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Thank you for your patients

An unusual synergy between cancer researchers, clinical centers, and industry leads to promising clinical trials for a new combination therapy for prostate cancer.

Bendta Schroeder | Koch Institute
March 21, 2020

As Jesse Patterson, an MIT research scientist, and Frank Lovell, a finance industry retiree with a penchant for travel, chatted in the Koch Institute auditorium after a public lecture, they realized the anomaly of the experience: Cancer patients rarely get to meet researchers working on their treatments, and cancer researchers rarely get to put a name and a face to the people they aim to help through their work.

Lovell was participating in a clinical trial for a prostate cancer therapy that combines the widely-used targeted therapy abiraterone with the Plk1 inhibitor onvansertib. Patterson, working in the laboratory of Professor Michael Yaffe, the David H. Koch Professor of Science and director of the MIT Center for Precision Cancer Medicine, played a significant role in identifying the new drug combination and its powerful potential.

While their encounter was indeed fortunate, it was not random. They never would have met if not for the human synergy showcased at that evening’s SOLUTIONS with/in/sight event, the result of collaborative relationships built between research labs, clinical centers, and industry. Patterson and Yaffe were on hand to tell the story of the science behind their new drug combination, and were joined by some of the partners who helped translate their results into a clinical trial: David Einstein, clinical oncologist at Beth Israel Deaconess Medical Center, and Mark Erlander, chief scientific officer of Trovagene Oncology, the biotech company that developed onvansertib.

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The need for new prostate cancer therapies is acute. Prostate cancer is the leading diagnosis among men for non-skin cancer and the second-leading cancer killer among men in the United States. Abiraterone works by shutting off androgen synthesis and interfering with the androgen receptor pathway, which plays a crucial role in prostate cancer cells’ ability to survive and divide. However, cancer cells eventually evolve resistance to abiraterone. New, more powerful drug combinations are needed to circumvent or delay the development of resistance.

Patterson and his colleagues in the Yaffe lab hypothesized that by targeting both the androgen receptor and other pathways critical to cancer cell proliferation, they could produce a synergistic effect — that is, a combination effect that is much greater than the sum of each drug’s effect by itself. Plk1, a pathway critical to each stage of cell division, was of longstanding interest to the Yaffe group, and was among those Patterson strategically selected for investigation as a potential partner target for androgen receptor. In screens of prostate cancer cell lines and in xenograft tumors, the researchers found that abiraterone and Plk1 inhibitors both interfere with cell division when delivered singly, but that together, those effects are amplified and far more often lethal to cancer cells.

An unexpected phone call from Mark Erlander at Trovagene, a San Diego-based clinical-stage biotech company, was instrumental in translating the Yaffe Lab’s research results into clinical trials.

Erlander had learned that MIT held a patent for the combination of Plk1 inhibitors and anti-androgens for any cancer — the result of Yaffe Lab studies. Although he did not know Yaffe personally and lived a continent away, Erlander picked up the phone and invited Yaffe for coffee. “This was worth flying across the country,” Erlander said.

Still in scrubs, Yaffe, who is an attending surgeon at Beth Israel Deaconess Medical Center in addition to his academic roles, chatted with Erlander during his shift break at the hospital. The new collaboration was on its way.

Speaking Frankly

While Erlander had the Plk1 inhibitor and the Yaffe Lab had the science behind it, they were still missing an important component of any clinical trial: patients. Yaffe enlisted doctors David Einstein and Steven Balk, both at Beth Israel Deaconess Medical Center and Dana Farber/Harvard Cancer Center, with whom he had worked on related research supported by the Bridge Project, to bring clinical translation expertise and patient access.

By the time clinical trials began in 2019, Frank Lovell was ready for a new treatment. When his prostate cancer was first diagnosed about a decade ago, he was treated with surgery and radiation. When the cancer came back five years later, he received a hormonal treatment that stopped working within three years. He started to see Einstein, an oncologist who specialized in novel therapies, and tried yet another treatment, this one losing effectiveness after a year. Then he joined Einstein’s trial.

For Lovell, the new combination of drugs was “effective in a wonderful way.” Many of the patients in the trial — 72 percent of those who completed phase 2 — showed declining or stabilized levels of prostate-specific androgen (PSA), indicating a positive response to the treatment. Lovell’s PSA levels stabilized, too, and he reports that he experienced very few side effects.

But most importantly, noted Lovell, “I say thank you to Dr. Einstein, Dr. Patterson, and Dr. Yaffe. They brought me hope and time.”

The gratitude is mutual.

“I especially want to thank Frank and all the patients like him who have volunteered to be on these clinical trials,” says Yaffe. “Without patients like Frank, we would never know how to better treat these types of cancers.”

Lovell is no longer in the trial for now, but enjoying making his rounds from Cape Cod in the summer; to Paris and Cannes, France, and then Hawaii in the autumn; and to Naples, Florida, in the winter, on top of visiting with family and a wide circle of friends. “Illness has not stopped me from living a normal life,” Lovell said. “You wouldn’t think I was sick.”

