiblackness in Boston and the history of racism in science. The goal was to provide a space for white and non-Black People of Color (POC) to educate themselves and offer support to Black colleagues, as well as determine ways to make the Biology community more equitable.

In a letter to the department publicizing the June 10 event, the organizers wrote: “We have a responsibility as scientists to educate ourselves and initiate and continue difficult but necessary conversations on race and how systemic racism impacts ourselves and our field, particularly through the lens of recent events and how we can better support, amplify, and listen to our Black community members within the department and within our larger communities.”

Although the event came together in just a few days, more than 45 community members volunteered to help facilitate — and over 200 participated in concurrent sessions at any given time throughout the day.

Graduate student Talya Levitz heard about the #ShutDownSTEM initiative through various student activism channels a week prior. She brought the idea to department affinity groups, including the Biology Diversity Community (BDC), and ultimately aggregated over nine co-organizers. Other departments, labs, and centers across MIT developed their own initiatives, and Levitz’s team worked closely with their counterparts in the Department of Chemistry to share resources.

When they built the day’s agenda, Levitz says they had two main goals. “First, we wanted people to think about how their own identities intersect with anti-Blackness and anti-racism efforts,” she says. “The other big goal was to meet people where they are, and recognize that everyone is at a different place on their personal growth trajectories.”

Meghann Kasal, graduate student and co-founder of the BDC, responded to Levitz’s call to action immediately. “The #ShutDownSTEM program seemed like a great way to continue conversations that the BDC was already having, and transform dialogue into action,” she says. “It was a chance to empower people to make changes on an individual level and have those personal commitments ripple out to the larger community.”

SaRa Kim, administrative assistant and research technician, joined Levitz, Kasal, and others to help encourage other staff members to get involved. “The onus to make changes shouldn’t fall solely on those experiencing injustices,” she says, “and many of the co-organizers already had an active network of peers ready to provide support.”

Before the event, the team sent out a list of relevant resources, and afterwards they collated a docket of action items to ensure that the conversation would continue — especially regarding recruiting and retaining Black and non-Black POC graduate students, staff, and faculty. Plans are also coalescing to apply for a Quality of Life grant to sponsor similar programs in the future, and students have spearheaded a faculty-matched donation drive within the department.

Graduate student and co-organizer, Gerardo Perez Goncalves, aims to take the day’s discussions and turn them into tangible plans with concrete timelines. “We need to hold each other accountable, and make sure those goals don’t get lost in committees,” he says. “Even though I’m just one person, I can be involved in a number of different ways, such as helping to craft actionable plans to spread awareness of current initiatives to those near me. The whole department needs to be made aware of these initiatives and plans so that we can establish community accountability.”

Sora Kim, a fellow graduate student and co-organizer, adds that scientists are often expected to separate their personal lives from their work. “You’re not supposed to bring what you personally think into the workplace,” Kim says, “but we know from history and current events that these things bleed into one another, and not talking about them creates a culture of silence and isolation.”

In the past, students have voiced concerns via anonymous polls and surveys, but there have been few opportunities for the entire community to come together, acknowledge current issues, and brainstorm solutions collaboratively.

The #ShutDownSTEM.MITbio event marked the beginning of what the organizing committee hopes will become substantive action to combat anti-racism and build a more diverse, inclusive, and equitable community within both the department and the Institute. Already, open letters and petitions are circulating asking for concrete actions from leadership.

“#ShutDownSTEM was not the start of these conversations for many people, but a continuation of ongoing discussions,” Kasal says. “We’ve wanted to hold these kinds of events before, but didn’t have the bandwidth in the BDC. This has given me hope that people will come together and help, and that it’s possible to organize something like this with just a few days of planning.”

