Nordic Life Science 1
he completion of the human genome project in 2003
and recent improvements in DNA sequencing have allowed resear-chers to look at tumors to determine which genes have been altered. That inspired the creation of drugs that are the best fit for a specific mutation. “More of these drugs are being developed and now we can start to use them in combination, because there is always a chance one cell is resistant to any single treatment,” explains William Kaelin. “We can directly kill cancer cells based on their genetic makeup. We are also treating cancer with drugs that rev up the immune system.” First introduced to this research topic when he was a thirdyear medical student at Duke University, Kaelin studied tumor blood flow and tumor angiogenesis. During his clinical training he learned more about cancer as a clinical entity and the clinical aspects of the disease. Kaelin briefly practiced medicine after becoming board certified in medical oncology in the late 1990s, before feeling the pull towards full-time research. “As I started seeing patients it became clear that we had inadequate treatments for cancer, and we needed a better understanding of the molecular aspects of cancer,” he explains. Kaelin began his studies as a medical oncology fellow with David M. Livingston, MD at Dana-Farber Cancer Institute in 1988. “David Livingston is the reason I am a scientist today,” Kaelin adds. Work with the retinoblastoma (RB1) gene gave Kaelin the tools to study other tumor suppressor genes. “By the time I became a clinical fellow in the 1980s, it was becoming clear that modern molecular biology was the way to study cancer,” he says. “I did so with some skepticism that I actually could do it, however. I started working at David Livingston’s lab, and I said I would do it until it was not fun, or I was not making meaningful contributions. It has now been 30 years!” Later starting his own laboratory, Kaelin studied von HippelLindau disease, a hereditary disorder caused by anomalies of the VHL gene, which, like the RB1 gene, is a tumor suppressor gene. Patients with von Hippel-Lindau disease develop benign and malignant tumors in multiple organs, beginning in early adulthood, according to information from Dana-Farber. What he observed was that the VHL protein normally helps regulate the levels of an oxygen-sensitive protein called HIF. HIF can trigger the production of red blood cells and new blood vessels. Cancer cells with mutated VHL genes seize control of this system to order the construction of new blood vessels to feed their growth, according to Dana-Farber. One of the reasons Kaelin studied the VHL gene is that mutations of this gene are also important in some non-hereditary cancers. Here the mutations are not inherited from a parent but are acquired after birth. “I started looking at hereditary, then non-hereditary cancers, such as kidney cancer,” he says. “I used the VHL cancer as a Rosetta Stone to understand how kidney cancer operates. I wanted to help put together a combination of treatments that cured kidney cancer. Also, now that I understand oxygensensing pathways, I’m looking at these pathways in diseases such as heart attack and stroke, where oxygen delivery is impaired.” “Most scientists are happy puzzle-solvers,” he adds. “In this particular case when I solved the puzzle, it struck me as a beautiful and elegant tribute to nature.” Kaelin’s work has inspired others as well. Peppi Karppinen (publishing name P. Koivunen), MD, PhD, and Dean and Professor of Medical Biochemistry at the University of Oulu in Finland, began collaborating with Kaelin in 2006 and in 2007-2008 was a senior research fellow in his lab at DanaFarber. They have continued their collaboration and in January published their latest joint article with shared corresponding authorship in Science. The two are now working with another colleague on a review article. “Dr. Kaelin is a very intelligent person and an excellent scientist,” Koivunen says. “He is very demanding, but also fair and supportive. He has wide knowledge beyond science and is a world traveler.” William Kaelin at the press conference in Stockholm during the Nobel Week 2019 NORDICLIFESCIENCE.ORG 67 PHOTO JENNY ÖHMAN