HMS Discovery

Impact: 2018-2019 Dean's Report

School-wide initiatives

Therapeutics Initiative: To leverage a growing interest in translational opportunities, Harvard Medical School convened the Strategic Therapeutics Task Force, which defined three broad goals: enable the HMS community to more effectively identify therapeutic targets and strategies; formulate small molecules, proteins, antibodies, genes and cells as therapeutic candidates; and evaluate therapies through translational proof of concept. The Harvard Therapeutics Initiative is being created to pursue these goals.

Harvard-MIT Center for Regulatory Science: This inter-institutional program aims to accelerate the development of therapeutics for serious unmet medical needs. Located in the newly expanded Laboratory of Systems Pharmacology (LSP), the Regulatory Science Center has launched interdisciplinary fellowships and research programs combining medicine, engineering, data science and public policy. The effort is overseen by Peter Sorger, the Otto Krayer Professor of Systems Pharmacology, head of the Harvard Program in Therapeutic Science (HiTS) and founding director of the LSP.

National Cancer Institute Center for Cancer Systems Pharmacology: Also based in the LSP, this new center pools the expertise of basic and translational biologists, clinical oncologists, pathologists and computational scientists. The team characterizes interactions among immune and cancer cells, with the aim of identifying therapies that combine immuno-oncology and other types of drugs to optimally treat  aggressive tumors in individual patients.

Dean’s Innovation Grants in the Basic and Social Sciences: This year, HMS has awarded $14 million in grants to support collaborative research at the School, ensuring that HMS remains at the leading edge of basic biomedical and translational research. Substantial additional investments in innovative projects are planned over the next few years.

Technology Platforms: The new Harvard Cryo-Electron Microscopy Center for Structural Biology—a collaboration between HMS, Harvard University, Boston Children’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital—features instruments that reveal atomic-level structures of the molecular machinery of cells at cryogenic temperatures to enable in-depth understanding of molecular mechanisms in normal and disease states. Plans also are underway to augment other sophisticated imaging technologies across Harvard.

Therapeutics Education and Partnerships: To generate novel approaches in industry, HMS created iHub, which partners faculty, students and trainees with industry and finance experts, working in ideation sessions, seminars, symposia and coursework. It complements the Harvard Therapeutics Graduate Program (see related story).

Harvard Longwood Life Lab: The School’s plans include building incubator opportunities, including a shared laboratory space for high-potential life-science projects and biotechnology startups, which will accelerate discovery and connect researchers with business, legal and intellectual property counselors.

Harvard Catalyst | The Harvard clinical and translational science center

Harvard Catalyst celebrated its 10th anniversary with a newly awarded $89 million grant from the National Institutes of Health. Headed by Dean for Clinical and Translational Research Lee Nadler, the Virginia and D.K. Ludwig Professor of Medicine at Brigham and Women’s Hospital, Harvard Catalyst works to advance initiatives that strengthen the bridge between discovery science and improving human health. Examples include:

Education and Training: Creating a roadmap to success for the next generation of clinical and translational (C/T) researchers, Harvard Catalyst helps investigators and trainees navigate career development through course offerings, fellowships, grant-writing workshops and mentored research experiences.

Translational Innovator: To identify novel technologies and build collaborative partnerships, Harvard Catalyst is studying the impact of connecting researchers with groundbreaking technologies and resources. The effectiveness of external collaborations for crowdsourcing ideas and perspectives is also being explored.

Bioinformatic and Regulatory Tools: Among innovative informatics platforms that accelerate clinical trials, Harvard Catalyst provides leadership in SMART IRB, a national platform facilitating single IRB (Institutional Review Board) review for multi-site studies, and Accrual to Clinical Trials (ACT), which helps researchers design and complete clinical studies across a national network of C/T research centers.