Image credit: shutdownstem.com
Posted: 6.18.20
Bringing computers into the protein fold

In the lab, Biology Professor Amy Keating researches the interactions of proteins with a mix of modeling and synthetic lab work and diverse minds

School of Science
June 11, 2020

Almost everything in biology is a multistep process, from the metabolization of carbohydrates and fats as fuel to information transcription from DNA and RNA. Without proteins and their interactions, cells couldn’t perform any of these biological tasks. But how do proteins establish their individual roles? And how do they interact with each other?  These questions drive Professor Amy Keating’s research, and both lab experiments and computational modeling are helping her reveal the mysteries behind the basic functions of life.

In Keating’s field of research, as with most areas of science, the use of artificial intelligence is a relatively new – and growing – trend. “It’s pretty scary how fast new methods in machine learning are changing the landscape,” says Keating, who holds appointments in both the Department of Biology and the Department of Biological Engineering. “I think that we will see a disruptive change in protein modeling over the coming years.” She has found that incorporating basic machine learning methods in her own work has generated some success in uncovering how protein sequences determine their interactions.

However, there are limits to using only computational modeling due to the complexities of protein-protein interaction and a general need for empirical data to calibrate the models. Her lab group integrates computation with biological engineering in a laboratory setting. Keating’s team often starts by using computational modeling to narrow down their search from a massive collection of protein structure models. This step limits their output from an effectively infinite space (~1030) to something on the order of 106 potential promising molecules that can be experimentally tested. They can feed the results of experiments into other algorithms that help designate the specific features of the protein that prove important. This process is cyclical, and Keating emphasizes that experimental efforts are crucial for improving the success rate of this kind of work. That is where the lab comes in. There, they do what the computer cannot: they build proteins.

With the disruption of the COVID-19 crisis the Keating lab has focused their attention on computational projects, as well as on reviewing the literature and writing up papers and theses. The members are also using their time at home to brainstorm and plan their research. “We are having multiple group meetings per week by Zoom, including a ‘Keating Group Idea Lab,’ at which everyone throws out ideas, ranging from practical suggestions about current projects to out-there new concepts, for group discussion,” says Keating. “We are confident that we can use this time productively, to advance our science, even as we make long lists of things that we are eager to do as soon as we can get back into the laboratory.”

A topic of current interest to Keating and her group members is interactions among proteins with “short linear motifs” or SLiMs, which are abundant –more than one hundred thousand such motifs are thought to exist in one human. One family of these SLiM-binding proteins regulates movement of cells within the body and is implicated in the spread of cancer cells to a secondary location (metastasis). The lab’s novel mini-protein and peptide designs aim to disrupt these protein interactions and could be useful for eventually disrupting and treating cancer and other diseases.

FOSTERING MULTIPLE INTERACTIONS

Currently, Keating’s research team consists of six students who have backgrounds in almost as many different cultures. Her students’ diversity, which stems not just from different focuses in formal training but also from life experiences, is integral to their success, according to Keating. She wishes that more women like herself and members of underrepresented minority groups who love STEM would consider pursuing academic careers. “It’s hard work, but it’s very rewarding,” she entices. The best thing about being a faculty member, she believes, is having a team of bright minds who contribute unique ideas and insights to a problem and provide information beyond her own areas of expertise.

“I learn facts that they know and I do not. I learn interesting ways of thinking about science and also ways of doing science,” she says, noting that novel ideas in methodology lead to advances in research. “I’ve learned a lot of things about computer science from my students. I’m happy that one of my former biology students is [now] a professor of computer science,” she admits, appreciating his expertise as a benefit in frequent collaborations. “I love that students at MIT question everything.” Keating’s ever-expanding knowledge builds on top of a diverse background gleaned during her time as a student.

Keating’s bachelor’s degree from Harvard University is in physics. During her PhD at University of California, Los Angeles, she shifted to chemistry — specifically computational physical organic chemistry. When browsing for a postdoctoral position, she discovered the work of former MIT Department of Biology faculty and Whitehead Institute member Peter Kim and joined him. She maintained her interest in computation as a tool for biological research, concurrently co-advised by MIT Professor of Electrical Engineering and Computer Science Bruce Tidor. It was somewhat down to chance that her academic job search led her to MIT. “I certainly never thought I would be a biology professor, especially at MIT,” she remarks of her convoluted career path through the wide world of science.

