Strober, a professor and former chief of immunology and rheumatology, found a way for transplant recipients to reduce or abandon immunosuppressive drugs yet avoid organ rejection.
March 31, 2022 - By Bruce Goldman
Samuel Strober, MD, professor of immunology and rheumatology, died Feb. 11 at his home in Portola Valley, California, of multiple myeloma. He was 81.
Strober’s career was laser-focused on improving transplant recipients’ lives. Step by methodical step, he developed a way to wean some of these patients from a lifelong regimen of drugs that prevent the immune system from attacking and destroying the donated organ.
“Sam Strober made an observation in the 1970s that set the course of his research for the rest of his life,” said Lloyd Minor, MD, dean of the Stanford University School of Medicine. “His discoveries in the laboratory, and his ability to spur collaborators’ translation of those discoveries into clinical practice, have already transformed his dream into a reality in kidney transplantation.”
The approach Strober pioneered promises to benefit an expanding circle of organ-transplant recipients.
Colleagues described Strober as a multifaceted Renaissance man. He was an opera lover, a voracious reader of history books and a debater of big ideas. He loved downhill skiing, tennis and hiking.
But most of all, he was driven by a quest to free transplant recipients from the burden of immunosuppressant drugs, which increase their risk of cancer, diabetes, infection and other medical problems.
“Sam had a focus I’ve never encountered in anyone else,” said Robert Lowsky, MD, professor of blood and marrow transplantation and cellular therapy and a frequent collaborator of Strober’s. Lowsky met Strober during his job interview before joining Stanford in August 2001.
“He was 60. I was 40. We became wonderfully close friends within 30 seconds. It never stopped,” Lowsky said.
“Outside of my family, Sam was my best friend,” said another close collaborator, Edgar Engleman, MD, professor of pathology and of immunology and rheumatology. “We talked about everything, every day.”
A fascination with explosives
Strober was born in Brooklyn, New York, on May 8, 1940, to Julius and Lee Strober. He and his younger brother had 28 first cousins living nearby. At 7, he started riding the subway alone from Brooklyn to Manhattan to take accordion lessons. He skipped first grade.
Growing up in the dawn of the atomic age, Strober became fascinated by science, and it wasn’t long before he channeled that interest into pursuing explosives. As a teenager, he wasn’t above assembling 3-inch firecrackers, casually sneaking into a drive-in theater and rolling his creations under entering or exiting cars, “to see if the drivers would stop, thinking they’d had a flat,” according to his brother, Ross.
He was also an avid reader of science fiction, including the novels of Robert Heinlein — which he later remembered as “mind-boggling and horizon-lifting” — and saw himself becoming an atomic physicist. He tested his way into the fast-track, science-oriented Stuyvesant High School.
In his senior year, Strober entered a national science contest with a project that, ironically, was on the disorder that would end his life. On a meager high-school budget, he re-created a Nobel-prizewinning device that separated proteins by their bulk and electrochemical properties. He got hold of a blood sample from a patient with multiple myeloma, a cancer marked by the overproduction of a particular antibody, and ran it through his device. It accurately displayed a colored band reflecting the accumulation of large amounts of the patient’s aberrant antibody.
His entry took first place for Manhattan.
Strober attended Columbia College, where he earned a bachelor’s degree in 1961 before entering Harvard Medical School. In his second year at Harvard, he worked in the lab of Joseph Murray, MD, who won a Nobel Prize in physiology or medicine in 1990 for his pioneering kidney-transplantation research. Strober graduated magna cum laude in 1966.
After an internship at Massachusetts General Hospital, Strober worked as a research associate at the National Institutes of Health in Bethesda, Maryland, for three years.
“Sam came in already knowing a lot of stuff,” said Robertson Parkman, MD, an adjunct professor of pediatrics and of stem cell medicine at Stanford, who worked and became friends with Strober at the NIH. “His competency was apparent right from the beginning.”
Strober started his residency at Stanford’s Department of Medicine in 1970. He joined the medical school’s faculty as an instructor in immunology in 1971. He was promoted to assistant professor in 1972, to associate professor in 1978 and to full professor in 1982. He was a Howard Hughes Medical Institute investigator from 1976 through 1981 and led the division of immunology and rheumatology from 1978 through 1997.
Strober developed an interest in bone-marrow and organ transplantation. The former procedure can cause graft-versus-host disease, wherein white blood cells from the donor’s bone marrow attack and damage the recipient’s tissues. The latter procedure risks a reverse effect called host-versus-graft disease, in which the organ recipient’s white blood cells attack and destroy the donated organ.
Both of these outcomes are a byproduct of the immune system’s essential purpose: to differentiate between “self” and “foreign.” Without this capacity, and the ability of the immune system to attack and destroy invading pathogens or our own tumors, we couldn’t survive.
Self-versus-foreign recognition is enabled by the molecular flags all our cells display on their surfaces. There are hundreds of these flags, about a dozen or of which are of critical importance. Identical twins share all flag patterns, and a small number of conventional siblings share all dozen-plus critical flag patterns — they’re all considered “fully matched” — although nonidentical siblings still differ with respect to flags of lesser significance. Most siblings may share about half of the critical flags on average. The chances of two strangers sharing all of them are less than 1 in 1 million.
