The rockefeller university

Richard P. Lifton (Credit: Scutt Rudd)

If you’ve ever received a blood transfusion or watched someone’s life be saved by one; if you or someone you know has been cured of hepatitis C; if you’ve ever questioned why your body keeps you awake late into the night or pulls you out of bed at dawn—then you know The Rockefeller University, whether you realize it or not.

Founded in 1901 as the first biomedical institution in the United States, Rockefeller didn’t officially become a university until 1965. By that time, it had already generated more than half a century of major breakthroughs, including crucial early advances like discovery of the ABO blood groups that enabled safe blood transfusions; the first antibiotic to be put into clinical use: gramicidin, a topical antibiotic highly useful in treatment of wounds; and diagnostic tools that tamed once-rampant, life-threatening infections like scarlet fever. More recently, Rockefeller scientists have contributed countless insights into human health and disease, including discovering how the hepatitis C virus replicates, which led to assays that resulted in development of drugs that cure this chronic disease; the biochemical mechanisms that synchronize our sleep-wake cycle and metabolism to the times of sunrise and sunset; the discovery of GLP-1 and leptin and their roles in regulation of blood glucose and body weight; and the discovery of antibodies that can control HIV infection. Together, scientists who’ve worked and trained at Rockefeller have forever altered the trajectory of the biomedical sciences. In all, 26 Nobel Prize winners have been Rockefeller scientists.

Richard P. Lifton has served as the university’s president since 2016. As Rockefeller celebrates its 125^th anniversary, we sat down with President Lifton to discuss Rockefeller’s long history of innovation, why modern medicine would be unthinkable without basic science, and how the next wave of discoveries will shape the future.

When Rockefeller was founded, the average life expectancy in the US was under 50 years. This was a time before antibiotics could cure infections, before we understood that DNA carried our genetic inheritance—before scientists even had a functional map of the cell. How did the founding vision for Rockefeller emerge within that context?

The fact that lifespans were so much shorter was largely a consequence of how little we understood illness and disease—we could describe some of them, but we had virtually no knowledge of what the causes were. Without that knowledge, the history of medicine up to that point had been fraught with failure to meaningfully treat, prevent, diagnose, or cure diseases.

John D. Rockefeller was appalled that while we could describe the distinct clinical features of many diseases, we knew little about the fundamental causes of them, and therefore we were almost helpless in our ability to prevent or treat diseases. His goal in creating what was then called the Rockefeller Research Institute was to understand the fundamental causes of disease, with the expectation that this would be the surest route to developing ways to prevent or treat them. This invariably led to research that has given us increasingly detailed understanding of the fundamental processes involved in sustaining or restoring health. The power and uniqueness of this mission made the institute a magnet for the most visionary scientists. Our mission and our focus on recruiting bold thinkers in the life sciences has remained our north star for 125 years.

Part of the beauty of this deep investment in basic science is how often what we learn and the technologies we develop have been translated into revolutionary advancements in human health.

Can you give us an example?

CRISPR is a beautiful example of how curiosity-driven science has fueled an ongoing revolution in the treatment of disease. Twenty years ago, microbiologist Luciano Marraffini, now at Rockefeller, was drawn to the study of what appeared to be a bacterial program for preventing infection by viruses. A number of bacterial “immune systems” had been previously described, and these had all worked by acting on pathogen RNA molecules. Luciano’s study of this newly recognized system, called CRISPR-Cas9, revealed that it acted by using a stored memory of short viral DNA sequences to recognize specific viral DNA of invading viruses and cutting the DNA sequence, aborting viral infection. He recognized the uniqueness of this defense system and proposed that it could be inserted into cells of other organisms and used as a universal tool for performing genome editing.

Gene editing using CRISPR-CAS has revolutionized not just day-to-day operations in countless laboratories, but is also used for gene editing in a growing number of previously incurable human diseases such as sickle cell anemia.

Similarly, Svetlana Mojsov’s search for a long-sought hormone released from the intestines to stimulate insulin secretion in response to food intake led to her discovery of GLP-1. GLP-1 proved not just to be a stimulator of insulin secretion, but at high doses causes dramatic weight loss, a discovery that has fueled a therapeutic revolution, with 12% of the US adult population taking these drugs today.

