Why does SARS-CoV-2 shapeshift wildly from one person to the next, causing barely a sniffle in some but raging, lethal infections in others? Why do people diagnosed with the same cancer and receiving identical treatments have vastly different outcomes?
- By EKATERINA PESHEVA
Untangling the precise factors that underlie such medical mysteries can illuminate individualized treatments based on a person's genetic predispositions, immune profile, health history, and lifestyle. Such insights can propel forward the science and practice of precision medicine and have a profound effect on human health.
Now, in a decisive step forward on this quest, Harvard Medical School in Boston and Clalit Research Institute in Tel Aviv are launching a joint precision medicine effort, enabled by a donation from the Berkowitz family.
The gift-the amount of which remains undisclosed at the donors' request-will establish The Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.
The program will have two arms: The Ivan and Francesca Berkowitz Family Living Laboratory at HMS and The Ivan and Francesca Berkowitz Family Precision Medicine Clinic at Clalit. The two arms will work together to conduct joint research. The Clalit arm also will feature a clinical component that, in addition to research, will provide diagnosis and care for patients with rare, undiagnosed, and hard-to-treat conditions.
The research arm of the initiative will focus on generating insights from data and translating them into frontline clinical interventions. Under its educational arm, it will train the next generation of biomedical informaticians and computational biologists. The work will be led jointly by Isaac Kohane, chair of the Department of Biomedical Informatics in the Blavatnik Institute at HMS, and Ran Balicer, founding director of the Clalit Research Institute and chief innovation officer of Clalit Health Services.
"This work, powered by the passion and vision of the Berkowitz family, is an example of cross-pollination across countries, across institutions, and across disciplines," said George Q. Daley, dean of Harvard Medical School. "The scientific and educational paths forged by this collaboration and the medical insights enabled by these efforts will ripple beyond borders and across generations."
"A synergy exists between the aspiration for innovative insights and the desire to improve clinical care," said Eli Cohen, Acting CEO of Clalit Health Services. "The new initiative driven by the foresight of the Berkowitz family will achieve both aims in full alignment with Clalit's strategy to allow every patient personalized effective care, while achieving a profound effect on science and clinical care globally."
"It is our hope that through this effort, we can harness the strength of both Harvard Medical School and Clalit in a way that will allow this collaboration to produce enormous benefits to both health and medical care globally," said Ivan Berkowitz. "We are very happy to be one leg of this three-legged stool-the technology and medicine, the health care system and, ultimately, the philanthropy, which makes it all happen."
Greater than the sum of its parts
The collaboration will bring together-and amplify-each institution's traditional strengths.
Harvard Medical School's Department of Biomedical Informatics is a powerhouse in the fields of data science, machine learning, and computational biomedicine. Part of Israel's largest health insurance and medical provider, Clalit Research Institute is a global leader in translational science and innovation, applying Clalit's decades-long unique data repositories and Israel's top data-science talent to redesign and transform clinical care for the benefit of Clalit's 4.7 million members.
"The ideal of precision medicine is not new. Providing the right care to the right patient at the right time has tantalized and bedeviled physicians for many decades, perhaps centuries," said Kohane.
"This ideal is now being brought closer to reality through visionary philanthropy that will fuel research and education at our two institutions and magnify each of their strengths."
For example, researchers will be able to look for anything from telltale patterns in how individuals with the same disease respond to certain treatments and pinpoint subtle shifts in particular biomarkers that may indicate a patient's risk for disease relapse.
Under the agreement, Clalit will set up Israel's first precision medicine clinic dedicated to identifying tailored therapies for patients in whom no standard treatment has proven effective. The clinic will also work to untangle medical mysteries in patients with undiagnosed diseases-an approach modeled after the U.S. Undiagnosed Diseases Network, for which Harvard Medical School is a national coordinating center led by Kohane.
While the most immediate impact of the clinic's work will be for patients in Israel, the long-range goal is to yield insights and fuel therapies that ripple beyond borders and benefit people across the globe.
"We are aiming to enable profound health care improvements through groundbreaking medical research and discoveries, combining the world-leading clinical, data, and scientific experts at Clalit and at HMS through the Ivan and Francesca Berkowitz Family Living Laboratory," said Balicer. "We also look forward to saving lives at the Ivan and Francesca Berkowitz Family Precision Medicine Clinic."
Precision medicine has been described as care that takes into account individual variability to inform the most individualized treatment for each patient. As early as the 19th century, Sir William Osler, one of the founding fathers of modern medicine, cautioned his acolytes that the good physician treats the disease, while the great physician treats the patient with the disease.
New insights into human biology, genetics, genomics, big-data science, clinical medicine, and computation have given Osler's words a new meaning and brought precision medicine ever closer to reality.
For example, scientific advances in the past 20 years have transformed the treatment of several types of cancers and led to the design of targeted therapies based on individualized genomic profiles for lung cancer, breast cancer, and melanoma.
These successes in cancer therapy offer a potent illustration of the promise of precision medicine, but other conditions are also ripe for similar study and targeted approaches-metabolic disorders such as type 2 diabetes, various forms of cardiovascular disease, and immune diseases, including autoimmune conditions such as rheumatoid arthritis and type 1 diabetes.
