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Testing the waters

MIT sophomore Rachel Shen looks for microscopic solutions to big environmental challenges.

Lucy Jakub | Department of Biology
January 28, 2020

In 2010, the U.S. Army Corps of Engineers began restoring the Broad Meadows salt marsh in Quincy, Massachusetts. The marsh, which had grown over with invasive reeds and needed to be dredged, abutted the Broad Meadows Middle School, and its three-year transformation fascinated one inquisitive student. “I was always super curious about what sorts of things were going on there,” says Rachel Shen, who was in eighth grade when they finally finished the project. She’d spend hours watching birds in the marsh, and catching minnows by the beach.

In her bedroom at home, she kept an eye on four aquariums furnished with anubias, hornwort, guppy grass, amazon swords, and “too many snails.” Now, living in a dorm as a sophomore at MIT, she’s had to scale back to a single one-gallon tank. But as a Course 7 (Biology) major minoring in environmental and sustainability studies, she gets an even closer look at the natural world, seeing what most of us can’t: the impurities in our water, the matrices of plant cells, and the invisible processes that cycle nutrients in the oceans.

Shen’s love for nature has always been coupled with scientific inquiry. Growing up, she took part in Splash and Spark workshops for grade schoolers, taught by MIT students. “From a young age, I was always that kid catching bugs,” she says. In her junior year of high school, she landed the perfect summer internship through Boston University’s GROW program: studying ant brains at BU’s Traniello lab. Within a colony, ants with different morphological traits perform different jobs as workers, guards, and drones. To see how the brains of these castes might be wired differently, Shen dosed the ants with serotonin and dopamine and looked for differences in the ways the neurotransmitters altered the ants’ social behavior.

This experience in the Traniello lab later connected Shen to her first campus job working for MITx Biology, which develops online courses and educational resources for students with Department of Biology faculty. Darcy Gordon, one of the administrators for GROW and a postdoc at the Traniello Lab, joined MITx Biology as a digital learning fellow just as Shen was beginning her first year. MITx was looking for students to beta-test their biochemistry course, and Gordon encouraged Shen to apply. “I’d never taken a biochem course before, but I had enough background to pick it up,” says Shen, who is always willing to try something new. She went through the entire course, giving feedback on lesson clarity and writing practice problems.

Using what she learned on the job, she’s now the biochem leader on a student project with the It’s On Us Data Sciences club (formerly Project ORCA) to develop a live map of water contamination by rigging autonomous boats with pollution sensors. Environmental restoration has always been important to her, but it was on her trip to the Navajo Nation with her first-year advisory group, Terrascope, that Shen saw the effects of water scarcity and contamination firsthand. She and her peers devised filtration and collection methods to bring to the community, but she found the most valuable part of the project to be “working with the people, and coming up with solutions that incorporated their local culture and local politics.”

Through the Undergraduate Research Opportunities Program (UROP), Shen has put her problem-solving skills to work in the lab. Last summer, she interned at Draper and the Velásquez-García Group in MIT’s Microsystems Technologies Laboratories. Through experiments, she observed how plant cells can be coaxed with hormones to reinforce their cell walls with lignin and cellulose, becoming “woody” — insights that can be used in the development of biomaterials.

For her next UROP, she sought out a lab where she could work alongside a larger team, and was drawn to the people in the lab of Sallie “Penny” Chisholm in MIT’s departments of Biology and Civil and Environmental Engineering, who study the marine cyanobacterium Prochlorococcus. “I really feel like I could learn a lot from them,” Shen says. “They’re great at explaining things.”

Prochlorococcus is one of the most abundant photosynthesizers in the ocean. Cyanobacteria are mixotrophs, which means they get their energy from the sun through photosynthesis, but can also take up nutrients like carbon and nitrogen from their environment. One source of carbon and nitrogen is found in chitin, the insoluble biopolymer that crustaceans and other marine organisms use to build their shells and exoskeletons. Billions of tons of chitin are produced in the oceans every year, and nearly all of it is recycled back into carbon, nitrogen, and minerals by marine bacteria, allowing it to be used again.

Shen is investigating whether Prochlorococcus also recycles chitin, like its close relative Synechococcus that secretes enzymes which can break down the polymer. In the lab’s grow room, she tends to test tubes that glow green with cyanobacteria. She’ll introduce chitin to half of the cultures to see if specific genes in Prochlorococcus are expressed that might be implicated in chitin degradation, and identify those genes with RNA sequencing.

Shen says working with Prochlorococcus is exciting because it’s a case study in which the smallest cellular processes of a species can have huge effects in its ecosystem. Cracking the chitin cycle would have implications for humans, too. Biochemists have been trying to turn chitin into a biodegradable alternative to plastic. “One thing I want to get out of my science education is learning the basic science,” she says, “but it’s really important to me that it has direct applications.”

Something else Shen has realized at MIT is that, whatever she ends up doing with her degree, she wants her research to involve fieldwork that takes her out into nature — maybe even back to the marsh, to restore shorelines and waterways. As she puts it, “something that’s directly relevant to people.” But she’s keeping her options open. “Currently I’m just trying to explore pretty much everything.”

The new front against antibiotic resistance

Deborah Hung shares research strategies to combat tuberculosis as part of the Department of Biology's IAP seminar series on microbes in health and disease.

Lucy Jakub | Department of Biology
January 21, 2020

After Alexander Fleming discovered the antibiotic penicillin in 1928, spurring a “golden age” of drug development, many scientists thought infectious disease would become a horror of the past. But as antibiotics have been overprescribed and used without adhering to strict regimens, bacterial strains have evolved new defenses that render previously effective drugs useless. Tuberculosis, once held at bay, has surpassed HIV/AIDS as the leading cause of death from infectious disease worldwide. And research in the lab hasn’t caught up to the needs of the clinic. In recent years, the U.S. Food and Drug Administration has approved only one or two new antibiotics annually.

While these frustrations have led many scientists and drug developers to abandon the field, researchers are finally making breakthroughs in the discovery of new antibiotics. On Jan. 9, the Department of Biology hosted a talk by one of the chemical biologists who won’t quit: Deborah Hung, core member and co-director of the Infectious Disease and Microbiome Program at the Broad Institute of MIT and Harvard, and associate professor in the Department of Genetics at Harvard Medical School.

