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Choreographing a Cancer Treatment

Researchers consider a screen.

In October 2014, biochemist Dorothee Kern had her first investor meeting at Third Rock Ventures, a leading biotech venture-capital firm in Boston. Having spent her entire career in academia, Kern knew little about business, even less about how to land funding.

She was shown to a conference room where a dozen of the firm’s principals sat around a table. As they looked expectantly at a widescreen display on the wall, Kern, who speaks German-accented English at a rapid-fire pace, cued up her PowerPoint presentation on the research she was doing. The first slide showed a typical illustration of a protein molecule — a cluster of multicolored balls, each representing an atom, arranged in a rough circle.

With a click on her laptop screen, Kern launched the presentation. A Lady Gaga song began to play. The balls in the protein pulsed to the beat. Third Rock’s venture capitalists, among the most ambitious, discriminating and successful in the region, with billions of dollars in biotech investments, listened as Gaga sang, “Just dance / Gonna be OK / Da-da-doo-doot-n / Just dance.”

Kern told the investors she wanted to start a pharmaceutical company called Dance to develop breakthrough treatments for cancer and neurodegenerative diseases like ALS and Parkinson’s. Its approach would be rooted in her 30-plus years of research into how proteins move and change shape.

Her pitch included no financial information or revenue projections. Nevertheless, a few weeks later Third Rock told Kern they were interested. They offered an initial $57 million investment. But they wanted a different name. “Dance” sounded too frivolous. Eventually, the company was named Relay Therapeutics, suggesting the dynamism and coordinated activity of protein atoms in a relay race.

So far, Relay has raised more than half a billion dollars in funding. If all goes as planned, the company will begin a clinical trial of a novel cancer treatment next year.

If that goes well, many more drugs are likely to follow.

A high-energy scientist

Kern’s office on the fourth floor of Brandeis’ Volen National Center for Complex Systems is a mess — books jammed pell-mell onto shelves, papers and folders piled high on a desk. Kern, who goes by the nickname “Doro,” is old-school, preferring to take notes by hand in notebooks, which are scattered around, too.

“My rule is if I can find the stuff I’m looking for in two minutes, I don’t have to clean up,” she says. “Unfortunately, I can still find things in two minutes.”

To be around Kern is to experience her protean vitality. “Doro has the highest energy — the highest vapor pressure — of any scientist I’ve ever known,” says biochemistry professor and longtime colleague and friend Chris Miller. “She’s constantly bouncing around, in motion, both mentally and physically. It makes me feel very old.”

Growing up in what was then East Germany, Kern could never sit still. She remembers hurriedly doing her homework between classes so she could rush home and ride her bike around her hometown, Halle, about 100 miles south of Berlin. She started playing basketball at 7. By her teens, she was the point guard on the East German national team. At 5 feet, 6 inches, she was much smaller than the other players. Her speed, smarts and grit were her advantage.

Today, photos of her daughters, Nadja and Julia, hang on her office wall. Both are champion athletes, like their mom. Nadja played basketball for the University of California, San Diego, and is now a biophysics graduate student at UC San Francisco. Julia, a part-time undergrad at Dartmouth, is a cross-country skier on the U.S. Ski Team and recently competed in her first world championship. Kern coached them both.

Kern still plays basketball five days a week, either at the Gosman Sports and Convocation Center or the Waltham YMCA. All the other players are men. Chris Wilson, PhD’17, a former graduate student in Kern’s lab who’s now at Harvard, says he was warned not to go up against his mentor in basketball: She played hard and tough, and occasionally rough. There was no chance he’d beat her.

“My mom is one of the most competitive people I’ve met,” says Nadja. “When she’s guarding someone, she’s like, ‘I’m going to stop them. They’re not going to score on me at all.’”

Kern’s style is completely different in the lab. Collaboration, not competition, prevails. Her researchers hang out together on weekends and hold regular Friday beer-and-movie nights at Volen. When they publish a paper, they party at Kern’s Waltham home. Wilson says that if Kern catches a mistake you’ve made, you feel as if you’ve let down your parent.

Every summer, Kern and her husband, Gunther, who has worked in the biotech and pharmaceutical industries for years, organize a two-day camping retreat for the lab on a Cape Cod beach. The couple arrive in a weather-beaten Volkswagen bus filled with athletic equipment — nets and balls for volleyball, surfboards, kayaks, fishing poles and skis on wheels for summer cross-country training. At night, everyone sits around a campfire roasting Knüppelkuchen, German “stick bread” cooked over a flame and filled with applesauce.

