August 16, 2016—It has been more than two decades since Todd Waldman, MD, PhD, a professor of oncology at the Georgetown Lombardi Comprehensive Cancer Center and director of the Georgetown MD/PhD Program, published a study that led in part to earning his own MD/PhD degree at the Johns Hopkins School of Medicine.
It was one of the approximately 50,000 papers that the journal Cancer Research has published since its inception in 1941. But it was much more than that.
To celebrate the journal’s 75th anniversary, its editors picked “landmark” studies that were scientifically significant and influential at both the time of publication and today.
Waldman’s study was one of the 50 studies selected.
Editing human genes
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.
Tweaking and trial and error
He had thought about it in high school when he had interned at the National Institutes of Health. He thought about it again as an undergraduate at Yale. So at Hopkins, he decided to do it.
Yeast, bacteria, worms and flies had all long been used for gene knock-out studies, and mice with knock-out genes had just been developed before Waldman began his experiments.
But it hadn’t been done in humans. “Everyone had just figured knock-out studies in human cells couldn’t be done,” Waldman says.
But he did it. It took some laborious tweaking of the method used to create knock-out 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.
“Easy” gene editing
Other groups in England and Japan were also working on creating gene knock-outs in human cells, targeting other genes. “It is fair to say ours was among the first few knock-outs in human cells, but not the very first.”
Still, the finding about p21 and the method used were electric. Other researchers 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. It is technically different from Waldman’s procedure in that it is more efficient and can more easily be applied to entire organisms. However, the ultimate outcomes are the same — modified genes.
Waldman’s Cancer Research study led quickly to rapid-fire release of new research findings in high profile journals. He 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, leukemias, brain tumors, and other tumor types.
Does he continue to use his own gene editing method? Waldman says no, not the specific method described in the 1995 Cancer Research paper. Instead, his lab has switched to some of the more “modern” techniques, including CRISPR. However, he adds that he remains totally committed to this general approach of 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 just continue to get easier as even newer technologies are developed,” says Waldman.
To read Waldman’s 1995 study, click here.
To read Waldman’s commentary on the study published on August 15, 2016 click here.