Each January during Independent Activities Period, the Department of Biology organizes a seminar series that highlights cutting-edge research in biology. Past series have included talks on synthetic and quantitative biology. This year’s theme is Microbes in Health and Disease. The team of student organizers, led by assistant professor of biology Omer Yilmaz, chose to explore our growing understanding netbet sports bettingof microbes as both pathogens and symbionts in the body. Hung’s presentation provided an invigorating introduction to the series.

“Deborah is an international pioneer in developing tools and discovering new biology on the interaction between hosts and pathogens,” Yilmaz says. “She’s done a lot of work on tuberculosis as well as other bacterial infections. So it’s a privilege for us to host her talk.”

A clinician as well as a chemical biologist, Hung understands firsthand the urgent need for new drugs. In her talk, she addressed the conventional approaches to finding new antibiotics, and why they’ve been failing scientists for decades.

“The rate of resistance is actually far outpacing our ability to discover new antibiotics,” she said. “I’m beginning to see patients [and] I have to tell them, I’m sorry, we have no antibiotics left.”

The way Hung sees it, there are two long-term goals in the fight against infectious disease. The first is to find a method that will greatly speed up the discovery of new antibiotics. The other is to think beyond antibiotics altogether, and find other ways to strengthen our bodies against intruders and increase patient survival.

Last year, in pursuit of the first goal, Hung spearheaded a multi-institutional collaboration to develop a new high-throughput screening method called PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets). By weakening the expression of genes essential to survival in the tuberculosis bacterium, researchers genetically engineered over 400 unique “hypomorphs,” vulnerable in different ways, that could be screened in large batches against tens of thousands of chemical compounds using PROSPECT.

With this approach, it’s possible to identify effective drug candidates 10 times faster than ever before. Some of the compounds Hung’s team has discovered, in addition to those that hit well-known targets like DNA gyrase and the cell wall, are able to kill tuberculosis in novel ways, such as disabling the bacterium’s molecular efflux pump.

But one of the challenges to antibiotic discovery is that the drugs that will kill a disease in a test tube won’t necessarily kill the disease in a patient. In order to address her second goal of strengthening our bodies against disease-causing microbes, Hung and her lab are now using zebrafish embryos to screen small molecules not just for their extermination of a pathogen, but for the survival of the host. This way, they can investigate drugs that have no effect on bacteria in a test tube but, in Hung’s words, “throw a wrench in the system” and interact with the host’s cells to provide immunity.

For much of the 20th century, microbes were primarily studied as agents of harm. But, more recent research into the microbiome — the trillions of organisms that inhabit our skin, gut, and cavities — has illuminated their complex and often symbiotic relationship with our immune system and bodily functions, which antibiotics can disrupt. The other three talks in the series, featuring researchers from Harvard Medical School, delve into the connections between the microbiome and colorectal cancer, inflammatory bowel disease, and stem cells.

“We’re just starting to scratch the surface of the dance between these different microbes, both good and bad, and their role in different aspects of organismal health, in terms of regeneration and other diseases such as cancer and infection,” Yilmaz says.

For those in the audience, these seminars are more than just a way to pass an afternoon during IAP. Hung addressed the audience as potential future collaborators, and she stressed that antibiotic research needs all hands on deck.

“It’s always a work in progress for us,” she said. “If any of you are very computationally-minded or really interested in looking at these large datasets of chemical-genetic interactions, come see me. We are always looking for new ideas and great minds who want to try to take this on.”

Putting a finger on the switch of chronic parasite infection
Greta Friar | Whitehead Institute
January 16, 2020

Toxoplasma gondii (T. gondii) is a parasite that chronically infects up to a quarter of the world’s population, causing toxoplasmosis, a disease that can be dangerous, or even deadly, for the immunocompromised and for developing fetuses. One reason that T. gondii is so pervasive is that the parasites are tenacious occupants once they have infected a host. They can transition from an acute infection stage into a quiescent life cycle stage and effectively barricade themselves inside of their host’s cells. In this protected state, they become impossible to eliminate, leading to long term infection. Researchers used to think that a combination of genes were involved in triggering the parasite’s transition into its chronic stage, due to the complexity of the process and because a gene essential for differentiation had not been identified. However, new research from Whitehead Institute Member Sebastian Lourido, who is also an assistant professor of biology at the Massachusetts Institute of Technology (MIT), and graduate student Benjamin Waldman has identified a sole gene whose protein product is the master regulator, which is both necessary and sufficient for the parasites to make the switch. Their findings, which appear online in the journal Cell on January 16, illuminate an important aspect of the parasite’s biology and provide researchers with the tools to control whether and when T. gondii transitions, or undergoes differentiation. These tools may prove valuable for treating toxoplasmosis, since preventing the parasites from assuming their chronic form keeps them susceptible to both treatment and elimination by the immune system.

T. gondii spreads when a potential host, which can be any warm-blooded animal, ingests infected tissue from another animal—in the case of humans, by eating undercooked meat or unwashed vegetables—or when the parasite’s progeny are shed by an infected cat, T. gondii’s target host for sexual reproduction. When T. gondii parasites first invade the body, they are in a quickly replicating part of their life cycle, called the tachyzoite stage. Tachyzoites invade a cell, isolate themselves by forming a sealed compartment from the cell’s membrane, and then replicate inside of it until the cell explodes, at which point they move on to another cell to repeat the process. Although the tachyzoite stage is when the parasites do the most damage, it’s also when they are easily targetable by the immune system and medical therapies. In order for the parasites to make their stay more permanent, they must differentiate into bradyzoites, a slow-growing stage, during which they are less susceptible to drugs and have too little effect on the body to trigger the immune system. Bradyzoites construct an extra thick wall to isolate their compartment in the host cell and encyst themselves inside of it. This reservoir of parasites remains dormant and undetectable, until, under favorable conditions, they can spring back into action, attacking their host or spreading to new ones.

Although the common theory was that multiple genes collectively orchestrate the transition from tachyzoite to bradyzoite, Lourido and Waldman suspected that there was instead a single master regulator.

“Differentiation is not something a parasite wants to do halfway, which could leave them vulnerable,” Waldman says. “Multiple genes means more chances for things to go wrong, so you would want a master regulator to ensure that differentiation happens cleanly.”