Kern attributes much of her success to the students she’s worked with over the years. She says Brandeis attracts people who pursue science out of passion and curiosity, not out of a desire for prestige or career advancement.

“We get students and postdocs who are willing to take risks,” she says. “I always say, ‘No risks, no fun.’”

Targeting the weak spot

A few years ago, Kern and her husband got into a spat about the value of scientific research.

Kern made the classic argument for basic science: Only when you understand the fundamentals can you make true progress in treating disease. And even if this doesn’t happen — if research doesn’t prove relevant — pursuing knowledge is still worthwhile for its own sake.

“It’s only great research if you can apply it,” responded Gunther, who is vice president at C4 Therapeutics, in Watertown, Massachusetts, which is developing new cancer treatments. “What good is it if it can never be applied?”

Kern brooded for a few days. She thought Gunther was slighting her work. Then she thought he might have a point or, at the very least, might be issuing her a great challenge. Could she find practical applications for her work?

“I am an optimist by nature and like to go for big goals in life,” she says. “The word ‘doubt’ does not really come into my mind.”

She began looking at how several recent cancer drugs worked. She discovered that their success in inhibiting the activity of cancer-related proteins was rooted in protein dynamics, a fundamental novel finding. As the proteins moved and evolved, weak spots in their structure were exposed. The drugs targeted these locations and changed the protein’s behavior so it no longer contributed to its host cell’s growing tumorous.

Kern quickly grasped the implications. Protein dynamics were the key to developing new drugs. First, you find the molecule’s Achilles’ heel, then you look for the compound that will bind to it.

This was the novel concept Kern pitched to Third Rock. Kern and Third Rock brought in David Shaw, a successful New York hedge fund manager, to serve as a Relay Therapeutics co-founder. Shaw — who, according to Forbes, is the 85th-richest American — founded D.E. Shaw Research in 2002 to do work in computational biochemistry.

Shaw provided Relay with a specially designed supercomputer for simulating protein motion. Now in its second iteration, it’s called the Anton 2, named for Antonie van Leeuwenhoek, the 17th-century father of microbiology. A typical protein contains tens of thousands of atoms. Calculating all their possible interactions to simulate protein motion requires enormous computing power. Using conventional computers, it can take days to simulate one microsecond of a protein’s movement. On the Anton 2, simulations of 10 to 20 microseconds can be run in a single day.

Traditionally, pharmaceutical companies use a trial-and-error approach to finding new drugs, trying out compounds one by one until they find the best option. The Anton 2 takes some of the guesswork out of the process. Its simulation of protein motion makes it easier to find compounds that successfully interact with the protein.

“We’ve shown that Doro’s hypothesis — if you could understand how these proteins move, you could design better medicines — is true,” Shaw says. “We’ve been able to target some of the hardest problems in drug discovery that scientists have been wrestling with for decades.”

Science under communism

Kern always knew she wanted to be a scientist. Her parents, Gerhard and Gertraude Hübner, were biochemists at Martin Luther University Halle-Wittenberg. Family dinnertime conversation focused on biochemistry research.

In the 1960s and ’70s, East German academics had to cooperate with the communist regime if they wanted to advance their career. Several of the Hübners’ colleagues collaborated with the Stasi, the East German secret police. The Hübners refused to do this, says Kern. They also wouldn’t join the Communist Party.

As a result, Gerhard was denied a full professorship and remained a research scientist. One day when Kern was 6, Gertraude received a paycheck with zeros written in for the amount. It was the Party’s way of firing her. She went to work at a liquor factory, inventing artificial methods of aging cognac. Kern remembers hearing a click-click-click when she picked up the family’s home phone, the sign the Stasi had tapped their line. Government officials read any mail the family received that had been posted from the West.

Because high school was a privilege reserved for Party loyalists, Kern was initially told she couldn’t attend, despite being her lower school’s top student. Without high school, she would have been forced to work in a factory. But Kern had recently made the junior national basketball team, and her parents were able to convince the government this was a public service worthy of reward. (Fortunately for Kern, women’s basketball wasn’t an Olympic sport in East Germany, so the regime didn’t bother doping the players. Many of Kern’s friends who swam or ran track returned to school with facial hair and bulging muscles after several months of Olympic training.)