But it is an unexpected result for which Keating is grateful. “My undergrad self would have been surprised by the MIT School of Science,” she muses, which makes MIT “so much more than ‘just’ the world’s best engineering school.” That is something of a common misconception about the Institute, she feels. “I think a lot of people outside of MIT don’t know how outstanding our basic science programs are.” Keating is a part of the strong science education at MIT, which is constantly adapting to keep up with the digital age, which led to her receiving the most recent Fund for the Future of Science Award.

“I was thrilled, and pretty surprised, to receive the award; my fantastic colleagues in the School of Science are not people that you want to be competing with.” This support is invaluable to her research on the foundations of biological interactions, and to ensure a robust team that has what it needs to develop important advances.  The curious minds with which she collaborates are equally as invaluable.

“The people at MIT are amazingly smart, curious, and focused on things that I value,” Keating adds, “like good ideas, intellectual rigor, discovering new things, and education.”

This article appeared in the Summer 2020 issue of Science@MIT

Graduate student Kristina Lopez receives Ford Foundation Fellowship
Whitehead Institute
June 5, 2020

Kristina Lopez, a first-year graduate student at the Massachusetts Institute of Technology working in Whitehead Fellow Kristin Knouse’s lab, has received the Ford Foundation Fellowship, an award designated by the National Academy of Sciences and funded by the Ford Foundation to encourage diversity in education.

Lopez, a native of the mid-size South Texas city of McAllen is the first person in her family to go to college. When she graduated from high school, she moved to Cambridge to study biology at MIT.

During her undergraduate years, Lopez worked in the lab of Angelika Amon. There she met Kristin Knouse, a graduate student at the time. When Knouse joined Whitehead Institute’s Fellows Program, Lopez joined her lab, which focuses on how mammals sense and respond to organ injury.

Now in the first year of her PhD, Lopez is interested in how the body senses liver injury. “It’s well known that the liver is the only organ in the mammalian body that has the ability to regenerate,” she says. “However, it is entirely unclear how the body senses liver insufficiency in order to drive regeneration. My work aims to uncover this critical first step.”

The Ford Foundation Fellowship, which aims to increase the diversity of college and university faculties in the United States, will provide Lopez with $27,000 a year for three years of her graduate education. When she finishes her graduate work, Lopez plans to complete a postdoc and ultimately run her own research program.

“We are thrilled that the Ford Foundation has recognized Tina’s unique background and perspectives and the fearlessness, resilience, and passion with which she approaches science,” says Knouse.

Lopez is the first researcher at Whitehead Institute to receive this fellowship. “I’m very fortunate to be able to do what I love for a living,” she says. “I’m honored to receive a Ford Foundation Fellowship to support my research and look forward to using this as an opportunity to connect with other scientists who share this passion.”

Stem cell researcher Yukiko Yamashita joins MIT Biology
June 4, 2020

Whitehead Institute announced today that the internationally renowned developmental biologist Yukiko Yamashita will join the Institute as its newest Member in September 2020. Yamashita has also been appointed a Professor of Biology at Massachusetts Institute of Technology (MIT), and will be the inaugural incumbent of the Susan Lindquist Chair for Women in Science at Whitehead Institute.

Currently, Yamashita holds multiple academic and research roles at the University of Michigan:  James Playfair McMurrich Collegiate Professor of the Life Sciences; Professor of Cell and Developmental Biology; Research Professor in the Life Sciences Institute; and Director of the Michigan Life Sciences Fellows Program. She is also a Howard Hughes Medical Institute (HHMI) Investigator, and was named a MacArthur Foundation Fellow in 2011.