To investigate this hypothesis, Waldman used CRISPR-based screens to knock out T. gondii genes, and then tested to see if the parasite could still differentiate from tachyzoite to bradyzoite. Waldman monitored whether the parasites were differentiating by developing a strain of T. gondii that fluoresces in its bradyzoite stage. The researchers also performed a first of its kind single-cell RNA sequencing of T. gondii in collaboration with members of Alex Shalek’s lab in the department of chemistry at MIT. This sequencing allowed the researchers to profile the genes’ activity at each stage in unprecedented detail, shedding light on changes in gene expression during the parasite’s cell-cycle progression and differentiation.

The experiments identified one gene, which the researchers named Bradyzoite-Formation Deficient 1 (BFD1), as the only gene both sufficient and necessary to prevent the transition from tachyzoite to bradyzoite: the master regulator. Not only was T. gondii unable to make the transition without the BFD1 protein, but Waldman found that artificially increasing its production induced the parasites to become bradyzoites, even without the usual stress triggers required to cue the switch. This means that the researchers can now control Toxoplasma differentiation in the lab.

These findings may inform research into potential therapies for toxoplasmosis, or even a vaccine.

“Toxoplasma that can’t differentiate is a good candidate for a live vaccine, because the immune system can eliminate an acute infection very effectively,” Lourido says.

The researchers’ findings also have implications for food production. T. gondii and other cyst-forming parasites that use BFD1 can infect livestock. Further research into the gene could inform the development of vaccines for farm animals as well as humans.

“Chronic infection is a huge hurdle to curing many parasitic diseases,” Lourido says. “We need to study and figure out how to manipulate the transition from the acute to chronic stages in order to eradicate these diseases.”

This study was supported by an NIH Director’s Early Independence Award (1DP5OD017892), a grant from the Mathers Foundation, the Searle Scholars Program, the Beckman Young Investigator Program, a Sloan Fellowship in Chemistry, the NIH (1DP2GM119419, 2U19AI089992, 5U24AI118672), and the Bill and Melinda Gates Foundation.

Written by Greta Friar

***

Sebastian Lourido’s primary affiliation is with Whitehead Institute for Biomedical netbet online sports bettingResearch, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at the Massachusetts Institute of Technology.

***

Citation:

“Identification of a master regulator of differentiation in Toxoplasma”

Cell, online January 16, DOI: 10.1016/j.cell.2019.12.013

Benjamin S. Waldman (1,2), Dominic Schwarz (1,3), Marc H. Wadsworth II (4,5,6), Jeroen P. Saeij (7), Alex K. Shalek (4,5,6), Sebastian Lourido (1,2)

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

3. Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany

4. Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

6. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02319, USA

7. Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA

With these neurons, extinguishing fear is its own reward
Picower Institute
January 16, 2020

When you expect a really bad experience to happen and then it doesn’t, it’s a distinctly positive feeling. A new study of fear extinction training in mice may suggest why: The findings not only identify the exact population of brain cells that are key for learning not to feel afraid anymore, but also show these neurons are the same ones that help encode feelings of reward.

The study, published Jan. 14 in Neuron by scientists at MIT’s Picower Institute for Learning and Memory, specifically shows that fear extinction memories and feelings of reward alike are stored by neurons that express the gene Ppp1r1b in the posterior of the basolateral amygdala (pBLA), a region known to assign associations of aversive or rewarding feelings, or “valence,” with memories. The study was conducted by Xiangyu Zhang, a graduate student, Joshua Kim, a former graduate student, and Susumu Tonegawa, Professor of Biology and Neuroscience at RIKEN-MIT Laboratory of Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT and Howard Hughes Medical Institute.

“We constantly live at the balance of positive and negative emotion,” Tonegawa said. “We need to have very strong memories of dangerous circumstances in order to avoid similar circumstances to recur. But if we are constantly feeling threatened we can become depressed. You need a way to bring your emotional state back to something more positive.”

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In a prior study, Kim showed that Ppp1r1b-expressing neurons encode rewarding valence and compete with distinct Rspo2-expressing neurons in the BLA that encode negative valence. In the new study, Zhang, Kim and Tonegawa set out to determine whether this competitive balance also underlies fear and its extinction.

In fear extinction, an original fearful memory is thought to be essentially overwritten by a new memory that is not fearful. In the study, for instance, mice were exposed to little shocks in a chamber, making them freeze due to the formation of fearful memory. But the next day, when the mice were returned to the same chamber for a longer period of time without any further little shocks, freezing gradually dissipated and hence this treatment is called fear extinction training. The fundamental question then is whether the fearful memory is lost or just suppressed by the formation of a new memory during the fear extinction training.

While the mice underwent fear extinction training the scientists watched the activity of the different neural populations in the BLA. They saw that Ppp1r1b cells were more active and Rspo2 cells were less active in mice that experienced fear extinction. They also saw that while Rspo2 cells were mostly activated by the shocks and were inhibited during fear extinction, Ppp1r1b cells were mostly active during extinction memory training and retrieval, but were inhibited during the shocks.

These and other experiments suggested to the authors that the hypothetical fear extinction memory may be formed in the Ppp1r1b neuronal population and the team went on to demonstrate this vigorously. For this, they employed the technique previously pioneered in their lab for the identification and manipulation of the neuronal population that holds specific memory information, memory “engram” cells.  Zhang labeled Ppp1r1b neurons that were activated during retrieval of fear extinction memory with the light-sensitive protein channelrhodopsin. When these neurons were activated by blue laser light during a second round of fear extinction training it enhanced and accelerated the extinction. Moreover, when the engram cells were inhibited by another optogenetic technique, fear extinction was impaired because the Ppp1r1b engram neurons could no longer suppress the Rspo2 fear neurons. That allowed the fear memory to regain primacy.

These data met the fundamental criteria for the existence of engram cells for fear extinction memory within the pBLA Ppp1r1b cell population: activation and reactivation by recall and enduring and off-line maintenance of the acquired extinction memory.

Because Kim had previously shown Ppp1r1b neurons are activated by rewards and drive appetitive behavior and memory, the team sequentially tracked Ppp1r1b cell activity in mice that eagerly received water reward followed by food reward followed by fear extinction training and fear extinction memory retrieval. The overlap of Ppp1r1b neurons activated by fear extinction vs. water reward was as high as the overlap of neurons activated by water vs. food reward. And finally, artificial optogenetic activation of Ppp1r1b extinction memory engram cells was as effective as optogenetic activation of Ppp1r1b water reward-activated neurons in driving appetitive behaviors. Reciprocally, artificial optogenetic activation of water-responding Ppp1r1b neurons enhanced fear extinction training as efficiently as optogenetic activation of fear extinction memory engram cells. These results demonstrate that fear extinction is equivalent to bona fide rewards and therefore provide the neuroscientific basis for the widely held experience in daily life: omission of expected punishment is a reward.

