The Promise of Discovery

This essay was written for the 2017-2018 HMS Dean's Report in answer to the question "What is the promise of biomedicine to me?"

For me, biomedicine is a spaceship that allows us to travel to center of one of the universe’s great mysteries: ourselves.

Consider that we are part of an unbroken chemical reaction that started billions of years ago from the first life forms. Look how far we have come and how nature has shaped us into ever more complex beings.

Biomedicine is propelled by the quest to understand the great mysteries of life and by our collective mission to keep each other and the planet healthy.

Biomedical research is a portal we can use to gain insight into the molecular and genetic determinants of life. Our collective effort involves examining and understanding all of the various forms, structures, and beauty within life, the exquisite orchestration of function, and the deeply mysterious processes of development and healing.

The promise of biomedicine is an understanding of how life works, so that we can recognize when and why things go wrong. Biomedicine is now integrating with previously separate disciplines, such as computer science, so that we may study hundreds of thousands of human genomes, each containing billions of data points. The goal is to discover causal relationships between differences in people’s genes and their risk for certain diseases.

The process of sifting through this data has attracted some of the world’s most talented computer programmers, while it has also leveraged the power of supercomputers using advanced artificial intelligence methodologies. The computational frontier of biomedicine is helping to give us a system’s view and understanding of life, which is, in turn, revealing new avenues for cures and therapies.

As new fields converge in biomedical research, we continue to learn more about ourselves, our nature, and the epic history which has gotten us to where we are now. And this understanding provides us with new ways to help and protect life.

For instance, biomedical research guides the process of establishing links between harmful environmental exposures and the onset of certain diseases, the breakdown of ecosystems, and the losses of biodiversity. This allows scientists to make the case for prohibiting certain chemicals due to harmful effects; their studies shape new laws and approaches to policy.

Biomedical research has also generated entirely new paradigms to address global challenges, such as the planet’s unfortunate reliance on fossil fuels. New developments in the field of synthetic biology have resulted in the ability to produce biofuels from algae that require little more than sunlight, water and carbon dioxide. These organisms and others are being designed to manufacture hundreds of chemicals so that we will no longer require petroleum, toxic mining, processing and pollution. The process is like brewing beer. Biomedicine is borrowing the technology from nature to brew environmental and medical solutions.

Related developments have removed the need to even use a living host for the manufacture of biomolecules, supporting the production of vaccines and medicines on-demand. Such a strategy bypasses the burden of cold storage and expensive transport, permitting more people in need to acquire essential medicines.

Biomedicine has propelled molecular design and engineering to a place where tiny sensors, genetically encoded and close to a billionth of a meter in size, can be employed in natural ecosystems for the discovery of new medicines, such as antibiotics. Similar sensors can monitor farms and report on crop and soil health, and they can be employed as wearable devices for real-time personal health monitoring. They can even be used inside our bodies to track the state of our health.

Biomedicine is propelled by the quest to understand the great mysteries of life and by our collective mission to keep each other and the planet healthy.

The Promise of Discovery
Alex Garruss. Image: Aaron Washington

Alex Garruss is propelled by his quest to understand the great mysteries of life

A Promise to Heal

This essay was written for the 2017-2018 HMS Dean's Report in answer to the question "What is the promise of medicine to me?"

During the presidency of Park Chung-Hee in South Korea in the 1960s and ‘70s, my grandfather was interrogated for political opposition. Upon release, he learned that our family would be interrogated in a more “traditional” style, and he immediately determined to escape the following day.

With five children and carrying only seven suitcases, my grandparents left behind their livelihood in Korea. They sought new beginnings in America, in West Los Angeles, where they made a humble living as convenience store owners. My grandfather succumbed to cancer soon after arriving in the U.S., trying to navigate death in a confusing and foreign land. My college-aged father and grandmother continued to run the store. 

The promise of medicine rests within its unique capacity to serve as a bridge to peace.

This family backdrop of political and inner resilience guided my entry into medicine. As a young man, I discovered a buried trove of literature on “health as a bridge to peace,” which showed me the promising nexus between medicine and political resilience. Through this new lens, my existing friendship with a South Sudanese doctor, Chol Makur, evolved into a partnership as co-founders of a medical social venture in South Sudan.

During graduate school, this lens led me to conduct research with the Liberian Ministry of Health during the Ebola outbreak. Closer to my ancestral home on the Korean Peninsula, we helped conduct the first systematic review of health literature in North Korea and organized North Korea’s first international surgical symposium. We brought together neurosurgeons from 12 countries with North Korean neurosurgeons to share research. An intangible value surfaced as surgeons from many nations learned to look beyond the media’s caricatured portrayals of “the other,” and instead connected in shared humanity as clinicians. It taught me an early lesson in health diplomacy as a rare opportunity to share love across barriers often deemed impenetrable.

I also discovered medicine’s role for healing across other seemingly impenetrable barriers at an individual level. In our longitudinal clerkship, I met a 50-year-old woman named Rosa during her diagnosis with incurable metastatic angiosarcoma.

At each clinic visit she snapped in anger—at God, the health care system she had trusted, the unfairness of it all—and she refused to speak with us about her illness. I recalled the advice of a palliative care mentor, “don’t just do something… sit there.” And so we tried.

For nine months, I would stop by the infusion room on Friday mornings to sit with Rosa to chat about the latest David McCullough book, play Rummy 500 or trade gardening tips. Though I had studied assiduously on the science of angiosarcoma, it was through these immensely human experiences that we could broach the conversations that would help her find peace at the end of life.

Reflecting upon my time at HMS, similar humanistic endeavors stand out most—organizing our anatomical donor memorial service, coordinating a course on medical reflective practice called The Healer’s Art, and leading multiple retreats for an interdisciplinary group of fellows through the Harvard Graduate School Leadership Institute. My past work in “health as a bridge to peace” had now flipped to “peace as a bridge to health.”

Professionally, this experience has modeled for me a new purpose—to serve as a bridge for people affected by serious illness to live out their lives meaningfully. For me, primary care serves as this ultimate bridge in medicine. It resides at the intersection between my passions of longitudinal human relationships, advocacy for underserved communities and rigorous scientific inquiry. And so, my hope is to pursue a tightly interwoven career in primary care, palliative care and health diplomacy.

In pursuing this career, I stand firmly in two roots of my family history and professional experience. First, the promise of medicine rests within its unique capacity to serve as a bridge to peace. And second, my contribution to healing arises from both scientific rigor and compassionate presence. With the support of these roots, I hope to facilitate medicine’s ability to bridge conflicts in the two Koreas and elsewhere, and to foster peace within the human experience of serious illness.