“Yukiko’s work has been extraordinarily creative and productive,” says David C. Page, Whitehead Institute Director and Member. “Her approach is to take curious observations that cannot easily be explained, and consider them as hints given by nature. It’s a high-risk, courageous approach to science that has led to a series of important discoveries. Her creativity and her bold vision will find a welcoming environment at Whitehead Institute.”

Yamashita’s research focuses on the process by which stem cells are renewed, in normal and diseased contexts. A balance between differentiated daughter cells and self-renewing stem cells is critical for life, and asymmetric cell division creates problems: an excess of self-renewal can lead to cancer; an excess of differentiation can deplete the stem cell pool necessary for long-term health. Yamashita seeks to understand the mechanisms underlying asymmetric stem cell division, which are now poorly understood, using Drosophila male germline stem cells (GSCs) as a model system. Among her lab’s current research focuses are the orientation of GSCs’ mitotic spindle during cell division; stem cell-specific centrosomal components and their roles in asymmetric division; and the mechanisms of non-random sister chromatid segregation. Yamashita’s research is also expanding into new territories—such as functions of satellite DNA, a little-understood constituent of the genome—prompted by curious observations made in her investigations.

“I find that pursuing the unexpected results and anomalous hints that we find in our studies is both exciting and anxiety-provoking—like riding a rollercoaster,” Yamashita says. “I look forward to sharing this experience with my new colleagues at Whitehead Institute and MIT, who are fearless in their pursuit of new and often unanticipated opportunities.”

“I am delighted that Yukiko is joining our community,” says Alan D. Grossman, Praecis Professor of Biology and Department Head at MIT. “She is remarkably creative and her passion for science and service is infectious.”

Yamashita earned both her B.S. in Biology (1994) and her Ph.D. in Biophysics (1999) from Kyoto University, where she conducted her graduate research in the lab of Mitsuhiro Yanagida. From 2001 to 2006, she did postdoctoral research in developmental biology in Margaret Fuller’s lab at Stanford University. She was appointed to the Michigan faculty in 2007 and was named an HHMI Investigator in 2014.

A prolific author and speaker, Yamashita has published more than 80 peer-reviewed studies, research review articles, and book chapters; and has delivered more than 100 invited lectures and addresses around the world. She also serves as an advisory board member for the Searle Scholars Program; as Associate Editor of Molecular Biology of the Cell; and as an editorial board member for eLifeScientific Reports, and PLoS Biology. A committed mentor and educator, she has guided the work and career development of 32 undergraduate, graduate, and postdoctoral researchers.

In addition to being named a MacArthur Foundation Fellow, Yamashita has been a Searle Scholar and received a Keck Foundation Award. She has also received the Tsuneko and Reiji Okazaki Award from Nagoya University, the Rackham Faculty Recognition Award and the Dean’s Basic Science Research Award from University of Michigan, and the Women in Cell Biology Junior Career Recognition Award from the American Society for Cell Biology.

National Medal of Science recipient Susan Lindquist—who was a Member and former director of Whitehead Institute and a Professor of Biology at MIT—served on the Johnson & Johnson Board of Directors from 2004 to 2016. Johnson & Johnson endowed the Susan Lindquist Chair for Women in Science to honor Lindquist’s achievements as a researcher, scientific leader, mentor, and wise counselor. “We established this Chair in Sue’s name to recognize a greatly respected and beloved scientist and a passionate advocate for women in science,” says Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer, Johnson & Johnson. “Sue was a prolific scientific pioneer who changed fundamental understanding of the biology of human health. As part of the Johnson & Johnson Board of Directors, she challenged us to use science and technology in new ways to help improve the health and lives of people all around the world.”

“The Susan Lindquist Chair for Women in Science is to be held by a distinguished female scientist who is advancing biomedical research,” Page explains. “And I believe that Sue would be very proud that Yukiko Yamashita is its first incumbent.”

