The future of medicine can't come fast enough.
- By JAKE MILLER
Over the past 20 years, revolutionary developments in the fields of genomics, molecular biology, and computational biology have ushered in a new age of biomedical discovery and expanded our knowledge about how human health and disease function at the molecular, genetic, and cellular levels. Yet, relative to the sheer magnitude and dizzying pace of these discoveries, few of those insights have become treatments that directly improve human health.
As Harvard Medical School researchers continue to contribute to this rapid acceleration in the fundamental life sciences, the school is developing a complementary suite of programs designed to speed the transition from basic insights in the lab to lifesaving therapies on the clinical frontlines.
"Millions of people worldwide suffer from major illnesses for which we have no effective therapies," said George Q. Daley, dean of Harvard Medical School. "As we continue to push the frontiers of fundamental discovery, we also need to nurture ideas with therapeutic potential to speed their passage from the laboratory to the clinic."
Vast unmet need
To meet the basic medical needs of billions around the world, we need better, cheaper medicine, and we need it fast, Daley said. The need is driven by aging populations in many industrialized countries and demographic changes in low- and middle-income countries, and by global forces like climate change and other social and environmental crises. It is fueled by increasing insight into the burden of disease in such underserved areas as mental health, noncommunicable disease, surgical disease, and by the international community's growing emphasis on global health equity and a new vision of health as a human right.
The U.S. Food and Drug Administration approved 53 new drugs and other treatments in 2020, the second highest number ever, falling just short of 2018's all-time high of 59, and tying with the 1996 total.
"While the world needs a flood of new treatment options, the current rate of progress seems like a trickle, especially compared to the steady flow of insights generated in laboratories across the world," Daley said. "No single institution-let alone a single lab or a solitary researcher-has all the knowledge and resources needed to tackle the complex problems that puzzle modern medicine. To solve them, we need new ways of thinking and working together."
Some of the most vexing treatment gaps are well-known. Tuberculosis, one of the oldest known human diseases, still kills millions of people every year, and available treatment options can have devastating side effects that some patients find worse than the disease. Alzheimer's disease, cancer, cardiovascular illness, diabetes, depression, kidney disease, schizophrenia, sickle cell disease, and a host of other diseases all need better treatments and cures.
And then there are the deadly newcomers, including COVID-19.
When a new strain of respiratory virus was identified as a causal agent for a cluster of pneumonia cases in Wuhan, China, in January 2020, the entire genome of the virus was published online within days. Since the initial outbreak less than two years ago, nearly a half million papers have been published about the virus and the disease it causes, with remarkable insights into the epidemiology, genetics, and chemistry of SARS-CoV-2 and into how the pathogen interacts with its host.
The discovery and production of the first vaccines against the virus took place in record time, with multiple different vaccines being distributed to the public less than a year after the virus was identified. When vaccinations began in December 2020, there were hopeful predictions that the worst of the pandemic would soon be behind us. But nearly a year later, the death toll continues to rise, hospitals around the U.S. and around the world continue to be overwhelmed with seriously and critically ill patients, and billions of people worldwide have yet to receive a shot.
So, despite the swift advent of COVID-19 vaccines, the trajectory of the novel coronavirus and the devastation it has wrought are a stark example of the gaping divide between the pace of scientific discovery and the production of useful therapies needed to treat the disease once exposure or infection occurs.
So far, novel therapies for the disease are scarce on the ground. Only a handful of drugs or biologics have been approved or authorized for emergency use by the FDA or its peers worldwide. These include monoclonal antibodies, which are most effective during the first few days of infection, expensive, and difficult to administer, requiring IV infusion.
Patience and persistence
"To find a new drug, the most important first step is identifying which new insights about basic biology are most likely to yield useful interventions in a disease," said Mark Namchuk, executive director of therapeutics translation and professor of the practice in the Department of Biological Chemistry and Molecular Pharmacology at HMS.
Namchuk, a former pharmaceutical executive with a background in immunology and bio-organic chemistry, joined HMS in January 2020, two months before the COVID pandemic was declared. Namchuk oversees the School's therapeutics initiative, dedicated to optimizing and enabling the current system of discovery to harness basic insights and apply them to clinical therapies.
This process requires specialized scientific skills and a great deal of patience and persistence, Namchuk said. The challenges become increasingly complex as the potential medicine moves from an idea or a simple experiment in a lab dish through testing in animal models and, eventually, to human patients in clinic, he said. Namchuk noted that once an idea has been identified as having potential clinical benefit, keeping the goal of creating a useful medicine in mind at the early stages of exploration can help investigators more quickly zero in on which of these new ideas are truly feasible drug candidates.
