Translational Research


Research Immersion

Visiting medical students gain skills and new network of mentors 

The use of machine learning to predict the growth rate of brain tumors. The documentation of brain cell changes in men and women after a season of playing college hockey. The study of the association of eye and kidney complications in Latinos with type 2 diabetes.

These projects represent the kind of research that six visiting medical students immersed themselves in during this summer’s Harvard Catalyst Visiting Research Internship Program (VRIP) at Harvard Medical School.

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The program, designed to foster diversity and interest in clinical and translational research, has been supported by the National Center for Advancing Translational Sciences, a part of the National Institutes of Health, since 2009.

This year’s students expected that they’d learn new research skills and knowledge; what they didn’t expect were the bonus experiences.

“I didn’t know that I’d also gain a network of mentors and get to know so many fabulous people and new ideas,” said Darrick Potter, a rising second-year student at the Frank H. Netter MD School of Medicine at Quinnipiac University, of the eight-week course.

Mentorship, immersion in a research laboratory, collaboration and relationship building are hallmarks of the program, says program manager Carol Martin.

“Once accepted, we consider the students part of the Harvard Catalyst community of clinical translational researchers,” Martin said.

VRIP and the 10-week Summer Clinical and Translational Research Program (SCTRP) for college students are part of pipeline efforts spearheaded by the Harvard Catalyst Program for Faculty Development and Diversity Inclusion.


The program also includes weekly seminars on diverse subjects such as bioinformatics and environmental determinants of health, a boot camp class on clinical and translational research and opportunities to shadow faculty and learn practical skills such as how to suture and intubate. Potter and the other students presented their research findings in medicine and public health on July 27. 

Olajumoke Akinsulire, from the Alpert Medical School of Brown University, is an aspiring surgeon who wants to conduct translational research to improve care for her patients. She presented an encouraging proof-of-concept study of a nutritional supplement given by feeding tube that could better stem the loss of fatty acids in premature infants and possibly prevent chronic lung disease that sometimes develops.

Akinsulire plans to continue to work on this project in the Beth Israel Deaconess laboratory of her mentors Camilia Martin and Steven Freedman.

 “They pulled me up from my starting point and taught me the importance of good mentorship and to love what you’re doing,” Akinsulire said.

Martin said that the power in mentorship lies in the guidance that’s offered amid the complicated task of navigating a career in medicine. She found her own mentor in Freedman.

“I didn’t know that I’d also gain a network of mentors and get to know so many fabulous people and new ideas” — Darrick Potter

“I learned late that you can’t do it alone,” Martin said. “When I found Dr. Freedman, it was eye opening. It opened new doors and pathways and a world of resources.”

 “This is the way we learn to do research experiments—like an apprenticeship,” Freedman said, adding that he had great mentors guiding him and is happy to do the same for others.

“It is amazing to be part of someone’s life and guide their pathway to success. I take great pride in the people over the years I’ve helped,” Freedman said.

Ronilda Lacson, in the Center for Evidence-Based Imaging at Brigham and Women’s Hospital, has been a mentor for VRIP or SCTRP since both programs began.  

“I always look forward to these interns,” she said. “They are smart, hardworking and enthusiastic.”

One of her former SCTRP mentees recently graduated from HMS, and she just hired last year’s summer intern, Eseosa Odigie, as a research assistant. This year, she watched VRIP intern Darrick Potter grow in confidence and acumen over the summer as he examined radiology reports to see if features of imaged lung nodules are sufficiently documented to determine which are potentially cancerous.

Barbara Jones, who’s enrolled in a clinical and translational program at the University of Massachusetts Medical School, completed a project on adipose-derived stem cells in the Tissue Engineering and Wound Healing laboratory of her mentors Giorgio Giatsidis and Dennis Orgill at Brigham and Women’s Hospital.

“This experience has given me a whole new outlook and focus for my career,” said Jones. “I find it so meaningful that Dr. Giatsidis has offered his advice and guidance beyond the eight weeks of the program.”

In addition to providing mentees with technical knowledge and skills, Giatsidis cited the importance of imparting the nontechnical skills needed in a research career. These include how to approach a scientific problem, how to think creatively about solutions and how to find the best ways to communicate.

Impressed with the caliber of students he’s hosted, Giatsidis said having Jones in the lab was like “having another fellow in the lab.” When they publish findings, Jones will get credit, as will his SCTRP intern from last summer, Trevon Waters.

 “This program has brought me closer to believing that I really am a clinical and translational researcher,” Jones said





Bertarelli Symposium Focuses on Learning, Perception, Memory

Annual meeting event fosters international collaborations in the neurosciences

The mysteries of the human mind have tantalized scientists, philosophers, writers and artists for centuries. Now an international collaboration of neuroscientists is poised to unravel some of the most confounding mysteries of human cognition, memory and learning.

Harvard Medical School scientists, including HMS Dean George Q. Daley, and colleagues from the École Polytechnique Fédérale de Lausanne (EPFL) teamed up in Switzerland on April 7 at the 2017 Symposium of the Bertarelli Program in Translational Neuroscience and Neuroengineering. The event was held at Campus Biotech in Geneva, a new center of excellence in biotechnology and life science research that is part of the Swiss Innovation Park.

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The annual symposium, a collaboration among the two schools and the Bertarelli Foundation, is an effort to spark transnational and translational partnerships among preeminent neuroscientists who are on a quest to propel knowledge from the lab to clinic.

