Xandra Breakefield has spent more than 50 years at the forefront of scientific discovery while quietly mentoring the next generation of researchers

By Mark Blackmon

 

“XOB.” That’s what’s written in permanent marker on the backs of stools that sit in front of the laboratory benches in one of the nation’s most noted molecular genetics and neuroscience labs. They are the unmistakable initials of the lab’s principal investigator, Xandra O. Breakefield ’64, a lauded scientist who very nearly had a career in a discount variety store.

“I had no desire to go to college at all,” said Breakefield, laughing, at the beginning of a wide-ranging interview at the Massachusetts General Hospital (MGH) campus at the former Charlestown Navy Yard, where her laboratory is located. Breakefield is a professor of neurology at Harvard Medical School and a geneticist with neurology and radiology services at MGH.

“My mother told me either I went to college or I worked in the dime store, so I decided I would try college.”  She did not, however, mount a serious assault on college admissions offices. “I only applied to one school—Wilson—and that was because [her sister, Susan Breakefield Fulton ’61] was there.”

She had attended public schools—and not very good ones, by her own reckoning—but within a week at Wilson, she said she was in love with the place and with learning. “I went to the bookstore and got 10 books and I was so excited that someone wanted me to read!”

Like many students when they begin college, Breakefield was unsure of her course of study. She explored English and philosophy, but found her Wilson science professors very inspiring.

And while she found science to be “fascinating intrinsically,” it was a chance reading of a newspaper article that really set her trajectory.

“When I was at Wilson—this is a classic story—I read in the Public Opinion that this scientist had discovered the code, OK, that three nucleotides can encode for an amino acid and this was the whole code of DNA, right? When I read that, I just was transported into another world. This was the most amazing thing I’d ever heard! Who would have thought?”

Breakefield decided to write this scientist a letter and told him that she would like to visit him. “And he actually invited me! So, I went to his lab and learned a lot about how they had found out this code and everything.”

Of course, the story doesn’t end there. As she was completing her doctorate at Georgetown University, she wrote to him again and said she would like to do her post-doctoral training with him. Again, he said yes. “So, I went back and did a post-doc with him.”

The scientist to whom Breakefield wrote was Marshall W. Nirenberg at the National Institutes of Health, one of the recipients of the 1968 Nobel Prize in Physiology or Medicine for breaking the genetic code.

After she finished her post-doctoral work, she took a job in the country’s first human genetics lab. Taking the same path she took at Wilson, she went to the bookstore and purchased all the books she could find on human genetics and after reading them, had an epiphany: “I was going to figure out what was wrong in these diseases and by figuring out what was wrong, I could figure out therapy.”
 
After more than a decade of working on human genetics and the role of genes in diseases, Breakefield led the team that discovered the first marker for the dystonia gene in 1989.

“We were part of the initial wave. Before they’d sequenced the human genome—before we even had computers—we were there at the bench just literally, blot by blot, working our way through. You do it through linkage,” she explained, “through association of pieces of DNA, but initially it was very hard work.”

Up to that point, Breakefield’s ideas had just been working theories; no one had ever found a gene that way before.

Dystonia is a neurological movement disorder in which sustained involuntary muscle contractions can twist and contort parts of the body. In 1997, Breakefield and her team identified and cloned the gene responsible for early-onset torsion dystonia and since that time, they have also worked to understand the function of the defective protein, torsinA.

Announcing the discovery, Breakefield called dystonia a “stealth crippler.” Despite dystonia’s frequency, its profile has not risen much in the popular media. “It’s quite unbelievable, actually,” she said, noting dystonia is the third most common movement disorder after tremor and Parkinson’s disease.

Breakefield’s indefatigable nature, determination and intellectual curiosity are particularly evident when she relates the story of the initial discovery of the dystonia gene.

All she had to go on was a theory, but she was determined to convince at least one neurologist to work with her to identify the gene. She felt that she needed a large family for the genetic samples, which proved to be difficult because the so-called “founder mutation” was in the Ashkenazi Jewish population, who tended to have smaller families.

She determined that once a large family was isolated, she would videotape the subjects and have movement disorder specialists rate the tapes to determine if the subjects were showing signs of the illness.

“I told this to a number of people and they couldn’t get me out of the room fast enough. They were like, ‘This lady’s crazy!’” she said, laughing. But, she pressed on.

“I’ve been kicked out of so many offices at this point,” she said, that it hardly mattered where she went next. So, she decided to call on Dr. Stanley Fahn, the physician who defined dystonia. Fahn told her, “OK, let’s do it.”

Breakefield found the family, proved her theory and continues to be at the forefront of discovery in her field. One of the projects she and her team are currently researching is the development of possible drug therapies to treat X-linked dystonia-parkinsonism (XDP), a genetic form of dystonia found almost entirely among males of Filipino descent.

Although people know how to isolate genes now, Breakefield stressed she is careful not to forget the human factor in her experimentation.