Like a treasure map, brain region emphasizes reward location
Picower Institute
June 1, 2020

We are free to wander but usually when we go somewhere it’s for a reason. In a new study, researchers at The Picower Institute for Learning and Memory show that as we pursue life’s prizes a region of the brain tracks our location with an especially strong predilection for the location of the reward. This pragmatic bias of the lateral septum suggests it’s a linchpin in formulating goal-directed behavior.

“It appears that the lateral septum is, in a sense, ‘prioritizing’ reward-related spatial information,” said Hannah Wirtshafter, lead author of the study in eLife and a former graduate student in the MIT lab of senior author Matthew Wilson, Sherman Fairchild Professor of Neurobiology. Wirtshafter is now a postdoc at Northwestern University.

Last year, Wirtshafter and Wilson, a professor of biology and of brain and cognitive sciences, analyzed measurements of the electrical activity of hundreds of neurons in the LS and the hippocampus, a region known for encoding many forms of memory including spatial maps, as rats navigated a maze toward a reward. In Current Biology they reported that the LS directly encodes information about the speed and acceleration of the rats as they navigated through the environment.

The new study continued this analysis, finding that while the LS dedicates a much smaller proportion of its cells to encoding location than does the hippocampus, a much larger proportion of those cells respond when the rat is proximate to where the reward lies. Moreover, as rats scurried toward the reward point and back again within the H-shaped maze, the pace of their neural activity peaked closest to those reward locations, skewing the curve of their activity in association with where they could find a chocolate treat. Finally, they found that neural activity between the hippocampus and the LS was most highly correlated among cells that represented reward locations.

“Understanding how reward information is linked to memory and space through the hippocampus is crucial for our understanding of how we learn from experience, and this finding points to the role the lateral septum may play in that process,” Wilson said.

Specifically, Wilson and Wirtshafter interpret the results of the two studies to suggest that the LS plays a key role in helping to filter and convert raw information about location, speed and acceleration coming in from regions such as the hippocampus, into more reward-specific output for regions known to guide goal-directed behavior, such as the ventral tegmental area. In the paper they discuss ways in which the hippocampus and the LS might be wired together to do so. They theorize that the LS may dedicate neurons to receiving reward-related location information from the hippocampus and may blend non-reward location information within neurons also tasked for processing other information such as motion.

“This is supported by our previous work that shows somewhat overlapping populations of place-encoding and movement-encoding LS cells,” Wirtshafter said.

Though it’s easy for most of us to take the brain’s ability to facilitate navigation for granted, scientists study it for several reasons, Wirtshafter said.

“Elucidating brain mechanisms and circuits involved in navigation, memory and planning may identify processes underlying impaired cognitive function in motor and memory diseases,” she said. “Additionally, knowledge of the principles of goal directed behavior can also be used to model context-dependent brain behavior in machine models to further contribute to artificial intelligence development.”

The National Defense Science & Engineering Graduate Fellowship Program and the JPB Foundation provided funding for the study.

3 Questions with Seychelle Vos

An unconventional geneticist uses cryogenic electron microscopy and crystallography to understand gene expression and cell fate.

Lucy Jakub
June 1, 2020

Seychelle Vos arrived in September 2019 as the Department of Biology’s newest assistant professor. Her lab in Building 68 uses cryogenic electron microscopy (cryo-EM), X-ray crystallography, biochemistry, and genetics to study how DNA and its associated proteins are organized inside the cell. Vos received her PhD from the University of California at Berkeley and completed her postdoctoral research at the Max Planck Institute for Biophysical Chemistry in Germany. She sat down to discuss her structural biology research, and why it’s so important to understand DNA as a physical structure.

Q: Your research is on the proteins that compress DNA so it can fit inside a cellular organelle called the nucleus. How does the genome organize itself in different shapes to perform different functions in the cell, and why is this an important process for us to understand?