What next?

By establishing this intimate connection between fear extinction and reward and by identifying a genetically defined neuronal population (Ppp1r1b) that plays a crucial role in fear extinction this study provides potential therapeutic targets for treating fear disorders like PTSD and anxiety, Zhang said.

From the basic scientific point of view, Tonegawa said, how fear extinction training specifically activates Ppp1r1b neurons would be an important question to address. More imaginatively, results showing how Ppp1r1b neurons override Rspo2 neurons in fear extinction raises an intriguing question about whether a reciprocal dynamic might also occur in the brain and behavior. Investigating “joy extinction” via these mechanisms might be an interesting research topic.

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

Whitehead Institute receives $10 million to study sex chromosomes’ impact on women’s health

Gift establishes the Brit Jepson d’Arbeloff Center on Women's Health.

Whitehead Institute
January 15, 2020

The Whitehead Institute has announced that Brit Jepson d’Arbeloff SM ’61 — a pioneering engineer, advocate for women in science, and philanthropic leader — has made a $10 million gift to support research uncovering the biological consequences of the sex chromosomes on women’s health and disease. The gift, one of the largest contributions ever made to the Whitehead Institute, will underwrite the establishment of the Brit Jepson d’Arbeloff Center on Women’s Health within the institute’s Sex Differences in Health and Disease Initiative.

The overall initiative is a comprehensive effort to understand sex differences at the molecular level — a long-neglected area of biomedical research — by building a fundamental understanding of how the female and male genome, transcriptome, epigenome, proteome, and metabolome differ. In the long run, determining the practical implications of those differences should lead to better, more effective treatments for both women and men.

The initiative holds particular promise for understanding health and treating disease in women. The d’Arbeloff Center is designed to drive progress toward that promise: catalyzing basic and translational research studies and collaborations that transform health care for women.

“Brit d’Arbeloff has been a trailblazer in science, research, and education,” says David C. Page, Whitehead Institute director and MIT professor of biology, who leads the sex differences initiative. “This is just the latest example of her determination to help drive biomedical research forward in significant ways. She is a staunch supporter of our work to understand the effects of the sex chromosomes on human health and disease, and her leadership and generosity have enabled us to build a solid research foundation.

“With this extraordinary new gift, she empowers us to build on that base by pursuing and translating discoveries that address the gaps in knowledge about health and disease in women,” Page says.

D’Arbeloff, a member of the Whitehead Institute’s board of directors since 2008, says, “I have long marveled at the stream of scientific discoveries and technical advances by Whitehead Institute researchers. For me, the most exciting of that work is being done within the sex differences initiative — exciting for both the imperative task it is taking on and the invaluable knowledge it is creating. The initiative will help to redress the longstanding inadequacy of research into women’s health and disease, and to catalyze development of therapeutics that are demonstrated effective for women.

netbet sports betting“I believe that this is an essential biomedical quest, one as challenging today as the Human Genome Project was in 1991,” d’Arbeloff says. “No institution is better positioned to lead it than Whitehead Institute. And, in creating the Center for Women’s Health, I cannot make a more important investment in the health of my grandchildren and their children.”

D’Arbeloff is known for her enduring commitment to advancing biomedical research and to ensuring opportunities for women scientists and engineers. It is a commitment born of her own experience. She was the first woman to earn a mechanical engineering degree from Stanford University, graduating at the top of her class, but she had difficulty finding a job. When she earned a master’s degree at MIT in 1961, she was the sole woman in the school’s mechanical engineering department. She went on to become part of pioneering industries — contributing to the design of the Redstone missile in the 1960s, then programming software for Digital Equipment Corporation and Teradyne. For decades since, she has supported the efforts of women to succeed in science and engineering by offering her energy and leadership, her knowledge and experience, and her philanthropy.

While d’Arbeloff has provided substantial philanthropic support to a range of nonprofit organizations, she has had a particular impact in education, science, and technology. For example, beyond her decades of support for the Whitehead Institute, she established an MIT-based summer program to introduce female high school students to engineering careers, founded the Women in Science Committee of the Museum of Science, Boston, and supported the MGH Research Scholars Program to advance the careers of emerging clinical researchers.

The d’Arbeloff Center will create synergies and collaborations among Whitehead Institute investigators and facilities and those at biomedical research organizations throughout the Boston, Massachusetts region, across the nation, and around the world. Leveraging the knowledge gained by the initiative’s investigations into the molecular mechanisms through which the X and Y chromosomes give rise to sex-specific differences in cells, tissues, and organs, the center will delve into the ways that those differences contribute to conditions of health and of disease in women.

It will bring together experts in sex chromosome biology and sex hormones, computational biology and cutting-edge analytics, and proteomics, epigenetics, and metabolomics — fostering the kinds of researcher collaborations never before undertaken and spurring new approaches to the many-variable problem inherent in sex differences research. The center will also pursue partnerships to translate and develop meaningful discoveries into clinical applications for diagnosing, preventing, and treating disease in women. Ultimately, Page envisions, center-driven collaborations and partnerships will include university or medical school-based and independent research organizations, pharmaceutical and medical device manufacturers, and federal agencies.

Page, who will conclude his term as director in June, is also an investigator of the Howard Hughes Medical Institute. He has run a thriving research lab throughout his 35 years at Whitehead Institute, and is globally renowned for his groundbreaking research on sex chromosomes: His studies on the Y chromosome changed the way biomedical science views the function of sex chromosomes, and the work of his laboratory was cited twice in Science magazine’s “Top 10 Breakthroughs of the Year” — first for mapping a human chromosome and then for sequencing the human Y chromosome.

D’Arbeloff observes, “I have very concrete hopes for the center: I want it to help ensure that biomedical research reflects and benefits all of humanity — women and men, young and old. And I believe it is not hyperbole to say that David Page’s sex differences initiative truly has the potential to change the future of health care — for everyone.”

