Placement: Promote to Homepage
April 2, 2020
March 30, 2020
Junior Emily O’Rourke traveled to South Africa to investigate epidemics and returned with a broader outlook on her fundamental disease research.
Raleigh McElvery
March 31, 2020
Growing up in El Paso, Texas near the border of the U.S. and Mexico, Emily O’Rourke could venture across cultures in less time than it takes most people to commute to work. In fact, her dad would make this short trip each day for his job as a mechanical engineer. Watching him cross over so frequently reminded O’Rourke that “ideas and skills don’t stop at the border.” O’Rourke herself would visit Mexico to see relatives, and these experiences seeded aspirations to spearhead international scientific collaborations. Now a junior in Course 7 (Biology), O’Rourke is continuing to add stamps to her passport while exploring the global implications of disease research.
O’Rourke chose MIT because it offered a particularly wide array of study abroad programs, in addition to having top-tier research opportunities. One such study abroad program, MIT International Science and Technology Initiatives (MISTI), operates 25 regional programs, matching undergraduate and graduate students with fully-funded internship, research, and teaching opportunities in over 40 countries. The summer after her first year, O’Rourke participated in MISTI’s MIT-Italy Program in order to gain some research experience in the realm of urban planning. For six weeks, she investigated the urban effects of sea level rise while living in Venice.
When she returned to campus for her sophomore year, O’Rourke was intending to double major in physics and biology. But she ultimately opted to drop physics and pursue the life sciences once she started working in Becky Lamason’s lab in the Department of Biology.
“I started to see how biology worked on a practical level,” she says. “I get to experience a hands-on connection by running DNA on a gel and doing other experiments. During our weekly lab meetings, I witness scientific stories as they unfold.”
More recently, the duo has begun to examine how Sca4 may coopt another protein in the host cell, known as clathrin, for its own malicious means. “Sca4 is a really big protein and we still don’t know its entire structure,” O’Rourke says, “and we’re hoping to uncover some new functions.”The Lamason lab investigates how parasites hijack host cells processes in order to spread infection. O’Rourke is working with graduate student Cassandra Vondrak to probe the proteins that allow the tick-borne Rickettsia parkeri to migrate from one cell to the next. Their protein of interest, surface cell antigen 4 (Sca4), is secreted by the bacterium and binds to the host’s cell membrane, reducing the tension across the membrane and allowing Rickettsia to punch through to the neighboring cell. O’Rourke and Vondrak aim to determine how Rickettsia releases Sca4, in the hopes of piecing together a general mechanism by which pathogens propagate.
While O’Rourke was studying infectious disease on a cellular level, she heard about an opportunity to explore epidemics on a global scale. Each January, the Harvard-MIT Program in Health Sciences and Technology sponsors a two-week class in South Africa called Evolution of an Epidemic. The class, taught by Professor of the Practice Bruce Walker, covers the medical, scientific, and political responses to new diseases, focusing on the HIV/AIDS epidemic. Walker, who is also the director of the Ragon Institute of MGH, MIT and Harvard, is a world leader in the study of immune control and evasion in HIV infection. Since then, he’s developed strong connections and research partnerships in South Africa where the disease is most prevalent.
O’Rourke enrolled in Evolution of an Epidemic, and MISTI helped her to plan her trip. On January 16, she landed in Johannesburg, the first of three destinations. The cohort of students from MIT, Harvard, and the African Leadership Academy attended lectures, spoke with patients, and met medical professionals.
After Johannesburg, the class traveled to Durban where they visited traditional healers who were learning to administer HIV/AIDS tests as part of the iTeach program.
“We had the chance to ask these healers how they felt about interacting with Western medicine, and whether it clashed with their traditional values,” O’Rourke says. “They said HIV was so new that they couldn’t draw upon ancient wisdom from their ancestors to treat it. They were directing patients towards Western treatments because they’d seen the devastation the disease could cause.”
At their third and final destination, the province of KwaZulu-Natal, O’Rourke toured the FRESH Program. Twice a week, as part of a clinical trial, healthy African women around O’Rourke’s age attend classes that address topics like self-esteem, gender-based violence, HIV prevention, career development, and computer training. Before each session, the women are tested for HIV/AIDS, so if they contract it the researchers can treat it early and learn more about the disease’s initial stages.
“I really liked going there because it helped me see a direct connection between science and social good,” O’Rourke says. “It showed the value of talking to patients and asking about their experiences, rather than just looking at study outcomes.”
After two weeks, O’Rourke returned to MIT Biology and the Lamason lab with a broader outlook on her parasite research. “I’m able to see how my works fits into a larger context,” she says, “and how it may eventually have far-reaching impacts on disease evolution and spread.”
O’Rourke still plans to pursue fundamental biological research, but intends to seek out international collaborations focused on global health as well. It’s hard to leave the MIT bubble, she says, but it’s worth it. “Traveling can really broaden your perspective as a scientist, and inform your research in unexpected ways.”
Photos courtesy of Emily O’Rourke
Posted 4.1.20
Repurposing a drug used for blood clots may help Covid-19 patients in danger of respiratory failure, researchers suggest.