A: If we take all the DNA inside of one human cell and stretch it out end to end, it extends 2 meters in length. But it needs to fit into the nucleus, which is only a few microns wide. It’s essentially like stringing a fishing line from here to New Haven and trying to put it in a soccer ball. That’s not an easy thing to do. There are lots of proteins that compact the genome either by wrapping the DNA around themselves or by forming loops in the DNA.

In order to replicate DNA or transcribe it to make a protein, the cell’s molecular machinery needs to be able to access and read it. Depending on how the DNA is wrapped and organized, different genes will be more accessible than others. In a stem cell, essentially any gene can be turned on. But as cells begin to differentiate into kidney cells, liver cells, and so on, only the genes specific to those functions can be turned on. Every cell has its own set of proteins that make it special, and most of that regulation happens at the level of RNA expression.

Our lab wants to understand how DNA organization impacts gene expression at the atomic level. This gets to the crux of how a stem cell becomes a specific cell type, and what happens when those programs go wrong. Without the right kind of compaction you can have cancer phenotypes, because things get turned on that shouldn’t be, or a cell thinks it’s a stem cell again and divides really fast. Many of the proteins we study are involved either in developmental disorders or cancers. If we don’t understand their basic biology, it’s very hard to come up with reasonable ways of treating these diseases.

Q: What was it about structural biology that hooked you during your early career?

A: When I started my PhD at UC Berkeley, I didn’t have much of an interest in structural biology. I thought that I wanted to study the immunology of nucleic acids, and I did my first lab rotation with Jennifer Doudna, one of the biochemists who was instrumental in developing CRISPR-Cas9 as a gene-editing tool. She might seem like a funny first person to do a rotation with if you were doing immunology, but CRISPR is essentially a bacterial immune system, and I went to her lab just to see a completely different way of viewing immunology. During that rotation, I fell in love with crystallography. What’s so beautiful about this technique is that it shows us how different atoms are communicating with each other, and how one molecule might be engaging with another molecule.

For the rest of my rotations as a graduate student, I did research in biochemistry and structural biology labs, and ended up joining James Berger’s lab, which did a combination of both. I worked on a class of enzymes called topoisomerases that bind to DNA and uncoil the DNA when it gets tangled. I was able to solve a number of very interesting structures, and do biochemistry and genetics all at the same time.

During my postdoc I studied RNA polymerase II, the enzyme that makes all the RNAs that turn into proteins in the cell and determine the cell’s identity. I wanted to know how it is regulated after the initiation stage of transcription. One of the proteins I was working with wouldn’t crystallize, and we had to come up with some other ways of seeing it. So we turned to cryo-EM, which had just become a very high-resolution technology — we could actually see the atoms touching each other! That was a game-changer for me. If you told me at the beginning of my PhD that these technologies could become central to my research, I would have told you there’s no way that would happen. But life has surprises.

Q: How does your expertise in genetics and biochemistry help you solve structural problems?

A: I’m definitely not your average structural biologist — I use structural tools to advance the genetics I want to do. My lab uses genetics to inform which protein complexes we want to look at, and then we use cryo-EM and X-ray crystallography to understand how those proteins actually affect RNA polymerase II. With what we learn about the structure, we can go back and use targeted genetic approaches to remove those proteins from the genome and see what happens to gene expression in particular cells. I also have projects where we’ll do a genetic screen first, and then use structural biology and chemistry techniques to get more information. The research is like a giant feedback loop. You need all of those perspectives to really understand the whole system.

Phillip Sharp wins 2020 AACR Award for Lifetime Achievement in Cancer Research
American Association for Cancer Research
May 28, 2020

PHILADELPHIA — The American Association for Cancer Research (AACR) is recognizing Phillip A. Sharp, PhD, Fellow of the AACR Academy and Nobel Laureate, with the 17th AACR Award for Lifetime Achievement in Cancer Research.