MIT and Sierra Leone professors collaborate on education strategy
Greta Friar | Whitehead Institute
January 13, 2020

Whitehead Member Hazel Sive, also a professor of biology at the Massachusetts Institute of Technology (MIT), is passionate about sharing MIT’s educational strategy for producing skilled, innovative problem-solvers with other educators. Sive, who was born in South Africa and is the founder and faculty director of the MIT-Africa initiative, also cares deeply about strengthening MIT’s connections to Africa—a goal that MIT shares. MIT-Africa has the tagline ‘Collaborating for Impact’ and has the goal to promote mutually beneficial engagement in research, education and innovation with African countries. The university made the African continent a global priority region for its international efforts in 2017. Consequently, Sive was thrilled by the opportunities for exchange that arose when Sierra Leone’s new president, Julius Maada Bio, selected MIT alumnus Moinina David Sengeh (SM ’12, PhD ’16) as his chief innovation officer. Sengeh, who heads the country’s Directorate of Science, Technology, and Innovation, used his MIT ties to catalyze connections between leaders at MIT and in Sierra Leone, including working with MIT-Africa to do so.

Bio and Sengeh visited MIT in March 2019 to officially launch the MIT-Sierra Leone Program.  The program’s early connections with MIT include Njala University membership in the MIT Abdul Latif Jameel World Education Lab, MIT student internships and faculty visits to Sierra Leone, and an ongoing discourse on higher education strategy. Njala University also participated in the summer 2019 launch of the MIT-Africa Short Course.

MIT-Africa Short Courses are 2- to 5-day-long, collegial workshops or lecture series, on topics of interest in research or education. MIT faculty will bring the courses to African colleagues at their home institutions. Sive led the first Short Course series, a three-day program titled, “Educating with Problem-solving Approaches,” in July and August at Njala University, the Central University of Technology in South Africa, and the Dar es Salaam Institute of Technology in Tanzania.

Sive and the three African universities selected the course topic as one of great interest. MIT has a philosophy of educating students in a problem-solving framework, where students practice problem-solving not only in class, but also in their homework, research, and independent projects.

“The great thing that we give our students at MIT, in terms of employability and flexibility to respond to shifts in careers, is the ability to solve problems, a training that is applicable across every field,” Sive said.

That skillset is one that Sierra Leone’s education leaders likewise want to foster in their students.

Sive brought two MIT students with her to each iteration of the Short Course to speak about their experiences at the Institute, six in total, including Michelle Huang, Jia-Hui Lee, Alice Li, Ashwin Narayan, Keith Puthi, and Michal Reda.

When Sive and the students ran the course in Sierra Leone, it was attended by university, technical college and higher education policy leaders. Discussion ranged from exploring MIT approaches, to considering which may be useful in Sierra Leone, to big-picture higher education strategy.

Sive is excited about connections being made between MIT and Sierra Leone, and the possibilities for important projects that can be carried out together.

“It’s outstanding to make connections with colleagues in higher education across the world,” Sive said. “The frameworks of universities across the world overlap enormously, making it easy to connect and work together toward the same goals.”

Written by Greta Friar

Pushing the field of chemical biology in a new direction
Lucy Jackub
January 8, 2020

n 1996, Virginia Cornish had the idea that would define her career in synthetic biology. She had been working in chemistry labs that were trying to imitate, in test tubes, the complex chemistry that occurs in living organisms. Inside a cell, genes code for hundreds of enzymes that are produced to catalyze different chemical reactions. But what if a cell’s natural machinery could be co-opted to do new chemistry, even chemistry that doesn’t occur in nature? She saw the potential for living cells to become tools.

Stuart Schreiber, now at the Broad Institute of MIT and Harvard, discovered early in his career that a certain immunosuppressant drug worked by allowing proteins in the cell to dimerize, or link together, with proteins they wouldn’t normally interact with strongly. These new protein-protein interactions led to new reactions in the cell. He suggested that other small molecules, or “chemical dimerizers,” could be synthesized that would cause other novel protein-protein interactions, with therapeutic potential to trigger a range of biological functions in the cell, such as gene expression, protein degradation, and apoptosis. But it struck Cornish that chemical dimzerizers could instead be used to screen for specific enzymes in a cell’s genetic library, by dimerizing transcription factors so that they would only activate gene expression in the presence of a specific enzyme. Paired with molecular engineering, this could guide directed evolution in the lab. “I called this chemical complementation,” she says.

She brought the idea to professor Bob Sauer, who had just admitted her as a postdoc to his lab in MIT’s Department of Biology. Only three months after she’d begun working with him, Cornish received an unexpected invitation to interview for an assistant professorship in the Department of Chemistry at Columbia University, where she’d gotten her undergraduate degree in biochemistry. She bused down to New York with the plans for chemical complementation in her pocket. By the end of the day she’d been offered her own laboratory.

The offer was tempting, but Cornish asked Columbia if they’d wait for her to finish her postdoc, and ended up staying in the Sauer lab for two years. Those years turned out to be vital, she says. netbet sports betting app“I had a lot of biology to learn.”

A Changing Field

Cornish came to Columbia from Savannah, Georgia in 1987, and joined the lab of Ronald Breslow, who had been chair of the committee that had urged the university to begin admitting female students in 1983. Columbia was renowned for organic chemistry, and Breslow’s work in biomimetic chemistry — synthesizing molecules in round-bottomed flasks that resemble molecules found in living systems — was laying the groundwork for the nascent field of chemical biology.

After graduating from Columbia, Cornish took her rigorous training in organic chemistry West to do her PhD in the lab of Peter Schultz at the University of California, Berkeley. Schultz’s lab had just succeeded in synthesizing unnatural amino acids that could be encoded into a cell’s DNA and fed into its translational machinery to create novel proteins. This was an unconventional project for a chemistry lab, but Schultz was interested in bringing together organic chemistry and molecular biology to manipulate large molecules, even ones as large and complex as those of the ribosome.

Cornish’s thesis used Schultz’s method of unnatural amino acid mutagenesis to introduce a chemical group called a ketone, rather than an amino acid, into the cell. The ketone could then be tagged with a fluorescent label, and serve as a biosensor for certain chemicals. This was early work in what would later become the field of bio-orthogonal chemistry.

