An Epi Phenomenon

As an investigator at the National Institutes of Health (NIH) in the late 1960s and early ’70s, Baylin began to address those questions, studying the genetic underpinnings of an inherited form of thyroid cancer. “My research started out very clinically related, but over the years it became more and more basic,” he says. “Then I stopped seeing patients and put on a lab coat for good.”

“I don’t think young investigators today have that kind of luxury,” says Baylin, who is now deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. “With funding issues, there’s such pressure to get into things and decide what you’re going to do quickly. But I had the luxury, over many years, to try my hand at research, to go from clinical research to more basic research—and then to come back to studying cell biology and cancer biology in the context of disease. So I’ve come full circle.”

Along the way, Baylin has made fundamental discoveries about the epigenetic modifications that underlie all human cancers—findings that he’s using to develop new treatments for the disease. Here, Baylin talks about his experience as a “Yellow Beret,”  how his early work was declared esoteric, and what it’s like to be a rock star of science.
 

Baylin from the beginning

War on cancer. Baylin enlisted in his crusade against cancer during the Vietnam war. “They called us the Yellow Berets—MDs who opted to do their public service by engaging in research at NIH. I was interested in an inherited form of thyroid cancer, called medullary thyroid carcinoma.” Baylin found that these tumors produce large amounts of the hormone calcitonin, as well as an enzyme that seemed like a good candidate to serve as a biomarker for tumor detection. “We also found that not all the cells in the tumors were producing these proteins, which introduced me to the concept of tumor heterogeneity”—findings he published in the New England Journal of Medicine in 1970. “So, though medullary thyroid carcinoma is not a very common cancer, it was a terrific one for learning about tumor heterogeneity, hormone production, and biomarkers.”

“My first first-author paper was cited as a piece of arcana that nobody would need to know to do good medicine. I still have a yellowed copy of that piece.”

The emergence of methylation. Thyroid tumors are not the only ones that produce calcitonin—so do lung cancers. “And we wanted to understand why. At around that time—this was the mid-1980s—people knew about DNA methylation and that it could play a part in turning genes off and on. So a graduate student and I started to play around, looking at methylation at the start of the calcitonin gene. We thought that maybe methylation is being lost in these tumors. But we found that it’s actually being gained—at hundreds of chromosomal regions, on hundreds of other genes. That started us on this quest to understand why the start sites of all these genes were piling up DNA methylation.”

Cutting the brakes. It would take another 10 years for Baylin and his colleagues to determine that some of these densely methylated genes encode tumor suppressors whose activities are lost in cancers. “I think the first we found, with my colleague Jim Herman, was the von Hippel-Lindau gene, which contributes to renal cancers. And then with David Sidransky we found that the p16 gene is hypermethylated. So by the mid-1990s we had hit on a couple of bona fide tumor suppressor genes that harbor this change. And I think that’s what helped to legitimize the field.” They also showed that a nucleoside analog called 5-azacytidine disables the enzyme that normally methylates cytosine residues in DNA. By taking the enzyme out of commission, the chemical prevents the excessive methylation and reactivates the genes. Three years later, Baylin and Herman discovered that a DNA repair gene called MLH1 is also silenced by methylation in a sizeable portion of sporadic colon cancers.  “It’s one of the most amazing things,” says Baylin. “I am not aware of any cancer type that’s been studied in any depth that doesn’t show altered methylation. And about half of the classic tumor suppressors involved in hereditary cancers”—genes like p16 and von Hippel-Lindau—are also the targets of runaway methylation.  

Staying stemlike. Baylin and his team are still trying to understand what this collective mis-methylation is doing in various cancers: Which of the modifications drive cancer, and which merely come along for the ride? “People have asked that question about genetic mutations. Now it’s coming into play for epigenetics,” says Baylin. One intriguing possibility is that the suite of modifications locks down genes that are needed to drive differentiation. “That could help keep tumor cells more stemlike,” says Baylin—a troubling hallmark of cancers. The good news: Baylin has found that stemlike cancer cells are just as susceptible to treatment with 5-azacytidine as any other tumor cell. “That could be a big deal, because most cancer therapies hit hard at the non-stemlike cells, allowing the stemlike cells to escape unharmed.”

The epigenome and beyond. Baylin was one of the original PIs—together with Peter Laird of the University of Southern California (USC)—on the epigenetic portion of the Cancer Genome Atlas project, whose goal is to identify all the genomic changes that occur in a wide variety of cancers. Looking at genome-wide DNA methylation “has been very valuable and has added to the story for each of the diseases that have been studied so far.” In glioblastoma, for example, the Cancer Genome Atlas confirmed that patients in whom a DNA repair gene called MGMT is epigenetically silenced are more sensitive to the leading drugs used to treat the disease. But the genome-wide study further revealed that when tumors recur in these patients after therapy, they show an increased burden of genetic alterations—mutations that accumulate in numerous genes. “That observation fleshed out our understanding of the evolution of glioblastoma,” says Baylin—and could lead to more effective approaches to treating the cancer when it recurs.

“I don’t think anything replaces revisiting your data—waking up and coming in and saying, ‘Let me look at that again. What am I missing?’ ”

Expert translation. Along with USC’s Peter Jones, Baylin leads one of eight collaborative “Dream Teams” established by the Stand Up to Cancer initiative. “The mandate was to take what we were learning in the laboratory and, in a 3-year period, make it part of patient management. It’s been terrifically exciting—team science in a way I hadn’t done before.” Their work has focused on 5-azacytidine, the chemical that reverses DNA methylation. “Over the years, the drug has proved to be very toxic. But we’ve found that using it at much lower doses has given us traction in treating common cancers. Treating patients with this agent first sensitizes them to subsequent therapies, so that even patients with advanced lung cancer seem to be responding. We’ve got this in clinical trials now and the drug is very tolerable at these doses, so we think it has great therapeutic potential.”