Six of the 12 presenters were scientists from HMS. Other speakers participating in the symposium included scientists from EPFL, the Jules-Gonin Ophthalmic Hospital, New York University and the University of Pennsylvania.

Topics included mechanisms of visual perception, tissue engineering approaches to vision restoration, the molecular underpinnings of memory storage, gene therapy for hearing restoration, brain stimulation, and memory modulation, among others.

“Advances in the neuroscience of learning, memory and sensory perception are giving us new hope for treatment of some of the most devastating neurologic and psychiatric disorders,” said David Corey, a neurobiologist and the Bertarelli Professor of Translational Medical Science at HMS. “The cross-pollination that occurs from our international association with the Bertarelli Foundation and École Polytechnique Fédérale de Lausanne is just the sort of catalytic effort that can propel us toward delivering on that promise.”

“Advances in the neuroscience of learning, memory and sensory perception are giving us new hope for treatment of some of the most devastating neurologic and psychiatric disorders” — David Corey

"This symposium, at which our teams of scientists join together to share their work, is a demonstration of the mission of the Bertarelli Program as a whole: to foster collaboration across continents and across disciplines,” said Ernesto Bertarelli, co-president of the Bertarelli Foundation and a member of the HMS Board of Fellows.

“As with every symposium we hold, to hear in person the extraordinary progress being made across our joint projects is to be hugely encouraged. I—and everyone in the room at Campus Biotech—left with great hope for what is being achieved now and what will be achieved in the future,” he said.

Bertarelli is also this year’s recipient of the Albert Gallatin Award. Named for a Swiss immigrant to the colonial United States who served the new country in many ways, it is given by the Swiss-American Chamber of Commerce in recognition of exceptional contributions by individuals who foster a better understanding and appreciation between the peoples of Switzerland and the United States.

The Bertarelli Program in Translational Neuroscience and Neuroengineering was launched with a gift from the Bertarelli Foundation in 2010 to address some of the most important questions in medical neuroscience that, once solved, would have life-changing outcomes for patients across the globe. Its focus is not just on stimulating new cross-disciplinary research but also on establishing cross-border and cross-institutional working communities for knowledge sharing. The aim of these collaborations is to bridge the gap between basic and translational neuroscience by supporting basic and clinical research oriented toward translational opportunities, by creating stronger ties among scientists, engineers and clinicians, and by training the next generation of leaders in the field.






Helping Beta Cells Divide to Conquer

Why do insulin-producing beta cells often fail to proliferate in people with diabetes?

If you become resistant to insulin, a condition that is a precursor to type 2 diabetes, your body tries to compensate by producing more of the beta cells in the pancreas that produce the critical hormone.

Image: Rohit Kulkarni

Researchers have long sought to understand why these cells often fail to proliferate in people who go on to develop the disease. Studying both humans and mice, Harvard Medical School scientists at Joslin Diabetes Center now have pinpointed one key biological mechanism that can prevent the cells from dividing successfully.

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Better understanding of the beta-cell proliferation process eventually may lead toward therapies for diabetes patients, whose supplies of these cells often shrink over time, said Rohit Kulkarni, an HMS professor of medicine, a Joslin senior investigator, and senior author on a paper about the work published in the journal Cell Metabolism.

Previous studies of beta-cell proliferation generally have focused on mechanisms that kick off the cell cycle that leads to successful cell division.

“Most adult mammalian beta cells are in a quiescent phase, and so if you want to push them into the cell cycle, you need to shake them out of their sleep,” said Kulkarni.

Over the years, scientists have discovered a number of biological mechanisms that help to initiate the cell cycle.

“However, very often many of the beta cells that begin the cell cycle don’t complete it because the regulatory signals aren’t appropriate,” Kulkarni noted. “The cells choose to die because that’s an easier route than completing the cell cycle.”

Seeking to understand this failure to divide, Kulkarni’s lab previously analyzed beta cells that were modified to lack an insulin receptor and didn’t divide as easily as normal beta cells.

“Most adult mammalian beta cells are in a quiescent phase, and so if you want to push them into the cell cycle, you need to shake them out of their sleep,” — Kulkarni.

Among their findings, the scientists saw that these cells generated significantly smaller amounts than normal beta cells of two proteins that partner to help separate the cell’s chromosomes just before the cell divides.

In their latest research, the Joslin team performed many experiments to explore the actions of these two proteins, called centromere protein A (CENP-A) and polo-like kinase-1 (PLK1), in mice and in cells from humans and mice.

Among their experiments, the researchers studied beta cell signaling in mice that lacked expression of the proteins and experienced insulin resistance because of high-fat diets, aging or pregnancy.

“We showed that mice that lacked the CENP-A protein could not compensate for insulin resistance by making more insulin-secreting cells,” Kulkarni said.

Additionally, his team examined human beta cells and found lower levels of CENP-A and PLK1 proteins in cells from donors with diabetes compared to cells from healthy donors.

To better understand how insulin signaling affects beta-cell growth, the scientists next studied a pathway involving a protein called FOXM1.

This protein acts as a transcription factor that regulates genes by binding to their DNA regions. FOXM1 helps to drive cell proliferation, and it can promote the expression of CENP-A and PLK1.

“We found that insulin signaling can initiate the binding of this transcription factor with PLK1 and CENP-A, in both mouse and human beta cells,” Kulkarni said. “This binding is lost in beta cells lacking the insulin receptor, and the loss of binding leads to cell death rather than division.”