Meanwhile, Yaffe, Patterson, and their research collaborators are still at work. They are optimizing drug delivery NetBet live casinoregimens to maximize the time on treatment and minimize toxicity, as well as finding biomarkers that help identify which patients will best respond to the combination. They are also looking to understand the mechanism behind the synergy better, which in turn may help them find more effective partners for onvansertib, and to identify other cancer types, such as ovarian cancer, for which the combination may be effective.

Women at the forefront of MIT Biology

In honor of Women’s History Month, meet two of the first female students to earn biology degrees at MIT.

Saima Sidik
March 19, 2020

In MIT’s 1887 annual report, former Institute President Francis A. Walker included a section titled, “Women as students in the Institute.” He predicted: “The number of young women attending the Institute of Technology is never likely to be large, considering the nature of the professions to which our courses lead, and the severity of our requirements for admission and for graduation.” More than 100 years later, it’s clear Walker was sorely mistaken; today, women comprise around 40% of the student body and 58% of the students in the Department of Biology. But, for decades, only about 5% of MIT’s students were female.

In 1958, decades after Walker’s report, Marilynn Bever was one of 28 women in her first-year class of 652 students. “I was aware that MIT women are often regarded with suspicion, as being somehow ‘different’ from normal coeds,” Bever later wrote. She was so fascinated by this attitude that she wrote a thesis for her bachelor’s degree in anthropology in which she catalogued early female MIT students and documented their experiences. Bever reported that Caroline Augusta Woodman was the first woman to obtain a Course 7 bachelor’s degree in 1889, and that Helen Louise Breed became the first woman to earn a PhD from MIT’s Department of Biology in 1937. In honor of Women’s History Month, meet these two women who helped set MIT on a path toward gender equality.

Caroline Augusta Woodman

Woodman (pictured above, second from the left) was born in 1844 in Minot, Maine near a textile manufacturing center. After graduating from high school in nearby Portland, Maine in 1866, Woodman taught at Portland’s Center Grammar School for Girls. By 1874, she’d moved from the coast of Maine to the banks of the Hudson River and earned a bachelor’s degree from Vassar College, which had recently opened as an all-women’s institution.

According to the Vassar Registrar’s Office, early Vassar students took a prescribed set of courses rather than declaring a major, so Woodman studied art, science, languages, and religion, among other topics. Her transcript indicates that she supplemented these classes with “special courses,” which the 1870-71 course catalogue described as “intended only for ladies of maturity,” as the college’s faculty felt that students should complete the usual curriculum before venturing on to these more complex topics. Vassar’s faculty must have seen Woodman as an accomplished scholar, as she was allowed to take extra classes in German, chemistry, math, astronomy, and geography.

The foreign language skills that Woodman learned in these special courses must have served her well after completing her degree, as she traveled around Europe before moving to the Finger Lakes in upstate New York, where she taught at a high school for girls for about twelve years. But in 1889 she found herself back in college and earning a second bachelor’s degree, this time at MIT.

Just as Woodman joined Vassar during its incipient years, she came to MIT when the Institute consisted of only a handful of buildings near Copley Square in Boston’s Back Bay. Graduate degrees had only been established a few years earlier, and the first dormitory wouldn’t be built for another decade. Today’s MIT undergraduates can choose interdisciplinary programs in Chemistry and Biology (Course 5-7) or Computer Science and Molecular Biology (Course 6-7). But in Woodman’s time, even the name “Biology” was new to the department, which had been previously called “Natural History” and re-named to encompass modern aspects of the expanding discipline such as techniques for preserving food safely.

Black and white image of lab
An MIT Biology lab photographed the year Woodman earned her degree. Credit: Photogravure Views of the Mass. Institute of Technology, Boston, 1889, by Henry Lewis Johnson

Course 7 was a small program when Woodman arrived. MIT’s yearbook, MIT Technique, shows that there were only about 10 biology undergraduate students. Although few women attended the Institute as a whole, MIT Biology had a strong female presence by comparison; there were at least five women in the program. However, many of these women were classified as “special” students — a category intended for students taking select classes rather than pursuing full degrees — and few of them were able to complete the classes necessary to earn a bachelor’s degree.

Woodman did earn her second bachelor’s degree, later becoming a physiology instructor in the Zoology Department at Wellesley College, where the student newspaper described her as “a teacher of experience.” A picture from the Wellesley Archives (above) depicts her overseeing a group of young women as they examine a model human body, concoct mixtures of chemicals, and take notes on their experiments.

In 1895, Woodman moved back to her home state and accepted a position as a librarian at Bates College in Lewiston, Maine. Five years later, a student publication reported that she had added substantially to the library’s collections, instituted the Dewey decimal system, and was constructing a card catalogue.

By the time Woodman died in 1912, she had experienced much more of the world than most people from the rural mill town where she was born. From studying at Vassar during the school’s first decade, to traveling through Europe and paving the way for women in MIT Biology, she strayed far from home, then returned to tell the tale.

Helen Louise Breed

Black and white yearbook photo
A picture of Helen Louise Breed when she earned a Bachelor of Arts in 1931. Credit: Wellesley College Archives, Library & Technology Services.