In the case of XDP, much of the affected population is in a poor region of the Philippines and “they literally sometimes chain these people in the basement. They’re never allowed out,” Breakefield said. “And now our clinical team is going there and trying to set up clinics, and some of these people are coming to the clinic [who] haven’t been out of their house for 10 years. They’re putting them in a truck because they can’t move there on their own. These are normal, intelligent people and they’ve literally been lying strapped to a bed for 10 years, maybe in part so they won’t hurt themselves, and now they are finally bringing them to the clinic so they can try to get them some medical care.”

There is always a dramatic story that unfolds when researchers begin to probe into the whys and wherefores of a disease—and that, Breakefield said, is what makes it meaningful. “You’re not working on an abstract problem. There are people suffering and you have the potential to find out what’s going on and to try to help them.”

Breakefield not only has been passionate about helping to alleviate suffering, but also in developing and mentoring the next generation of scientists and physicians.

In 2013, the Society for Neuroscience presented Breakefield with its Mika Salpeter Lifetime Achievement Award honoring individuals with outstanding neuroscience careers who also actively promote women’s professional advancement in the field.

In writing Breakefield’s nomination, Harvard’s D. Cristopher Bragg pointed out her unflagging efforts to promote the accomplishments of those who work for her, writing that “if there is one lesson that she has tried to teach [her trainees], it is that the focus of any lab should be on discovery, with all perspectives and contributions respected equally and all persons given equal opportunity and resources to succeed.”

Someone who agrees with that assessment is Jyotsna Dhakal ’14, a research technician in the Breakefield lab.

“It’s just sort of serendipity that I hired her,” Breakefield said, describing receiving an email from Wilson Associate Professor of Biology Brad Engle, recommending Dhakal just as she was on the cusp of offering the position to a postdoctoral candidate. It was also a gamble to offer the position to someone without advanced training.

Breakefield committed to Dhakal, but the true test came after she was hired, as the work requires an extremely high level of skill, precision and dexterity. “People either have it or they don’t,” Breakefield said. Soon after she began, it was clear that Dhakal did have it.

“She just started churning out the data,” Breakefield said. “We’d say, ‘Here’s the question, here are the samples, let’s ask this question,’ and she’d bring us back data we could learn something from.

“Brad Engle is really training at a high skill level,” she concluded.

Last year, Breakefield, who was elected to the American Academy of Arts and Sciences in 2013 and who earlier this year received the inaugural Bachmann-Strauss Prize for Excellence in Dystonia Research from the Michael J. Fox Foundation, was also a recipient of Harvard Medical School’s William Silen Lifetime Achievement in Mentoring Award.

“To be honest,” the self-effacing Breakefield said, “the first time I got one of these awards, nobody could have been more surprised than me.” And while Breakefield confesses that she’s still not sure exactly what makes her a great mentor, others are.

Dhakal said she believes that what makes Breakefield stand apart is that she relies on kindness. “Xandra says all these great things about us and we work to achieve them.”

“I just have complete confidence in her and so I think she responds to that,” Breakefield said of Dhakal. “She can do it. I know she can do it.”

Said Dhakal, “Just coming from Nepal, it’s been such a privilege for me to see a fantastic woman leader like Xandra because back home, you don’t get to witness many women in leadership positions and I think I’m really lucky to have her as a role model.”

For Breakefield, seeing the impact of her own work change lives is one of the driving factors in her determination to continue. Dhakal, meanwhile, is unsure of what her next steps might be.

“I told her she had to work for us for two years; then she can go off to graduate school,” joked Breakefield. “We can’t actually do that, but…,” she said, eyes twinkling. “I’m hoping Jyotsna will go to graduate school or medical school, depending on her orientation, and continue to work in the field and make contributions.”

Breakefield says that Wilson College was an enormous influence on her because it “did really turn me into a scholar.”

Later, she turned the focus of a question onto Dhakal. “The big story to me is that someone coming out of a small school could have received the superb training that [Jyotsna] received so that she could enter into a very high-powered research laboratory and just know exactly what’s going on,” Breakefield said, demonstrating precisely the behavior that her nominations for mentoring mention.

Wilson’s Brad Engle, who characterized Dhakal as having a “brilliant mind,” said that he believed training with Breakefield would expose Dhakal to new methods of scientific inquiry. He also felt that Dhakal’s already strong research skills would allow her to succeed. And while Breakefield believes that much of Dhakal’s prowess does stem from her own intelligence, she said it’s obvious that Dhakal gained a deep understanding of the rules of science and genetics during her undergraduate career.

Having a very capable student coupled with a superlative teacher is, said Breakefield, “a combination that can create an individual who is really ready for the workplace. [Jyotsna had] no hesitation. Never had a moment’s hesitation as far as I could see. You explain the experiment to her and she does it. Perfectly clear.”

After a moment, the mentor becomes more reflective. “I had to learn a lot along the way. Jyotsna seems to have come with a very clear idea of what we need to do and how to do it.”