“We also discovered that this type of regulation is, interestingly, specific to beta cells and not seen in other metabolic cell types such as liver and fat cells,” he said.

Given this new insight into how beta cells divide or fail to divide, “our next step will be to begin to ask whether we can target FOXM1 or other proteins in the pathway to enable a better progression through the cell cycle and to generate more beta cells,” Kulkarni said.

The research may hold the eventual promise of treatments not only for type 2 diabetes but for type 1 diabetes, in which beta cells are wiped out by autoimmune attack, he adds.

The National Institutes of Health provided lead funding for the study.

Adapted from a Joslin news release.


Divide and Conquer

New study charts single-cell composition of two major types of brain tumor

Detailed analysis of two brain tumor subtypes has revealed that they may originate from the same type of neural progenitor cells and may be distinguished by gene mutation patterns and by the composition of their microenvironments.

The results of the study, led by Harvard Medical School investigators at Massachusetts General Hospital and collaborators at the Broad Institute of MIT and Harvard, were published in the March 31 issue of Science.

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“Our study redefines the cellular composition of two closely related gliomas characterized by mutations in the IDH gene—astrocytomas and oligodendrogliomas,” said Mario Suvà, HMS assistant professor of pathology at Mass General, and co-senior author of the Science paper. “While we know these are genetically distinct tumor types, we did not know whether they had similar cells of origin or if their expression differences could be explained by genetics, by the cells from which they developed or by the tumor microenvironment.”

Several recent studies, including The Cancer Genome Atlas, have identified mutations driving tumor growth and defined tumor subtypes based on analyzing gene expression in tissue samples that include both tumor cells and cells from the surrounding microenvironment. But the fact that these analyses are done in bulk pieces of tumors masks many critical pieces of information.

Single-cell RNA sequencing, which measures RNA transcription on a cell-by-cell basis, offers detailed insights into tumor biology, but can be done only in a limited number of tumors due to financial and logistic constraints. The Mass General team hypothesized that combining single-cell RNA data from a limited number of tumors with existing bulk expression data from large study groups could reveal many key aspects of brain tumor biology.

Both astrocytomas and oligodendrogliomas are considered incurable, but surgery and radiochemotherapy can significantly extend survival. The tumors are believed to develop from subtypes of the glial cells that support and protect neurons, and are known to differ in terms of genetics, appearance and gene expression. While both types of tumor contain cells similar to the glial cells for which they are named—astrocytes and oligodendrocytes—they also each contain markers of both cell types, calling into question the common belief that they originate in those distinct cell types.

Combining RNA sequencing results from more than 9,800 cells from 10 astrocytomas and more than 4,300 cells from six oligodendrogliomas with 165 bulk expression profiles from The Cancer Genome Atlas revealed that both types of tumor contained three different types of cancer cells: nonproliferating cells that have differentiated into either astrocyte- or oligodendrocyte-like cells, as well as cells that resemble neural stem or progenitor cells and drive tumor growth. Differences between the two types of tumor appear to be determined primarily by genetic differences and in the composition of the tumor microenvironment, such as the abundance of specific immune cells.

“We were surprised to find that cancer cells from these two tumor subtypes share similar stem cell programs and glial lineages of differentiation,” Suvà said. “Additionally, we observed that cancer cells that become more differentiated do not proliferate, even in more advanced tumors. That suggests that pushing cells towards differentiation—something we currently do not know how to do in patients—could significantly halt tumor growth.

“As these tumors share stem cell programs that drive their growth, an alternative approach could be to target specific cell types with immunotherapies,” Suvà added. “We now plan to use similar approaches to study other types of adult and pediatric gliomas to get additional insight into their origins and the programs driving their aggressiveness.”

Support for the study includes the Smith Family Foundation, the V Foundation for Cancer Research, the American Cancer Society, the National Cancer Institute, the Rachel Molly Markoff Foundation, the Howard Hughes Medical Institute and the Klarman Family Foundation.

Adapted from a Mass General news release.


Puzzling It Out

Symposium examines cluster randomized trials

Suppose you’d like to determine if a new hand sanitization product is a better choice for hospitals than the product in standard use. A randomized trial is in order. But what is the best way to randomize the interventions?

Randomizing the patients—those whose outcomes will be measured to see if, say, infection rates fall because of the new product—are not a good choice; they won’t be using the products.

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The hospital staff members who will be using it seem a better choice, but there is no practical way to be sure they use the appropriate sanitizer as they move around the hospital.

Enter the cluster randomized trial (CRT), a study design that randomizes clusters of individuals to receive one intervention or another. In this case, a CRT could randomize hospitals to use one or the other product.

The simplicity ends there, said Barbara Bierer, Harvard Medical School professor of medicine (pediatrics) at Brigham and Women’s Hospital who spoke at a symposium examining the issues on Nov. 3 called “Cluster Randomized Trials: Ethics, Regulations, Statistics and Design.”

Held at the Joseph B. Martin Conference Center, the event brought together experts to discuss the complexities of CRTs with an audience equally split between investigators, statisticians and institutional review board (IRB) members.

The event, sponsored by Harvard Catalyst | The Harvard Clinical and Translational Science Center, kicked off what Bierer described as an ongoing conversation.

“We’re here to figure out the issues and spend time together now and in the future addressing them,” Bierer said.