It would be 30 more years before Helen Louise Breed joined MIT in the fall of 1933 and became the first woman to earn a PhD from MIT Biology. The Great Depression was in full swing; although enrollment, staff, and funding had decreased, life went on relatively normally for those lucky enough to remain at the Institute. On September 25, 1933, the student newspaper The Tech reported that the first-year class had successfully captured the sophomore class president and dunked him in Lake Massapoag during their orientation. Several alumni were also returning to the Institute to offer career advice to current students, and the Architecture Department had added a course in city planning to its curriculum. “People didn’t talk much about the Depression,” said one MIT alumna whom Bever interviewed. “We were all busy studying.”

Breed had a strong interest in medicine before attending MIT. Her PhD thesis contains a short biography in which she wrote that after completing a bachelor’s of arts at Wellesley college, she took premedical courses at Harvard and at Radcliffe. But research caught her attention, and she ended up devoting the next few decades to studying the microbes that cause disease rather than treating patients in the clinic.

Breed’s interests were well in line with MIT’s research priorities, as Course 7 had a strong focus on microbiology, infectious disease, and food safety when she attended. In fact, MIT Biology was called Biology and Public Health in Breed’s time, having been re-named from simply Biology in 1911. Many graduate students took classes in bacteriology, planktonology, and fermentation, whereas today’s students might be more likely to study nucleic acid structure or the mutations that lead to cancer. The department’s student population had increased dramatically since Woodman’s time, and there were around 90 biology students when Breed attended, a quarter of which were in graduate programs. Female students were relatively rare, and Breed was one of around 10 female biology students.

Breed performed her PhD research in Murray Horwood’s lab in the Biology Department, where she assessed how efficiently bacteria use various organic molecules to generate the cellular energy that they use to live and reproduce.

Diagram
Breed’s automatic pipette. Credit: “The Comparative Availability of Monohydric Alcohols As Sole Sources of Carbon for Certain Bacteria,” 1937, by Helen Louise Breed, Massachusetts Institute of Technology Distinctive Collections, Cambridge Massachusetts.

Today, these types of experiments might be performed by high school students, but the techniques Breed employed were novel at the time. To quantify bacterial growth, she needed a device that could measure the amount of light absorbed by a liquid culture of bacteria. Such instruments are common in today’s labs, but Breed’s was custom-built by Marshall Jennison, a professor in the Department of Biology.

Breed used her own engineering skills to advance her studies as well. The long hours of pipetting required to grow many species of bacteria in many kinds of media motivated her to construct an automatic pipette (left) using a series of tubes and flasks. While today’s graduate students often use a much smaller version of this device, called a repeater pipette, Breed’s creation warranted an appendix in her thesis.

Job prospects were limited for all MIT graduates during the Depression, but Breed found work in her field after graduating. In 1940, census records showed that in addition to having married and changed her last name to Arnold, she was working as a bacteriologist. Similarly, her death certificate from 1999 shows that Breed had a career in scientific research at Harvard University and Massachusetts General Hospital.

For her thesis, Bever also interviewed several women who were Breed’s contemporaries at MIT during the 1930s. Attitudes towards the few women who studied at the Institute varied, and one student recalled a faculty member telling her, “We tolerate females around here, but we don’t encourage them.” In contrast, another student suspected the dean of the Architecture Department may have paid for her scholarship out of his own pocket because he was so determined to keep her at MIT.

Despite the hardships, Bever and her interviewees said they obtained a thorough education at MIT, and it’s likely that Breed and Woodman left the Institute with the same impression. “I had some marvelous teachers,” one woman said. “We were pushed, we were pushed, we were pushed.”

Top image: “Physiology Class: Woodman oversees a group of Wellesley’s physiology students as they perform lab experiments.” Credit: Wellesley College Archives, Library & Technology Services.
Special thanks to the MIT Libraries and Institute Archives, the Registrar’s Office at Vassar College, and Deb Smith.
Bacterial enzyme could become a new target for antibiotics

Scientists discover the structure of an enzyme, found in the human gut, that breaks down a component of collagen.

Anne Trafton | MIT News Office
March 17, 2020

MIT and Harvard University chemists have discovered the structure of an unusual bacterial enzyme that can break down an amino acid found in collagen, which is the most abundant protein in the human body.

The enzyme, known as hydroxy-L-proline dehydratase (HypD), has been found in a few hundred species of bacteria that live in the human gut, including Clostridioides difficile. The enzyme performs a novel chemical reaction that dismantles hydroxy-L-proline, the molecule that gives collagen its tough, triple-helix structure.

Now that researchers know the structure of the enzyme, they can try to develop drugs that inhibit it. Such a drug could be useful in treating C. difficile infections, which are resistant to many existing antibiotics.

“This is very exciting because this enzyme doesn’t exist in humans, so it could be a potential target,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute Investigator. “If you could potentially inhibit that enzyme, that could be a unique antibiotic.”

Drennan and Emily Balskus, a professor of chemistry and chemical biology at Harvard University, are the senior authors of the study, which appears today in the journal eLife. MIT graduate student Lindsey Backman and former Harvard graduate student Yolanda Huang are the lead authors of the study.

A difficult reaction

The HypD enzyme is part of a large family of proteins called glycyl radical enzymes. These enzymes work in an unusual way, by converting a molecule of glycine, the simplest amino acid, into a radical — a molecule that has one unpaired electron. Because radicals are very unstable and reactive, they can be used as cofactors, which are molecules that help drive a chemical reaction that would otherwise be difficult to perform.