Excited by the molecular engineering she’d learned in the Schultz lab, Cornish wanted to explore it further in living cells. That meant joining a biology laboratory. She’d heard that MIT’s Department of Biology was a great place to be a postdoc, and was drawn to the molecular engineering Bob Sauer’s lab was doing with bacteria. Then the idea for chemical complementation came to her as she was getting coffee with a friend from the Schreiber lab, and she knew exactly what she wanted to do with her postdoc.

“The main thing I remember about Virginia is that she was just fearless,” Sauer recalls. Cornish’s project, to synthesize a small molecule that could be easily adapted to dimerize a large variety of proteins, was a problem the Sauer lab had never taken on before. “As biochemists, we were interested in protein-protein interactions, and how those mediated networks of genetic regulation, because a lot of the proteins that bind DNA specifically do so as dimers or tetramers,” says Sauer. “She took it to a different level by thinking about how you can use chemical biology to actually dimerize things.”

Cornish remembers the “intellectually vibrant environment” at MIT and the cross-fertilization between labs in the department, and learned as much from other postdocs as from faculty. Petra Levin, a postdoc in professor Alan Grossman’s lab, spent hours patiently teaching her genetics. At that time, Sauer’s lab held joint group meetings to discuss their research in protein folding and transcription with two other labs in the department at that time, headed by Peter Kim and Carl Pabo. It was the genesis of a larger collaboration, informally known as “the structural biology supergroup.”

“I still remember the first time I presented my idea of chemical complementation to this group,” Cornish says. “Peter Kim grilled me for a good fifteen to twenty minutes, going so far as to ask me what my transcription factor was.”

Sauer’s lab works with Escherichia coli, but Cornish decided that her model organism of choice chemical complementation wasn’t a bacterium. It was a yeast, Saccharomyces cerevisiae. Researchers at Johns Hopkins had just found a method for chemically dimerizing proteins in yeast, and it had “all the right parts and pieces” that Cornish needed for her own experiment. She began spending more and more time in Chris Kaiser’s lab next door, borrowing their media to culture yeast. She was introduced to a postdoc in Gerald Fink’s lab, Hiten Madhani, who taught her the fundamentals of yeast genetics. She still has the pieces of paper from their meetings, where Madhani sketched out the yeast plasmids and genetic markers.

“She was down the hall learning stuff from the Kaiser lab, over in the Chemistry Department learning stuff from them,” says Sauer. “I provided a bench for her.”

Synthetic Solutions

When Cornish finished her postdoc and finally took her position at Columbia in 1999, chemical complementation became the foundation for the research in her lab. Working in yeast distinguished Cornish from other scientists who came out of MIT and were doing similar experiments in bacteria in the early 2000s, synthesizing molecules to work together in living cells — the first forays in what is now known as synthetic biology.

Cornish is now the Helena Rubinstein Professor in the departments of Chemistry and Systems Biology at Columbia. She has become a leader in her field, serving on the executive committee of Genome Project-Write, a group of synthetic biologists that has come together to establish ethical standards and self-regulation of new technologies to edit and synthesize genetic information.

She stays focused on how synthetic biology can advance medicine and make products that solve real problems. In 2017, the Cornish Group engineered baker’s yeast to detect fungal pathogens and react by turning red, creating a cheap biosensor with the potential to save lives in regions without medical access. Synthetic biologists have, up until now, focused on engineering individual cells, but Cornish’s next project is to engineer entire communities of yeast cells to work together, like our microbiome does, by taking advantage of the complex communication networks between them. Cornish says that in the lab, “the most exciting moment really is when you’re doing something that you can’t quite articulate.”

She credits her mentors — Breslow, Schultz, and Sauer — with instilling that creative drive in her. All of them were “pushing the field in a new direction,” as she puts it. She pays that mentorship forward to her students. “Sometimes there’s a sense that great science and mentorship are at odds with one another,” she says, but she’s found that the opposite is true. “I think the best way to do great science is just to enable your students to be everything that they can be. And then it really becomes an exciting collaboration.”

Images courtesy of Virginia Cornish
Bose grants for 2019 reward bold ideas across disciplines

Three innovative research projects in literature, plant epigenetics, and chemical engineering will be supported by Professor Amar G. Bose Research Grants.

MIT Resource Development
December 30, 2019

Now in its seventh year, the Professor Amar G. Bose Research Grants support visionary projects that represent intellectual curiosity and a pioneering spirit. Three MIT faculty members have each been awarded one of these prestigious awards for 2019 to pursue diverse questions in the humanities, biology, and engineering.

At a ceremony hosted by MIT President L. Rafael Reif on Nov. 25 and attended by past awardees, Provost Martin Schmidt, the Ray and Maria Stata Professor of Electrical Engineering and Computer Science, formally announced this year’s Amar G. Bose Research Fellows: Sandy Alexandre, Mary Gehring, and Kristala L.J. Prather.

The fellowships are named for the late Amar G. Bose ’51, SM ’52, ScD ’56, a longtime MIT faculty member and the founder of the Bose Corporation. Speaking at the event, President Reif expressed appreciation for the Bose Fellowships, which enable highly creative and unusual research in areas that can be hard to fund through traditional means. “We are tremendously grateful to the Bose family for providing the support that allows bold and curious thinkers at MIT to dream big, challenge themselves, and explore.”

Judith Bose, widow of Amar’s son, Vanu ’87, SM ’94, PhD ’99, congratulated the fellows on behalf of the Bose family. “We talk a lot at this event about the power of a great innovative idea, but I think it was a personal mission of Dr. Bose to nurture the ability, in each individual that he met along the way, to follow through — not just to have the great idea but the agency that comes with being able to pursue your idea, follow it through, and actually see where it leads,” Bose said. “And Vanu was the same way. That care that was epitomized by Dr. Bose not just in the idea itself, but in the personal investment, agency, and nurturing necessary to bring the idea to life — that care is a large part of what makes true change in the world.”

The relationship between literature and engineering

Many technological innovations have resulted from the influence of literature, one of the most notable being the World Wide Web. According to many sources, Sir Tim Berners-Lee, the web’s inventor, found inspiration from a short story by Arthur C. Clarke titled “Dial F for Frankenstein.” Science fiction has presaged a number of real-life technological innovations, including the defibrillator, noted in Mary Shelley’s “Frankenstein;” the submarine, described in Jules Verne’s “20,000 Leagues Under the Sea;” and earbuds, described in Ray Bradbury’s “Fahrenheit 451.” But the data about literature’s influence on STEM innovations are spotty, and these one-to-one relationships are not always clear-cut.