Subject Matters

Among the big questions were concerns about ethics, particularly regarding questions around who can be a research subject and who must give consent to participate in a cluster randomized trial. Take the hand sanitizer example, said Holly Fernandez Lynch, executive director of the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School.

“Do hospital staff members need to consent? Are patients involved in the research?” she asked.

Answers to these questions vary depending on the individuals in the cluster, the intervention in question and how the two intersect. It may not be necessary to obtain consent from patients who are visiting doctors participating in hand sanitation research, for example. In contrast, an intervention in an emergency room that directly affects every patient who visits that ER would require patient consent.

But ER patients cannot give consent in advance, since anyone can walk through the doors of an ER. Nor can they consent if they are incapacitated by a medical emergency. In this case, consent should be obtained as early as possible.

“If you’re doing something to someone that you wouldn’t do but for the research, you get consent,” — Holly Fernandez Lynch

“It’s important to consider the public trust in research,” said Michele Russell-Einhorn, vice president of oncology services for the Central Oncology Review division of Schulman IRB.

“When you’re randomizing health professionals or facilities and patients don’t know they’re involved, you run into concerns: ‘No one told me; you used my data without permission.’ It’s important to think about this in advance,” she said.

Both Lynch and Russell-Einhorn referred to the “but for” test as a way to determine who needs to be asked for consent.

“If you’re doing something to someone that you wouldn’t do but for the research, you get consent,” said Lynch. “We really have to home in on who counts as a subject because this is who we have to get consent from.”

Lynch and Russell-Einhorn also directed researchers to recent recommendations that have come from advisory groups interested in the ethics and regulations related to CRTs: The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials was developed by bioethicists funded by the Canadian government and lists 15 principles of CRTs.

The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protections (SACHRP) also recently published recommendations regarding CRTs.

Calculating Concerns

The design of a CRT also raises important and complicated questions about statistical analysis. In one example, Michael Hughes, professor of biostatistics at the Harvard T. H. Chan School of Public Health, presented the design of a cluster randomized tuberculosis prevention trial called PHOENIx (protecting households on exposure to newly diagnosed Index multidrug-resistant tuberculosis patients). In the trial, individuals at high risk of contracting tuberculosis, and sharing a household with an individual with multi-drug resistant TB, were given one of two preventive drugs. In this trial, each household forms a cluster because study subjects in the same household receive the same drug.

One design challenge Hughes grappled with was intra-cluster correlation — the idea that people within a cluster tend to be more similar to one another than those in different clusters.

This is possible in any cluster, but in this trial, the similarities stem from the fact that people in the same household will be frequently exposed to the same pathogen, which could be more or less virulent than in other clusters.

They are also exposed to the same household conditions, which could be more or less conducive to infection. In addition, household members could influence one another to take the drug or to skip it.

The likelihood that outcomes will be more similar within a cluster must be factored into statistical analyses and in study design.

“With intra-cluster correlation, you have less information compared to a trial with randomized individuals, so you need more clusters to get the same power as an individually randomized clinical trail,” said Hughes. “There is an inflation factor.”

Such considerations add time to the design process.

“PHOENIx took five years to develop, with cluster issues contributing to a significant amount of the complexity,” said Hughes. “My idea of fun is getting the study designed nicely so that the data is super simple. It’s important to get statisticians involved early.”

“From the beginning,” added Rebecca Betensky, professor of biostatistics at the Harvard Chan School and a symposium moderator. “It’s better science to involve statisticians from the beginning to help with design.”

Investigators must also worry about clusters interfering with one another, a phenomenon called cross-contamination.

For instance, Rui Wang, HMS assistant professor of medicine at Brigham and Women’s, presented a community randomized HIV prevention trial in Botswana in which she randomized villages to receive either an HIV prevention intervention or standard care. She found out, however, that sexual networks crossed between villages and, therefore, between her clusters.

“The randomized effect shrinks when participants have partners outside the cluster,” she said.

Wang, who is also assistant professor in the Department of Biostatistics at Harvard Chan School, addressed this by increasing the number of clusters and also by analyzing sexual networks of individuals in the study to get a better sense of their statistical impact.

These examples demonstrate the power of CRTs to enable research interventions that cannot be directed to singularly selected individuals. Yet they also illustrate the complexities involved in conducting such trials ethically and with certainty that they will produce reliable, statistically powerful results.

Even with guidelines and regulations, each study will come with its own puzzles.

“We’re trying to design these studies—and our statisticians are trying to figure out how to analyze them—on the fly,” said Bierer. “It’s an evolution.”


Sweet Math

Scientists devise a more accurate way to gauge blood sugar averages in people with diabetes

Combining the power of advanced math with tests commonly used to measure blood sugar, scientists from Harvard Medical School and Massachusetts General Hospital have created a new model that more accurately accounts for long-term blood sugar fluctuations in people with diabetes. The disease affects more than 422 million people worldwide, according to the World Health Organization and more than 29 million Americans, according to the Centers for Disease Control and Prevention.

By factoring in the age of each patient’s red blood cells, the new method offers a more precise, individualized gauge of three-month blood sugar averages and reduces in half the error rate of the most commonly used — but sometimes inaccurate — test known as A1C. Findings of the study are described Oct. 5 in Science Translational Medicine.

“What we currently deem the gold standard for estimating average blood glucose is nowhere as precise as it should be,” said senior investigator John Higgins, an associate professor of systems biology at HMS and a clinical pathologist at Massachusetts General Hospital. “Our study not only pinpoints the root of the inaccuracy but also offers a way to get around it.”

