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Dr. Stuart Orkin: The World’s Most Influential Hematologist Oncologist
WHEN STUART ORKIN, MD, describes his work, he uses terms like “micrograms” and “kilobase pairs” because what he’s measuring is so small. When everyone else talks about his work, they use words like “global” and “seismic.”
Indeed, his impact over five decades is almost too big to measure. Only recently, Dr. Orkin’s research gave hope to 20 million people worldwide affected by sickle cell disease when the U.S. Food and Drug Administration approved Casgevy, a novel genome editing technology, to treat the condition. Dr. Orkin’s dedication and commitment to share his work with the wider scientific community provided the foundation for that cure.
Dr. Orkin began his foray into sickle cell in 1978, during his fellowship at Boston Children’s and Dana-Farber Cancer Institute. While researching thalassemia, a related blood disorder, he attended “the most exciting” conference. “This was where the first cloning of the human globin gene was described,” says Dr. Orkin, referring to the key regulator of red blood cell development. Conference organizers promoted the theory that synthesizing fetal hemoglobin would deliver a treatment for sickle cell, sparking a career-long mission.
By the early 1980s, Dr. Orkin, working with Haig Kazazian, MD, from Johns Hopkins Medicine, was cloning globin genes from patients with thalassemia and had amassed a catalog of mutations. They hoped to find the switch that told the body to resume making fetal hemoglobin, which doesn't sickle, and stop making adult hemoglobin. “But our research didn’t answer the central question: How do you make a red blood cell,” says Orkin.
That changed in 1989. Dr. Orkin and Leonard Zon, MD, then a fellow, identified the gata-1 gene as the “master regulator” of blood cell development—a discovery that shed light on the genetic principles of fetal hemoglobin production.
Over the next decade and a half, researchers racked up some wins, most notably the realization that the cancer drug hydroxyurea prevents sickle cells from forming. But repeated attempts to restart fetal hemoglobin fizzled. Researchers all but gave up and refocused their attention on other medical mysteries.
Serendipity then intervened. Vijay Sankaran, MD, PhD, who was pursuing his dual degrees at the time, arrived in Dr. Orkin’s lab. Encouraged by Dr. Orkin’s mentor, David Nathan, MD, Dr. Sankaran renewed the hunt, this time using DNA banked away by the National Institutes of Health.
At the same time, 4,000 miles away in Sardinia, scientists were conducting a genome-wide search for clues to thalassemia. Joel Hirschhorn, MD, PhD, was familiar with their work and connected the teams. That led Drs. Sankaran and Orkin to identify the bcl11a gene as the place to look for the fetal hemoglobin switch.
The search was far from over. The reinvigorated team had to locate the portion of the gene that contained the switch. Dan Bauer, MD, PhD, joined the quest in the Orkin laboratory and, in 2013, suggested Dr. Orkin look in the non-coding portion of bcl11a. That narrowed the search to 10,000 base pairs of DNA—still huge ground to cover. Fortunately, their search coincided with the 2015 arrival of CRISP gene editing.
Their progress inspired the Doris Duke Foundation to award Drs. Orkin and Bauer critical grants to identify core genetic sequences that upon CRISPR intervention create healthy red blood cells. They partnered with Massachusetts Institute of Technology’s Feng Zhang, PhD, a CRISPR inventor, to locate the precise section of DNA to edit.
The groundbreaking work by Dr. Orkin and colleagues enabled Vertex and CRISPR Therapeutics to develop Casgevy. The life-changing gene therapy received FDA approval in 2023.
However, the $2.2 million per-treatment price tag and limited availability mean few patients with severe sickle cell disease will get relief soon. To reach more people, there will need to be additional clinics capable of administering the gene therapy, or a drug will need to be delivered in a pill. True to form, Dr. Orkin and team are pursuing both options. “We’re learning as much as we can about bcl11a, how it works, to get clues about the best way to make small molecules and targeted therapies,” says Orkin.
