Stuart H. Orkin

Stuart Orkin grew up in post-World War II New York City. His father was a urologist with a practice in Manhattan, and his mother helped part-time in the office. While in high school, Orkin took a chemistry class from an enthusiastic teacher who had recently graduated from the Massachusetts Institute of Technology (MIT). Inspired by that class, Orkin enrolled at MIT in 1963. “I thought I wanted to do some kind of physical science, like physics,” he recalls, “but I soon realized that although I was pretty good at physics, there were 600 students in the class who were equally good at it.”

During his second year at MIT, Orkin enrolled in an introductory biology class taught by Salvador Luria, who, within a few years, would earn a Nobel Prize for his discoveries on the genetic structure and replication of viruses. This was Orkin’s introduction to the then-nascent field of molecular biology, which, as Orkin notes, was “more of a cottage industry at that time at MIT.” Orkin was intrigued by the possibility of applying molecular genetics to medicine, however, and spent his remaining summers during his undergraduate years working in various biology laboratories in New York City.

After graduating from MIT, Orkin enrolled at Harvard Medical School. He wanted to continue to study molecular biology, but at that time, Harvard did not offer a joint MD-PhD degree program. “The rule at the time was: one Harvard degree was sufficient,” Orkin recalls. Instead, students who were scientifically inclined were encouraged to take a year off between the second and third year of medical school to gain research experience. Orkin joined the laboratory of John Littlefield at Massachusetts General Hospital, who was an early pioneer in somatic cell genetics. As Orkin was coming into his final year of medical school, he applied to—and was accepted into— a two-year postdoctoral program for physician-scientists in the US Public Health Service at the National Institutes of Health (NIH), which constitute an alternative to military service during the Vietnam War. So, after receiving his medical degree and completing a year of internship at Boston Children’s Hospital (a requirement of the government program), Orkin entered the lab of molecular biologist Philip Leder on the NIH campus in Bethesda, Maryland. “At the time, Phil was a relatively young scientist who was on the ground floor in the field of molecular biology,” says Orkin. “It was an exciting place to be.” Because of his experiences in Leder’s lab, Orkin decided to make understanding the molecular underpinnings of blood cell development his lifelong quest.

Orkin returned to Massachusetts to complete a one-year pediatrics residency at Boston Children’s Hospital, which was followed by a clinical fellowship in hematology and oncology in the combined Children’s Hospital-Dana Farber Cancer Institute program overseen by hematologist David Nathan. Early on in the fellowship, Nathan offered Orkin a faculty position and his own laboratory in the program—with the specific instructions to apply to the NIH and the March of Dimes for grants to support his research. Fortunately, the applications were funded and his laboratory became established. “David gave me a unique opportunity to become independent at a young age,” Orkin recalls. “In retrospect, that was kind of crazy.”

In 1978, Orkin became an assistant professor at Harvard Medical School. That summer, he, Nathan, and others published a paper in the New England Journal of Medicine that described one of the first instances of prenatal diagnosis of a form of thalassemia by DNA analysis. Thalassemia, which affects millions of people around the world, is an inherited blood disorder characterized by inadequate production of the protein hemoglobin, the oxygen-carrying component of red cells. Different forms of the disease occur in different ethnic populations. In collaboration with Haig Kazazian at Johns Hopkins University, Orkin set out over the next few years to identify nearly all of the inherited genetic mutations behind the various types of thalassemia. This ambitious undertaking resulted in the first comprehensive “catalogue” of the genetics of a human molecular disease. Knowing the various mutations in different populations greatly facilitated prenatal diagnosis, allowing parents to avoid having children destined to suffer from the debilitating chronic disorder.