Office of Technology Development

The Harvard Office of Technology Development (OTD) fosters innovations arising from research with the aim of developing products and services that benefit society. Committed to fulfilling each lab’s vision of translational impact, OTD advances and executes strategic commercialization plans to achieve transformative benefits for patients. Through OTD’s corporate partnerships, the Blavatnik Biomedical Accelerator, technology licensing and the launch of new startups, HMS biomedical innovations enter preclinical and clinical development poised for success. This year, OTD created research alliances with leading biotech and pharmaceutical companies studying infectious diseases and other disease areas. The Blavatnik Biomedical Accelerator sped development of commercially promising technologies through awards to nine HMS labs. OTD also launched 21 startups university-wide, a record number. For example, from the lab of George Church, the Robert Winthrop Professor of Genetics, eGenesis Inc. has licensed innovations in genome engineering that could make pig organs safe for transplantation into human patients. To promote this culture of entrepreneurship, OTD launched Entrepreneur-in-Residence and Bench-to-Business Boot Camp programs.

Departmental Research

Biological Chemistry and Molecular Pharmacology

Structure of Safety Scissors

HMS researchers have deciphered the atomic structure of ADAM10, an enzyme that plays a critical role in normal cell-to-cell communication. When malfunctioning, it is implicated in neurodegenerative diseases such as Alzheimer’s, asthma and certain cancers. ADAM10 is one of 22 ADAMs, short for “a disintegrin and metalloproteinase,” made in the human body. These scissorlike enzymes typically help cells respond to their environment by cutting other proteins on the cell surface. When functioning normally in the brain, ADAM10 helps process amyloid precursor protein in such a way that it doesn’t become amyloid beta, the plaque-forming substance believed to drive Alzheimer’s disease. In work published in Cell, Stephen Blacklow, the Gustavus Adolphus Pfeiffer Professor and chair of the Department of Biological Chemistry and Molecular Pharmacology, with Tom Seegar, instructor in the department, and Andrew Kruse, associate professor of biological chemistry and molecular pharmacology, used x-ray crystallography to uncover a fail-safe mechanism that prevents ADAM10 from cutting proteins with abandon. These findings will help researchers understand how ADAM10 works normally and what happens when it goes awry, identifying new strategies for treating diseases fueled by its malfunction. MORE

Biomedical Informatics

Gender Patterns in Autism

Analyzing the records of 1.5 million families, a big data study led by HMS scientists has for the first time quantified the likelihood that a family that has one child with autism would have another child with the same disorder based on the siblings’ gender. Published in JAMA Pediatrics, the results confirmed previous research showing that, overall, boys are at higher risk than girls for having autism and related disorders. But a curious pattern emerged: Siblings born after the birth of a female child with autism had a higher risk than siblings born after a male child with autism. Isaac Kohane, the Marion V. Nelson Professor of Biomedical Informatics and chair of the Department of Biomedical Informatics, and Nathan Palmer, director of the Healthcare Data Science Program at HMS, also determined that autism is somewhat rare, affecting 1.2 percent of the general population. These insights provide context for physicians and genetic counselors to advise families who have a child with autism. MORE

Cell Biology

Visualizing Membrane Proteins

Using a powerful structural imaging technique called cryo-electron microscopy (cryo-EM), scientists can now see high-resolution details of proteins that reside in cellular membranes, where they play important roles in physiology and diseases. Until recently, studying these membrane proteins’ structures has been challenging. In the first of two papers in Nature, a team led by Maofu Liao, assistant professor of cell biology, used cryo-EM to reveal how the membrane protein MsbA transports lipopolysaccharide, which is critical to the antibiotic resistance of Gram-negative bacteria. The second study showed how the membrane protein Hrd1 helps form a channel to move potentially harmful misfolded proteins out of the endoplasmic reticulum into the cell’s cytoplasm for degradation. The molecular details of these protein machines have provided unprecedented insights into their functional mechanisms and will aid targeted drug development.