A Promise to Heal
Andrew Kim. Image: Aaron Washington

Andrew Kim sees medicine as a bridge to health and peace

The Promise of Advocacy

This essay was written for the 2017-2018 HMS Dean's Report in answer to the question "What is the promise of medicine to me?"

This fall I will be applying to residency in family medicine, which to me, embodies all that the promise of medicine offers. Upon starting at Harvard eight years ago, this choice was not immediately clear to me. Having spent my undergraduate years focused on neurobiology research, I was excited to see what promise there was for translating my basic science skills into clinical care. On the other hand, I was becoming increasingly interested in women’s health, global health and the structural processes that hinder progress in both of these areas.

HMS afforded me the opportunity to explore this new set of interests with activities that included testing and counseling people with HIV at the Dimock Center, a community health organization, and helping to start HMS’s first student-faculty practice, the Crimson Care Collaborative, as well as a summer of research on postpartum hemorrhage in Zambia. These experiences reinforced my desire to become a physician but also made apparent the complex social factors that contribute to the production of disease.

I hope to always think about the person who sits in front of me, their families, and their environment. This will motivate me to continue fighting the structures, whether they be bacterial or institutional, genetic or socioeconomic, that stand in the way of a person’s health.

By the time I started my third year in medical school, it became clear to me that my medical education would not be complete without in-depth training in critical analysis of the social processes that impact health. After finishing my clinical year, I took a leave of absence from HMS to do just this. I started a PhD in the joint medical anthropology program at the University of California, San Francisco, and the University of California, Berkeley. My dissertation explores the causes of maternal mortality in Nigeria as they relate to social, political, economic and religious processes that were set in place as far back as British colonization.

I believe it is important that we understand how postcolonial dynamics continue to impact health in many countries despite the hundreds of millions of dollars being invested into lowering maternal mortality. I learned there is no quick fix to maternal mortality. It will take a longer-term, sustained commitment to women and the communities in which they live. This realization is what brought me to family medicine.

Back at HMS for my fourth year, I am excited about the prospect of close longitudinal relationships with my patients as I accompany them over the course of every stage in their lives. I look forward to taking care of individuals, families and communities. The philosophy of family medicine exemplifies the promise of medicine in many ways but especially because of its commitment to social justice.

Yes, the promise of medicine means caring for patients, standing by them through their various stages of health and illness, and offering cutting-edge treatment supported by rigorous research. But, in my opinion, it also means calling senators and advocating to keep health care accessible for all. It means marching in the streets on behalf of each victim of police violence. It means going to Standing Rock to stand with the Sioux Tribe against the Dakota Access Pipeline. It means speaking out against polluted water in Flint, Michigan. It means writing a letter to a utility company to prevent them from shutting off a patient’s utilities. It means contributing to bail funds and speaking out against the prison-industrial complex. It means mentoring disadvantaged high school students. It means community organizing. It means campaigning for candidates who support public health as a right.

It also means calling a patient to check in after a particularly emotional office visit or starting food banks or offering mindfulness classes in clinics. It means acknowledging racial, sexual and other forms of trauma that a patient may bring with them into the office. It means not only acknowledging that implicit bias affects our medical decision-making, but putting in place institutional policies that can minimize its effect. It means both community-driven research and community-led intervention.

Of course, none of this can be accomplished alone, so it also means working with multi-disciplinary teams that include social workers, physicians, nurses, researchers, public health workers, psychologists and community leaders.

This is the promise of medicine that I hope to carry throughout my career. I hope to always think about the person who sits in front of me, their families, and their environment. This will motivate me to continue fighting the structures, whether they be bacterial or institutional, genetic or socioeconomic, that stand in the way of a person’s health.

The Promise of Advocacy
Adeola Oni-Orisan. Image: Aaron Washington

Delivering family medicine means advocating for patients, according to Adeola Oni-Orisan

The Promise of Hope

This essay was written for the 2017-2018 HMS Dean's Report in answer to the question "What is the promise of medicine to me?"

My vision of medicine has continuously evolved throughout my training, but there is one thing that has endured: medicine promises people hope.

Before I started medical school, my grandmother passed away from Alzheimer’s disease, and my family and I felt the comforting hand of medicine during this time of hardship. Although I initially thought medicine had failed, the many efforts from skillful providers to alleviate her declining condition inspired me and my family to hope that one day, medicine in the future could achieve what seemed impossible at the time. Once I started medical school, my exposure to countless patient experiences and translational medicine made it even clearer that medicine promises people hope. Hope rooted in the discoveries of the past and felt in the therapies of the present. Hope that is inspiring the future.

Medicine promises people hope. Hope rooted in the discoveries of the past and felt in the therapies of the present. Hope that is inspiring the future.

Medicine is riddled with a history of countless breakthroughs that today have become standard of care in many clinical settings. With the first successful vaccine for smallpox by Edward Jenner in 1796 to the most recent trials of an effective Ebola vaccine, I have been able to tell patients in my primary care clinic that the vaccines they receive will help prevent deadly infections they probably haven't even heard of because vaccines have made those infections so rare today (or even extinct!)

I have had the experience of comforting many patients and family members undergoing surgery, ensuring that they would not feel any pain or remember anything, thanks to one of the earliest successes of surgical anesthesia in 1846 by William Thomas Green Morton in the famous Ether Dome at Massachusetts General Hospital.

In addition, one of my favorite historical moments is the serendipitous discovery of the first antibiotic penicillin by Alexander Fleming in 1928. If he had not noticed that bacteria did not grow around the fungus contaminating his culture plate, I might not have been able to tell many of my patients today that with a course of antibiotics their illness would disappear. Building upon this history of achievements, medicine has given me solid ground to be able to treat patients with diseases that would have been fatal centuries ago.

One of the most wonderful aspects of practicing medicine is having the privilege to tell patients that there is hope for a treatment—even a cure—for their illness. One particular experience I had was interviewing a patient, a mother of three children, who had metastatic diffuse large B-cell lymphoma that was debilitating her due to invasion of her nervous system.

She had undergone multiple rounds of chemotherapy and radiation therapy but the cancer kept relapsing, and she and her family were starting to lose hope. They felt that medicine was failing them. During the time I saw her, however, we began a conversation about enrolling her in a clinical trial that employed that use of CAR T cells. She and her family were awed to hear that despite multiple rounds of failed chemoradiotherapy, this new treatment had a good chance of curing her cancer. Seeing her family rejoice was a magical experience that reaffirmed my decision to pursue a career in medicine, and it also challenged me to continually push the boundaries of modern medicine so that I can make “miracles” like this possible for future families.

