Two Friends, 40 Years, and One Fresh Cancer Prevention
Tom Kensler and John Groopman's recipe for keeping cancer at bay
No turtle, thanks.
Tom Kensler had his fill of this delicacy decades ago, back in the early days of his cancer prevention research in eastern China. As study leader—and honored guest at many a rustic banquet—he had the dubious privilege of gnawing the gelatinous cartilage out of turtle shells clamped between chopsticks.
He nixes Brussels sprouts, too. Tom’s loathing of the mini cabbages, which traces back to boyhood, is only slightly more enduring than his scientific alliance with his best friend, John Groopman.
John, meanwhile, disses all dishes harboring hard-boiled eggs.
These few aversions aside, the pair peruses the menu. After feigning nostalgia for a burly hunk of pig’s lung and extolling the virtues of Singapore noodles—a staple that sustained them during grad school in the 1970s, at MIT—they settle on a platter of eel. And a side of garlicky eggplant. Both long for the green eggplants of the Yangtze River delta where they’ve led research studies for decades. But here, in a Chinese restaurant in Baltimore, the standard purple variety will have to suffice.
Curiously, neither is inclined—until prodded—to order broccoli. For two self-proclaimed “cancer guys” who occupy a daring public health niche they call “individualized prevention,” the omission is glaring.
Glasses in hand, John casts aside the menu in the manner of one who’s comfortable doing what he wants, even if it raises eyebrows. Even if it means going it alone on a complicated scientific journey.
Except, he hasn’t gone alone.
Tom’s been right there with him, presenting a united front for the long haul. Even when John “pushed him off a cliff” in 1991 (more about that incident later), Tom remained steadfast.
A shared vision as colleagues—a togetherness as friends—has made it tolerable, sweet even, to commit to taking research risks that might not amount to publishable results for decades, much less pay off in terms of grant money or glory.
Demonstrating with data that rats—and people—can stave off liver and lung cancer, requires, at the very least, an unusually tenacious force that’s both complementary and synergistic.
Tom: tall, lean, former first baseman; green-eyed; bio-chemical; reserved and intense; a challenger prone to caution; sporting a chunky MIT ring and a plaid shirt that’s predominantly green, the color of the mountains he loves to climb.
John: shorter, broader, former catcher; dark-eyed; analytical-chemical; animated and fiery; a free-thinking agitator; also wearing an MIT ring (though a tad smaller than Tom’s); his shiny black moisture-wicking shirt evoking the wet suit he wears while scuba diving.
The pair’s natural bond is underwired by an us-against-the-world mindset, one that esteems prevention over treatment.
“The truth is,” John says, “that no matter how early a tumor is diagnosed, 90 percent of all the biology that leads to its formation has already occurred. The time of diagnosis through therapy, and often to death, is relatively a small fraction of the life course of that tumor development. That’s the area called medicine. Prevention can happen during the 90 percent of the time prior to diagnosis. Which means there’s tremendous opportunity.”
Eighty combined years’ worth of expertise and painstaking data collection backs up this duo’s conviction that food-based strategies—a broccoli sprout brew, for instance—can intervene in how the body handles environmental assaults known to cause cancer.
Tom pours tea from a clay pot.
John taps the table—a Chinese signal for thank you, that’s enough.
The pair raises steaming cups. Their Mandarin toast, uttered in unison, translates, aptly enough, “To your liver!”
It all began with the liver.
John and Tom met in the 1970s as doctoral students at MIT, working in Gerald Wogan’s lab where the research focus was aflatoxin. The toxin, then known to cause liver cancer in animals, was a hot research topic. Aflatoxin, produced by a fungus, contaminated much of the food supply in many regions of the world; notably, in corn and peanuts improperly stored in the humid heat in parts of China.
Flash forward to a cancer meeting in San Diego in 1983.
Having purposely parted after MIT to avoid any competition that might erode their friendship, the pair were building academic science careers independent of each other—John at Boston University School of Public Health and Tom as a new assistant professor at Johns Hopkins. Energized by the meeting, they were critiquing posters on aflatoxin and sharing beers with Bill Roebuck, PhD, an expert in animal modeling and a friend from MIT who was at Dartmouth (and still is a professor of pharmacology and toxicology there). “We could do better than this,” one said. The idea: to investigate compounds they thought might reduce aflatoxin-induced DNA damage.
On bar napkins, they scribbled a plan that would become their first NIH grant together: a grant that has renewed every five years and still supports their research to this day.