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The A1C test led to notable off-target estimates in about a third of more than 200 patients whose test results were analyzed as part of the research. The team found these inaccuracies stemmed entirely from individual variations in the life span of a person’s red blood cells.


In a final step, the scientists calculated new, age-adjusted estimates and tested their predictive accuracy by comparing them to actual blood sugar levels measured directly via continuous glucose monitors — wearable devices that read a person’s blood sugar every five minutes. 

Incorporating the new model into existing tests, the researchers said, could lead to more precise diagnosis, monitoring and better-tailored treatments.

Estimating a person’s three-month blood sugar average is the best indicator of disease control and the most accurate predictor of looming complications, according to experts. Persistently elevated blood sugar can, over time, damage the heart, brain, kidneys, eyes, nerves and other organs.

Because blood sugar varies by the hour and even by the minute, capturing “an average” to account for fluctuations over an extended period is a far better indicator of disease status than taking a “snapshot” measurement at one time.

To estimate blood sugar averages, physicians use the A1C test as a proxy. The A1C measures so-called glycated hemoglobin — the amount of sugar soaked up by red blood cells over an extended period of time.

“Like a water-soaked sponge that’s been sitting on the kitchen sink for days, older red blood cells tend to have absorbed more glucose, while newly produced red blood cells have less because they haven’t been around as long,” --John Higgins​

The test, however, is somewhat imprecise. As little as 15 milligrams of glucose per deciliter of blood could signal the difference between high normal values in a person without diabetes and low abnormal values in someone with the disease. The A1C test can lead to identical readings for people with average blood sugar levels that differ by as much as 60 mg/dl. At the same time, people with similar blood sugar levels can end up having widely divergent results. Researchers are not sure what fuels this discrepancy, but the age of red blood cells has recently emerged as a prime suspect.

“Like a water-soaked sponge that’s been sitting on the kitchen sink for days, older red blood cells tend to have absorbed more glucose, while newly produced red blood cells have less because they haven’t been around as long,” Higgins said.

Thus, the researchers said, two people with the same amount of sugar in their blood but could end up with different results on their A1C test depending on the average lifespan of their red blood cells.

To eliminate the influence of age-related variation, the HMS team developed a formula that factors in the life span of a person’s red blood cells. The formula is based on several values, including directly measured glucose levels, and, crucially, on earlier findings by Higgins’ team showing that in each person, the lifespan of red blood cells is tightly regulated, within 1 percent or so. Next, researchers compared the age-adjusted blood sugar estimates to estimates derived from the standard A1C test and then to readouts of glucose levels measured directly by continuous glucose monitors.

The standard A1C test provided values that were significantly off target — by 15 mg/dl or more — in one out of three patients. By factoring in red blood cell age, however, the scientists reduced the error rate to 1 in 10.

For example, using the standard A1c test, one patient’s glycated hemoglobin levels measured at 8.1 percent, leading to an estimated blood sugar level of 186 mg/dl. When the researchers factored in the person’s red blood cell age — 45 days — the estimate went up to 209 mg/dl. Compared with the actual glucose levels measured by a continuous glucose monitor — 210mg/dl — the age-adjusted estimate was off by a mere point. By contrast, the standard estimate was off by 24 points.

Incorporating the age-adjusted formula into current A1C testing approaches would significantly boost the accuracy of glucose estimates, the researchers said. Under the new model, patients could wear a glucose monitor for a few weeks to have their blood sugar tracked as a baseline, also allowing physicians to calculate the average age of a person’s red blood cells before having the monitor removed.

“Physicians treating recently diagnosed patients would immediately know what a patient’s red blood cell age is,” Higgins said. “The patient’s test results can then be adjusted to factor in the red blood cell age and get a result that more accurately reflects the actual levels of blood sugar, allowing them to tailor treatment accordingly.” 


Kaelin Honored with Lasker Award

HMS scientist awarded for pivotal discovery in cells' response to oxygen deprivation

Harvard Medical School Professor of Medicine William G. Kaelin Jr. has been named a recipient of the 2016 Lasker Award for Basic Medical Research from the Albert and Mary Lasker Foundation.  The Lasker is one of the world's most prestigious biomedical research awards.

William Kaelin Jr.  Image: Courtesy Dana-Farber Cancer Institute

Kaelin, based at Dana-Farber Cancer Institute, was cited along with Peter J. Ratcliffe of the University of Oxford/Francis Crick Institute and Gregg L. Semenza of the Johns Hopkins University School of Medicine, for the discovery of the pathway by which cells from humans and most animals sense and adapt to changes in oxygen availability—a process essential for survival.

"Dr. Kaelin is an outstanding physician, scientist and educator," said Barbara J. McNeil, acting dean of Harvard Medical School.  We are very proud of Bill's achievements. I am delighted that his extraordinary dedication, his years of hard work and his remarkable discoveries have been recognized by the Lasker Foundation." 

"Bill Kaelin is an extraordinary researcher and highly deserving of this honor. His work has guided and inspired cancer researchers and caregivers all over the world in understanding the mysteries of cancer," said Edward J. Benz Jr., president and CEO of Dana-Farber.

Kaelin's research explores why mutations in genes known as tumor-suppressor genes can lead to cancer. His study of a tumor-suppressor gene called VHL provided key insights into the body's response to changes in oxygen levels.