These enzymes work best in environments that don’t have a lot of oxygen, such as the human gut. The Human Microbiome Project, which has sequenced thousands of bacterial genes from species found in the human gut, has yielded several different types of glycyl radical enzymes, including HypD.

In a previous study, Balskus and researchers at the Broad Institute of MIT and Harvard discovered that HypD can break down hydroxy-L-proline into a precursor of proline, one of the essential amino acids, by removing the hydroxy modification as a molecule of water. These bacteria can ultimately use proline to generate ATP, a molecule that cells use to store energy, through a process called amino acid fermentation.

HypD has been found in about 360 species of bacteria that live in the human gut, and in this study, Drennan and her colleagues used X-ray crystallography to analyze the structure of the version of HypD found in C. difficile. In 2011, this species of bacteria was responsible for about half a million infections and 29,000 deaths in the United States.

The researchers were able to determine which region of the protein forms the enzyme’s “active site,” which is where the reaction occurs. Once hydroxy-L-proline binds to the active site, a nearby glycine molecule forms a glycyl radical that can pass that radical onto the hydroxy-L-proline, leading to the elimination of the hydroxy group.

Removing a hydroxy group is usually a difficult reaction that requires a large input of energy.

“By transferring a radical to hydroxy-L-proline, it lowers the energetic barrier and allows for that reaction to occur pretty rapidly,” Backman says. “There’s no other known enzyme that can perform this kind of chemistry.”

New drug target

It appears that once bacteria perform this reaction, they divert proline into their own metabolic pathways to help them grow. Therefore, blocking this enzyme could slow down the bacteria’s growth. This could be an advantage in controlling C. difficile, which often exists in small numbers in the human gut but can cause illness if the population becomes too large. This sometimes occurs after antibiotic treatment that wipes out other species and allows C. difficile to proliferate.

“C. difficile can be in your gut without causing problems — it’s when you have too much of it compared to other bacteria that it becomes more problematic,” Drennan says. “So, the idea is that by targeting this enzyme, you could limit the resources of C. difficile, without necessarily killing it.”

The researchers now hope to begin designing drug candidates that could inhibit HypD, by targeting the elements of the protein structure that appear to be the most important in carrying out its function.

The research was funded by the National Institutes of Health, a National Science Foundation Graduate NetBet live casinoResearch Fellowship, Harvard University, a Packard Fellowship for Science and Engineering, the NSERC Postgraduate Scholarship-Doctoral Program, an Arnold O. Beckman Postdoctoral Fellowship, a Dow Fellowship, and a Gilliam Fellowship from the Howard Hughes Medical Institute.

Cathy Drennan earns Dorothy Crowfoot Hodgkin Award
The Protein Society
March 13, 2020

Protein Society Awards

The nominating process for the 2021 Protein Society Awards is now open. To learn more and submit your nomination for one of our seven awards, click here. Membership is required to submit a nomination, but the nominee does not have to be a member of the Society.

TPS awards recognize excellence across the diverse disciplines that collectively advance our understanding of proteins; their structure, function, design, and application. The Awards honor researchers who have distinguished themselves with significant achievements in protein research and those who have made outstanding contributions in leadership, teaching, and service. TPS members submit nominations, which are awarded by Executive Council, and recipients are honored at the Annual Symposium.

Catherine Drennan,
2020 Dorothy Crowfoot Hodgkin Award Winner

(Massachusetts Institute of Technology)

The 2020 recipient is Professor Catherine Drennan (Massachusetts Institute of Technology). Dr. Drennan  has made enormous contributions  by solving high-resolution structures of proteins and protein complexes that  enhance our understanding of the biology of metalloproteins. Dorothy Crowfoot Hodgkin was famous for using X-ray crystallography to determine the structure of Vitamin B12, and Dr. Drennan has provided monumental insights into the structure and function of proteins that bind to B12.  Dr. Drennan is known for going beyond single proteins and elucidating structures that illuminate entire pathways, capturing multiple snapshots of enzymes as they proceed through their reaction cycles. Among her many notable accomplishments, Dr. Drennan determined the first structure of the cobalamin-dependent ribonucleotide reductase, one of the three enzymes that catalyze the final step in production of deoxyribonucleotides in all organisms. Dr. Drennan’s insights are solidly etched into textbooks and the fabric of our field. Drennan is also an outstanding and widely recognized educator and a tireless advocate for inclusion and equity in science. 

Dorothy Crowfoot Hodgkin Award

Dorothy Crowfoot Hodgkin was a founder of protein crystallography as well as a Nobel laureate. The Dorothy Crowfoot Hodgkin Award, sponsored by Genentech, is granted in recognition of exceptional contributions in protein science which profoundly influence our understanding of biology.
Pioneering researcher Jonathan Weissman joins MIT Biology
Whitehead Institute
March 9, 2020

Whitehead Institute announced today that the globally respected cell biologist Jonathan Weissman has become the Institute’s newest Member and will be the inaugural Landon T. Clay Professor of Biology at Whitehead Institute. Weissman has also been appointed a Professor of Biology at Massachusetts Institute of Technology (MIT). Until joining the Institute, Weissman was Professor and Vice Chair of Cellular and Molecular Pharmacology at University of California, San Francisco (UCSF). He has also been—and continues to be—a Howard Hughes Medical Institute (HHMI) Investigator.