Experiences like this have also fueled my passion for translational research, which aims to bring lab bench discoveries to the bedside of patients seeking innovative medical care. The area of research I focus on is the immune system, an intricately complex defense system that covers our entire body from head to toe. I am helping to develop a mouse model that can bear a human immune system, which will allow modeling of human infections and testing of vaccines and biologic pharmaceuticals that may be used to treat cancers and autoimmune diseases.

It is clear that our immune system has great potential. Through the scientific and medical community mastering its potential, I am confident that we will be able to understand and treat a wide array of human disorders. That is why, with every experiment I do in the lab, I have my own personal hope that one day, the findings I make can contribute to the development of a therapy that can help treat a disease and alleviate the suffering of those afflicted by it.

As such, whether someone is born with an inherited disease, recovering from an accident, struggling with mental illness or battling with the normal process of aging, medicine promises to alleviate suffering and give people hope. This hope I have encountered goes beyond the factual knowledge of therapies I have gained and touches people’s lives in a very personal way, as it has touched mine. As Hippocrates said, medicine will continue to “cure sometimes, treat often and comfort always” with the promise that even for fatal, incurable diseases, medicine will provide hope for more effective treatment in the future.

The Promise of Hope
Wilfredo García Beltrán. Image: Aaron Washington

Wilfredo García Beltrán believes in the power of medicine’s miracles

Puerto Rico after Maria

Michael Charness, Chief of Staff of the VA Boston Healthcare System and HMS Professor of Neurology, recently spent two weeks deployed in Puerto Rico with other VA colleagues, all working together with a Health and Human Services Disaster Medical Assistance Team (DMAT) to provide critical health care services in the wake of the devastation left behind when Hurricane Maria struck on Sept. 20.

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Charness talked to Harvard Medicine News about his experience in the immediate aftermath of the destructive storm, and about the challenges for health care that Puerto Rico now faces going forward. Charness is also faculty associate dean for Veterans Hospital Programs at HMS and professor of neurology and associate dean at Boston University School of Medicine.

HMN: What was your mission in Puerto Rico?

MC: We had the privilege of serving our fellow citizens at the Manati Federal Medical Station in the north central region of Puerto Rico. Like the rest of Puerto Rico, Manati and its environs were devastated by the one-two punch of Hurricanes Irma and Maria. Our mission was to provide emergency care and chronic medical care for Puerto Ricans with chronic medical conditions who could no longer survive in their communities. We were also tasked with sending teams into hill communities to assess their need for food, water and medical care.

HMN: What was the situation on the ground?

MC: Many homes in Puerto Rico were destroyed or severely damaged, some roads remain impassable, electrical power is unavailable across most of the island, food, potable water and basic amenities are scarce, and communication by phone, text, or email is difficult or impossible.

In addition to the immediate need for food, water, shelter and communication, this situation has profound implications for the health and wellbeing of 3.4 million of our fellow Americans. Diabetes and hypertension are highly prevalent in Puerto Rico and are readily treatable with medication. But what if you can’t reach your doctor to prescribe a medication because the phones don’t work? What if you can’t fill a prescription, because you’re not receiving your paycheck, the ATMs aren’t functional and you can’t afford your prescription co-pay? What if you do obtain your insulin, but you can’t keep it cold, because refrigeration requires electricity and you don’t own a generator?  

HMN: What are the long-term consequences of that lack of infrastructure?

MC: As the days and weeks pass without the restoration of electrical service and communications, Puerto Ricans are running out of medications for myriad treatable conditions. Over time, the population burden of preventable illness, including the long-term complications of diseases such as diabetes and hypertension — blindness, neuropathy, kidney failure, heart attack, and stroke – will increase. While we were there, in the very early days of this crisis, we were already seeing the harbingers of this looming health care crisis - systolic blood pressures above 250 and blood sugars above 500 in patients who simply ran out of medication. The impact of this catastrophe on the health of Puerto Ricans will be felt for years.

HMN: What kind of care do people with these chronic illnesses need?

MC: Many people require home health services to stay alive. Home ventilators and oxygen concentrators require electricity. Patients dependent on tube feedings require a reliable source of specialized food and medical equipment. Patients with end stage kidney disease require regular dialysis. How will these services be provided? In the face of a collapsed infrastructure, public health agencies in Puerto Rico have been stretched thin in their attempts to meet these needs.

Finally, because there is no power, most hospitals in Puerto Rico remain in service only with the electricity generated by diesel generators. Fuel delivery remains erratic, and generators that were never meant to operate for more than a few days have been running, sometimes continuously, for weeks. Not surprisingly, generators fail sporadically, abruptly removing entire hospitals from the health care grid and leaving acutely ill patients with limited options until fuel can be delivered or repairs can be completed.

HMN: So, what kind of help were you able to provide?

MC: The Federal Medical Station where we were based was established at an indoor sports arena centrally located in Manati. There, under the aegis of the U.S. Department of Health and Human Services, VA employees and Disaster Medical Assistance Teams are providing acute and long-term care for patients with medical conditions that can no longer be managed at home, because there is no electricity and sometimes no home. Our services are free. We have rewritten hundreds of prescriptions that could be filled at selected pharmacies without co-payment, courtesy of FEMA. We have provided a temporary medical shelter for patients with home ventilators and oxygen concentrators, feeding tubes, and complex home-care needs, saving many from certain death. And we augment the hospital system when hospital generators fail and patients need to touch down quickly at a different location. When care needs exceed our capacity, we work with local hospitals to find suitable dispositions. For example, while we were there, several patients were transferred to the USNS Comfort, one of the Navy’s top-of-the-line hospital ships that has been deployed to Puerto Rico to supplement the kind of care we’re able to provide on the ground.

HMN: How do you coordinate all this with the community when the communications system is all down?

MC: Even though we had established services at a prominent location in Manati, the communications blackout meant that our activities were unknown, even to the local community. We sent health care teams to the long queues in front of banks, restaurants and stores to conduct health screens and to announce our presence. We sent strike teams to more isolated hill communities to survey their health needs. Over a week’s time, our patient visits increased from just a few to nearly 200 every day.

HMN: What were the working conditions like?

MC: We were forewarned that conditions would be austere. When we arrived in Manati, the arena was more than 100 degrees, there was no running water, and generator power was ephemeral. To cool the patient care area, we opened doors and windows, an invitation to flies, mosquitoes, and other local fauna. Through the ingenuity of the DMAT, air conditioning was established and running water became a more regular pleasure, allowing staff to flush toilets and enjoy the respite of a cold shower (a Puerto Rican cold shower is warmer than a Boston cold shower). Staff split into 12-hour day and night shifts. We slept in sleeping bags on cots in a large co-ed room with 70 other staff, lulled by the ostinato drone of snoring and the tossing and turning of restless, weary bodies. We ate MREs, the meals ready to eat staple of our military colleagues, and occasional local fare. Through meticulous hand hygiene and vigilance, no one developed food borne illness, and there were no injuries. While staff noted the austerity of our conditions, a striking contrast to our daily lives, we were all acutely aware that our patients were living with much less, and they never complained. And unlike the veterans whom we serve, our tour was just two weeks and no one was shooting at us. 