It's not enough to find a compound that can bind to a target, he said. You have to know whether it binds often enough and in the right places to have a medicinal effect, and if that effect is consistent from person to person. You have to know if it binds to other sites or other targets in ways that may potentially cause harm to the patient. You have to know if the dosage you're using to get good results in a dish in the laboratory would be fatal to a human.
"The difficulty in making a broadly useful therapeutic is making sure that as you escalate into systems with more and more complexity, you can continue to see an effect that's useful," Namchuk said. "That's the work of taking the fundamental idea and walking it towards where it would be useful to heal people who are sick."
In the face of COVID-19, the challenges are especially daunting.
"To have a really useful COVID therapeutic, it has to be something we can ship worldwide, manufacture relatively cheaply, and potentially give prophylactically," Namchuk said. "If you're hoping to give it to people who aren't sick yet, it has to have a relatively benign side effect profile. Designing a medicine with that combination of elements is extraordinarily challenging."
Namchuk came to HMS after more than 20 years working on research and development programs spanning a number of therapeutic areas, including cancer, immune modulation, infectious diseases, multiple sclerosis, depression, schizophrenia, pain, and cystic fibrosis. He noted that HMS has great strengths in fundamental discovery, and a long history of transforming these discoveries into therapies. In addition, HMS has a wide network of clinical affiliates in Boston and worldwide collaborations aimed at improving the delivery of care wherever it is needed, as well as an educational enterprise that can help share new ways of thinking and educating people who will work in academic medicine, basic science, the pharmaceutical industry, and health systems around the world.
Science is the source
"If the science isn't right, then nothing else will work," Namchuk said.
Indeed, a 2018 study published in Science Translational Medicine by Mark Fishman, a professor in the Harvard Department of Stem Cell and Regenerative Biology, and colleagues from the Novartis Institutes for BioMedical Research found that eight out of 10 of the most innovative and powerful new medicines approved in the U.S. between 1985 and 2009 were the result of fundamental discoveries made without regard to practical outcome. In most cases, the relevance of the discoveries to the clinic did not become apparent until decades later.
The vast majority of the most transformational drugs of the last decades-including drugs to treat hypertension, leukemia, and HIV/AIDS-came from curiosity-driven fundamental science, and took an average of 30 years from discovery to the time a new drug was approved, the authors found.
This paper illustrates the imperative to do basic science, while underscoring the need to translate these insights into treatments faster, Namchuk said.
"The Harvard biomedical community produces some of the most exciting discoveries in the world, and we are deeply committed to curiosity-driven science," Daley said. "It's in the bones of this institution, and we will continue to invest most heavily in our faculty's efforts to unravel the mysteries of human biology."
"To make sure that we realize the clinical potential of those discoveries quickly and efficiently, we also want to make sure that we provide the infrastructure and resources needed to propel promising ideas into new medicines and therapies as quickly as possible," Daley said.
Smoothing the path
This has been a constant theme of Daley's own work as a physician-scientist and a common refrain since he became dean in 2017.
With the support of a historic gift from the Blavatnik Family Foundation, the School has invested deeply in basic research infrastructure while also establishing the critical infrastructure to support faculty efforts to advance the clinical potential of their most promising ideas.
Daley describes the growth of therapeutics at HMS as part of a process of continuous progress and evolution over the School's 239-year history. What began as the Department of Anatomy has become the Department of Cell Biology, and Materia Medica evolved into the Department of Biological Chemistry and Molecular Pharmacology.
In recent years the School has continued to embrace new ways of thinking.
The Department of Social Medicine is now the Department of Global Health and Social Medicine, and the School has added new centers and departments to reflect new academic disciplines working at the heart of curiosity-driven science, therapeutic development, and care delivery, including the Department of Systems Biology and Department of Biomedical Informatics. HMS has also invested in building shared research cores, including the Harvard Cryo-Electron Microscopy Center for Structural Biology, to allow the entire community to access specialized equipment that's critical for fundamental science and therapeutics development.
The increasing focus on the nexus between basic discovery and therapeutics development has been an important trend in academic medicine for decades. The 2003 NIH Roadmap for Medical Research called for efforts to speed the movement of research from the laboratory to the patient's bedside, which, among other developments, led to the creation of a network of centers of excellence to help close the gap between basic and clinical research, including Harvard Catalyst.
In October 2020, the therapeutics initiative set several new projects in motion, marking the start of a new era of therapeutics research at HMS. The aim is to support the efforts of researchers at every step in the process, from generating ideas to getting therapeutics to the clinic.
Overcoming hurdles
Before an idea becomes a medicine, it must pass a series of increasingly complex tests in order to make the grade, and a single failure can mean the end of the line.