Anne Trafton | MIT News Office
March 26, 2020
Researchers at MIT and the University of Colorado at Denver have proposed a stopgap measure that they believe could help Covid-19 patients who are in acute respiratory distress. By repurposing a drug that is now used to treat blood clots, they believe they could help people in cases where a ventilator is not helping, or if a ventilator is not available.
Three hospitals in Massachusetts and Colorado are developing plans to test this approach in severely ill Covid-19 patients. The drug, a protein called tissue plasminogen activator (tPA), is commonly given to heart attack and stroke victims. The approach is based on emerging data from China and Italy that Covid-19 patients have a profound disorder of blood clotting that is contributing to their respiratory failure.
“If this were to work, which I hope it will, it could potentially be scaled up very quickly, because every hospital already has it in their pharmacy,” says Michael Yaffe, a David H. Koch Professor of Science at MIT. “We don’t have to make a new drug, and we don’t have to do the same kind of testing that you would have to do with a new agent. This is a drug that we already use. We’re just trying to repurpose it.”
Yaffe, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and an intensive care physician at Boston’s Beth Israel Deaconess Medical Center/Harvard Medical School, is the senior author of a paper describing the new approach.
The paper, which appears in the Journal of Trauma and Acute Care Surgery, was co-authored by Christopher Barrett, a surgeon at Beth Israel Deaconess and a visiting scientist at MIT; Hunter Moore, Ernest Moore, Peter Moore, and Robert McIntyre of the University of Colorado at Denver; Daniel Talmor of Beth Israel Deaconess; and Frederick Moore of the University of Florida.
Breaking up clots
In one large-scale study of the Covid-19 outbreak in Wuhan, China, it was found that 5 percent of patients required intensive care and 2.3 percent required a ventilator. Many doctors and public health officials in the United States worry that there may not be enough ventilators for all Covid-19 patients who will need them. In China and Italy, a significant number of the patients who required a ventilator went on to die of respiratory failure, despite maximal support, indicating that there is a need for additional treatment approaches.
The treatment that the MIT and University of Colorado team now proposes is based on many years of research into what happens in the lungs during respiratory failure. In such patients, blood clots often form in the lungs. Very small clots called microthrombi can also form in the blood vessels of the lungs. These tiny clots prevent blood from reaching the airspaces of the lungs, where blood normally becomes oxygenated.
The researchers believe that tPA, which helps to dissolve blood clots, may help patients in acute respiratory distress. A natural protein found in our bodies, tPA converts plasminogen to an enzyme called plasmin, which breaks down clots. Larger amounts are often given to heart attack patients or stroke victims to dissolve the clot causing the heart attack or stroke.
Animal experiments, and one human trial, have shown potential benefits of this approach in treating respiratory distress. In the human trial, performed in 2001, 20 patients who were in respiratory failure following trauma or sepsis were given drugs that activate plasminogen (urokinase or streptokinase, but not tPA). All of the patients in the trial had respiratory distress so severe that they were not expected to survive, but 30 percent of them survived following treatment.
That is the only study using plasminogen activators to treat respiratory failure in humans to date, largely because improved ventilator strategies have been working well. This appears not to be the case for many patients with Covid-19, Yaffe says.
The idea to try this treatment in Covid-19 patients arose, in part, because the Colorado and MIT research team has spent the last several years studying the inflammation and abnormal bleeding that can occur in the lungs following traumatic injuries. It turns out that Covid-19 patients also suffer from inflammation-linked tissue damage, which has been seen in autopsy results from those patients and may contribute to clot formation.
“What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with Covid-19 are hypercoagulable, meaning that they are clotting off their IVs, and having kidney and heart failure from blood clots, in addition to lung failure. There’s plenty of basic science to support the idea that this concept should be beneficial,” Yaffe says. “The tricky part, of course, is figuring out the right dose and route of administration. But the target we are going after is well-validated.”
Potential benefits
The researchers will test tPA in patients under the FDA’s “compassionate use” program, which allows experimental drugs to be used in cases where there are no other treatment options. If the drug appears to help in an initial set of patients, its use could be expanded further, Yaffe says.
“We learned that the clinical trial will be funded by BARDA [the Biomedical Advanced Research and Development Authority], and that Francis Collins, the NIH director, was briefed on the approach yesterday afternoon,” he says. “Genentech, the manufacturer of tPA, has already donated the drug for the initial trial, and indicated that they will rapidly expand access if the initial patient response is encouraging.”
Based on the latest data from their colleagues in Colorado, these groups plan to deliver the drug both intravenously and/or instill it directly into the airways. The intravenous route is currently used for stroke and heart attack patients. Their idea is to give one dose rapidly, over a two-hour period, followed by an equivalent dose given more slowly over 22 hours. Applied BioMath, a company spun out by former MIT researchers, is now working on computational models that may help to refine the dosing schedule.
“If it were to work, and we don’t yet know if it will, it has a lot of potential for rapid expansion,” Yaffe says. “The public health benefits are obvious. We might get people off ventilators quicker, and we could potentially prevent people from needing to go on a ventilator.”
The hospitals planning to test this approach are Beth Israel Deaconess, the University of Colorado Anschultz Medical Campus, and Denver Health. The research that led to this proposal was funded by the National Institutes of Health and the Department of Defense Peer Reviewed Medical Research Program.
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.
Network synergy
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 regimens 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.
March 17, 2020
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.
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
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.
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.
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 Research 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.
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,
|