Eliminating the suppressive elements of the immune system combined with better vaccine stimulation of the antitumor response may be a winning combination in defending against cancer, according to Joost Oppenheim, M.D., Chief of the Laboratory of Molecular Immunoregulation. Such "immune approaches" have been successful in producing remission or prolonging life in 15 to 20 percent of patients, but complete cure has been rare so far. "In a sense, it's like putting the jack back in the box," he said. "Once you detect the cancer, there are billions of abnormal cells present, and to get rid of them with the immune system has proven to be very difficult." Despite the difficulty, Dr. Oppenheim has devoted his entire career to understanding the intricacies of the human immune system in hopes of harnessing it against cancer.
From Psychiatry to Science
Dr. Oppenheim didn't set out to be a scientist, but he clearly always had a scientist's curiosity. Born in the Netherlands, he immigrated to this country with his family in 1946, in the aftermath of World War II. The war left a powerful impression on the 12-year-old boy, who grew up feeling it "necessary to make a positive contribution because my childhood had a very negative impact." At the same time, the war left him convinced that "people were crazy," and he wanted to become a psychiatrist to find out why. However, during a sub-internship in psychiatry while he was in medical school, he was struck by the ambiguity of patient analysis. Each analyst offered a different analysis of the same patient. Finding this imprecision of diagnosis disheartening, he entered general medicine "to find some other specialty."
Following medical school, Dr. Oppenheim set his sights on the National Institutes of Health. The echo of World War II still haunting him, he wanted to be in public health service, as well as to avoid being sent to Korea or Vietnam. "I'd had enough of war and wanted to escape the opportunity by any means possible," he said. He spent several years in the Chemotherapy Branch (forerunner of the Medicine Branch)of the National Cancer Institute, where he worked with a group that used experimental drugs to treat cancer patients. Because the patient outcomes were so unpredictable and often negative, he found the work unsatisfying and began working in an NCI laboratory with Dr. Jacqueline Whang-Peng, who was doing chromosome analysis.
It All Started with Kidney Bean Extract
In his work with Dr. Whang-Peng, Dr. Oppenheim became intrigued by the use of kidney bean extract to stimulate the growth of lymphocytes, or white blood cells. For Dr. Whang-Peng, the extract was used simply as a step in the process for analyzing chromosomes. But for Dr. Oppenheim, the effects of a biochemical component in the extract, phytohemagglutinin, opened a door to the study of the body's defense system, an aspect of science with which he remains fascinated to this day.
In 1965, he was recruited by the National Institute of Dental and Craniofacial Research (NIDCR) to study inflammation in the gums using tissue culture models. During the next 17 years, Dr. Oppenheim would become a pioneer in studies of the regulation of immune cell responses, beginning with his work on cytokines, substances produced by cells that he first observed in the supernatants of tissue cultures. "In a sense, they are the hormones of the immune system," he explains, because they enable the cells to communicate with one another to stimulate the immune response. This work led to more discoveries. "I worked initially on interleukin-1, which was the first of many of these cytokines, and then I found a contaminant, which turned out to be chemokines." Chemokines are a family of agents that create a path over which inflammatory cells migrate to the site of an infection. His group discovered and patented one of the chemokines, interleukin-8, "one of the main attractants of neutrophils, which are the acute inflammatory pus cells," according to Dr. Oppenheim.
Enter Defensins and Alarmins
In the early eighties, Dr. Oppenheim left NIDCR to join the National Cancer Institute at Frederick as chief of the Laboratory of Molecular Immunoregulation (LMI), where he has remained. Under his leadership, LMI has identified yet another family of mediators that induces migration to the site of an infection, similar to chemokines. Known as defensins, these antimicrobial agents defend the body against bacterial infection. "They're homemade antibiotics," Dr. Oppenheim explains. More recently, his lab determined that defensins are part of a diverse group of structurally unrelated molecules known as alarmins, which act as first responders to an injury. Dr. Oppenheim explains that alarmins "wake up" the immune system to attract cells and to immediately activate cells to engage in host defense as rapidly as possible.
Today Dr. Oppenheim's laboratory is focused on three areas of research. One area, he said, is the study of alarmins "to identify a potent wake-up signal that we can perhaps use as a vaccine adjuvant that might be less toxic than currently available boosters or vaccines." Such a vaccine would boost the immune response to favor cellular immunity, which would increase the body's resistance to tumors.