First, researchers need to ask if they understand the biology of the disease of interest well enough to turn a new insight into a therapeutic that could prevent, treat, or cure it. Is the disease caused by a bacterial, viral, or fungal infection capable of circumventing the immune system, or is it a result of a weakness in the immune system that allows microbes to morph from harmless to life-threatening? If the disease is a product of aging, is it a hallmark of the cumulative, normal wear and tear on cells, or is there some environmental trigger that causes normal cellular processes to go awry? Why do some cancers spread to different tissues while others stay put? Why do some people with COVID-19 develop lingering symptoms while others feel better quickly? Why does the same infection cause some people to get sick and not others? In the most confounding cases, the answers to these basic questions describe an extraordinarily complex problem with no single solution.
"Despite many major advances in our understanding of biology and disease, we still have holes in our ability to take that fundamental understanding and figure out how to apply it to either reverse or stop a disease process," Namchuk said. "There are still many big things that we need to learn about biology. That remains one major challenge."
If a researcher has an idea that offers a clear target for interrupting a disease, they have to figure out how to hit the target. Researchers need to decide which tools they are going to use to do the job, and what kind of package they can send to deliver the tools to the site where the work needs to be done. It could be a gene therapy, a small molecule, or a lab-made antibody that mimics the body's immune response.
Each of these packages will have different advantages and disadvantages and will need to pass different tests in order to prove their effectiveness. It's important to understand how a drug will be used in patients to choose the type of therapeutic to pursue. Does the drug need to be given every day? Will someone be taking the drug for years or decades? The rhythm of how a therapy is administered must match how a disease will be treated. A drug to treat the common cold can't require a therapy that can be administered only in a hospital, and it can't have common side effects that are worse than the disease it's intended to treat.
In order not to waste time and resources in later stages of clinical trials, it's best to weed out unlikely candidates early on. That means that even in the early stages of experimentation on a potential drug candidate, it's best if researchers understand how that drug might be delivered to a patient, and how well it has to work to produce the desired clinical results, Namchuk said.
Roughly three in 100 projects started in the pharmaceutical industry end up as something that looks like a useful drug. But the good news is that there are ways to help improve those odds and to speed up the process, Namchuk said.
The therapeutics initiative offers several research programs to provide funding for ideas with potential therapeutic benefit at different stages of development. One entry point for professors who want to begin the process is Q-FASTR (Quadrangle Fund for Advancing and Seeding Translational Research), which provides seed money for ideas with potential for therapeutic benefit and encourages collaboration between researchers in the HMS Quadrangle's basic science departments and clinicians. The fund was established with an anonymous gift in 2014 and has now found an administrative home in the therapeutics initiative.
Several early recipients have already used Q-FASTR to propel their insights down the pipeline, launching new companies, licensing their technology to industry, or securing space at the incubator Lab1636, a collaboration between Harvard's Office of Technology Development and Deerfield, an investment management firm that works to advance health through investment, information, and philanthropy.
Other Q-FASTR recipients have received funding from the Blavatnik Therapeutics Challenge Awards (BTCA), another therapeutics initiative research program designed to support more-established projects that can be spun off as new companies or licensed to existing companies within two years.
In addition to providing direct financial and technology support for current projects, the initiative also has an educational component.
"Our goal is to train the next generation of leaders in therapeutics research in industry and academia, with a focus on experiential learning and on the science of how medicines are made," said Tim Mitchison, Hasib Sabbagh Professor of Systems Biology at HMS. Mitchison is also the director of the initiative's ideation hub, a home base for the education, training, and community-building components of the therapeutics initiative for postdocs, graduate students, and faculty.
The ideation hub houses the Therapeutics Graduate Program, a certificate program for graduate students in any of the Harvard Integrated Life Sciences (HILS) programs. The curriculum focuses on pharmacology, toxicology, and drug discovery, emphasizing research in both HMS labs and in real-world internships to provide students with practical skills necessary to be productive researchers in therapeutics discovery throughout the workforce.
Namchuk is assembling a team of staff scientists with decades of experience in therapeutics development who can support faculty research efforts with expertise that would usually be available only through outside consultants. In addition to providing specific services to faculty, Namchuk envisions the staff scientists sharing their knowledge and experience with faculty, postdocs, and students.
"By embedding this expertise in the community and making it available to all of our academic partners broadly, we will be able to identify the best opportunities a bit earlier and ask some of the critical questions about whether we can turn an idea into a therapeutic earlier," Namchuk said. "We also hope that all of the members of these teams will be learning from one another as they go."
The ideation hub has also begun to launch and support small working groups designed to tackle challenging problems in medical science by focusing on a single disease or area of technology. Two Disease and Technology Groups have already been established, Mitchison said. One is addressing COVID-19 and the other the unmet needs of Lyme disease. Mitchison noted that Therapeutics Innovation Fellows will play a key role in supporting these efforts.