HMN: What’s your number one takeaway from this experience?

MC: The people of Puerto Rico were our inspiration. Patients arrived telling extraordinary and harrowing stories: the elderly woman who breathed into the tracheal tube of her husband throughout the night of Maria’s rampage when his home ventilator lost power; the elderly women who floated her elderly husband with Alzheimer’s disease above her shoulders as their home washed away. The home care patients who arrived at our facility had received meticulous care by their family members. We provided electricity and they did much of the rest. The devotion of Puerto Ricans to family and community was striking. Many individuals who had lost homes would not leave their villages and families to seek shelter or care elsewhere. With school canceled, our arena was filled with bright, engaged student volunteers who worked as our translators by day and returned home to darkness. At every interaction, patients, families and government officials expressed their deepest, most heart-felt appreciation for the assistance that we provided.

We arrived to a disaster expecting despair and resignation. Instead, we found faith, hope and gratitude. On our last day, a “parrado” of volunteers filled our facility with blaring music and songs of joy, moving many of us to tears. So many Puerto Ricans who had so little had lost everything. That people so ravaged by this catastrophe could summon such optimism gives hope that, with the right help, Puerto Rico will recover.

 

In this colorized infrared image from the NOAA/NASA Suomi NPP satellite, taken on September 20, the well-defined eye of Hurricane Maria can be seen approximately three hours before the storm made landfall in Puerto Rico as a Category 4 hurricane, with maximum sustained winds of around 150 mph. Image:  NOAA/NASA

Harvard doctor on providing critical health care in Puerto Rico 

 

Sight Unseen

A study led by scientists from Harvard Medical School reveals “hidden” variability in how tumor cells are affected by anticancer drugs, offering new insights on why patients with the same form of cancer can have different responses to a drug.

“Gene expression profiling allows us to identify drugs that are potentially useful when given in combination." —Marc Hafner

The results, published in Nature Communications on Oct 30, highlight strategies to better evaluate drug effectiveness and inform the development of synergistic drug combinations to overcome the ability of tumors to evade treatment.

Based on analyses of over 600 drug and breast cancer cell pairings, researchers showed that, for some cells, drug exposure can cause significant changes in gene expression—indicating the successful action of a drug on its target—without affecting cell growth or survival. This appears to be caused by adaptive resistance mechanisms, which, when identified, can be blocked by other drugs given in combination.

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“Our findings suggest new ways of tackling the still-difficult task of working out which patients should receive which drug and how drugs should be combined to maximize therapeutic benefit,” said senior study author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology and director of the Harvard Program in Therapeutic Science and the Laboratory of Systems Pharmacology at HMS.

Unrecognized Differences

In collaboration with the Broad Institute of Harvard and MIT, Sorger and colleagues leveraged an approach developed as part of the National Institutes of Health’s Library of Integrated Network-Based Cellular Signatures (LINCS), a large-scale program that aims to amass molecular data from cells following drug exposure to study the mechanisms of drug response.

They collected gene expression data from six genetically diverse breast cancer cell lines, which were each exposed to 109 small-molecule drugs at multiple dosages and time points. Cell growth and survival were assessed in parallel using a method developed by the Sorger lab that corrects for growth rate variations and makes large-scale comparisons of drug response more accurate.

In total, the researchers identified almost 8,000 gene expression signatures that they compared across several dimensions of drug response, including by cell line, drug class, biological pathway, cellular function and more. An interactive visualization of the dataset is available online.

The team found that cell lines appeared to respond to drugs in two broad patterns. One group of drugs—primarily targeting machinery involved in the cell cycle, protein chaperoning or DNA repair—elicited similar patterns of response across all cell lines.

A second group triggered responses that were specific to cell type. Different cell types respond to these drugs in qualitatively different ways. Such drugs largely targeted the signaling pathways that are disrupted by oncogenic mutations—for example, trametinib and alpelisib, which inhibit MEK and PIK3 pathways, respectively, and have been FDA-approved or are undergoing clinical trials for treating certain breast cancers.

“We find that drug-sensitive tumor cells respond in similar ways to some classes of drugs and very different ways to other classes of drugs,” Sorger said. “This was unexpected and suggests fundamental but unrecognized differences in drug action in tumor cells from different individuals having the same disease—in this case, breast cancer.”

Better Combinations

While gene expression in most drug-cell line pairings correlated with cell growth and survival, a small subset, roughly 3 percent, had a unique pattern of response. In these cases, drug exposure caused significant changes in tumor cells’ gene expression profile but had no lasting physical effect.

An estrogen receptor-negative cell line known as BT-20, for example, displayed a gene expression response to both trametinib and alpelisib when given individually. Cells continued to grow in both cases, even when exposed to high concentrations of the drugs.

When given in combination, however, the two drugs had a strong synergistic effect and caused cell death across a wide range of concentrations.

Additional analyses revealed that exposure to certain classes of drugs induced molecular changes that allowed BT-20 cells to adapt to the drug, making it less effective. Trametinib appeared to inhibit this adaptive resistance pathway, thereby increasing the effectiveness of the drug it was given in combination with.

“Gene expression profiling allows us to identify drugs that are potentially useful when given in combination. If we had measured only cell survival, it would seem as though each drug was ineffective on its own and should be ignored,” said Marc Hafner, co-lead author of the study and a research fellow in therapeutic science in the Laboratory of Systems Pharmacology.

“The cells can cope when exposed to one of these drugs, but when both are put together, the response is strong enough to stop cell growth and induce death,” he added.

These examples underscore the value of gene expression profiling for revealing subtle mechanisms of drug sensitivity and resistance and providing clues into which drugs might be most effective when tested in combination, according to the authors. The approach could support efforts to develop individualized, precision-targeted treatment for patients based on their tumor’s unique molecular characteristics.

The team is now working to expand their work to include more cell lines and drugs, and they hope to leverage improved datasets to help interpret patient data in future research.

“Our study is not a recipe for generating effective drug combinations, but it can help narrow down candidates and identify which drugs might be most promising when tested in combination,” Hafner said. “In order to go beyond targeting an oncogene and just hoping for the best, we need to understand the actual biological effects of drugs inside cells. That’s how we can have better and smarter use of drugs.”