The team showed, using Roebuck’s aflatoxin-exposed rats, how early generation cancer prevention molecules worked and, ultimately, why they were effective. The scientists demonstrated how a drug called oltipraz (originally used to treat intestinal worms), when given to rats exposed to aflatoxin, protected the animals from getting cancer by altering the way in which aflatoxin was metabolized.
They were so successful in preventing liver cancer in rats that, one fine day in 1991, John issued a declaration: “Tom, we’ve got to go into people.”
John’s parents had raised him to make a difference, impressing on him the importance of action. And Wogan, PhD, his mentor at MIT, espoused the philosophy that while understanding a mechanism is vital to good science, the ultimate purpose is to do something with that understanding.
Passive description was no longer enough, John insisted. He was tired of reading and writing research papers that concluded with “and the eventual implications of this finding . . . blah blah blah.” It was one thing to do the basic science; another to cure rats. Now they needed to look in people. It was time to stop playing it safe.
Tom and John join Gerald Wogan’s lab at MIT, bond over aflatoxin research.
John and Tom's team wins MIT softball championship.
Tom arrives at the Johns Hopkins School of Hygiene and Public Health.
The pair, with Bill Roebuck, launch ideas for their first NIH gran together. The grant begins in 1985.
John arrives at the Johns Hopkins School of Hygiene and Public Health.
Tom and John travel for the first time together to China to visit the Qidong Liver Cancer Institute.
Clinical chemoprevention trial of oltipraz is conducted in Qidong.
The terracotta warrior Qin assumes protective oversight of the laboratory in Baltimore.
Clinical chemoprevention trial of sulforaphane is launched in Qidong.
Qidong study collects its 5,000th urine sample.
The duo, with colleagues, publish the latest key paper on aflatoxin and liver cancer in humans.
John and Tom et al. publish broccoli sprout brew/chemoprevention paper in Cancer Prevention Research.
"But we don’t know anything about doing clinical trials involving people,” Tom countered.
A few weeks later, Tom gave his usual rat-mechanism-of-action talk at the American Association for Cancer Research meeting. Having been prodded by John—“What harm can come of it?”—he added an afterthought at the end of the lecture: “Since oltipraz is already safely used in people to treat schistosomiasis, we are very excited about moving this forward into clinical trials in people.”
He was nonchalant; just throwing out a concept; running the flag up the pole to see if anyone might salute.
One of his heroes—Lee Wattenberg, a founding father and guru of chemoprevention—instantly corralled him. “That was a great talk! Tell me more about this clinical trial you are running in China!”
Tom grimaces at the 23-year-old memory. “John pushed me off the cliff. I was in free fall.”
Now, the challenge was to design a study that would yield convincing evidence that their intervention was actually doing something. And learn how to write clinical trial protocols. And secure funding. And determine a study site.
China seemed a logical choice. Although vast and complicated, it was a hotbed of liver cancer. Plus, John had connections there—scientifically and emotionally. Closed to outsiders until the mid-1970s, it had loomed enigmatic throughout his life. His father, a flight surgeon in China with the Flying Tigers, had brought home a 1945 restaurant menu, among other remarkable souvenirs. (A Yunnan tin vase now in John’s Bloomberg School office seems particularly auspicious—and ironic—given John’s passion for environmental health and cancer prevention: Yunnan tin miners, he says, had among the highest rates of lung cancer in the world.)
John called on the head of the carcinogenesis program at the Shanghai Cancer Institute who arranged in 1993 for him and Tom to visit the Qidong Liver Cancer Institute (QDLCI). Their trip there from Shanghai involved a five-hour journey on an old Russian boat that finally tied up at a rickety dock, beyond which was flat farmland. QDLCI leaders drove them down a dirt road to the only hotel in town, a two-story concrete structure where the hot water ran (on a good day) a few hours in the morning.
Banquets were held. Protocol was observed. Plans were discussed. A foundation was laid for a clinical trial of oltipraz in humans. Trust, if it came, would take longer than it did for John and Tom to become experts at eating turtle with chopsticks. They were purposeful. Longevity and endurance were key.
“We needed to show we were not about grabbing samples, doing a one-off paper and moving on,” Tom says.
The following year, the QDLCI leaders returned the visit. At a meeting in the School’s boardroom at Johns Hopkins, Tom said his academic schedule would allow him in November to begin screening subjects in Qidong for a prospective trial. A senior QDLCI scientist countered thoughtfully that Qidong peasant farmers wear five layers of clothes throughout the winter and likely would not strip down then for blood draws, ultrasounds and EKGs.
“I realized at that moment the importance of making this a partnership. Of working together,” Tom says.
There would be more make-or-break moments.