Mojsov was looking for a better way to treat diabetes when she conducted her groundbreaking experiments that led to weight-loss drugs like Ozempic. As with CRISPR, her focus on understanding how a process works—in her case, a gut hormone that regulates blood sugar—resulted in applications that no one predicted. What are we now learning about human disease from GLP-1 medications?

We’ve long known about the association of obesity with cardiovascular disease and kidney failure as well as cancers, including those of the breast, ovary, liver, and colon, but we have not had strong evidence that reducing obesity would reduce these risks. Now that we have potent weight loss drugs, randomized trials have shown that GLP-1s indeed reduce risk of cardiovascular disease and progression of kidney failure as well as risk of many obesity-related cancers.

Of course, this is just one remarkable example of the impact of our science. What does Rockefeller do differently from other institutions which contributes to overall success?

Rockefeller has a deep focus found in our credo: Science for the benefit of humanity. This singular mission gives us great clarity of purpose. There is no ambiguity in why we are here. By design, we are small in size, with only about 70 laboratories, each with a head of lab recruited with a unique vision of how to approach a critical problem in life sciences. Great scientists are often restrained by limited resources, so rather than spread resources thinly across a very large number of scientists, we make major ongoing investments in our laboratories to maximize the impact they can have. In addition, they are immersed in vibrant scientific community and have time to develop distinctive visions.

A good example of this is Rod McKinnon’s work on ion channels, which allow specific ions to selectively traverse the plasma membrane of cells. It was commonly believed that determining an atomic level structure of an ion channel would be virtually impossible and foolhardy to attempt, but Rod was deeply committed to pursuing this goal. This was a perfect fit for Rockefeller. Rod’s success transformed the field and laid the foundation for understanding how channel selectivity is achieved, leading to drugs that alter channel activity for clinical benefit. Twenty years later, the biotech company Vertex extended the paradigm by taking on a similarly audacious effort to develop drugs that would correct the misfolding and chloride transport defect of CFTR, the membrane protein whose dysfunction causes cystic fibrosis. The unexpected success of this effort has transformed the lives of people with cystic fibrosis who are treated early, from having a tragic lifelong disease resulting in premature death to one that is manageable with likely normal lifespan.

Is the advent of therapies like that the reason there’s been much talk recently about a new “golden age of medicine”?

There is no doubt that we are in an explosive era of new ability to prevent, diagnose, treat and cure disease. This owes directly to the investments in fundamental life science research that have been consistently made since World War II. The dramatic leaps we are seeing now in medicine derive directly from the foundation of knowledge about life processes built by prior generations.

For example, the discovery made in 1943 at the Rockefeller Hospital that DNA is the chemical of heredity is undoubtedly among the most important discoveries in the history of biomedical science. We have since learned how DNA sequence is faithfully replicated and transmitted in cell replication and is passed from generation to generation, and that all cells use the same genetic code to direct the synthesis of the all the proteins made in a human body. And we know the specific biochemical functions of a large fraction of these proteins. We also know the consequences of mutations that alter the functions of many of these genes and how these contribute to thousands of human diseases. This foundational knowledge provides insight into how we might prevent or alter the course of these diseases.

These advances have ushered in a therapeutic revolution. We now have deep understanding of the causes of the major causes of death in humans—cardiovascular disease, cancer, respiratory disease, neurodegeneration and infectious disease—as well as the causes of thousands of individually rare or uncommon diseases. These discoveries have spawned diverse and remarkable therapeutic approaches.

