University of Colorado Denver School of Medicine professor Charles A. Dinarello, MD, is one of the awardees of the $500,000 Albany Medical Center Prize in Medicine and Biomedical Research. The prize recognizes Dinarello for isolating, purifying and leading the cloning effort of the body’s own molecule that causes fever and inflammation associated with some forms of cancer, rheumatoid arthritis and other chronic inflammatory diseases. The prize, presented Friday morning at the Albany Medical Center in Albany, N.Y., is the largest award in medicine or science in the United States.
It is the second major research award garnered by Dinarello in the past few months. In January, the Royal Swedish Academy of Sciences recognized Dinarello’s work in isolating and cloning the fever molecule he and others dubbed Interleukin 1 with a share of its $500,000 Crafoord Prize. Dinarello picks up that award May 11 in Stockholm from the King of Sweden.
Judges of both prizes pointed to the way Dinarello’s research broke new ground in understanding diseases that led to better treatment for patients.
In honoring Dinarello, Ralph M. Steinman, MD, of New York City’s Rockefeller University, and Bruce Beutler, MD, of The Scripps Research Institute in La Jolla, Calif., with the Albany Medical Center prize, James J. Barba, president and chief executive officer of Albany Medical Center said, “Collectively, the work of these scientists has led to a dramatically better understanding of the human immune system, in health and in disease. That knowledge has already directly resulted in new therapies for people with conditions including rheumatoid arthritis, diabetes, Crohn’s disease and cancer. And, the discoveries they have made about how the body senses and responds to infection remain the basis of active research that holds the promise of new and improved vaccines and innovative ways to harness the power of the immune system to better fight viruses and bacterial illness. Their achievements are nothing short of astounding.”
Dinarello’s isolation of Interleukin 1 – also known as IL 1 – in the 1970’s and his cloning of the fever molecule in the 1980’s led to a new scientific discipline called cytokine biology. Cytokines is the name given to the larger group of molecules involved in inflammation discovered since Dinarello’s isolation and cloning of Interleukin 1. The body needs to produce cytokines to keep the body safe from attacks by outside elements. But as Dinarello proved with IL 1, unlimited production of cytokines can be deadly or debilitating. With unlimited production, the body literally attacks and destroys itself, as it does with cancer and rheumatoid arthritis.
“There needs to be a balance between pro-inflammatory cytokines and anti-inflammatory cytokines,” Dinarello says. “Evolution gave us both.”
And researchers such as Dinarello provide ways to identify and measure them and now, ways to regulate their production.
In Dinarello’s case, it took years in a painstaking process of elimination to figure out what caused fever without infection.
“I’d take white blood cells from healthy humans and put dead bacteria with them,” he explains. “The white cells would eat the dead bacteria and produce ‘stuff’ containing thousands of different substances.”
Extracting the single molecule that caused fever from that “stuff” took many steps and chemical processes. It also took overcoming skeptical peers and the self-doubt that comes with proposing new concepts. Year after year, Dinarello injected rabbits with different preparations and took their temperatures to see which of the animals developed fever.
“You lived in constant fear you were wrong because the concept you were introducing was novel,” says Dinarello, who joined the UCD medical school faculty in 1996.
The Yale Medical School graduate worried – even after he isolated a molecule so powerful that it caused fever when it was too small to be measured as a protein. His biggest moment of relief came when he and immunology researcher Lanny Rosenwasser, MD, met one Saturday morning in the 1970’s at a lab at the National Institutes of Health, where they both worked at the time. Rosenwasser, who later worked at National Jewish Health in Denver, studied something called lymphocyte activating factor that had many of the same properties that Dinarello had started to notice as he tried to purify the fever molecule.
When Rosenwasser used his NIH laboratory to test Dinarello’s molecule on lymphocytes, he was able to dilute the fever molecule more than 1 million times, and it still activated the lymphocytes. At that moment, both doctors knew they were on to something. How big that something was took decades to be recognized.
Having found the fever molecule, Dinarello spent the years 1982 to 1984 trying to clone it. At the time only three other molecules – human growth hormone, interferon and insulin – had been cloned.
“I estimate that I used 60 liters of human blood in the cloning project for Interleukin 1,” Dinarello says. “It was the beginning of the AIDS epidemic, but we didn’t know it. I was injecting rabbits. If the ear moved, I’d prick my finger.”
Fortunately, Dinarello didn’t get HIV. What he got instead was a rejection by the prestigious scientific journal “Nature” when he and his colleagues at MIT and Wellesley College tried to publish the IL 1 cloning results. Peers were still convinced his cloned molecule was contaminated with bacteria that caused the fever.
So Dinarello with his co-workers published their cloning paper in the “Proceedings of the National Academy of Sciences.”
“Then,” he says, “the synthetic molecule is made. It’s 100 percent pure. It did everything we had proposed and more. It was the beginning of cytokine biology. The whole thing exploded at that point. It became available for everyone to test.”
Dinarello’s research passed those tests. His research sparked other researchers to try to find ways to stop the uncontrolled production of cytokines, which caused or intensified dreaded and sometimes deadly diseases. Many succeeded.
Dinarello, now 65, continues to run an active lab with hopes of eliminating rejection in human tissue transplants and reducing the inflammation of cancer and other diseases.
“I stay in this business because you always make discoveries you don’t anticipate,” he says. “The reason I stay is because of the expanding ability to block cytokines safely.”
Dinarello’s collected publications are among the most cited by other researchers, but his ultimate peer review came in a letter from the wife of a man in the early stages of multiple myeloma, a form of cancer that full blown is often fatal.
Her husband, the woman wrote to Dinarello, had been treated at the prestigious Mayo Clinic with “IL 1 receptor antagonists” that had kept her husband’s cancer from progressing for four years. When she thanked her husband’s physician for saving her husband’s life, the woman wrote, the Mayo Clinic doctor told her the person she should be thanking was Charles Dinarello. Dinarello, meanwhile, thanks others, including his colleagues at MIT and Wellesley, his post-docs and UCD medical school faculty members, including William Arend, MD, a professor of medicine who is one of the discoverers of the IL 1 receptor antagonist.
That’s why Dinarello is forming the Interleukin Foundation and will donate his share of the money from the Albany Medical Center Prize and Royal Swedish Crafoord Prize to the new foundation. He’ll also donate money from subsequent prizes, including the Piso Prize that he recently won and will accept in Italy May 18. The foundation, says Dinarello, will make grants to other researchers to do such things as buy lab equipment and do pilot projects that are not funded by traditional methods.
“Using the money for medical research is another way of saying I’m not taking credit for all of this,” he explains.
In fact, it really is about the field and its impact on medicine and patients more than the money or the recognition.
“The scientist’s dream,” says Charles Dinarello, “is knowing you’re right.”
The School of Medicine faculty work to advance science and improve care as the physicians, educators and scientists at University of Colorado Hospital, The Children’s Hospital, Denver Health, National Jewish Health, and the Denver Veterans Affairs Medical Center. Degrees offered by the UC Denver School of Medicine include doctor of medicine, doctor of physical therapy, and masters of physician assistant studies. The School is part of the University of Colorado Denver, one of three campuses in the University of Colorado system. For additional news and information, please visit the UC Denver newsroom online.