Kaelin discovered that VHL helps control the levels of a protein known as HIF, which ratchets up or down the response to low oxygen, such as in the production of red blood cells and new blood vessels.

His subsequent discovery of a molecular switch that renders HIF oxygen-sensitive was critical to the understanding of how cells react to variations in oxygen level.

"The work of this year's honorees epitomizes the power and impact of dedication to rigorous and innovative medical research,” said Claire Pomeroy, president of the Lasker Foundation. “These outstanding advances have illuminated fundamental aspects of life, developed a cure for a deadly disease, and raised public engagement with science."

Kaelin received his medical degree from Duke University in 1982 and was a house officer and chief resident in internal medicine at Johns Hopkins Hospital. He became a medical oncology clinical fellow at Dana-Farber and a postdoctoral fellow in the laboratory of Dr. David Livingston, where he began his studies of tumor suppressor proteins. Kaelin was named an independent investigator at Dana-Farber in 1992 and a Howard Hughes Medical Institute Investigator in 2002.

"The 2016 Lasker winners combined exceptional insight, creativity and perseverance in pursuing crucial questions in medical science," said Joseph L. Goldstein of the University of Texas Southwestern Medical Center and chair of the Lasker Medical Research Awards Jury. Goldstein is a recipient of the 1985 Lasker Award for Basic Medical Research and the Nobel Prize in Physiology or Medicine.

For 71 years, the Lasker Awards, America's most prestigious biomedical research awards, have recognized the contributions of scientists, clinicians and public citizens who have made major advances in the understanding, diagnosis, treatment, cure or prevention of human disease.

Eighty-seven Lasker laureates have received a Nobel Prize, including 41 over the past three decades. The Lasker Awards carry an honorarium of $250,000 for each category. This year’s awards will be presented on Friday, Sept. 23, in New York City.

More details on the Lasker Award recipients, the full citations for each award category, video interviews and photos of the awardees and additional information on the Foundation are available at


Keeping Up with HIV Mutations

New model technology offers nimble AIDS vaccine testing

AIDS vaccines able to fight any HIV strain have thus far eluded science. HIV frequently mutates its coat protein, dodging vaccine makers’ efforts to elicit sufficiently broadly neutralizing antibodies.

Sometimes HIV-infected people can produce such antibodies on their own. But this usually requires years of exposure to the virus, allowing the immune system to modify its antibodies over time to keep up with HIV mutations, and generally occurs too late to prevent infection.

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“Only a small fraction of patients are able to develop broadly neutralizing antibodies, and by the time they do, the virus has already integrated into the genomes of their T-cells,” said Ming Tian, lecturer on genetics at Harvard Medical School and a research associate in the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s Hospital.

Tian is part of a group led by HMS Professor of Genetics and PCMM Director Frederick Alt that has developed a technology to greatly speed up HIV development.

Described Sept. 8 in Cell, the group’s method generates mouse models with built-in human immune systems. The models recapitulate what the human immune system does, only much more rapidly, enabling researchers to continuously test and tweak potential HIV vaccines.

A souped-up human immune system

People exposed to HIV (or any pathogen) first make precursor antibodies, which then mature via mutation and natural selection—an evolution-like process that makes the antibodies more protective over time.

“This is a long-term process involving many intermediate antibodies, making it very challenging to design HIV vaccines to protect uninfected individuals,” said Alt, who is also the Charles A. Janeway Professor of Pediatrics at Boston Children’s and co-senior author on the paper.

“To facilitate this effort, we wanted to design a new type of humanized mouse model that would be more physiological and allow us to very quickly test new vaccination strategies,” he said.

How do broadly neutralizing antibodies to HIV naturally arise? The team began with the basic components of the known human antibody response to HIV.

Building a diverse immune repertoire

Our immune system’s B lymphocytes assemble antibody genes from building blocks known as V (variable), D (diversity) and J (joining) segments. Through various V-D-J combinations, our B lymphocytes are able to produce enormous numbers of different antibodies—enough to recognize almost any invader.

After a B cell recognizes a pathogen, it further mutates the V-D-J sequence, often in successive steps, enabling its progeny B cells to produce even stronger antibodies.

Prior work had revealed the structure of broadly neutralizing antibodies against HIV and deduced the V-D-J combinations that constituted their precursors. The team inserted the corresponding DNA into mouse embryonic stem cells.

The researchers then used the modified embryonic stem cells to rapidly generate mice whose B cells were primed to assemble a highly diverse set of HIV antibody precursors—combining the human precursor broadly neutralizing antibody V segment with various D or J segments.

An iterative process

The mice began by making immature “ancestor” antibodies. Collaborators at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center, together with colleagues at the Duke Human Vaccine Institute, the Scripps Research Institute, the Fred Hutchinson Cancer Research Center and other institutes, then sequentially exposed the Alt lab’s test mice to a series of specially designed HIV antigens.

Through this sequential exposure, the animals’ B cells “learned” to produce ever more diverse and effective humanized antibodies that eventually were able to neutralize some HIV viral strains.

“Rather than go through generations of mouse breeding to make models, our approach allows us to quickly delete and replace genomic elements to create changes in B cells,” explained Alt.

“Thus, we can rapidly reprogram this mouse model with the intermediate antibody genes selected from the first successful immunizations and expose them to new antigens,” said Alt. “Over time, we hope this process will lead to the generation of broadly neutralizing HIV antibodies.”

As the engineered antigens engaged the system, upping the ante each time, the researchers could watch the antibodies acquire mutations.