Genetics

Variable Sensitivities to Cancer Genes

New research has revealed that different tissue types have startlingly variable sensitivities to cancer-causing genes. In a study led by Stephen Elledge, the Gregor Mendel Professor of Genetics and Medicine and professor of medicine at Brigham and Women’s Hospital, researchers built a library of 30,000 bar-coded genes and then used the bar codes to determine which genes drove growth, unmasking hundreds of previously unknown cancer-causing genes. When they tested the bar-coded genes in three types of noncancerous tissues—breast cells, pancreatic cells and fibroblasts—each responded in a distinctive way. Genes that drove proliferation in one tissue often had no effect or even suppressed growth in another. As described in Cell, these discoveries promise to improve scientists’ understanding of normal and malignant cell proliferation. They also help explain why certain cancer drivers appear in some tumors and not others, potentially inspiring more tissue-specific strategies for cancer treatment. MORE

Global Health and Social Medicine

Molecular Tests Drive Tuberculosis Decisions

An interdepartmental study revealed that new molecular tests for tuberculosis may be as good as or even better than standard lab cultures in predicting response to treatment and risk of dying. Culture-based lab tests are the gold standard for diagnosing TB resistance to a class of drugs called fluoroquinolones, but results can take up to eight weeks. By contrast, point-of-care molecular tests provide results within hours. A retrospective study of patients in Peru was co-led by Carole Mitnick, associate professor of global health and social medicine, and Maha Farhat, assistant professor of biomedical informatics and a pulmonologist at Mass General. The findings, published in Clinical Infectious Diseases, provide early evidence that molecular tests could soon become a mainstay and a faster alternative to traditional testing for helping clinicians choose the best drug, with specific focus on fluoroquinolones, and predicting the clinical course of a patient’s TB infection. MORE

Health Care Policy

Understanding Variation in End-of-Life Care

A new model for understanding variation in medical care received by cancer patients may improve health care policies and doctor-patient communication. Laura Hatfield, associate professor of health care policy, led a study published in Health Affairs that analyzed more than 14,000 Medicare patients with extensive-stage small-cell lung cancer. Despite short expected survival in this usually terminal condition, the research team found large variation in patient experiences from diagnosis through death. Grouping patients with similar patterns of care, they documented marked differences in care settings, survival times and intensity of care. Accounting for this variation could inform policies to align care with patients’ needs and prognoses. For example, patients with very short predicted survival could benefit from expanded hospital-based palliative care. In addition, using clusters of “typical experiences” can help clinicians communicate to patients what they might experience following a serious diagnosis. MORE

Microbiology and Immunobiology

Flesh-Eating Bacterium Hijacks Neurons

When the body is injured, nerve cells normally send two different signals—one to the brain to convey something is wrong and another to the immune system, telling it to stay away—a balancing act to keep overzealous immune cells from damaging healthy tissues. Research led by Isaac Chiu, assistant professor of microbiology and immunobiology, with postdoctoral fellow Felipe Pinho-Ribeiro, revealed the tactics used by Streptococcus pyogenes to foil the body’s defenses. This bacterium, which causes strep throat, is also the leading cause of necrotizing fasciitis. As it eats into connective tissue and muscle, the infection is hard to diagnose and treat promptly and can become rapidly fatal. As published in Cell, the bacterium induces neurons to release calcitonin gene-related peptide (CGRP), a neurotransmitter that impedes the body’s ability to summon immune cells called neutrophils to the infection site. CGRP also inhibits neutrophils that do get to the infection from releasing a germ-killing substance. When infected mice were treated with CGRP-receptor-blocking molecules, the infection did not progress, results that hold promise for drug-based treatments. MORE

Neurobiology

What Babies See and When

 The primate brain is organized into “maps” for the different senses, but how the brain creates these maps has been a mystery. Research by Margaret Livingstone, the Takeda Professor of Neurobiology, together with Michael Arcaro, instructor in neurobiology, revealed that a primitive blueprint of organization is already present in the primate brain a few days after birth and fills in gradually with age and visual experience. As described in eLife, investigators began by monitoring the brain activity of neonatal macaques, using functional magnetic resonance imaging. Even when asleep, with eyes closed, different parts of the visual cortex were co-active, suggesting that a functional organization connecting these areas is present early in life. Although the neonates exhibited some of the large-scale organization of adults, they were missing prominent adult features. Brain regions for recognizing faces were absent the first several months after birth. With maturity, the early maps gradually refined, acquiring the ability to process faces, but only after visual experience. Ever since the work by 1981 Nobel laureates David Hubel and Torsten Wiesel, founding members of the HMS Neurobiology Department and mentors of Livingstone, neurobiologists have known the earliest visual experiences are critical for a child’s perceptual development. These findings underscore the importance of correcting visual deficits, such as congenital cataracts, promptly at birth to prevent blindness and ensure development of higher visual and cognitive functions. MORE