Additional authors include co-lead author Mario Niepel, Qianan Duan, Zichen Wang, Evan Paull, Mirra Chung, Xiaodong Lu, Joshua Stuart, Todd Golub, Aravind Subramanian and Avi Ma’ayan.

This study was supported by the NIH LINCS grants U54-HL127365, U54-HL127624, U54-CA189201 and U54-HG006093 and a Swiss National Science Foundation fellowship.

 

Image: CIPhotos/Getty Images Plus

Gene expression study reveals “hidden” variability in how cancer cells respond to drugs

Awards & Recognition: November 2017

Regan Bergmark
Regan Bergmark

Regan Bergmark, HMS clinical fellow in otolaryngology at Massachusetts Eye and Ear, was among six individuals selected to participate in the 2017-2018 Visiting Scholars Program of the American Board of Medical Specialties (ABMS) Research and Education Foundation.

Bergmark was named the Gliklich Healthcare Innovation Scholar for her project Standardized Health Outcomes Measures: Utilization by Specialty.

This one-year, part-time program facilitates scholarly projects relevant to physician certification that support early career physicians and scientists in their pursuit of improving patient care and furthering medical education. It also exposes the scholars to the fields of professional assessment and education, health and public policy, and quality improvement (QI), as well as provides leadership development. 


Four Harvard Medical School scientists have been named to the 2018 Forbes 30 Under 30 in Healthcare list. This year’s list features 600 individuals in 20 different industries.

Omar Abudayyeh and Jonathan Gootenberg, both in the Harvard-MIT MD-PhD Program, were named to the list for pioneering two advances for CRISPR—a new enzyme for editing genes and a new technique for editing the chemical messenger, RNA.

Oren Miron, research associate in biomedical informatics at HMS, was named to the list for his work in using an auditory test, which is already used to screen for hearing problems in infants, to recognize autism at birth.

Douglas B. Jacobs, HMS clinical fellow in medicine at Brigham and Women’s Hospital, was named to the list for shining a light on insurance practices that dissuade patients from getting care. Some insurers placed all treatments for certain conditions in the highest cost tier. The Department of Health and Human Services labeled this discrimination.


Four Harvard Medical School scientists were among 396 individuals to be elected 2017 Fellows of the American Association for the Advancement of Science (AAAS), in recognition of their work to advance science or its applications. 

From left: Alan Garber, David Hooper, Pier Paolo Pandolfi and Bernardo Sabatini

Alan Garber, Harvard University provost and the Mallinckrodt Professor of Health Care Policy at HMS, was elected for his distinguished contributions to the field of medical decision-making and advancing our understanding of methods for improving health care delivery and financing.

David Hooper, HMS professor of medicine at Massachusetts General Hospital, was elected for elucidating mechanisms and epidemiology of antibiotic resistance in bacteria, with a major focus on the molecular determinants of quinolone action and resistance.

Pier Paolo Pandolfi, the HMS George C. Reisman Professor of Medicine at Beth Israel Deaconess Medical Center, was elected for seminal contributions to the elucidation of the molecular genetics and biology of human cancer, which also led to the cure of Acute Promyelocityc Leukemia (APL).

Bernardo Sabatini, the Alice and Rodman W. Moorhead III Professor of neurobiology at HMS, was elected for his contributions to elucidating mechanisms of synapse formation, function, and regulation, and their link to modulation of brain circuitry in development, behavior and disease.


Laura Mauri
Laura Mauri

Laura Mauri, HMS professor of medicine at Brigham and Women’s Hospital, received the Joseph A. Vita Award from the American Heart Association on Nov. 12 at the association’s 2017 Scientific Sessions. This award is presented annually to an investigator whose research has had major impact in the field of cardiovascular biology or cardiovascular health.

Mauri was recognized for her leadership of transformative clinical investigations identifying and clarifying optimal treatment methodologies for a variety of cardiovascular disorders.

Studies led by Mauri include a large trial clarifying risk versus benefit of continued blood-clot prevention therapy in patients with coronary artery disease and stents. The trial showed marked reductions in heart attacks with treatment beyond one year. Mauri's research group also has developed decision tools to individualize treatment choices by identifying patients most likely to derive desired benefits without increased bleeding risk.


Charles Nelson III
Charles Nelson III

Charles Nelson III, HMS professor of pediatrics and HMS professor of psychology in the Department of Psychiatry at Boston Children’s Hospital, was one of nine scientists honored by the Brain and Behavior Research Foundation with 2017 Outstanding Achievement Prizes for work in schizophrenia, mood disorders, child and adolescent psychiatry, and cognitive neuroscience on Oct. 27.

Delving into a long-standing interest on how early experience impacts early brain and behavior development, Nelson's research centers on a variety of problems in developmental cognitive neuroscience, including the development of social perception; developmental trajectories to

autism; and the effects of early adversity on brain and behavioral development. Most recently, Nelson looked at how individual differences in processing facial emotion in infancy are associated with later psychopathology.

Nelson is also director of developmental medicine in the Division of Developmental Medicine and the Richard David Scott Chair in Pediatric Developmental Medicine Research at Boston Children’s; professor in the Department of Society, Human Development and Health at the Harvard T.H. Chan School of Public Health; and professor of education at Harvard Graduate School of Education


Martin Pollak, HMS professor of medicine at Beth Israel Deaconess, received the Homer W. Smith Award, which is presented annually to an individual who has made outstanding contributions which fundamentally affect the science of nephrology, broadly defined, but not limited to, the pathobiology, cellular and molecular mechanisms, and genetic influences on the functions and diseases of the kidney. He received the award at the annual meeting of the American Society of Nephrology held Oct. 31–Nov. 5.

Pollak, who is also chief of the Division of Nephrology at Beth Israel Deaconess, was recognized for his contributions to the field of nephrology using the tools of human genetics to study rare syndromes that illuminate renal health and diseases as well as common genetic drivers of disease risk, especially kidney health disparities in minority populations. His current research is focused on identifying and understanding genes involved in the development of focal segmental glomerulosclerosis (FSGS), in addition to studying the extracellular calcium receptor. 


Elazer Edelman
Elazer Edelman

Elazer Edelman, HMS professor of medicine and senior attending physician at Brigham and Women’s Hospital, was presented with the Transcatheter Cardiovascular Therapeutics Career Achievement Award on Oct. 30 during the annual scientific symposium of the Cardiovascular Research Foundation.

Edelman and his students have been credited as some of the key contributors and pioneers of the coronary stent. His research examining the cellular and molecular mechanisms that produce atherosclerosis and coronary artery disease critically advanced the development and optimization of the first bare-metal stents and subsequent iterations, including drug-eluting stents. His most recent publications have focused on how tissue engineered cells might be used for the local delivery of growth factors and growth inhibitors in the study of the vascular homeostasis and repair, cancer invasiveness and metastases and the homology between endothelial paracrine and angiocrine regulation in cancer and vascular diseases.