Sandy Alexandre, associate professor of literature, intends to change that by creating a large-scale database of the imaginary inventions found in literature. Alexandre’s project will enact the step-by-step mechanics of STEM innovation via one of its oft-unsung sources: literature. “To deny or sever the ties that bind STEM and literature is to suggest — rather disingenuously — that the ideas for many of the STEM devices that we know and love miraculously just came out of nowhere or from an elsewhere where literature isn’t considered relevant or at all,” she says.

During the first phase of her work, Alexandre will collaborate with students to enter into the database the imaginary NetBet live casinoinventions as they are described verbatim in a selection of books and other texts that fall under the category of speculative fiction—a category that includes but is not limited to the subgenres of fantasy, Afrofuturism, and science fiction. This first phase will, of course, require that students carefully read these texts in general, but also read for these imaginary inventions more specifically. Additionally, students with drawing skills will be tasked with interpreting the descriptions by illustrating them as two-dimensional images.

From this vast inventory of innovations, Alexandre, in consultation with students involved in the project, will decide on a short list of inventions that meet five criteria: they must be feasible, ethical, worthwhile, useful, and necessary. This vetting process, which constitutes the second phase of the project, is guided by a very important question: what can creating and thinking with a vast database of speculative fiction’s imaginary inventions teach us about what kinds of ideas we should (and shouldn’t) attempt to make into a reality? For the third and final phase, Alexandre will convene a team to build a real-life prototype of one of the imaginary inventions. She envisions this prototype being placed on exhibit at the MIT Museum.

The Bose research grant, Alexandre says, will allow her to take this project from a thought experiment to lab experiment. “This project aims to ensure that literature no longer play an overlooked role in STEM innovations. Therefore, the STEM innovation, which will be the culminating prototype of this research project, will cite a work of literature as the main source of information used in its invention.”

Nature’s role in chemical production

Kristala L.J. Prather ’94, the Arthur D. Little Professor of Chemical Engineering, has been focused on using biological systems for chemical production during the 15 years she’s been at the Institute. Biology as a medium for chemical synthesis has been successfully exploited to commercially produce molecules for uses that range from food to pharmaceuticals — ethanol is a good example. However, there is a range of other molecules with which scientists have been trying to work, but they have faced challenges around an insufficient amount of material being produced and a lack of defined steps needed to make a specific compound.

Prather’s research is rooted in the fact that there are a number of naturally (and unnaturally) occurring chemical compounds in the environment, and cells have evolved to be able to consume them. These cells have evolved or developed a protein that will sense a compound’s presence — a biosensor — and in response will make other proteins that help the cells utilize that compound for its benefit.

“We know biology can do this,” Prather says, “so if we can put together a sufficiently diverse set of microorganisms, can we just let nature make these regulatory molecules for anything that we want to be able to sense or detect?” Her hypothesis is that if her team exposes cells to a new compound for a long enough period of time, the cells will evolve the ability to either utilize that carbon source or develop an ability to respond to it. If Prather and her team can then identify the protein that’s now recognizing what that new compound is, they can isolate it and use it to improve the production of that compound in other systems. “The idea is to let nature evolve specificity for particular molecules that we’re interested in,” she adds.

Prather’s lab has been working with biosensors for some time, but her team has been limited to sensors that are already well characterized and that were readily available. She’s interested in how they can get access to a wider range of what she knows nature has available through the incremental exposure of new compounds to a more comprehensive subset of microorganisms.

“To accelerate the transformation of the chemical industry, we must find a way to create better biological catalysts and to create new tools when the existing ones are insufficient,” Prather says. “I am grateful to the Bose Fellowship Committee for allowing me to explore this novel idea.”

Prather’s findings as a result of this project hold the possibility of broad impacts in the field of metabolic engineering, including the development of microbial systems that can be engineered to enhance degradation of both toxic and nontoxic waste.

Adopting orphan crops to adapt to climate change

In the context of increased environmental pressure and competing land uses, meeting global food security needs is a pressing challenge. Although yield gains in staple grains such as rice, wheat, and corn have been high over the last 50 years, these have been accompanied by a homogenization of the global food supply; only 50 crops provide 90% of global food needs.

However, there are at least 3,000 plants that can be grown and consumed by humans, and many of these species thrive in marginal soils, at high temperatures, and with little rainfall. These “orphan” crops are important food sources for farmers in less developed countries but have been the subject of little research.

Mary Gehring, associate professor of biology at MIT, seeks to bring orphan crops into the molecular age through epigenetic engineering. She is working to promote hybridization, increase genetic diversity, and reveal desired traits for two orphan seed crops: an oilseed crop, Camelina sativa (false flax), and a high-protein legume, Cajanus cajan (pigeon pea).

C. sativa, which produces seeds with potential for uses in food and biofuel applications, can grow on land with low rainfall, requires minimal fertilizer inputs, and is resistant to several common plant pathogens. Until the mid-20th century, C. sativa was widely grown in Europe but was supplanted by canola, with a resulting loss of genetic diversity. Gehring proposes to recover this genetic diversity by creating and characterizing hybrids between C. sativa and wild relatives that have increased genetic diversity.

“To find the best cultivars of orphan crops that will withstand ever increasing environmental insults requires a deeper understanding of the diversity present within these species. We need to expand the plants we rely on for our food supply if we want to continue to thrive in the future,” says Gehring. “Studying orphan crops represents a significant step in that direction. The Bose grant will allow my lab to focus on this historically neglected but vitally important field.”

Human-human and protein-protein interactions.

A change in fields and a two-body problem ultimately led Biology and BE Professor Amy Keating to MIT to study coiled-coils and other protein interactions.

J. Carota | CSB Grad Office
December 17, 2019

About 330 miles west of Cambridge lies the small academic town of Ithaca, New York: the location of Cornell University and the hometown of Professor Amy Keating. Surrounded by academics (her father is a professor of computer science at Cornell), Keating was eager to continue her education after high school—just not in Ithaca.