On May 7, 1999, four months into a second, yearlong clinical trial of oltipraz, NATO forces bombed the Chinese Embassy in Belgrade. The trial was doomed, all assumed. Tom and his Qidong colleagues met with the villagers who felt compelled to protest America’s action; it was a matter of honor.
Luckily, by then, the people had been convinced of the merits of the study. They kept taking their oltipraz pills. They would boycott Coke instead of Tom and John’s study.
The chemoprevention clinical trial ultimately proved a principle, demonstrating for the first time that aflatoxin biomarkers could be reduced in humans in a way that would predict decreased disease risk.
“I don’t think it’s exaggerating to say their work is among the best in the field of cancer prevention,” says Wogan, then and still a professor of Chemistry and Biological Engineering at MIT.
By showing they could blunt the impact of aflatoxin exposure, Wogan says, John and Tom mitigated an important risk for liver cancer, which, globally, still claims the lives of a population equivalent to that of Baltimore each year.
The aflatoxin work gave the team the cred it needed to continue its quest to find new and better ways of providing the same cancer-preventing protection that oltipraz did.
As John said at the time, “The grand strategy here would be to develop a food source that provides the same protection at a lower cost.”
The changes in Qidong—indeed all over China—within just the past 20 years are breathtaking. Literally.
Tom recalls in the early ’90s being subsumed by a wave of bicycles—15 across and 40 deep—while stopped at an intersection in Shanghai. Not a private car on the roads.
“I do remember seeing a blue sky in China,” John recalls. “I think there were those two days in October 1993, in Beijing, when we saw blue sky. But the air pollution has been extraordinary, and getting worse.”
Far worse, in fact. Just last year, a doctor treating the country’s youngest patient ever diagnosed with lung cancer—an 8-year-old girl—attributed the disease to air pollution.
A choking yellow-brown cloud masks the horizon of the Yangtze delta, which includes the Qidong study site. Air pollution issues here, in the country’s fastest growing economic development area, don’t seem likely to be solved any time soon, John observes.
Which is why he and Tom—intent on refining a frugal and effective way to empower even the poorest individuals of high-risk populations to protect themselves from unavoidable environmental exposures to toxins—are so excited about broccoli tea.
A concoction of freeze-dried broccoli sprouts reconstituted with pineapple and lime juice, the brew was the centerpiece of a recent trial involving peasant farmers in Qidong’s He-He Township. The gist was: 291 participants drank either a broccoli sprout beverage or a placebo beverage every night for three months, and provided the research team with copious urine samples throughout. (The flare of attention from the global press when their results were published June 2014 in Cancer Prevention Research was foreshadowed several years earlier in a quiet Qidong field when Tom and colleagues set off fireworks to commemorate the 5,000th urine sample being collected.)
The research team measured biomarkers in the urine samples for products of air pollutants—most notably, benzene, a human carcinogen—and found a 61-percent increase of benzene elimination by broccoli-brew drinkers compared to people sipping the placebo. The broccoli brew worked rapidly, and caused a sustained change throughout the 12 weeks. The implication: Individuals adopting this simple strategy could safely thwart the harmful process of some cancer-causing substances by quickly eliminating the bad stuff instead of metabolizing it.
“In essence, we’re looking to mimic Al Sommer’s ‘4-cents-a-year-for-vitamin-A’ model,” Tom says, alluding to the Dean Emeritus’ groundbreaking strategy that was both frugal and effective in saving the lives of millions.
“This is not, underscore not, in any way, shape or form advocating that if you drink a broccoli sprout brew, you can go out into a polluted environment and breathe all you want,” John adds. “This is not to give license to polluters to keep on polluting. Rather, it’s part of a matrix of prevention strategies that need to be implemented to protect population and individual health.”
Often, in public health, prevention focuses on the removal of an exposure, such as taking lead out of house paint or cleaning up a water source. John and Tom’s tack is decidedly different. Their interest is in protecting people who don’t have the luxury of avoiding exposure, whether to air pollution or aflatoxin. Their answer is to reduce the dose that an exposed individual gets by tinkering with the body’s molecular processes.
Here’s a simple way of looking at it, John explains: You and three friends go to the beach. You all sit out in the sun for five hours. You wear a sunscreen with an SPF 50. Your friends wear SPF 30, SPF 10 and no sunscreen. Your exposure is exactly the same, but the dose of damaging UV rays that each of you gets is dramatically different.