Stem Cell and Regenerative Biology

Exercise Creates New Heart Muscle Cells

Doctors and health organizations all agree that exercise is good for the heart, but the reasons why are not well understood. In a new study performed in mice, researchers from HMS, the Harvard Department of Stem Cell and Regenerative Biology, Mass General and the Harvard Stem Cell Institute (HSCI) discovered that exercise stimulates the heart to make new muscle cells, both under normal conditions and after a heart attack. The researchers first studied two groups of healthy mice: one group had access to a treadmill, on which they voluntarily ran about five kilometers each day. The other group was sedentary. Using a labeled chemical that became incorporated into newly made heart cells, the researchers found that exercising mice made more than four times as many new heart muscle cells as those without treadmill access. They next studied mice that had experienced a heart attack. Compared with sedentary mice, those that exercised showed an increase in the area of the heart where new muscle cells are made. Published in Nature Communications, the study’s two senior authors were Richard T. Lee, professor of stem cell and regenerative biology at Harvard and a principal faculty member of HSCI, and Anthony Rosenzweig, the Evelyn and James Jenks and Paul Dudley White Professor of Medicine in the Field of Cardiology and chief of the cardiology division at Mass General and a principal faculty member of HSCI. MORE

Systems Biology

From One Cell, Many

In three landmark studies published in Science, researchers revealed how a single-celled embryo becomes a multicellular organism. Principal investigators included Allon Klein, assistant professor of systems biology; Marc Kirschner, the John Franklin Enders University Professor of Systems Biology; Sean Megason, associate professor of systems biology; and Alexander Schier, the Leo Erickson Life Sciences Professor of Molecular and Cellular Biology in Harvard’s Department of Molecular and Cellular Biology. Using single-cell sequencing in a single experiment, they recapitulated decades of painstaking research on the decisions cells make in the earliest stages of life. Focusing on zebrafish and the western claw-toed frog, they generated a detailed roadmap of which genes turned on and off, and when. In addition to identifying otherwise difficult-to-detect details, such as rare cell types and subtypes, the researchers linked new, highly specific, gene-expression patterns to different cell lineages. In several cases, they found cell types emerging far earlier than previously thought. The unprecedented data produced could be powerfully illuminating to scientists striving to answer questions about cell differentiation and the origins of human disease. MORE

Harvard School of Dental Medicine

Regulating Metabolism and Bone Density

In the brain, the hypothalamus regulates energy and bone metabolism. Alteration of activating protein 1 (AP1) signaling in the hypothalamus has been known to increase energy expenditure, glucose utilization and bone density, yet the specific neurons responsible were unknown. Using neuron-specific, genetically targeted AP1 alterations in adult mice, a team led by Roland Baron, head and professor of oral medicine, infection and immunity at HSDM and professor of medicine at Mass General, found two types of neurons—AgRP and POMC—that stimulate energy expenditure, glucose utilization and bone formation and density. In contrast, AP1 alterations to a third type of neuron, SF1, increased energy but decreased bone density. AP1 signaling also affected the level of galanin, a neuromediator in the hypothalamus that transmits messages between neurons. When the researchers genetically deleted galanin or pharmaceutically blocked galanin receptors, energy and bone metabolism decreased. This study, published in the Journal of Clinical Investigation, is the first to show that galanin acts centrally to regulate bone mass, which is potentially important to developing novel therapies to prevent bone loss that occurs in osteoporosis. MORE