Until the last 15 years, drugs were almost entirely limited to either small molecules or monoclonal antibodies. Since then, a remarkable range of additions to the therapeutic armamentarium have been developed or are currently in development. CRISPR-Cas and base-editing methods have already been mentioned. Novel engineering of antibodies by Jeff Ravetch that modify antibody Fc segments can direct antibodies to receptors on particular immune cells that, for example, can inhibit immune function, providing efficacy in autoimmunity and other diseases. Michel Nussenzweig has developed robust methods to purify, clone and express the genes encoding broadly neutralizing antibodies from donor plasma and has used to control viral infections including HIV, hepatitis B and hepatitis D. Tom Tuschl showed that short interfering RNA machinery discovered in round worms that can target and degrade specific RNA molecules can be transferred to human cells, paving the way for its use in a variety of human diseases. Bispecific antibodies that can bind to two protein targets on different cell types have been developed to augment cancer immunotherapy and to effectively treat hemophilia. Newly developed RNA vaccines not only attenuated the Sars-CoV-2 pandemic and saved millions of lives, but also are being used in clinical trials to direct the immune system to attack cancer cells harboring mutated protein sequences on their cell surface. Chimeric Antigen Receptor T cells (CAR-Ts) are a novel cellular therapy in which, for example, a cancer patient’s T cells are engineered to have an antibody combining site fused to a T-cell receptor, with antibody binding activating its attached T cells to attack the cell bound by the antibody. These “living drugs” can be very effective in difficult-to-treat cancers.

Additionally, the development of robust methods for rapidly and inexpensively sequencing the RNAs expressed in single cells from any organ or tissue, as developed and deployed by Jun Cao and Nat Heintz has provided new ability to follow the levels of individual cell types over the lifespan and describe characteristic features of the aging process. It has also been used to show how and why mutations that cause Huntington’s Disease are further mutated in specific cell types in the brain that cause disease progression.

Advances in our understanding of the brain are just as groundbreaking. How memories are formed, stored and retrieved has been a deep mystery. Priya Rajasethupathy has identified specific cell surface receptors in the thalamus involved in this process, and has shown how memories are encoded for transient, short term or long-term persistence, as well as how single memories are divided into components that are stored separately in the cerebral cortex, and follow a different path in retrieval than in formation. These studies have obvious implications for Alzheimer’s Disease and other dementias. Alipasha Vaziri has developed methods for following the activity of millions of neurons in the brain in real time as behaviors are executed, with the patterns of neural activity accurately predicting subsequent behavior. Vanessa Ruta has deduced how millions of odors are decoded by the brain and how they activate specific olfactory receptors. Gaby Maimon has shown how the brain keeps a running tally, calculating the distance and direction traveled from an origin. Winrich Freiwald has identified specific neurons that uniquely respond to faces and that project to higher brain centers that are activated by the perception of social interactions.

Lastly, small molecule drug development has been hampered by the challenges of wet-lab screening and the complexities of chemical synthesis of promising compounds JK Lyu has developed robust methods for virtual screening of billions of small molecules of known structure for their ability to bind to protein targets in virtual screening. Screening molecules are then selected for their ability to be easily synthesized and used in wet-lab screens. This method increases by multiple orders of magnitude the chemical diversity that can be screened and tested in biological assays. Virtual screening has the potential to dramatically accelerate screening of small molecules on important protein targets.

I, of course, could go on, but it is apparent that basic science is not only illuminating disease mechanisms, but that these insights are also increasingly rapidly yielding useful new therapies.

Speaking of therapies: vaccines remain one of the clearest triumphs of science in service of public health. But there are still no vaccines against numerous infectious diseases—many of which are not just life-threatening, but also can leave survivors with lasting, life-altering conditions. Meanwhile, antibiotic resistance continues to rise, imperiling some of our most trusted treatments and contributing to millions of deaths annually. What gives you cause for optimism in the face of these realities?

As we learned in the SARS-CoV-2 pandemic, viruses, bacteria and other pathogens are constantly evolving, with new or newly resistant agents emerging, along with long-known infections without effective therapies. From our founding, Rockefeller has played a critical role in the identification of infectious agents and the development of effective therapies and vaccines. A recent example was Charlie Rice’s work leading to effective treatment for Hepatitis C, for which he received the Nobel Prize in 2020.

Rockefeller scientists played important roles in the SARS-CoV-2 pandemic, characterizing the immune response to the virus, developing assays for neutralizing antibodies that enabled initial therapeutic use of plasma from people who recovered from infection and subsequent development of cloned highly potent anti-SARS-CoV-2 human antibodies.

Bacterial antibiotic resistance, meanwhile, is a continuing problem, requiring consistent development of new antibiotics. Sean Brady’s “drugs from dirt” project is sequencing DNA from soil samples collected from around the world and identifying novel biosynthetic clusters from which his lab has decoded the sequences and structures of novel antibiotics for both gram-positive and gram-negative bacteria.