“Jonathan’s extraordinary scientific creativity and productivity, entrepreneurial spirit, and profound expertise will mesh perfectly with Whitehead Institute’s community of innovative, accomplished, and deeply knowledgeable investigators,” says David C. Page, Whitehead Institute Director and Member. “We are thrilled that he will join our quest for new knowledge that ultimately leads to improved human health.”

Weissman is globally renowned for both scientific discovery and building innovative research tools. At Whitehead Institute, he will continue to study the mechanisms used by cells to ensure the correct folding of proteins; develop experimental and analytical tools and approaches to investigate the organization of complex biological systems; and work to develop new applications of the CRISPR-Cas9 gene editing system for biological research and the development of new therapeutics.

“I am excited to be part of the extraordinary communities of Whitehead Institute, MIT, and greater Boston,” says Weissman, who has already built strong research connections in those communities. Those include robust collaborations with MIT’s Aviv Regev and Tyler Jacks; and service on the Science Advisory Board of the Klarman Cell Observatory at Broad Institute. Indeed, Weissman knows Cambridge well, having earned a B.A. in Physics from Harvard University in 1988 and a Ph.D. in Physics from MIT in 1993. At MIT, he conducted research in the lab of former Whitehead Institute Member Peter Kim, where he began studying protein folding. He went on to conduct postdoctoral research at Yale University from 1993 to 1996, working with Arthur Horwich to study the mechanism of GroEL, a molecule key to proper protein folding. Weissman was appointed to the UCSF faculty in 1996 and was named an HHMI Investigator in 2000.

“Jonathan is an outstanding scientist, mentor, and public citizen. He has done transformative work, has developed and applied powerful new technologies, and shared those technologies generously and broadly,” says Alan D. Grossman, Praecis Professor of Biology and Department Head. “Jonathan combines breadth and depth of analyses in ways that very few others can do and we are tremendously pleased that he will be part of the communities at the Whitehead Institute, the Biology Department, and MIT.”

Weissman has published more than 220 peer-reviewed studies, plus numerous research review articles and book chapters; and he has delivered scores of invited lectures and addresses around the world, including the 2019 TY Chen Lecture in Chemical Biology at MIT. A talented educator, Weissman has mentored many leading researchers—notably including Whitehead Fellow Silvi Rouskin and MIT Assistant Professor of biology Gene-wei Li.

Among his many scientific achievements, Weissman developed the ribosome profiling approach that has transformed researchers’ ability to probe the molecular mechanism of translation in vivo; and his lab has subsequently elucidated many fundamental aspects of translation. In addition, Weissman and colleagues—including Stanley Qi, Assistant Professor of Bioengineering and of Chemical and Systems Biology at Stanford University, and Jennifer Doudna, Professor of Biochemistry, Biophysics and Structural Biology at the University of California, Berkeley (UC Berkeley)—developed a CRISPR-associated catalytically inactive dCas9 protein as a general platform for RNA-guided DNA targeting. That work revealed the potential of using “CRISPR interference”—now known as CRISPRi—to precisely regulate gene expression and drive a new type of therapeutic discovery.

Earlier this year, Weissman and Doudna were named as two of the co-leaders of the new Laboratory for Genomic Research (LGR), a $67 million, five-year partnership funded by GlaxoSmithKline to drive development of CRISPR-based therapeutics. Weissman will retain his leadership role in LGR and will maintain close connection with the Innovative Genomics Institute, a joint initiative of UCSF and UC Berkeley that focuses on unraveling the mechanisms underlying CRISPR-based genome editing and applying this technology to improve human health.

In addition, Weissman continues to be a member of the Chan Zuckerberg BioHub’s President’s Advisory Group; to chair the Scientific Advisory Board (SAB) of the Stowers Institute of Medical Research; and to serve on SABs for Amgen and the Helen Hay Whitney Foundation.

An elected member of the National Academy of Sciences (NAS), Weissman received the Protein Society’s Irving Sigal Young Investigator Award in 2004, the Raymond netbet sports betting appand Beverly Sackler International Prize in 2008, and the NAS Award for Scientific Discovery in 2015. This coming April, Weissman will receive the Genetics Society of America’s Ira Herskowitz Award for outstanding contributions in the field of yeast research in the last 20 years.

Weissman holds five patents (with five more pending) and has been a founder of two biotech companies: Maze Therapeutics and Kendall Square-based KSQ Therapeutics.

Enduring connections

During graduate school, the Schmidts formed lasting ties to the MIT Biology community and one another, which continue to strengthen over time.

Raleigh McElvery
March 9, 2020

Eric and Tracy Schmidt arrived at the MIT Department of Biology in 1990, just two strangers excited to begin their PhDs. Six years later, they left with critical thinking skills that extended beyond the lab bench, and — perhaps more importantly — with each other, marrying in 1999. It’s been over two decades since the Schmidts graduated, but their ties to the department remain strong. Both continue to give back to the department, in order to support the mentorship opportunities and cutting-edge research they experienced as graduate students.