The analogous SPF in broccoli brew is sulforaphane, a biologically active phytochemical found in cruciferous veggies; most abundantly in the young broccoli sprout. (It was in 1992 that the molecular structure of sulforaphane was published in PNAS and described as a “major inducer of anticarcinogenic protective enzymes.” Study co-author and Johns Hopkins School of Medicine professor Paul Talalay, MD, later working with nutritional biochemist Jed Fahey, ScD ’04, then set about demonstrating that broccoli sprouts are an exceptionally rich source of the compound.)
Sulforaphane targets a detox pathway known as NRF2, ramping up the production of enzymes that attach sugars or amino acids to toxins and make them more water soluble, so they slide out into the urine at a faster rate. Clearly, the less time a carcinogen spends meandering about in the liver or lungs, the better. But does this translate to better health and less cancer? The team didn’t measure health outcomes. They measured the rate of elimination of toxic stuff.
Still, the implications are delicious.
“If you believe that there’s a certain amount of exposure you need over a course of time to drive to a tumor endpoint, and if we can lengthen that amount of time by lowering amount of exposure, we can push that end point further out into the future, maybe adding 10, 20 or 30 years,” John says. He’s eager to begin the next clinical trial, set for this winter, again in China, where the team will measure the protective effect of lower doses of sulforaphane in a broccoli brew.
“No question, this is a career highpoint,” Tom adds, characteristically quiet but filled with emotion. “Not the end point—but the high point. I’m convinced there’s an opportunity here to improve public health.”
At the core of this team’s research is a quiet 2012 paper published in the journal China Cancer. It begins with the word “friendship.”
It’s a concept not often addressed in scientific papers, or cited by researchers. Indeed, John and Tom’s focus on friendship in this context is almost as rare as a wildly successful cancer prevention clinical trial. And almost as rare as an argument-free 40-year relationship—a phenomenon that each, independently, attests to. Heated but healthy discussions about scientific approaches, yes. There have been many. But arguments arising from anger, resentment or ego—not one.
“Did we decide at MIT to be colleagues for four decades, much less know how? No,” Tom muses. “In the beginning, we purposely went in opposite directions scientifically and academically. In order to stay friends, we went off to carve our own identities. And we realized over some beers that we could do better if we worked together.”
Team science was not the norm back then, especially “team” as in real, honest-to-goodness trusted friends, and not as in an arranged marriage or hierarchical fly-by-night groupings.
“You’ve heard that half of marriages end in divorce?” asks John. “I would estimate that 90 percent of scientific collaborations end in divorce. Maybe more.”
A fierce, if symbolic, protector of the pair’s unique partnership is Qin, the life-sized reproduction of a terra-cotta warrior that a couple of thousand years ago guarded the mausoleum of China’s first emperor, and today stands poised for battle at the doorway of John and Tom’s merged lab, a scientific sanctuary on the seventh floor of the Bloomberg School. This lab is the nucleus of an alliance that is as extensive as it is lasting. John and Tom have embraced a breadth of expertise: team members from China; from the Wogan lab (notably Bill Roebuck as well as Jerry Wogan); and, of course, from throughout Johns Hopkins.
Alvaro Muñoz, PhD, MS, a Bloomberg School Epidemiology professor, has figured prominently for 20 years in both the design and data interpretation of the pair’s liver and lung studies. All would attest that he has added his own blend of salsa to the mix. (A Colombia native prone to referring to acquaintances as “amigos,” Muñoz immediately endeared himself to QDLCI leaders when, prior to competing in a soup-slurping contest, he introduced himself as a former goat farmer from north of Beijing.)
“They love to have a good time,” says Bloomberg School senior scientist Patricia Egner, MS, a master of mass spectrometry who has served as clinical coordinator for the studies in China. “John and Tom are very loving people.”
The pair has shared the love—particularly, the acclaim that comes from a much-coveted first authorship—with each other, with grad students and with colleagues like her, says Egner. Her name appears with John and Tom’s on the “friendship paper,” formally titled “Twenty Years of Collaboration with the Qidong Liver Cancer Institute: The Johns Hopkins Experience.”
It could be that, in an enduring friendship that is mutually nurturing, John and Tom have found the holy grail of cancer prevention, muses Wogan: that is, partnership seems likely to be a key to success in this complicated field marked by long-standing principles yet little progress.
“Others have done good work and deep studies and produced very strong data in animals. But translating that to people has proven a frustrating undertaking,” Wogan notes.
Those “others” he refers to have tended to be individual investigators. They didn’t have a best friend to push them off a cliff.
“The dynamic that’s at work between them is unusually complementary,” Wogan says. “There are very few examples of this kind of successful interaction and longtime collaboration that I can think of.”