Sharp, an Institute professor at Massachusetts Institute of Technology’s David H. Koch Institute for Integrative Cancer Research, is being honored for his exceptional body of groundbreaking and high-impact basic research, including his seminal co-discovery of RNA splicing. For this discovery, Sharp was awarded the 1993 Nobel Prize in Physiology or Medicine, along with Sir Richard J. Roberts, PhD. This body of research fundamentally changed scientists’ understanding of the structure of genes, shaping our understanding of RNA biology and our knowledge of the genetic causes of cancer and other diseases.

“Dr. Sharp is a luminary in the fields of molecular biology and biochemistry who has dedicated his research career to advancing our understanding of the molecular biology of gene expression as it pertains to cancer and the mechanisms of RNA splicing,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “He is one of the most creative scientific thinkers of our time, always looking to push the boundaries to address the enormous challenges that cancer still poses.  We are very proud to honor him with this special award.”

The AACR Award for Lifetime Achievement in Cancer Research was established in 2004 to honor individuals who have made significant fundamental contributions to cancer research, either through a single scientific discovery or a collective body of work. These contributions, whether they have been in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.

After first describing the phenomenon of RNA splicing, Sharp’s work focused on elucidating the biochemical mechanisms of RNA splicing and mammalian transcription. Today, his research continues to enhance our understanding of RNA structure and function and has been particularly focused on defining the biology of small RNAs and other types of noncoding RNAs. Additionally, his research has led the emerging field of convergence science for many years, resulting in the generation of the first CAS9 mouse model, which has proven vital to in vivo screening experiments dedicated to identifying genes involved in metastasis. To date, Sharp’s career publications in peer-reviewed journals total more than 440.

Sharp’s scientific influence extends far beyond his research accomplishments and has informed public policies and funding decisions at the nation’s highest level. Additionally, he has been an inspiration and mentor to more than 90 postdoctoral fellows and almost 40 graduate students, many of whom are now preeminent scientists in their respective areas of expertise.

Sharp, an AACR member since 1986, was elected to the inaugural class of the Fellows of the AACR Academy in 2013 and has been Chair of the Stand Up To Cancer (SU2C) Scientific Advisory Committee for more than a decade, leading the selection of 26 “Dream Teams” of top researchers and other SU2C research groups. The AACR is the Scientific Partner of SU2C. Further he served as program chair of the AACR’s Inaugural Special Conference in 1988. That conference, “Gene Regulation and Oncogenes,” has been characterized as a watershed meeting that stimulated novel, transformative thinking about the molecular biology of cancer. Sharp has provided steadfast support for the AACR Special Conferences Program over the past three decades, and served as co-chair for the 30th Anniversary Special Conference, “Convergence: Artificial Intelligence, Big Data, and Prediction in Cancer,” in 2018. In 2006, Sharp received the AACR-Irving Weinstein Foundation Distinguished Lectureship award, and in 2010, Sharp was honored with the AACR-Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research. In 2018, Sharp was presented with the AACR’s Distinguished Service Award for Extraordinary Scientific Innovation and Exceptional Leadership in Cancer Research and Biomedical Science.

Sharp has received countless scientific awards over his brilliant career in addition to the Nobel Prize, including the Gairdner Foundation International Award (1986), the Albert Lasker Basic Medical Research Award (1988), the Louisa Gross Horwitz Prize (1988), and the 2004 National Medal of Science, among many others. He is an elected member of the National Academy of Sciences and the American Academy of Arts and Sciences. He also holds more than 18 honorary Doctor of Science degrees from institutions of higher learning around the world. Sharp has a distinguished record of public service, serving as cochair of the National Cancer Advisory Board (2000-2002) and as a member of both the President’s Council of Advisors on Science and Technology (1994-1997) and the Committee on Science, Engineering, and Public Policy (1992-1995).

Outside of his academic research, Sharp cofounded two successful biotech companies, Biogen and Alnylam, both of which have developed therapeutics including rituximab and obinutuzumab for lymphoma, natalizumab and peginterferon for multiple sclerosis, and the first small interfering RNA-based therapy for transthyretin-mediated amyloidosis.