Before coming to MIT, Eric completed his degree in chemistry at the University of Pennsylvania. He aimed to understand life at a molecular level, and determined a PhD in biology would complement his chemistry background. He applied to MIT Biology because it was one of the first life science departments in the nation to embrace this molecular focus. “I was keen to immerse myself in the science and learn alongside the very best, from the very best,” he says. His father had also attended MIT for graduate school, which only made Eric more enthusiastic about joining the Institute.

Tracy (née Tracy Smith) received her bachelor’s degree from Carleton College in Minnesota, majoring in biology. She chose to pursue graduate work at MIT Biology because the department’s energy was, as she puts it, “palpable.” From collecting data in the lab to attending lectures and striking up casual conversations with colleagues, she can still recall the intense intellectual atmosphere. “MIT Biology was, and continues to be, a cutting-edge and collaborative research community,” she says.

Tracy worked in Robert Sauer’s lab studying cooperative DNA binding and transcriptional regulation, while Eric was in Paul Schimmel’s lab investigating transfer RNA synthetases. But they both learned more than just the scientific principles of their respective fields — they gleaned analytical skills, strong work ethics, and the ability to objectively assess the pros and cons of a given situation.

Eric remembers his academic experience as being rigorous, but also collaborative and fun. “The department had a nonhierarchical structure that helped to soften the intensity that is often associated with innovative research,” he says. He recalls playing intramural sports alongside accomplished professors, and discussing current events with senior faculty members over drinks.

Post-MIT, Eric co-founded Cambridge Biological Consultants, and went on to become vice president and research analyst at UBS Securities. Later, he served as the managing director and senior biotechnology analyst at Cowen and Company. In 2018, he joined Allogene Therapeutics as their chief financial officer, furthering their goal of creating off-the-shelf CAR-T therapies to treat cancer.

Tracy went on to complete her postdoc at the University of California, San Francisco under Cori Bargmann PhD ’87, and eventually became the chief editor at Nature Structural Biology (now Nature Structural and Molecular Biology). Since 2001, she’s been working as a freelance scientific writer and editor, and she is also an aspiring children’s book author.

“Both my graduate research at MIT and my work as a scientific editor and writer helped to hone my critical thinking skills, as well as my writing abilities,” she says. “These experiences helped me to develop patience in achieving long-term goals.”

Today, the Schmidts remain active members of the MIT Biology community from their home in New York. As part of the Visiting Committee, Eric returns to campus at least every other year to discuss important trends, provide an industry perspective, and help guide the trajectory of the department.

Both Eric and Tracy continue to assist the department, and serve as a resource for Department Head Alan Grossman. Since graduating, they have supported MIT Biology philanthropically on an annual basis, and will be presented with the 77 Society Medallion later this year for their leadership and generosity.

“Having benefited so much from MIT Biology, we feel fortunate to be able to give something back,” Eric says, and recommends that other alumni get involved with the department. “If you do become involved, I think you’ll find that while much has changed, the department’s goals and values have not, and it is easy to reconnect no matter how long you have been away.”

Their time at MIT allowed Eric and Tracy to form enduring ties to the community — and each other — which continue to strengthen to this day. “MIT has been largely responsible for our family,” Eric says. “We now have three wonderful children, who may or may not pursue a degree in biology.” Tracy agrees, “We have many friends that we met at MIT, and we will always have a bond through shared MIT experiences.”

Chimeras offer a new way to study childhood cancer in mice
Eva Frederick | Whitehead Institute
March 5, 2020

In a new paper published March 5 in the journal Cell Stem Cell, researchers in Whitehead Institute Member Rudolf Jaenisch’s lab introduce a new way to model human neuroblastoma tumors in mice using chimeras — in this case, mice that have been modified to have human cells in parts of their nervous systems. “This may serve as a unique model that you can use to study the dynamic of immune cells within human tumors,” says Malkiel Cohen, a postdoc in Jaenisch’s lab and the first author of the paper.

Neuroblastoma is a rare and unpredictable form of childhood cancer that affects around 800 young children in the US each year. Neuroblastoma tumors often occur in parts of the sympathetic nervous system, which includes the nerves that run parallel to the spinal cord and the adrenal medulla, part of the glands that produce hormones such as adrenaline. Neuroblastoma is notoriously hard to study primarily because of its disparate behavior: the tumors often shrink spontaneously in infants, while in toddlers they are highly aggressive and often fatal. “The seeds for the cancer are sown during fetal life,” says Rani George, MD, PhD, an associate professor of pediatrics at Harvard Medical School and a neuroblastoma researcher and physician at Dana-Farber Cancer Institute and Boston Children’s Hospital, and a co-senior author on the paper. “For obvious reasons, you can’t really study the development of these tumors in humans.”

Until now, researchers didn’t have many realistic ways to study these tumors in animal models, either. They could create transgenic mice with cancer-causing genes, but the resulting tumors were mouse tumors, not human ones, and had some key differences. Another method involved taking human tumor cells and implanting them in a mouse — a process called xenotransplantation — but that only worked in mice with compromised immune systems, and didn’t allow researchers to study how the tumors formed in the first place or how they interacted with a fully functioning immune system. “This is where we think the new model is a perfect fit,” said Stefani Spranger, PhD, an assistant professor of Biology at the Massachusetts Institute of Technology (MIT) and the Koch Institute for Integrative Cancer Research at MIT and a co-senior author on the paper.