“You move the B cells in a direction and find out what works and the potential hang ups,” said Alt. “You then work to figure out how to next adapt the mouse model and the immunogens to eventually get to a broadly neutralizing antibody stage.”

Speeding up AIDS vaccine development

There’s still a long way to go, but Alt believes the technology could hasten the search for a truly effective HIV vaccine, as well as vaccines against other viruses.

It may also allow researchers to generate highly specific therapeutic antibodies.

“We’re hoping it will be broadly useful,” Alt said.

John Mascola, director of the NIAID Vaccine Research Center, was co-first author of the study. Tian and Hwei-Ling Cheng of the Alt lab and Cheng Cheng, Xuejun Chen and Hongying Duan of the Vaccine Research Center were co-first authors.

The study was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01AI077595, AI020047, P01AI094419, U19AI109632), the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (AI100645, 5UM1AI100645, 1UM1AI100663), the International AIDS Vaccine Initiative Neutralizing Antibody Consortium, the Collaboration for AIDS Vaccine Discovery, the NIAID Vaccine Research Center, the Howard Hughes Medical Institute and the Ragon Institute of MGH, MIT and Harvard.

Adapted from a post on Vector, the clinical and research innovation blog at Boston Children’s.


An Agent of Demise

Scientists identify spark plug that ignites nerve cell damage in Lou Gehrig’s disease

Scientists from Harvard Medical School have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis, or ALS, a progressive and incurable neurodegenerative disorder. 

Researchers say the findings of their study, published Aug. 5 in the journal Science, may lead to new therapies to halt the progression of the uniformly fatal disease that affects more than 30,000 Americans. One such treatment is already under development for testing in humans after the current study showed it stopped nerve cell damage in mice with ALS. 

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The onset of ALS, also known as Lou Gehrig’s disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells that transmit signals from one cell to the next. The HMS study reveals that the aberrant behavior of an enzyme called RIPK1 damages neuronal axons by disrupting the production of myelin, the soft gel-like substance enveloping axons to insulate them from injury.

“Our study not only elucidates the mechanism of axonal injury and death but also identifies a possible protective strategy to counter it by inhibiting the activity of RIPK1,” said the study’s senior investigator Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at HMS.

The new findings come on the heels of a series of pivotal discoveries made by Yuan and colleagues over the last decade revealing RIPK1 as a key regulator of inflammation and cell death. But up until now, scientists were unaware of its role in axonal demise and ALS. Experiments conducted in mice and in human ALS cells reveal that when RIPK1 is out of control, it can spark axonal damage by setting off a chemical chain reaction that culminates in stripping the protective myelin off of axons and triggering axonal degeneration—the hallmark of ALS. RIPK1, the researchers found, inflicts damage by directly attacking the body’s myelin production plants—nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein that wraps around axons to support their function and shield them from damage. Building on previous work from Yuan’s lab showing that the activity of RIPK1 could be blocked by a chemical called necrostatin-1, the research team tested how ALS cells in lab dishes would respond to the same treatment. Indeed, necrostatin-1 tamed the activity of RIPK1 in cells of mice genetically altered to develop ALS. 

In a final set of experiments, the researchers used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Necrostatin-1 not only restored the myelin sheath and stopped axonal damage but also prevented limb weakness in animals treated with it.

“It was as if we saw the chemical footprints of cell death left behind by RIPK1 and its recruits,” - Junying Yuan

Connecting the Dots

At the outset of their experiments, investigators homed in on a gene called optineurin  (OPTN). Past research had revealed the presence of OPTN defects in people with both inherited and sporadic forms of ALS, but scientists were not sure whether and how OPTN was involved in the development of the disease. To find out, researchers created mice genetically altered to lack OPTN. Examining spinal cord cells under a microscope, the scientists noticed that the axons of mice missing the OPTN gene were swollen, inflamed and far fewer in number, compared with spinal cord cells obtained from mice with the OPTN gene. These axons also bore signs of myelin degradation. Strikingly, the researchers noticed the same signs of axonal demise in spinal cord cells obtained from human patients with ALS. Mice with OPTN deficiency also exhibited loss of strength in their hind legs. Further experiments revealed that lack of OPTN was particularly harmful to myelin-secreting cells. Thus, the researchers concluded, OPTN deficiency was directly incapacitating the nervous system’s myelin factories. But one question remained: How did the absence of OPTN damage these cells?

A Smoking Gun

Looking for the presence of chemicals commonly seen during inflammation and cell death, the researchers noticed abnormally high levels of RIPK1—a known promoter of cell death—in spinal cord cells from mice lacking OPTN. Moreover, the scientists observed traces of other damaging chemicals often recruited by RIPK1 to kill cells.

“It was as if we saw the chemical footprints of cell death left behind by RIPK1 and its recruits,” --Junying Yuan

That observation, Yuan added, was the smoking gun linking RIPK1’s misbehavior to OPTN deficiency. In other words, researchers said, when functioning properly, the OPTN gene appears to regulate the behavior of RIPK1 by ensuring its levels are kept in check, that it is broken down fast and that it is cleared out of cells in a timely fashion. In the absence of such oversight, however, RIPK1 appears to get out of control and cause mischief.