The promise of precision medicine goes beyond the ability to forecast how a patient would respond to a given treatment based on their genomic profile and choosing the best targeted medication for that patient. Done right, precision medicine could enable tailored predictions of disease well into the future, long before it manifests clinically.
"The many synergies of this collaboration will allow us to realize the vision of precision medicine and move towards a future of predictive medicine, where the power to anticipate medical risk can prevent people from getting sick in the first place," said Ben Reis, affiliate faculty member in the Department of Biomedical Informatics at Harvard Medical School and director of the Predictive Medicine Group at the Boston Children's Hospital Computational Health Informatics Program. "The Berkowitzs' generous gift creates profound opportunities both for Harvard and our partners at Clalit. We look forward to realizing the enormous potential of this transformational opportunity for the benefit of patients worldwide."
Lab to clinic and beyond
Researchers at Clalit's Precision Medicine Research Clinic will work side by side with scientists at the Living Laboratory in the Department of Biomedical Informatics at Harvard Medical School. Real-life data from millions of patients accumulated over decades, when analyzed in aggregate, can provide invaluable insights about the real-time behavior of a disease, but it could yield deeper answers as well.
"Such insights can beget further ones by compelling researchers to ask questions about the origins of disease-the fundamental mechanisms that give rise to dysfunction," said Shay Ben-Shachar, director of precision medicine and genomics at Clalit Research Institute. "This is the true long-term value of this effort."
The teams' initial focus will be on two distinct groups of patients-those who respond exceptionally well to treatment and those who respond remarkably poorly.
Exceptional responders are individuals who respond to therapies in unexpected and dramatically positive ways. This category also includes people at very high risk for disease but with surprisingly good outcomes. In an effort to understand why these people have such outstanding results, researchers will focus on untangling the array of factors that drive this unusual response. Initial areas of clinical focus include chronic conditions such as cardiovascular illness, chronic obstructive pulmonary disease, and diabetes, as well as emerging infectious diseases such as COVID-19. For example, scientists might probe the biologic and lifestyle factors that may allow some elderly, lifelong smokers to remain relatively healthy without developing lung cancer or other forms of lung disease. Insights could inform novel therapies and preventive approaches for others.
At the other end of the spectrum, exceptional nonresponders are patients in whom standard therapies fail. Researchers will gather and analyze data from patients with autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis, for example, for whom standard treatments do not work. Understanding which underlying factors may prevent or interfere with response to treatment could inform ways to overcome these hurdles and design new treatments or tweak and optimize existing ones. Another subgroup of patients will be those with complex and mystifying conditions, for whom no clear diagnosis or treatment plan exists.
Using a systems approach, clinicians and researchers at Clalit will work with scientists and medical investigators at HMS to unravel these medical mysteries by using computational methods to analyze patients' genomic, protein, microbiome, and metabolic profiles in an effort to illuminate complex interactions between and across these variables that may lead to disease development or resistance to treatment.
The COVID-19 pandemic has led to an accumulation of clinical data that may reveal interesting patterns about who gets infected and who goes on to develop minimal or severe disease, or why certain people experience long-haul COVID-19 symptoms that can linger for months. Using patient samples from survivors and analyzing their genomic, immune, metabolomic, and microbiome profiles, the researchers will try to glean valuable lessons from these unusual responders to identify protective factors at play.
The idea that gleaning insights from a single patient or a handful of patients could be amplified and propagated to help countless others captivated the imagination of Adam Berkowitz, son of Ivan and Francesca, and the youngest of three children.
"This is an opportunity to extract knowledge from very specific cases and generalize these insights to help people in Israel and around the world, and all we need is one of those insights to power a general extract," Adam said. "That's the beauty and the true power of data. The fact that with a single insight you could potentially help millions."
"With a little bit of money and the right scientists and the best data-or just about the best data out there-we are creating a petri dish from which many, many insights can be extracted for many years to benefit everybody," he added.
The vision and excitement are echoed by Adam's siblings, Elizabeth Lewinsohn and Eric Berkowitz, who is the oldest of the three.
"The rewards of this innovative collaboration for global health care could be immense," Elizabeth said.
"Through data-driven insights, this historic collaboration will lead to new knowledge, novel treatments and cures and, ultimately, to a better quality of life," Eric said.
Training the next generation of precision medicine physician-scientists
A cadre of postdoctoral trainees from Israel will be selected as Berkowitz Postdoctoral Fellows to conduct part of their research at HMS and part of it at Clalit, forging stronger training and research ties between the two institutions.
A group of clinical researchers from Israel, chosen through a nationwide search, will attend a summer bootcamp in biomedical informatics at HMS. During this three-month program, these Berkowitz Scholars will study the latest precision medicine approaches, with a focus on designing and leading their own clinical research projects upon returning to Israel.
Likewise, a group of faculty members from HMS serving as mentors in the postdoctoral program will work directly with Clalit researchers with the option of serving in residence at Clalit. Clalit scholars will have the opportunity to spend time at HMS as visiting scholars.