The LMI is also involved in the study of T-regulatory cells, or T-regs, which act as the "brakes" for the immune response. Dr. Oppenheim explains that "the immune system not only defends us against invasive organisms and injurious damage to the tissue, but it also sends out regulatory cells [T-regs] that calm us and promote repair of injured tissue." Inflammation is suppressed, and healing can occur. "It's really an intricate and fantastic system," he adds. This work is leading to studies of how to suppress the T-regs that erroneously invade tumors to promote their repair and inadvertently interfere with antitumor immune responses. "These two parts of the program, the alarmins, which wake up the positive immune response, and ways of diminishing the T-reg suppressive effects, together may be more effective than either one by itself," Dr. Oppenheim said.
Third, his laboratory is collaborating with a Chinese traditional medicine hospital in Beijing to analyze traditional medicines that have been shown to have antitumor effects. His group has learned that "antigens from the tumor actually attract inflammatory cells to the tumor," but the tumor also sends signals to attract T-regs and other cell types that interfere with the immune response. They are working to identify those drugs "that have a long history of being used and being effective in the Chinese traditional medicine hospitals," he said.
Satisfaction Now Comes from Enjoying Science with Others
As a young scientist, Dr. Oppenheim says, he "used to go to the scintillation countercranking out the results, and after a while, I began to believe it was sort of like Las Vegas." His persistence in watching for positive findings seemed to spring from "the same sort of instinct that...enables people to gamble," he said. The only drawback, he concedes, is that in science, "the rewards are much fewer and slower than in Las Vegas." However, as a senior scientist, he says his greatest satisfaction comes not from the findings themselves, but from "thinking about the findings, and then actually watching and learning from other people, and watching my younger scientists develop and hoping that they can find the same joy that I occasionally do....When a young scientist finds a way to succeed, which involves an incredible amount of devotion and hard work and enthusiasm, it's really fun to enjoy it with them."
To say he's modest about his accomplishments would be an understatement. "I think inventing the word 'chemokines' and 'alarmins' has been important because people like a catchy phrase," he quips. Accomplishments aside, he believes that "what matters most is that you have the ability to reward yourself. Because if you rely on others for rewards, you'll be sorely disappointed." His sense of accomplishment comes from having a good intellectual curiosity and the motivation to "improve life down the lane,...to have a positive impact on people."
"So What?"
Dr. Oppenheim has moved his career forward on a two-word mantra: "So what?" In fact, he keeps a plaque hanging on a wall in his office with this all-important question written in twelve languages. He believes that when a discovery is made, this question is the most important one you can ask. "Since we really don't know what we're doing, we have to make guesses about what will be beneficial and what will be most helpful," he commented. "What does it mean? Where does it fit in? Is it really important?"
Asking these questions has always been a part of his pioneer mentality. He admits that everything he has ever been involved with "has been taken over by other people who then roll along and make tremendous progress in it." But he likes to stay ahead of the curve. "I try to do things that are a little bit different, which sometimes gets me into trouble. Sometimes it leads me off the cliff, but sometimes I do okay." Judging by the discoveries he's made over the years and the successes of his laboratory, Dr. Oppenheim has definitely done okay.
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Eliminating the suppressive elements of the immune system combined with better vaccine stimulation of the antitumor response may be a winning combination in defending against cancer, according to Joost Oppenheim, M.D., Chief of the Laboratory of Molecular Immunoregulation. Such "immune approaches" have been successful in producing remission or prolonging life in 15 to 20 percent of patients, but complete cure has been rare so far. "In a sense, it's like putting the jack back in the box," he said. "Once you detect the cancer, there are billions of abnormal cells present, and to get rid of them with the immune system has proven to be very difficult." Despite the difficulty, Dr. Oppenheim has devoted his entire career to understanding the intricacies of the human immune system in hopes of harnessing it against cancer. 
Today Dr. Oppenheim's laboratory is focused on three areas of research. One area, he said, is the study of alarmins "to identify a potent wake-up signal that we can perhaps use as a vaccine adjuvant that might be less toxic than currently available boosters or vaccines." Such a vaccine would boost the immune response to favor cellular immunity, which would increase the body's resistance to tumors. 
To say he's modest about his accomplishments would be an understatement. "I think inventing the word 'chemokines' and 'alarmins' has been important because people like a catchy phrase," he quips. Accomplishments aside, he believes that "what matters most is that you have the ability to reward yourself. Because if you rely on others for rewards, you'll be sorely disappointed." His sense of accomplishment comes from having a good intellectual curiosity and the motivation to "improve life down the lane,...to have a positive impact on people."