After high school, Kern studied biochemistry at Martin Luther University, where she would earn her bachelor’s, master’s and doctoral degrees. In 1987, she heard Swiss biophysicist and future Noble Prize winner Kurt Wüthrich speak in Halle at the Leopoldina, one of the world’s oldest scientific academies (Kern was inducted into it last year). When the communists were in control, East German scientists were not allowed to travel to Western countries, and the Leopoldina’s annual meeting was the only way East German scientists came in contact with international researchers. Otherwise, East Germans caught only glimpses and rumors of research underway in the rest of the world.

In his talk, Wüthrich discussed nuclear magnetic resonance spectroscopy, a technique he had pioneered for taking images of proteins at atomic resolution. By subjecting proteins to a powerful magnetic field, NMR spectroscopy produces detailed and complete images of a protein’s structure. Wüthrich’s use of NMR was a revelation to Kern — not so much because of what he was doing with it but because of what it inspired her to think about. Wüthrich made images of static proteins. Kern knew proteins inside our cells are not static. She wanted to use NMR to create movies of proteins as they changed and functioned.

East German researchers lacked adequate equipment to carry out experiments. Kern managed to get her hands on a very basic NMR spectroscopy machine, which didn’t come close to the power of those in the West.

In 1989, the Berlin Wall fell. Sture Forsén, professor of physical chemistry at Sweden’s Lund University, who had heard about Kern’s experiments, invited her to collaborate with him. This gave her access to Lund’s cutting-edge NMR machine.

Growing up, Kern and her family had gone on annual camping trips to Rügen, a Baltic Sea island in East Germany’s far north. The East German government didn’t allow anyone to take a boat, even a dinghy, out to sea because they feared people would try to defect. In the far distance, Kern would see the ferry that brought Swedes to East Germany for brief outings. “Oh, if I could one day be on it,” she’d think.

Now she would take that ferry every month, her proteins in little vials in her backpack, to study their motion at Lund.

Rewinding a billion years

In 1991, Kern attended a scientific conference in Bayreuth, Germany. Bored by a monotonic lecturer, she struck up a conversation with the researcher sitting next to her, who introduced himself as Gunther Kern. They invited each other to their poster sessions. Soon she and Gunther, who was raised in West Germany, were dating. “I guess we took the unification of the country literally,” says Doro.

The couple returned to Halle when Gunther took a position as a postdoctoral fellow in Doro’s father’s lab. Doro became pregnant with Nadja during the last year of her PhD. Her adviser didn’t think a woman could be both a scientist and a mother, and stopped paying her.

Kern finished her dissertation without pay while nursing her newborn, then grew restless for a new project. Her father had long studied how vitamin B1 is activated by enzymes, a type of protein that catalyzes biochemical reactions. Working with her father and her husband, she applied NMR spectroscopy to create a film of the process. “Gunther, my father and I took turns doing experiments and taking care of the baby,” she says.

Their findings appeared in 1997 in the journal Science. “It’s still some of the most exciting researchI’ve ever done,” says Gunther.

Since Kern was a child, she’d dreamed of playing basketball and studying science in the United States. As an undergraduate, Gunther had done a fellowship at the University of Colorado Boulder. After they both received postdoctoral fellowships at the University of California, Berkeley, they decided to move to the U.S. permanently.

In 1998, Kern’s vitamin B1 research helped her land a tenure-track professorship at Brandeis, where she began pursuing additional techniques for studying protein dynamics. One technique, X-ray crystallography, transforms proteins into solid crystals that resemble tiny shards of glass, then exposes them to X-ray beams. Measuring the beams’ diffraction helps scientists infer the location of the molecule’s atoms in the crystal. Although X-ray crystallography has greater resolving power than NMR, it reveals less about a protein’s movement. Kern’s lab combines the experimental results with massive computer simulations to predict protein dynamics.

Since few scientific labs use such a diverse range of approaches, Kern is known for her versatility in approaching a problem from multiple perspectives. “There are a lot of labs that will specialize in one method, and use and use it,” says Chris Wilson. “Doro’s much more, ‘If the question leads to a certain place, then let’s use the best approach to answer it.’”

By 2005, Kern had been named a Howard Hughes Medical Institute investigator, an award that includes an annual stipend of $1 million in unrestricted funding.