Human-mouse chimeras have been used in the past to study Alzheimer’s disease and brain development. Jaenisch, who is also a professor of biology at MIT, and his lab had been working for years to create chimeric mice with human cells in the neural crest &#netbet sports betting app8212; the group of developing cells that go on to form parts of the sympathetic nervous system — and published their findings in 2016. “In this study, we hoped to use these mice with human neural crest cells to study how neuroblastoma tumors form and respond to immune system attacks,” Jaenisch says.

To create these chimeric mice, Cohen and coauthors at MIT’s Koch Institute and the Dana-Farber Cancer Institute first engineered human pluripotent stem cells to express two genes known to be abnormal in neuroblastoma, MYCN and mutated ALK, and modified them so they became neural crest cells, from which human neuroblastomas are derived. The genes could be turned on and off with the addition of doxycycline, an antibiotic. They also inserted the gene for eGFP, a brightly glowing fluorescent protein originally isolated from jellyfish. This would allow the team to tell whether the cells were spreading correctly through the bodies of the mice, and would cause any tumors originating from these human cells to be luminous under fluorescent light.

The researchers injected mouse embryos with these cells, and watched over the course of embryonic development as the cells proliferated and human tissues crept into the developing peripheral nervous systems of the tiny mice. To activate the two cancer-causing genes, researchers spiked the pregnant mice’ water with doxycycline, and over the next few days in utero — and in the weeks and months after the pups were born — the researchers inspected the chimeras to see whether tumors would appear.

Over the course of the next 15 months, 14% of the mice developed tumors — 29 mice out of 198 total. The tumors mostly appeared in the space behind the abdominal cavity close to the nerves along the spinal cord, although one mouse developed a tumor in its adrenal gland. Both locations are common places for human children to develop neuroblastoma. The researchers took samples of the tumors and found that they contained the glowing protein eGFP, which confirmed that they were of human origin.

When the team examined the growth patterns of the cancerous cells, they found that the tumors were remarkably similar to human neuroblastomas: they contained cell markers typical of human tumors, and some grew in characteristic rosette shapes — features that did not often appear in tumors implanted in immunocompromised mice through xenotransplantation.

Having successfully induced neuroblastoma tumors in the chimeric mice, the researchers took the opportunity to examine the communication between immune cells and tumors — and specifically, how the tumors evaded destruction by anti-cancer immune cells called T cells. One factor that makes human neuroblastomas and many other cancers dangerous is their sophisticated strategy for avoiding being destroyed by T cells. “The cancer tricks the immune system,” Cohen says.  By activating chemical signals that exhaust the T cells, the tumors effectively weaken their attack. The tumors in the chimeric mice, Cohen found, use a similar method to human neuroblastomas to evade immune responses.

Cohen and others plan to test the new system’s potential for modeling other cancers such as melanoma, and to use it to investigate potential treatments for neuroblastoma patients. “The obvious next step is to study how treatment of these tumors will allow these chimeric mice to be cured,” he says. “This is a model that will allow us to approach not only how to get rid of the tumor, but also to fix the immune system and recover those exhausted T cells, allowing them to fight back and deplete the tumor.”

This research was funded by the National Institutes of Health, as well as grants from the Emerald Foundation, the LEO Foundation, the Melanoma Research Foundation, and the St. Baldrick’s Foundation.

Citation: Cohen, M., et al. Formation of Human Neuroblastoma in Mouse-Human Neural Crest Chimeras. Cell Stem Cell. March 5, 2020. DOI: https://doi.org/10.1016/j.stem.2020.02.001

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Written by Eva Frederick

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QS World University Rankings rates MIT No. 1 in 12 subjects for 2020

Institute ranks second in five subject areas.

MIT News Office
March 4, 2020

MIT has been honored with 12 No. 1 subject rankings in the QS World University Rankings for 2020.

The Institute received a No. 1 ranking in the following QS subject areas: Architecture/Built Environment; Chemistry; Computer Science and Information Systems; Chemical Engineering; Civil and Structural Engineering; Electrical and Electronic Engineering; Mechanical, Aeronautical and Manufacturing Engineering; Linguistics; Materials Science; Mathematics; Physics and Astronomy; and Statistics and Operational Research.

MIT also placed second in five subject areas: Accounting and Finance; Biological Sciences; Earth and Marine Sciences; Economics and Econometrics; and Environmental Sciences.

Quacquarelli Symonds Limited subject rankings, published annually, are designed to help prospective students find the leading schools in their field of interest. Rankings are based on research quality and accomplishments, academic reputation, and graduate employment.

MIT has been ranked as the No. 1 university in the world by QS World University Rankings for eight straight years.

Exploring How Cells Repair and Tolerate DNA Damage
National Institute of Environmental Health Sciences
March 2, 2020

Graham Walker, Ph.D., studies the processes cells use to repair and tolerate DNA damage from environmental pollutants. For more than 40 years, he has worked to understand how cells respond to DNA damage, and how these processes can introduce mutations that lead to cancer and other human diseases.