Tuberculosis is the most common cause of death from infectious disease world-wide, with resistance to therapeutics a major challenge. Elizabeth Campbell has discovered the biochemical basis of resistance to inhibitors of RNA polymerase and potential means to overcome resistance. Jeremy Rock has developed a novel approach to identify the gene products in the Mtb genome that are most vulnerable to inhibition, providing a roadmap to the development of new drugs to treat this global pathogen.

Research in infectious disease at Rockefeller is generously supported by the Stavros-Niarchos Institute for Global Infectious Disease Research.

Of course, the human immune system isn’t just a primary source of protection from infection, but also plays a critical role in immunosurveillance, eradicating a wide variety of precancerous lesions or early cancers before they become clinically apparent. Rockefeller scientists are partners with Columbia and Yale in the ambitious CZ Biohub New York to be able to read out what the immune system is responding to as a means of identifying incipient disease before it becomes a clinical problem.

While much progress has been made in the diagnosis and treatment of cancer, this remains a major cause of death and disability world-wide. What are the most pressing questions in the field?

In the last 15 years, we have dissected the biology of the development of cancer, and we now understand that the development of cancer is caused by mutations in specific genes that lead to uncontrolled proliferation of particular cell types. Drugs that inhibit the activity of some of these mutated genes are useful in many cancers; however in many cases they do not cure or produce long-term remissions of these cancers. Importantly, primary cancers often are not the cause of deaths from cancer; rather, it’s resistance to treatment and metastatic spread to other tissues and organs that cause the most cancer deaths.

Interestingly, despite substantial exploration, scientists have not found that metastatic cancers have new cancer-driving mutations. Rather, they have often rewired cellular metabolism to develop resistance to immunotherapy or to other targeted therapeutics. We’re just beginning to understand what enables them to adapt to harsh, nutrient-poor environments to which they metastasize. For example, Kivanç Birsoy recently showed that in early colonization of metastatic breast cancer, mitochondrial glutathione levels are markedly elevated, reflecting the increased metabolic demand in establishment of metastatic cancers.  There is tremendous potential here for changing how we think about and design more effective therapies. Efforts in understanding altered metabolism in cancer is being pursued by the Weill Cancer Biohub East, a collaboration among Rockefeller, Weill Cornell Medicine, Princeton and the Weill Family Foundation.

How will artificial intelligence affect biomedical research?

Dramatic advances in technology have created sudden leaps in understanding of life sciences. Discovery of DNA and how it provides the blueprint for development and the production of every protein in the body; the development of recombinant DNA, monoclonal antibodies, CRISPR and other RNA-based reagents, immunotherapy, and cryogenic electron microscopy are among the discoveries that have changed this history of biomedicine.

Artificial Intelligence/machine learning is the latest of these disruptive technologies. It announced its application to biology by solving the near-atomic level structure of every protein of known sequence in the biosphere. As discussed above, it is being used to streamline discovery of small molecules that can selectively bind to protein targets. It has countless applications ranging from describing behavior of millions of individual neurons in the brain to predicting which proteins physically interact with one another. It’s particularly adept at identifying unexpected correlations among disparate data types in large complex data sets. The applications will be myriad.

Lastly, what qualities—of mind, of character, of spirit—do you think define a Rockefeller scientist?

We are creative and bold intellects, eager to ask big questions that may seem impossible to answer. We are an eclectic collection of scientists working in diverse fields who are genuine fans of science and are constantly amazed by the science being done by our colleagues. We enjoy immense freedom to stretch our work into new areas without departmental or disciplinary boundaries or competition from colleagues working on the identical problem. Our environment invites discovery of collaborative opportunities. Our remarkable track record of discovery has catalyzed exceptional philanthropy from our benefactors that has allowed us to take risks on important problems. We realize the special opportunity and responsibility afforded by doing research at Rockefeller. The productivity of our laboratories—evidenced by recognition and objective measures of impact—justifies our distinct approach to science.

The people who have worked here throughout the last 125 years constitute a continuing source of inspiration matched by the current inhabitants of our laboratories who are creating the legacy for next generation. It will be fascinating to see the directions taken and discoveries made in the coming years.