To celebrate the 75th anniversary of Cancer Research, the journal’s editors picked 50 landmark studies that were scientifically significant and influential at both the time of publication and today. This was no easy task, as the journal has published approximately 50,000 papers since its founding in 1941.
One of the selected landmark studies presented a breakthrough in gene editing by Todd Waldman, MD, PhD, a professor of oncology at the Georgetown Lombardi Comprehensive Cancer Center and director of the Georgetown MD/PhD Program. Twenty years ago, he published the study that led in part to earning his own MD/PhD degree at the Johns Hopkins School of Medicine.
For those in the field, the title of the November 15, 1995 study—“p21 Is Necessary for the p53-Mediated G1 Arrest in Human Cancer Cells”— says it all. It found that the p53 tumor suppressor gene, the “guardian of the genome,” interacts with another gene, p21, to arrest growth of stressed cells.
p53 is a big deal. In 1989, Bert Vogelstein, MD, a titan in the field of cancer genomics, discovered that p53 acts as a tumor suppressor. p53 is mutated in half of all human cancers.
Waldman was beginning his PhD research in Vogelstein’s lab at Johns Hopkins when he asked if he could try to “edit” genes in human cancer cells. He wanted to “knock out” specific genes in these cells to find out how they function when compared to cells with the gene.
He had thought about it as a high school intern at National Institutes of Health. He thought about it again as an undergraduate at Yale. At Hopkins, he decided to do it.
Yeast, bacteria, worms, and flies had long been used for gene knockout studies, and mice with knockout genes had just been developed before Waldman began his experiments.
But it hadn’t been done in humans. “Everyone had just figured knockout studies in human cells couldn’t be done,” Waldman says. They were wrong.
It took some laborious tweaking of the method used to create knockout mice, but it worked in human cells. “My method was trial and error,” he says with a laugh.
He and his co-authors, Vogelstein and Kenneth Kinzler, PhD, revealed how, through the p53 and p21 genes, cancer cells stop dividing after being exposed to damaging anti-cancer treatments. This major finding was not possible without Waldman’s gene editing technique.
Other groups in England and Japan were also working on creating gene knockouts in human cells, targeting other genes. “It is fair to say ours was among the first few knockouts in human cells, but not the very first,” says Waldman.
Still, the findings about p21 and the methods used were electric. Other research - ers adopted the technically difficult process for about four years, until a simpler system surfaced. That method stayed in use until 2013, when CRISPR, the “easy” gene editing technique, was developed.
CRISPR is now the subject of news reports, Nobel Prize speculation, and ethical musings the world around. Compared to Waldman’s procedure, it is more efficient and can more easily be applied to entire organisms. However, the ultimate outcomes are the same— modified genes.
Waldman continues to study cancer gene function in his Georgetown lab, and has recently identified a new cancer gene called STAG2 that is among the most commonly mutated genes in cancer, involved in causing bladder cancer, pediatric bone tumors, leukemia, brain tumors, and other tumor types.
Although Waldman now uses newer techniques, he remains committed to using human gene editing to study human cancer genes in human cancer cells themselves.
“Studying gene function in cancer cells is now a lot more straightforward and will continue to get easier as even newer technologies are developed,” says Waldman.