In the early 2010s, after her argument with her husband over the purpose of scientific research, Kern turned her attention to a cancer drug called Gleevec (known generically as Imatinib), hailed as revolutionary when it came on the market in 2001. Unlike chemotherapy, which wipes out tumorous cells but also decimates healthy ones, Gleevec homes in on its target — an enzyme called Abl, implicated in myeloid leukemia — with ultra-precision. Because Gleevec doesn’t inhibit any other enzymes, leukemia could be cured with minimal side effects.

Another enzyme, Src, is almost identical to Abl. What’s more, the pocket in Abl where Gleevec attaches itself has the same structure as one in Src. So why does Gleevec bind to Abl 3,000 times more tightly than it does to Src?

Kern solved this riddle using a novel technique. Essentially, she programmed a computer to run the clock back a billion years, when the planet had only one continent, life mostly consisted of ocean-growing algae and fungi, and Abl and Src had yet to evolve from their common ancestor. Once Kern’s team discovered the common ancestor’s structure and dynamics, she let time go forward, identifying the mutations that differentiated its descendants along the way.

What she found validated her 30-year approach to proteins. The key differences between Abl and Src lay in how they moved. A difference of merely 15 amino acids changed the amount of time the enzymes spent in different transformation structures. Kern’s paper about her discovery, which she co-authored with her postdoc Roman Agafonov, and graduate students Chris Wilson and Marc Hömberger, PhD’18, appeared in Science in February 2015. The journal’s editors later named it one of the year’s breakthrough papers.

Next, Kern studied three other cancer drugs and found their success also resulted from capitalizing on the proteins’ dynamic nature. It was a watershed moment. If you understood protein dynamics, you could find the molecule’s weak spot. Then you could identify the right drug to go after it.

In a paper in press, Kern has shown she could do just that. She focused on a class of proteins known as kinases, which are a major cause of many cancers. On any kinase molecule, there are numerous allosteric sites, essentially toeholds and footholds where other molecules bind to change the protein’s behavior.

Kern demonstrated she could successfully target these allosteric sites to dampen kinase activity, potentially turning them noncancerous. Just as important, she showed she could increase kinase activity as well. Upping the activity level could be a way of fighting many neurodegenerative diseases characterized by decreases in protein activity. As Kern sees it, allosteric sites act as knobs, which can be dialed up or down to modulate kinase behavior and fight disease.

The combination of understanding how cancer drugs work on proteins and identifying a novel method of going after allosteric sites convinced Kernshe’d discovered a radical approach to drug discovery.

Collaboration meets commercialization

In February, Relay Therapeutics moved into its new, nearly 50,000-square-foot headquarters in Cambridge. It features the latest trends in office design — open floor plan, common areas with beanbag chairs and dining spaces, taps that dispense iced tea and coffee. In a separate area, gleaming under fluorescent white lights, are labs filled with high-tech equipment.

The company’s co-founders include Matthew Jacobson, a chemistry professor at the University of California, San Francisco, and Mark Murcko, who previously worked at Vertex Pharmaceuticals, one of the biggest biotechnology firms in the world. Relay’s 95 employees include biologists, biochemists, biophysicists, chemists and computer scientists. They make proteins and compounds on an industrial scale, input experimental data into the Anton II supercomputer and verify the machine’s findings.

Kern schedules “Doro Relay days” every few weeks, going over to company headquarters to talk to the scientists and the leadership team. She discusses the latest research results, brainstorms next steps and, just as important, conveys her enthusiasm for the work.

Last year, the Boston Business Journal named Relay the best place to work among the region’s small businesses. Sanjiv Patel, Relay’s president and CEO, says the company’s work environment is inspired by the collaborative ethos of Kern’s lab. “She was just as focused on building a great culture as building a great company,” he says. “She sees it as critical to doing great science. One leads to the other.”

Moving back-and-forth between academia and the business world is still a bit awkward for Kern. She’s used to being at a university where, she says, she has “the intellectual freedom to do things everyone else says is crazy and can’t be done.” In the for-profit sector, there’s more urgency to producing revenue and satisfying investors.

The truth is, Kern would have been content focusing on her research at Brandeis for the rest of her career. But the prospect of starting Relay was just too compelling.

“Discovering a novel concept for drug design opened a unique chance to save human lives with our research,” she says. “I had to go for it.”

By Lawrence Goodman

This content was originally posted by Brandeis University