His current NIEHS-funded work focuses on translesion synthesis (TLS). This damage tolerance process allows specialized enzymes that copy DNA, called TLS DNA polymerases, to replicate past lesions in damaged DNA. The process can help cells tolerate environmental DNA damage, but because TLS polymerases frequently insert the wrong DNA base, they can also lead to DNA mutations.

“The TLS process is critically important to human health because it helps cells survive DNA damage, but it can come at a cost,” said Walker. “It isn’t the kind of repair system you would think we would want because it makes a lot of mistakes. However, as we drill into these details, we are finding that there is so much more to be learned than just the strict biochemistry.”

In 2017, Walker was one of eight environmental health scientists to receive an inaugural Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) Outstanding Investigator Award from NIEHS. The grant, which funds researchers rather than specific projects, provides Walker with flexibility to explore novel directions in his research.

From the Ames Test to TLS

Walker was drawn into the world of DNA repair and mutagenesis as a postdoctoral fellow at the University of California, Berkeley, under the guidance of Bruce Ames, Ph.D. Ames’ group created the Ames test, still used today, to determine whether a given chemical is likely to cause cancer. The Ames test uses bacterial strains that include a derivative of a naturally occurring drug-resistant plasmid, a small circular DNA molecule, known as pKM101. This molecule significantly increases the mutation rate of bacterial genes in response to chemical exposures, playing an important role in this quick and convenient test to estimate carcinogenic potential.

“I decided there must be something really interesting on that plasmid because it led to much higher mutation rates in bacteria for the same amount of damage,” said Walker.

After arriving at the Massachusetts Institute of Technology, his current employer, Walker continued to study the mechanisms behind these mutations.

Walker and his research team discovered the specific genes of pKM101 that are needed for it to produce more mutations. They showed that these genes are orthologs, or genes that evolved from a common ancestral gene, in the Escherichia coli (E. coli) chromosome that are required for the bacteria to mutate in response to DNA damage. netbet sports bettingThis work helped lay the groundwork for the discovery of TLS DNA polymerases and how they are controlled.

“When we first sequenced these genes, nothing like them had been previously reported, but subsequently more and more related genes were discovered in all domains of life,” said Walker. “After decades of work by many labs, we now know that these are all TLS DNA polymerases and that the pKM101 plasmid encodes a polymerase that is responsible for the increased mutations.”

Using Bacteria to Understand DNA Damage

Walker’s prior research on the mutagenesis-enhancing function of pKM101 also led him to analyze E. coli’s SOS system, a set of biological responses that are activated to rescue cells from severe DNA damage. Walker and his team identified genes turned on by DNA damage that are regulated as part of E. coli’s SOS response. Many of the genes encode functions involved in DNA repair or mutagenesis. This work on the SOS response of E. coli was the first to directly demonstrate, in any organism, that DNA damage from environmental sources can change gene expression.

By further exploring TLS DNA polymerases in E. coli, he also identified the biological role of one of the most conserved DNA-damage response enzymes, DinB, which encodes a TLS DNA polymerase, and reported that the gene is required for resistance to some DNA-damaging agents. His work on DinB also suggested an additional mechanism by which antibiotics can become toxic to bacterial cells.

Blocking TLS in Cancer

“While a postdoc in the mid 1970’s with Bruce Ames, my ambitious hope was that by studying pKM101, I would learn something about the fundamental mechanism of how mutations arose in bacteria and humans, and might even learn how to control it,” said Walker. “That is now happening with my current, NIEHS-funded work.”

Some tumors can withstand damage from chemotherapy drugs by relying on TLS, which allows them to survive by replicating past damaged DNA caused by the drugs. In eukaryotes, including humans, mutagenic TLS is carried by two TLS DNA polymerases known as Rev1 and Pol zeta.

In addition to his innovative research, Walker is devoted to improving education and helping undergraduate students. In 2002, Walker became a Howard Hughes Medical Institute Professor and used his funding to establish a science education group modeled on his laboratory research group.

“I feel that training the next generations of scientists is as important as the science itself, and I have been incredibly lucky to have a spectacular set of grad students and post docs work with me over the years,” said Walker. “I have tried to focus as much on training, through teaching and mentoring, as on advancing the science.”

“Not only are these TLS polymerases responsible for introducing a lot of mutations that cause cancer, they also help cancer cells survive in the face of chemotherapy drugs that introduce DNA damage that would otherwise kill them,” said Walker.

Recently, Walker and his colleagues discovered that a small molecule and compound known as JH-RE-06 can block the Rev1-Pol zeta mutagenic TLS pathway by interfering with the ability of the Rev1 domain to recruit Pol zeta. The researchers tested the molecule in human cancer cell lines and showed that it enhanced the ability of several different types of chemotherapy to kill cancer cells, while also suppressing their ability to mutate in the presence of DNA-damaging drugs. In a mouse model of human melanoma, they found that not only did the tumors stop growing in mice treated with a combination of the chemotherapy drug cisplatin and JH-RE-06, those mice also survived longer.

“I am able to take more chances and try more high-risk experiments with the RIVER award,” said Walker. “The flexibility and extra resources are now allowing me to identify TLS inhibitors, which are offering startlingly unexpected mechanistic insights and also show potential to improve chemotherapy.”