Edelman’s research integrates multiple disciplines including polymer based controlled and modulated drug delivery, growth factor biology and biochemistry, tissue engineering, biomaterials-tissue interactions and the vascular response to injury. Edelman is also the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT, a core member of the Institute for Medical Engineering and Science, and director of the Harvard-MIT Biomedical Engineering Center.


David W. Bates
David W. Bates

David W. Bates, HMS professor of medicine at Brigham and Women’s Hospital, received the 2017 John P. Glaser Health Informatics Innovator Award, which is presented annually to a leader in health care informatics.
 
On Oct. 30, Bates was presented with the award and formally inducted into the John P. Glaser Health Informatics Society. He delivered a lecture titled "The Use of Big Data to Improve Care." In the lecture, Bates defined big data and discussed an array of approaches for harnessing data, both in the near future and over the longer term, to enhance the value of health care and achieve the triple aim, as delineated in the Affordable Care Act, by improving the patient experience, ameliorating population health and reducing per capita costs.

Bates is chief of the Division of General Medicine and Primary Care at Brigham and Women's Hospital; medical director of clinical and quality analysis at Partners HealthCare System an professor of health policy and management at the Harvard T.H. Chan School of Public Health.


Fatima Lunze
Fatima Lunze

Fatima Lunze, HMS instructor in pediatrics at Boston Children’s Hospital, has been named with her husband, Karsten Lunze, assistant professor of medicine at Boston University School of Medicine, to receive the Victor Sidel and Barry Levy Award for Peace from the American Public Health Association, which is awarded to an APHA member who has made outstanding contributions to preventing war and promoting international peace.

The Lunzes are receiving the award for their work in serving victims of war and terrorism, specifically for their work benefiting survivors of war and terror in the Russian North Caucasus over the past decade or so.


Molly Schumer
Molly Schumer

Molly Schumer, research fellow in genetics at HMS, was one of five recipients of the L'Oréal USA 2017 For Women in Science Fellowship, which recognizes and supports female scientists at a critical stage in their careers with $60,000 grants to advance their postdoctoral research.

Schumer’s research focuses on investigating how evolutionary forces shape our genes. Specifically, she is working to understand why a trait that can cause melanoma has persisted in swordtail fish for over a million years. Through this research, Schumer hopes to identify signals that may ultimately help us learn the genetic and evolutionary causes of diseases.


Hajirah Saeed
Hajirah Saeed

Hajirah Saeed, HMS instructor in ophthalmology at Massachusetts Eye and Ear, and Miguel González, HMS research fellow at Mass. Eye and Ear, are co-winners of the 2017 Claes Dohlman Fellowship Award.

This award recognizes outstanding fellows and junior faculty members who are training in the area of cornea, refractive surgery and external diseases. They will receive their awards on November 11 during the American Academy of Ophthalmology annual meeting.

Miguel González
Miguel González

Saeed is a full-time member of the Cornea and Refractive Surgery Service at Mass. Eye and Ear, who specializes in ocular surface disease and refractive surgery, with specialized expertise in burns, keratoprosthesis, ocular surface tumors, and pediatric cornea. As the inaugural Gliklich Innovation Scholar at Mass. Eye and Ear, she is developing a Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) registry and bio-repository in order to investigate the immunopathogenesis and genetics of the disease. SJS/TEN is a rare, immune-mediated mucocutaneous disease with the potential for severe ocular complications including corneal blindness. She aims to identify genetic risk factors for developing this fatal and blinding disease and identify biomarkers to help detect early disease.

​González is a research fellow who works with Claes H. Dohlman, MD, PhD, as part of the keratoprosthesis group at Schepens Eye Research Institute of Mass. Eye and Ear and Mass. Eye and Ear. As a clinician-scientist, his research focuses on developing new materials and new designs for the Boston Keratoprosthesis that could improve its biocompatibility and biointegration into corneal tissue. He evaluates its complications and develops new therapeutic and bioengineered approaches to improve the clinical results of this device.


Paul Farmer
Paul Farmer

Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine, has won the 2017 MacLean Center Prize in Clinical Medical Ethics. Farmer will receive a $50,000 award and deliver a lecture about bioethics and the 2013-2106 Ebola outbreak in West Africa during the 29th annual Dorothy J. MacLean Fellows Conference on Clinical Medical Ethics on Nov. 10.

 Farmer, who co-founded Partners In Health, is a medical anthropologist, researcher, global health advocate and educator. He was selected by the MacLean Center for his decades-long efforts to bring health care to some of the world’s poorest people. Farmer is also the chair of the Department of Global Health and Social Medicine and chief of the Division of Global Health Equity at Brigham and Women's Hospital.


Frederick Jakobiec
Frederick Jakobiec

Frederick Jakobiec, the HMS Henry Willard Williams Professor of Ophthalmology, Emeritus, and Professor of Pathology, Emeritus, at Massachusetts Eye and Ear has received the Merrill Reeh Pathology Award from the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) for his winning paper entitled "Pigmentation of the Lacrimal Sac Epithelium."

This award is given to an individual who has written the most important eye pathology paper on the subject of oculoplastics during the preceding academic year, as judged by the ASOPRS membership.

Jakobiec is currently Director of the Cogan Eye Pathology Laboratory at Massachusetts Eye and Ear. He is the former Chief and Chair of the Department of Ophthalmology at Mass. Eye and Ear and Harvard Medical School.


Two Harvard Medical School professors have been recognized by the American Neurological Association (ANA) for their outstanding work in academic neurology. 

Reisa Sperling
Reisa Sperling

Reisa Sperling, HMS professor of neurology and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital was awarded the Raymond R. Adams Lectureship.

Sperling was recognized for her research focusing on the early diagnosis and treatment of Alzheimer’s disease. Her recent work involves the use of functional MRI and PET amyloid imaging to study alterations in brain function in aging and early Alzheimer's disease.

Clotilde Lagier-Tourenne
Clotilde Lagier-Tourenne

Clotilde Lagier-Tourenne, HMS assistant professor of neurology and assistant in neuroscience at Mass General Hospital was awarded the Grass Foundation-ANA Award in Neuroscience.

The Grass Foundation-ANA Award in Neuroscience established in 2007, honors outstanding young investigators conducting research in basic or clinical neuroscience. Lagier-Tourenna conducts patient-oriented research to understand the molecular mechanisms driving neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

 

 

Bench to Bedside

The Jeffrey M. and Lisa L. Leiden Family Professorship in Translational Medicine has been established at Brigham and Women's Hospital and Harvard Medical School through a donation from the Leiden family.