Baylin believes

All publicity is good publicity. Baylin’s early work was called out in the prestigious New York Review of Books. “It was in a review of some book on medical school training.” The reviewer was railing against the ridiculously esoteric questions that are trotted out during rounds to put med students in their place. “As an example of such an esoteric question, [the review] cited my New England Journal [of Medicine] paper on this enzyme in medullary carcinoma. So my first first-author paper was cited as a piece of arcana that nobody would need to know to do good medicine. I still have a yellowed copy of that piece.”

Seeking informaticists. “There’s currently a desperate need for people with knowledge in bioinformatics. In my laboratory I see individual graduate students or postdoctoral fellows who have a sort of precocious ability to handle the programs you need to do these analyses. I really encourage them to add those skills to their armamentarium because it gives them a breadth and a depth that will make them in demand—and will also accelerate their ability to frame their own questions and mine their own data.”

Mining and mulling. “I don’t think anything replaces revisiting your data—waking up and coming in and saying, ‘Let me look at that again. What am I missing?’ In this age, when everything is moving so fast, you have to say, ‘Wait a minute.’ And really keep doing it. One new question can lead you to re-mine the data and come up with a beautifully important pattern that wasn’t part of your original vision. That’s what’s good about the Cancer Genome Atlas project—not only what’s in the original papers but what’s still sitting there in the database for anyone to revisit.”

Sitting and thinking. “I like the small meetings the best because you can sit in one place and chew on things rather than running around trying to catch the next talk. The big meetings are important for young people, so they can get in and meet a wide swath of the community. But to actually get things you can bring back to the lab, ideas you can grow, I like the small meetings.”

Raising the bar. “The biggest value of journals like Science and Nature is that they hold up a bar that says: ‘Make your work special. Do the extra five experiments that will make your story worth publishing in a high-impact journal.’ Big awards are also like that. You shouldn’t come to work every day and be consciously aware of them. But awards that recognize someone who’s worked hard and done a great job are nothing to sneeze at.”

Redefining cure. “Cancer is such a complex, heterogeneous disease. If you block one signaling pathway, another takes over. So treatment can be tough. But if you can really slow the progression of the disease—slow metastasis or tumor growth—you’ll cut the probability that the next thing will happen to drive the cancer forward. I think that’s a realistic goal. I hope for an absolute eradication of cancer, but I’m less sanguine about that possibility. But reducing cancer to a chronic disease, slowing its progression, detecting it earlier—that’s a given. That’s going to happen.”

Baylin in Baltimore

Indulge. “I’m a well-controlled type 2 diabetic. Bagels are the worst. I love a good bagel, but they have a lot of sugar. So I miss those.” But Baylin is not beyond the occasional well-earned indulgence. In the wake of Hurricane Sandy, Baylin helped bail out the Cancer Center’s mouse colonies when sewage and rainwater flooded the basement. “The faculty were in waders, wandering through the fetid waters, rescuing freezer specimens and animal cages.” The reward? “They had bagels. So I ate half of one. And then I had a slice of pizza. You have to give in to whims and break the rules once in a while, do something crazy—in science and in life.”

Home sweet home. “Baltimore’s really a mystery to people who don’t know it. It’s got a lot of crime, a lot of murders.  But what people don’t realize is that Baltimore is a really great city near the water. The preservation of the waterfront has brought back tourists and conventions. Restaurants keep getting better and better. It’s got a great symphony. So there’s a lot to do here. Baltimore gets some bad press, but it’s a pretty good town to live in.”

Wailin’ Steve Baylin. “I play guitar—badly. And sing. I do it as therapy, for my own amusement. I love the blues. When I still worked in the lab, I’d go to a blues club and get my hand stamped. When the band took a break, I’d run back to the lab to change the fraction collector. Then I’d go back to the club, show my stamp, and catch the next set.”

Double take. In 2010, Baylin was featured in a public-service campaign designed to humanize biomedical research. The promotional event, dubbed “Rock Stars of Science,” paired researchers with celebrity performers for a photo spread that appeared in GQ magazine. “My shoot was with a rapper called B.o.B. I had no idea who that was, but when my grandchildren found out, they were ecstatic. I finally became the grandfather they always wanted.” Baylin didn’t get to see the spread until he picked up the magazine at the 7-Eleven he frequents for his morning coffee. “When I opened it up, the clerk leaned over and said, ‘Is that YOU?’ Then he added, ‘I always knew you were someone special.’”

 

Greatest Hits
• Characterized the biology and genetics of a rare, heritable form of thyroid cancer.
• Determined that methylation of cytosine bases in the promoter region of genes plays a key role in human cancers. Identified a handful of tumor suppressor genes that are silenced by this DNA methylation and continues to study how these alterations work in concert with mutations to drive the progression of cancer.
• Working with colleague Jim Herman, developed a technique, called methylation-specific PCR, for detecting and quantitating DNA methylation.
• Coordinates efforts to catalog the genome-wide epigenetic changes that contribute to human cancers.
• With research associate Heather O’Hagan and graduate student Wei Wang, discovered that chronic inflammation can rapidly promote the widespread methylation of genes, potentially laying the groundwork for cancer.