In a closing set of experiments, the researchers examined neurons obtained from mice with the most common inherited form of ALS, one caused by mutations in a gene called SOD1. Indeed, RIPK1 levels were elevated in those cells too. Thus, the investigators said, OPTN may not be the sole gene regulating RIPK1’s behavior. Instead, RIPK1 appears to fuel axonal damage across various forms of inherited and acquired forms of ALS. The findings suggest that RIPK1 may be involved in a range of other neurodegenerative diseases marked by axonal damage, including multiple sclerosis, certain forms of spinal muscular atrophy and even Alzheimer’s disease.

The Harvard Office of Technology Development (OTD) and collaborating institutions have developed a patent portfolio for RIPK1 modulating compounds. Harvard OTD has licensed the patent to a biotechnology company.

The work was supported in part by grants from the National Institute of Neurological Disorders and Stroke (1R01NS082257) and the National Institute on Aging (1R01AG047231), by the National Science and Technology Major Project of China (2014ZX09102001-002) and the State Key Program of the National Natural Science Foundation of China (31530041).



Cracking the Wall

Scientists discover new bacterial cell wall builders—and a target for antibiotic development

Harvard Medical School scientists have identified a new family of proteins that virtually all bacteria use to build and maintain their cell walls.

The discovery of a second set of cell wall synthesizers can help pave the way for much-needed therapies that target the cell wall as a way to kill harmful bacteria, said study leaders David Rudner and Thomas Bernhardt.

Findings of the research are published Aug. 15 in Nature.

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“We know these proteins are a great target because they are enzymes we can inhibit from the outside of the cell,” said Rudner, senior author of the paper and HMS professor of microbiology and immunobiology.

“Now we have a better handle on what these proteins do and how a potential drug might affect their activity,” said Bernhardt, the paper’s co-author and HMS professor of microbiology and immunobiology.

The cell wall plays a critical role in maintaining a bacterium’s structural integrity, dictating its shape and warding off external assaults from toxins, drugs and viruses.  The cell wall is made of chains of sugars linked together by short peptides.

For half a century, penicillin-binding proteins—molecules named for the drug that disables them—were thought to be the major, perhaps only, cell wall synthesizers.

“Now we have a better handle on what these proteins do and how a potential drug might affect their activity.” — Thomas Bernhardt. 

Penicillin was discovered in 1928 and first used to treat bacterial infections in 1942, but it wasn’t until 1957 that scientists understood how penicillin blocked the proteins that build the cell walls of bacteria. Research in the 1970s and 1980s on the bacterium Escherichia coli fleshed out the mechanism by which penicillin-binding proteins build the cell wall.

Clues that other players may be involved in cell wall biogenesis emerged later. A crucial discovery, made in 2003, was overlooked by many in the field: The bacterium Bacillus subtilis was capable of growing and synthesizing its cell wall even in the absence of penicillin-binding proteins. Some researchers were tantalized by the “missing polymerase,” sometimes called the “moonlighting enzyme.”

Tsuyoshi Uehara, former HMS research fellow in the Bernhardt lab and co-author of the paper, was one of those scientists. He thought a family of proteins responsible for a cell’s shape, elongation, division and spore formation, or SEDS proteins in scientific shorthand, might be prime suspects for the missing enzyme. SEDS proteins move around the circumference of the bacterial cell in a manner suggesting they might be involved in synthesizing the wall, and, if inactivated, perturb cell wall synthesis.

Testing the hypothesis

To test the hypothesis that SEDS proteins may be involved in cell wall synthesis, Alexander Meeske, HMS graduate student in the Rudner lab and the paper’s first author, deleted all the known penicillin-binding proteins involved in polymerizing the cell wall. Yet, SEDS proteins continued to move in much the same way as they always had. The observation made SEDS proteins look like the missing enzymes and more like major players than mere moonlighters.

Later experiments, both genetic and biochemical, confirmed that SEDS proteins are indeed a completely new family of cell wall synthesizers.

The scientists also showed that the two families of cell wall synthesizers could work in tandem: While SEDS proteins circumnavigate the cell wall making hoop-like structures, penicillin-binding proteins move diffusely, making smaller strands that, together with the hoop-like strands, build the cell wall.

Earlier studies showing that bacteria died when the penicillin-binding proteins were blocked obscured the importance of SEDS proteins, the researchers said.

In the current paper, the scientists found that SEDS proteins are more common in bacteria than are the penicillin-binding proteins, raising hopes that a potential antibiotic targeting SEDS proteins could be effective against a broad spectrum of bacteria.

“That’s what makes this so exciting. In this modern era of sequenced genomes, we’re still discovering new enzymes that work in this pathway.”— David Rudner

“For a long time in the field, it was thought that one set of enzymes worked in one set of complexes to build a wall. Now we have two sets of enzymes appearing to work in different systems,” Bernhardt said. “Somehow they have to coordinate to build this netlike structure that maintains integrity and expands as the cells grow and divide.”

How the two families of proteins work together is just one of many questions raised by the new work.

“Even though the history goes all the way back to the 1920s with penicillin, there’s plenty to learn,” Bernhardt said.

“That’s what makes this so exciting,” Rudner said. “In this modern era of sequenced genomes, we’re still discovering new enzymes that work in this pathway.”

This work was supported by the National Institutes of Health grants GM073831, RC2 GM092616, AI083365 and AI099144; and CETR grant U19AI109764.

Co-investigators included Eammon Riley, William Robins, John Mekalanos, Daniel Kahne, Suzanne Walker and Andrew Kruse. All six Harvard labs are participants in a Centers of Excellence for Translational Research (CETR) grant.