The $4 million gift will provide significant financial support for a physician-scientist to advance the field of translational medicine and build on basic research advances to develop transformative medicines for serious diseases. Recruitment for the incumbent is currently underway.  

Get more HMS news here

"Translational medicine is the bridge between discoveries made in the lab and life-saving, life-altering treatments at the bedside. This generous gift will help propel the development of such therapies,"  said HMS Dean George Q. Daley. "Most of modern medicine's greatest achievements emerged from observations in the lab that were transformed into therapies. Translational research makes that transformation possible.

"Jeff is a prime example of a physician-scientist who has translated basic scientific discoveries into breakthrough therapies for serious diseases. The Leidens' vision for accelerating the pace at which our biomedical advances lead to innovations that directly impact patient care is a shared one, and we are thrilled to partner with them on this initiative. We are truly grateful to him and his family for their generous gift and their support," said Betsy Nabel, president of Brigham Health.  

"Jeff Leiden embodies the highest aspirations of the translational scientist," Daley added. "He has contributed all along the spectrum of discovery-from fundamental laboratory work to venture capital to leadership of biopharma. His remarkable career epitomizes the best of translational medicine." 

Leiden, who is chair, president and CEO of Vertex Pharmaceuticals, is also a physician and scientist who, for the past 30 years, has dedicated his career to improving the lives of people with serious diseases.

Leiden has a long and deep affiliation with the mission of Brigham and Women's. He trained first as a medical intern at the hospital and then went on to complete his residency in internal medicine and a fellowship in cardiology.

In 1999, Leiden returned to Harvard as a professor of medicine at HMS. He was also the Elkan Blout Professor of Biological Sciences, the director of the Laboratory of Cardiovascular Biology and the director of the Center for the Prevention of Cardiovascular Disease at the Harvard School of Public Health.

Today, he is a member of the Harvard Medical School Board of Fellows and member of the Board of Trustees at Brigham and Women's, where he also serves as chair of the scientific advisory board. 

Through those experiences, Leiden has witnessed first-hand the important role that physician-scientists can have on the discovery and real-world application of life-saving therapies for patients.

He has applied that model of using insights from basic research to develop transformative medicines at Vertex, where the company has developed the first and only medicines to treat the underlying cause of cystic fibrosis. 

"Harvard Medical School and Brigham and Women's have a long tradition of training and supporting outstanding physician-scientists who are pioneers in translating basic science discoveries into innovative new therapies for patients," said Leiden. "I'm hopeful that this gift will help nurture and grow this commitment to translational medicine at a time when the scientific opportunities have never been more exciting."

In fall of 2016, Brigham and Women's opened the Building for Transformative Medicine, a hub for state-of-the-art outpatient clinical care, advanced imaging facilities and research space. It is home to researchers and clinicians from across many disciplines who share a vision for collaboration and for the acceleration and translation of laboratory discoveries into rapid and novel treatments for patients. In this building, Brigham and Women's has also established the translational accelerator, a team of experts that provides infrastructure, support and advisement to physician-scientists to quickly and effectively leverage their ideas and research into next-generation therapeutics and technologies. 

In addition to research, the Leiden gift will also support the teaching activities of the incumbent. 

Adapted from a Brigham and Women's news release.

 

Bench to Bedside
A newly established professorship in translational medicine is intended to transform basic discoveries into meaningful therapies for a range of diseases.
Photo: Getty Images

Leiden Professorship in Translational Medicine Established

Into the Unknown

The human mind has evolved a tendency to look for concrete facts and sharply delineated categories, such as true and false, or black and white. But the world around us is more often awash in nuance, ambiguity and gray areas. Understanding this is particularly important for physicians and patients facing the complexity and ambiguity of human health.

Richard Schwarzstein, the Ellen and Melvin Gordon Professor of Medical Education and director of The Academy at Harvard Medical School addressed the theme of uncertainty as he kicked off the Academy’s 2017 Medical Education Day program of workshops and speakers on Oct. 24 .

Get more HMS news here.

 “As far as the laws of mathematics refer to reality, they are not certain, and as far as they are certain, they do not refer to reality,” Schwartzstein began, quoting Albert Einstein.

“If that’s true for math, it’s really true for medicine,” Schwartzstein said.

This year’s Med Ed Day program offered workshops on the basic science of uncertainty and the challenges of communicating ambiguity to patients.

The breadth of workshop categories reflected the importance of emerging thinking about uncertainty from many different angles in medicine, the organizers and speakers said. The offerings ranged from how students are admitted to medical school based on their ability to choose a correct answer on multiple-choice tests or memorize facts, to the way clinicians and patients sometimes interpret relatively small but statistically significant effects, to the unwarranted faith that many in the health care field might place in results from imaging tools and genetic screenings.

Schwartzstein noted that in his own clinical work he has tried to move toward asking trainees for their hypothesis instead of their diagnosis.

“I ask, ‘What do you think is going on?’” he said. “The term ‘diagnosis’ connotes a certainty that is not always warranted.”

One of the biggest challenges for physicians—and patients—comes in interpreting complex statistical information, Schwartzstein said, noting that simple differences in the way information is communicated can change the way patients react.

He cited a study showing that patients who were told they had a 10 percent chance of dying after a surgical procedure made different choices about their treatment than patients who were told they had a 90 percent chance of surviving, even though both statements reflect identical risks.

The Med Ed Day featured speaker, Steven Hatch, an associate professor and infectious disease doctor at the University of Massachusetts Medical School and author of Snowball in a Blizzard: A Physician’s Notes on Uncertainty in Medicine, discussed examples of the challenges that physicians face when presented with ambiguity and complex data.

He said that he began exploring the question of uncertainty in medicine deeply when controversy erupted over changes in guidelines on the frequency of mammography screening in women.

Because of the relative rarity of breast cancer, even a fairly reliable screening technique like mammography can lead to many more mistaken diagnoses of breast cancer than correct diagnoses. For example, when 21.5 million women are screened, there will be 215,000 false positives and only 36,000 actual cases. The screening will also fail to diagnose 360 women who do have breast cancer.

Early guidelines suggested frequent testing over many years of a woman’s life, but the large number of false positives were ignored, resulting in many women suffering psychological stress from receiving a cancer diagnosis when they did not have cancer, in addition to the physical harm of receiving biopsies and other unnecessary procedures, Hatch said.

Whether it is due to the culture of medicine, or shared, evolved human errors of cognition, Hatch said, “we place a high value on certainty without also recognizing that uncertainty is ubiquitous.”