Collaborative science is the key
The Massachusetts Consortium on Pathogen Readiness (MassCPR) was founded in the early days of the COVID-19 pandemic with a mission to create a rapid-response system to address both the current outbreak and future health crises. A multidisciplinary, multi-institution, multi-national collaborative hosted at HMS, MassCPR was inspired by massive science and engineering projects like the Apollo program, which landed humans on the moon in 1968.
"MassCPR had this vision of bringing together epidemiology, therapeutics, diagnostics, clinical medicine, and more to create these pillars of fighting a disease," Galit Alter, HMS professor of medicine at Massachusetts General Hospital and an investigator at the Ragon Institute of MGH, MIT and Harvard told HM News.
When MassCPR was formed, Alter became a founding leader of its pathogenesis working group.
Before COVID, Alter's lab focused on identifying how some patients' immune systems are able to ward off diseases while other patients' do not. She developed a tool to profile antibody responses and used it to study HIV/AIDS, Ebola, and malaria.
Alter has said she believes that disease research will be fundamentally changed by collaborative responses to COVID-19, such as MassCPR. "It's led to collaborations that never would have happened otherwise. It is crystal clear that the more we break down the barriers to collaboration, the faster science goes," Alter said.
Jonathan Abraham, HMS assistant professor of microbiology and an infectious disease specialist at Brigham and Women's Hospital, works at the interface of discovery and therapeutics. One of his projects, examining the evolution of the SARS-CoV-2 genetic sequence to predict the mutations most likely to occur in variants, and to anticipate what might be coming next from COVID-19, was recently funded with a Star-Friedman award for high-risk, high-reward research.
Abraham's ambition is to model how the virus is most likely to evolve so that he can predict what would be needed to counter its maneuvers and outsmart it in the future. "This would be part of a proactive strategy to understand the functional consequences of viral spike protein mutations so that we're better prepared for variants before they emerge," he said.
Abraham was founding co-leader of the therapeutics working group of MassCPR, but his work illustrates how closely the basic sciences of viral evolution and pathogenesis and the applied field of therapeutic discovery need to work together.
"The further we got into the pandemic, the clearer it became how crucial it was to have pathogenesis working hand in hand with therapeutics discovery," said Namchuk, who has also served as co-leader of the therapeutics working group of MassCPR.
Those two working groups have now merged and evolved into a new collaboration with AbbVie, an American biopharmaceutical company. In August 2020, AbbVie and Harvard University announced a $30 million collaborative research alliance, launching a multi-pronged effort at HMS to study and develop novel therapies against emergent viral infections, with a focus on those caused by coronaviruses and other respiratory pathogens.
The AbbVie collaboration will feature five major research areas and to date includes 17 investigators from seven different institutions working on a daily basis in collaboration with AbbVie scientists to try and find COVID therapies.
"This is a chance to meld some of the best of both worlds, where we've got top level academic scientists working with people that are professional drug discovery folks," Namchuk said, adding that the working model draws heavily on the lessons learned in MassCPR and other collaborations that emerged around COVID-19.
Virtuous cycles
These kinds of collaborations are a hallmark of many of the most successful projects underway at HMS, Daley has pointed out. And not just in the realms of basic science and therapeutics.
Throughout the pandemic, HMS community members on the Quad, across its affiliated hospitals and research institutions, and around the world in a broad network of collegial organizations have worked to respond to the challenges of COVID-19, providing clinical care as well as measuring clinical impacts, monitoring rehabilitation outcomes, setting up contact tracing efforts, and facilitating social support for infected people to help them isolate safely.
At the same time members of MassCPR were using new technology to understand the basic biology of COVID-19, other faculty members and trainees were using mathematical modeling and data science to build predictive models of disease outbreaks in rural clinics in low-resource settings around the world. They used these tools to monitor the presence of SARS-CoV-2 in their communities and to make sure that long-term patients were able to continue to receive care for HIV and TB and get regularly scheduled preventive care, all the while building a new kind of multicountry collaborative research model.
The ecosystem of discovery, education, and service at HMS extends from the molecular level to the global stage, from the historical to the futuristic, and from curiosity-driven science to the delivery of lifesaving care in some of the most challenging conditions. This includes playing leading roles in global efforts to make HIV drugs affordable and available, piloting new drug regimens for multidrug-resistant TB, collaborating with the WHO and dozens of ministries of health to build comprehensive health systems, and scaling up cost-effective treatment services for mental health issues around the United States and the world.
"When we bring all of these skills together, when we help our community members and our partners and colleagues around the world build collaborations, there's no end to what we can achieve," Daley said. "I've never been more proud to be a member of this community. I'm looking forward to even greater things as we continue forging this path of collaboration."