Orkin next focused on the molecular biology of another inherited blood disorder, chronic granulomatous disease, a condition in which white blood cell (phagocytes) cannot kill certain bacteria and fungi. Children born with this disorder are highly susceptible to life-threatening bacterial and fungal infections. “Granulomatous disease was rare, but quite famous,” says Orkin. “The kids get an infection, and they can’t clear it, even with antibiotics. It’s a pretty dreadful disease. In fact, early on it was called “fatal granulomatous disease” At that time—the early 1980s—no one really knew what genes or proteins were mutated in the disease. Orkin set out to solve that molecular mystery. In 1986, in collaboration with geneticist Louis Kunkel of Boston Children’s Hospital and others, Orkin successfully identified the CYBB gene responsible for chronic granulomatous disease—a finding that was published in a manuscript accepted by the journal Nature only 4 days after submission. This was a milestone in the field of human molecular genetics, for it was the first use of positional cloning, a laboratory technique that locates the position of a disease-associated gene along the chromosome without prior knowledge of the encoded protein.  

To this point in his career, Orkin had studied how mutations cause blood disorders. He next sought to unravel how blood cells are formed and develop. To accomplish this, he needed to identify the transcription factors, or proteins, that control the expression of genes within stem and early blood cells. Using what was then a new technique, Orkin and his team isolated a protein—which later was named GATA1—that serves as the “master” regulator for the specialization (differentiation) of developing red blood cells. They went on to identify five related GATA transcription factors (GATAs 2-6). Taken together, the GATA “family” of factors control critical genes in specialized cells in many organs.  Much of what is known today about how blood cell development is programmed at the molecular level—and how disruptions in that programming are related to leukemias—can be traced directly to the pioneering studies of GATA1.

In the early 2000s, Orkin turned his attention to another major enigma in the hemoglobin field: What regulates the switch from fetal to adult hemoglobin during the latter part of gestation and the first few months after birth? Answering that question, scientists believed, might lead to new treatments for beta-thalassemia (a type of thalassemia in which the beta component of hemoglobin is not made) and for sickle cell disease, a disorder disorders that affects the structure of the beta-globin. The mutations that cause beta-thalassemia and sickle cell disease both affect the adult beta-globin gene. The fetal globin genes are normal. “Once you have adult red cells, you’re dependent on the adult gene,” explains Orkin. “So, the idea was that if you could turn on the fetal globin in adults, you could replace the missing or defective adult globin.”

At first, Orkin wasn’t sure that the molecular mechanism that triggers the switch from fetal to adult hemoglobin could be worked out as it might involve too many factors, each of which might only account for a small part of the total. He and his then-graduate student, Vijay Sankaran, decided, however, to take on the challenge. “We were a little despondent at times,” Orkin recalls. “We tried a number of things that failed.” Taking the hint from population studies (called genome wide association studies, GWAS), they focused on the gene called BCL11A, although at the time “there was no suggestion that BCL11A had anything to do with hemoglobin or red blood cells,” says Orkin. That hunch paid off spectacularly. In 2008, Orkin’s lab reported that reducing the expression of BCL11A in laboratory cultures of developing adult red cells reactivated production of fetal hemoglobin. They then went on to demonstrate that shutting off expression of BCL11A alone was sufficient to reverse the hallmarks of sickle cell disease in genetically engineered mice.

These stunning findings represented a major breakthrough in the field of hematology for they identified BCL11A as a genetic target for treating thalassemia and sickle cell disease. That promise is already being realized. Two small clinical trials published late in 2020 showed that genetic manipulation of BCL11A eliminated the symptoms of sickle cell disease and beta-thalassemia in patients, precisely as predicted by Orkin’s preclinical research. One of the two reports constituted a first-in-man application of CRISPR/Cas9 gene-editing.

Orkin continues to pursue his research at Harvard Medical School, where he is the David G. Nathan Distinguished Professor of Pediatrics. He has been an Investigator of the Howard Hughes Medical Institute since 1986. Through the years, Orkin has received numerous honors and awards for his work, including memberships in the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. Orkin is married to developmental biologist Rosyln W. Orkin, PhD, who shifted in the mid-2000s from conducting laboratory research at Massachusetts General Hospital to mentoring trainees and junior faculty at Boston Children’s Hospital and the Dana-Farber Cancer Institute on grant opportunities. They have one daughter.