“I could have stayed at Cornell, which is obviously an extremely good school in my hometown, but my family and I agreed that it was important that I go away,” recounts Keating. The scholar/athlete set her sights on Harvard University based on the excellent rowing team and outstanding academics. Physics particularly appealed to her, because it involved using math to explain mechanical and electrical phenomena, and she chose this as her major. She likes to tell people that she also “attempted pure math but failed miserably.” Keating admits that she was not very good at the abstract subject material, and tackling it side-by-side with math whizzes was a harsh awakening after performing well throughout high school. She switched to studying applied math, which was easier for her to manage and also more useful for a physics major.

With an intense rowing schedule, Keating often found herself working late into the night, struggling to solve problems alone. It took a year or two and a serious injury for her to realize that that most of the physics majors were working together in the library many afternoons while she was on the river. “That was very eye-opening. Now I’m a strong advocate of students teaching each other and learning from each other,” explains Keating.

Graduate study gridlock

As she approached the end of her senior year, she had no doubt that she would pursue a PhD, but she did face a crisis about what to study. Initially, she thought she would go to graduate school for physics and applied to and visited many schools. However, she was troubled by the fact that she had tried out a number of areas of physics but never found one that truly captured her interest. In addition to this, Keating began dating a young man, now her husband, who was majoring in chemistry and not set to graduate for another year. “I learned a lot of organic chemistry from him and got very interested in the subject.”

With the decision made to stay in Cambridge for an additional year, she picked up part time work at a Harvard student residence hall cooking, baking, and cleaning in exchange for room and board. Keating also took a few chemistry courses for credit, coached adult rowing, and spent the rest of her time working in the lab of Harvard Physics Professor Mara Prentiss. By the end of that year, she had developed a keen interest in the field of computational chemistry. Having faced difficult decisions about her own post-college plans, she has “a lot of empathy for students who are twenty-one and trying to decide what they want to do in the world.”

Keating and her future husband applied to the same chemistry PhD program at UCLA, where they were both admitted and joined separate labs. She looks back at the interview weekend at UCLA and remembers one faculty interviewer who pointed out the lack of chemistry in her background. “We were talking about cooking, and I told him I like to cook and had been cooking for a job. He said ‘if you can cook, you can do chemistry’, and there is some truth to that, of course.”  Keating netbet sports betting appacknowledges that the first few months of graduate school were traumatic. “I had exactly two undergrad chemistry classes under my belt. I didn’t really know much chemistry and then I was thrown into this PhD program with chemistry majors. And I was taking graduate level courses with my husband, who is a brilliant chemist. But I caught up and managed to learn a lot in a short time.”

Graduate life smoothed out when Keating joined the lab of Ken Houk, a leader in computational physical organic chemistry. Later in her doctoral studies, she added co-advisor Miguel Garcia-Garibay, an expert in experimental photochemistry. Having the two advisors worked out well and led to several joint publications over Keating’s graduate school career. After her husband’s advisor left UCLA for a company, the couple “had to decide what to do. So, we decided we should graduate quickly.” Now married, Keating and her husband earned their PhDs in under five years, but they would continue to be challenged by the “two-body problem” as they formulated a plan for after graduation.

Further afield

The couple knew they both wanted to find postdoc positions, so they looked in cities like San Diego, San Francisco, and Boston, where positions were abundant. Of that time, Keating says: “I was thinking about different problems or fields where my background might apply. I was reading a lot, just to find out what was out there.” This also marks the first time that she started thinking about problems in biology. “I was actually interested in two areas: material science, and biochemistry, both of which are exciting and rapidly growing areas where chemical principles are centrally important.” Keating’s hard work landed her a position back in Cambridge, where she was again co-advised, this time by former MIT Biology Professor Peter Kim at the Whitehead Institute and MIT Professor of Chemistry  Bruce Tidor(who was later the founding director of the CSB PhD Program).

The postdoc transition was another time in Keating’s life that she good-naturedly describes as “traumatic,” as she once again had to work to understand all-new vocabulary and experimental methods. Her postdoc provided Keating with her first exposure to large molecules; it was also when she first started working on protein interactions, which would become the crux of her future research.  It was in the Kim Lab that she was introduced to coiled-coil proteins. With her background in physics and chemistry, the simplified repeating interactions in these molecules appealed to her. A principle the Keating Lab continues to follow to this day is that they try not to study the most complicated interactions in biology, but rather simpler interactions that they seek to understand in fine detail.

More two-body problems

After four years, Keating hit the academic job market, but she wasn’t sure if she would be accepted as a biochemist because of her change in fields as a postdoc . Her concerns were short-lived as she ended up with a number of exciting offers, including one from MIT. Keating’s husband decided he would go into industry in Boston and with this decision she accepted MIT’s offer to join the Biology faculty in 2002. Later, she added a joint appointment in Biological Engineering.

Keating offers advice to students who are dealing with the two-body problem as she once did.“I think something that helped me and my husband is that we stayed in sync. So, we never had one person make a decision without knowing how that would impact the options of the other person. Of course, that’s not possible for everybody. But that did make our trajectory easier. We would collect our options, put them on the table, look for overlap, and then try to figure out what decision would work best for both of us. And we were very fortunate that we had good options. People have to be flexible to make this work out.” She also recommends looking in cities where there is a high density of opportunities.

The general interest of the Keating lab is in protein-protein interactions, how they work in nature, and how they can be re-engineered using computational and experimental methods. Her group studies proteins that regulate critical processes but are also relatively simple. For example, a system the Keating lab is attracted to is the Bcl-2 family of proteins that control cell death. They have developed a variety of methods that can be used to reprogram the interaction between proteins, and applying these methods to Bcl-2 proteins has generated short peptide molecules that inhibit processes that keep cancer cells alive. Recently the lab has been investigating other types of interactions in cells that are structurally different from the Bcl-2 family. Switching protein families challenges them to develop new methods and allows them to continue to change and evolve their research.

Students and postdocs from the Keating lab have gone on a wide variety of jobs where they study proteins and their interactions in both academia and industry. Keating is happy that young scientists today have so many options. She reflects: “When I was finishing my postdoc, the range of jobs in industry was nothing like it is today. It has been fun to watch my trainees apply their skills to antibody engineering, cancer biology, immuno-oncology and even to start their own companies.” She marvels at how many paths are open to young biologists and likes to tell them that they can’t possibly forsee where they will end up, given the myriad exciting possibilities. Certainly, as a young rower and physics student at Harvard, she had no idea she would end up as a Professor of Biology at MIT.