Because the vast majority of potential bone-marrow or organ donors, living or dead, are partially or, more often, fully incompatible with potential recipients, transplantation carries a risk of war between the bone-marrow donor’s white blood cells and the recipient’s body or between the recipient’s immune system and the donated organ.
‘Ceasefire in the war among the immunological gods’
At Stanford, Strober became intrigued by the research of the late Henry Kaplan, MD, founding chairman of Stanford’s Department of Radiology, on patients with Hodgkin’s lymphoma, a type of blood cancer. Standard treatment at the time was chemotherapy and total body irradiation. Both killed tumor cells but also induced wrenching side effects because they destroyed healthy, continuously dividing cells in skin, hair follicles, the lining of the gut and the immune system. They also increased recipients’ risk for infections and several chronic diseases.
Kaplan experimented with a less invasive, gentler therapy he called total lymphoid irradiation, which targets the thymus, spleen and lymph nodes rather than the entire body. After total lymphoid irradiation, researchers noted, patients who had exhibited positive results on tuberculosis skin tests showed no reaction for a while, indicating weakened immune reactivity, although they retained a relatively viable complement of blood and immune cells.
This suggested that the protocol could induce at least temporary immune tolerance in patients: Their immune systems were less disposed to mobilize and attack foreign cells.
Sam had a focus I’ve never encountered in anyone else.
“Sam noticed that these patients who got total lymphoid irradiation had profound changes in the frequency of immune cells in their blood, but didn’t seem particularly susceptible to infection,” Engleman said. “He wondered if this could be applied to transplantation. That’s what got him going.”
Strober began research on mice to see if this partial loss of immune response could be harnessed to keep patients’ immune systems from attacking solid-organ transplants or, conversely, to prevent donor-bone-marrow attacks on recipients’ tissues.
Step by step, he tweaked his approach — which in the case of organ transplants included total lymphoid irradiation of the recipient as well as an infusion of the donor’s bone marrow in a modified, weakened condition — until he achieved a kind of peace treaty between the two immune systems now cohabitating in one body.
Parkman described this condition as “a ceasefire in the war among the immunological gods.” The recipient mice’s immune systems had acquired tolerance of the transplant’s “foreigner” flag pattern, and vice versa. The mice no longer needed immunosuppressant drugs to maintain their transplants’ health.
Over the ensuing decades, Strober collaborated with a pool of Stanford nephrologists, bone-marrow specialists and transplant surgeons to test the protocol he developed. His work translated into clinical trials proving that many kidney-transplant recipients whose molecular-flag systems are fully matched with those of their respective donors can escape a lifelong regimen of immunosuppressant drugs.
In a paper published January 2020 in Science Translational Medicine, Strober and his Stanford colleagues reported that, owing to Strober’s protocol, about 80% of the patients receiving kidneys from fully matched siblings were able to stay off immunosuppressant drugs for at least two years, with some still drug-free 10 years out. And nearly half the patients receiving kidneys from partially matched siblings were able to get by on one immunosuppressant drug instead of three.
Strober’s system would likely apply to other solid organs as well, Parkman said.
Throughout, Strober probed the scientific cellular and molecular basis underlying organ-transplant tolerance. His pioneering work revealed the importance of suppressor T cells, naturally occurring immune cells that can dial down the responses of other immune cells to prevent graft rejection.
Irony and resolve
Strober was diagnosed with multiple myeloma in 2019 after what was supposed to be a routine blood test. Rather than retire, he forged on, telling nearly no one, working full-tilt until just two weeks before his death while playing an active role in steering his therapeutic regimen.
“Sam’s response to the illness was to work harder than anybody I’ve known,” Engleman said.
At age 80, Strober underwent a bone-marrow transplant at Stanford for treatment of his myeloma. His condition worsened in January 2022, when he was hospitalized for a few days before returning home. He died with his family at his bedside, 20 years before his subsidiary but often-stated goal: to live to 100 so he could complete his life’s work.
“He told me, ‘Robert, my moral imperative is my work.’ He wanted to just come into his office one day, put his head down on his desk and die on the job,” Lowsky said.
Several days before his death, Strober completed an NIH grant-renewal proposal to extend the research on induction of tolerance to include organs and bone marrow from dead donors. It is under review now.
Strober published some 400 scientific papers and book chapters and was an associate editor of several journals. He co-founded two companies: Dendreon (with Engleman) and Medeor Therapeutics (with Engleman and Lowsky). He was the board chairman at the La Jolla Institute for Immunology from 2005 through 2010; president of the Clinical Immunology Society in 1996; and a member of half-dozen other rheumatology-, immunology- and transplantation-oriented professional associations.
In addition to his brother, Ross, of Hauppage, New York, Strober is survived by sons Jason, of Los Altos Hills, California; Will, of St. Louis, Missouri; and Jesse, of San Francisco. He is also survived by a daughter, Liz, of Seattle, and four grandchildren.
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