Hatch said that some evolutionary psychologists have hypothesized that humans may have evolved not in spite of our cognitive errors but because of them.

He cited the error management theory, which suggests that those of our ancestors who were more likely to “overdiagnose” risks in their environment—by running away from a stick that looks like a snake, for example—were more likely than those who made the fatal error of “underdiagnosing” the potential risk of a snake “disguised” as a stick.

These cognitive biases may no longer make sense in the context of complex genetic screenings or imaging diagnostics that provide more data than current science is able to parse.

“Uncertainty is everywhere, and nobody in this room is immune,” Hatch said. “My hope for my students is that they become less certain without becoming less knowledgeable.”

Image: Getty Images

Addressing uncertainty in medical education

Parasites Suck It Up

Depletion of a fatty molecule in human blood propels malaria parasites to stop replicating and causing illness in people and instead to jump ship to mosquitoes to continue the transmission cycle, according to a new study by an international research team.

The discovery, published online in Cell Nov. 9, answers a longstanding question about what controls this critical step in the life cycle of Plasmodium falciparum, the parasite responsible for about half a million malaria deaths worldwide each year. It could also open doors to new strategies for malaria control and treatment.

Get more HMS news here 

The key molecule the researchers identified has the catchy name of lysophosphatidylcholine, or LPC for short. It appears to be a building block the parasites use to construct new cell membranes when they divide, the team found.

“When LPC is plentiful, the parasites happily reproduce in humans,” said J.P. Gerdt, a research fellow in the lab of Jon Clardy at Harvard Medical School and co-first author of the study. “When LPC drops, the parasites can’t multiply anymore and commit to a different pathway.”

“This is a first big step in dissecting the details of what’s going on,” added Gerdt.

The purpose of the research was to illuminate the biochemical motivators in Plasmodium’s decision making. Although important, the findings won’t immediately translate into new therapies, cautioned Clardy, the Hsien Wu and Daisy Yen Wu Professor of Biological Chemistry and Molecular Pharmacology at HMS and co-corresponding author of the study.

Even so, Clardy said, by pinpointing a previously unknown control switch, the work suggests new ways to try to prevent Plasmodium parasites from re-entering mosquitoes and infecting more people—a major goal of global malaria eradication programs.

“Treating patients with antimalarial drugs usually kills the replicating parasites, but if you don’t also block transmission, the disease will never disappear from the population,” said co-corresponding author Matthias Marti, adjunct professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health and professor at the Wellcome Centre for Molecular Parasitology at the University of Glasgow.

Zeroing in

Plasmodium parasites lead complex lives.

They pass into humans through the bite of an infected Anopheles mosquito, congregating first in the liver and later in red blood cells, where they multiply and burst forth in cycles that cause waves of illness.

Eventually, if the host is lucky enough to survive, some of the parasites stop multiplying and follow a different path known as sexual commitment or differentiation. In what Gerdt likens to a parasitic puberty, they morph from asexual into sexual creatures.

If mosquitoes bite an infected person during this phase, the parasites—now male and female—travel back into the insects and breed. The transmission cycle begins anew.

“Almost everything we try to do to treat malaria is at the blood stage, because that’s when you know people have it,” said Clardy. “Researchers are putting more effort lately into studying the transmission stage in light of campaigns to eliminate malaria.”

Even though sexual commitment is a linchpin in malaria dynamics, scientists didn’t know much about what prompts it. Three years ago, Marti, then an associate professor at the Harvard Chan School, and study co-first author Nicolas Brancucci, then a postdoctoral fellow in Marti’s lab, set out to discover whether any substances in human hosts—rather than in the parasites themselves—played a role.

To find out, they combined their expertise in parasitology with the Clardy lab’s specialty in tracing the source of molecular signals.

Something in the blood

When the researchers cultured Plasmodium cells in flasks without their usual bath of human blood serum, the parasites skipped replication and went straight for sexual commitment—hinting that a control switch lurked in the missing blood.

Next, the researchers grew Plasmodium with serum. As expected, after a while the parasites lost their zest for replicating and began to undergo sexual commitment. But when the team added fresh serum, the parasites went on replicating. They were indeed grabbing something from the serum.

The researchers decided to separate and study all the serum components to see if they could identify the molecule or molecules at play.

“Serum is so complex; no one would do a test like that,” Marti recalled. “But it actually worked. We found a single factor that’s necessary and sufficient for regulating sexual commitment.”

With each round of parasite replication, the researchers observed that LPC levels dropped. When LPC fell low enough, the parasites switched to sexual commitment.

Fluorescent microscopy revealed that Plasmodium cells were absorbing LPC from the bloodstream as they prepared to divide.

“The parasites suck it up,” said Gerdt.

The scientists believe that when the parasites sense that their raw materials are running low, they change strategies.

The researchers found similar patterns of LPC depletion in a mouse model of malaria. Their findings were further reinforced by blood serum data from previously published studies that showed LPC depletion is a hallmark of acute malaria infection in humans.

Testing the waters

The study is the first to identify a factor in human hosts that Plasmodium uses as an environmental sensor.

“This was surprising at first, but once you know about it, it makes sense,” said Marti. “Plasmodium is a blood parasite, after all, and it travels through many different environments during its life cycle. It samples those environments, and in this case, it responds to reduced LPC levels in the blood during acute malaria infection by deciding to move into the mosquito.”

Moving from the study findings to a malaria therapy won’t be straightforward, said Clardy. For instance, doctors can’t simply deplete LPC to prevent the parasites from replicating, because LPC plays important roles in the body, including forming healthy cell membranes.

Nonetheless, now that they know “at least the first step and a few downstream steps” of how the parasite regulates transmission, Marti said he envisions new combination strategies that would safely block transmission while also treating the people who already have malaria.

Brancucci is now at the Swiss Tropical and Public Health Institute in Basel.

Twenty-four additional study authors were based at the institutions listed above as well as the University of South Florida in Tampa; the University of Granada in Spain; the Lodz University of Technology in Poland; and the Swiss Tropical and Public Health Institute, an associated institute of the University of Basel.

This work was funded by the Wellcome Trust (Senior Investigator Award 172862, IRS Award 172805, Center Award 104111 and a Burroughs Wellcome Fund career development award), the National Institutes of Health (grants GM086258 and R01RHL139337 and NRSA fellowship F32GM116205) and the Swiss National Science Foundation (grants 31003A_163258 and BSCGI0_157729 and fellowships P300PA_160975 and P2BEP3_165396).

Malaria parasites must absorb a fatty molecule, shown in green, from the blood in order to replicate in human hosts. Video: Mariana De Niz/Nicolas Brancucci

Fatty molecule in human blood controls malaria parasites’ decision to leap to mosquitoes