CCB grad polishes gene editing, wins half-marathons, and tries her best not to knock anything over

By Caitlin McDermott-Murphy

 

 

Holly Rees thought she was too clumsy to be a chemist.

During an important college exam, she spilled copper sulfate all over her bench and, somehow, her eye. The nurse washed the chemical out easily enough, but self-doubt remained. So, undergraduate Rees sought solace from a chemistry graduate student visiting her school, Clare College.

“Today was just dreadful,” he told her. “I’ve been working on this thing for a week and then I just dropped it on the floor.” He mopped up a week’s worth of work.

“Wow,” Rees thought. “This only happened to you once? During your whole PhD? I’m never going to finish.”

For most students, graduate school’s competitive culture, publishing panic, long hours, elusive breakthroughs, and—for women like Rees—gender imbalance, intimidate the best of the Mensa. But Rees faced just one bulky obstacle: her own clumsiness.

Born in Scotland and raised in England, Rees speaks with a blended British accent, more London than anything else, and roller-coasters from laboring deliberations to unrestrained speech as springy as her hair.

Even before the clumsy question, Rees wasn’t keen on chemistry. When she received the lowest score out of all her secondary school classmates, she told her parents—including her chemist father—she would never do it again. “Unfortunately, it was compulsory,” Rees says. Unfortunate for the twelve-year-old Rees, maybe.

After chemistry shifted from liquid mixtures to theoretical problem-solving, she set aside her clumsy fears and got to solving. As the only woman out of about 30 undergraduates in her theoretical chemistry class, Rees felt no animosity, no gender-based doubts, no imposter syndrome. “Everyone kind of just got on with it,” she says.

Then, when graduate school loomed with high reputations, expectations, and gothic spires, her father—a former postdoc in E. J. Corey's lab at Harvard—calmed her fears. With all other barriers behind her, clumsiness seemed small, surmountable. She applied to her father’s former department and got in.

As a graduate student at Harvard, Rees joined the lab of David R. Liu where she re-focused her clumsy crusade on the CRISPR genome-editing tool, polishing the proteins to make them more precise, accurate, and efficient.

Our DNA has billions of base pairs, which can mutate at birth or over a lifetime. While most of these shifts are benign, sometimes a single change—a C:G base pair that mutates to a T:A, for example—can have devastating consequences. Sickle cell anemia, muscular dystrophy, and progeria, a disease that causes rapid aging and an average lifespan of just fourteen, can all result from one disastrous mutation.

 

	Holly (third from left) is not the only runner in the Liu lab. Here, she embraces her lab and running mates after a Cambridge, MA 5K. From left: Philip Lichtor, Jeff Bessen, (Holly), Alix Chan, Ahmed Badran, and Ariel Yeh
	Holly (left) stands with David Liu and Nicole Gaudelli in their lab at the Broad Institute.  Photo by Casey Atkins.

 

CRISPR promises a path to a solution. Often advertised as genetic scissors, the tool can find and cut a specific area of DNA, which triggers stochastic changes in the genetic code. So, if a mutated gene malfunctions because of one errant C: Snip! CRISPR slices through both strands of DNA and disrupts the problem gene. But fixing a genetic disease is not that easy.

For patients with some forms of progeria, for example, a T:A pair replaces a C:G pair, causing children to age at a rapid and fatal rate. If CRISPR cuts a patient’s DNA at the mutation site, the tool might just disrupt the problem gene. Or not. When DNA rushes in to repair the cut, random letters get shoved into the gap. And if the hasty repair is not performed perfectly, the progeria symptoms persist.

To solve this, Liu and his team transformed the CRISPR scissors into pencils, capable of erasing just one point mutation and replacing the gap with a letter of choice. Their genetic pencil is called base editing.

“The base editors actually make very precise mutations by doing chemistry on the genome,” Rees says. Their improved tool—sometimes referred to as CRISPR 2.0—can seek out and bind to a specific base and, once bound, perform chemistry to rearrange the atoms of one base and transform it into another.

When Rees first joined the Liu lab, “there was none of this chemical base editing stuff,” she says. Alexis Komor, a former postdoc in the lab and now an Assistant Professor at the University of California, San Diego, designed the first C to T editor shortly after Rees arrived. Then, together, Rees and Komor polished the tool, making sure the pencils didn’t erase and replace more than their intended targets.

So-called “off-target editing” is one obstacle the lab needs to overcome before base editing can be used in human clinical trials. So far, more than 1,000 researchers around the globe currently use base editors in research on bacteria, plants, mice, and primates. In mice, the genetic pencil has already been used to correct point mutations that cause human genetic diseases.

Rees hopes these trials will one day lead to safe treatments for humans, too. “Point mutations actually account for more than half of the known disease-associated mutations in humans,” she says. Once polished, they could potentially cure sickle-cell anemia, muscular dystrophy, progeria, and more.

The Lab has made progress: Nicole Gaudelli, another former postdoc, designed an elusive A to G base editor, and Rees and her lab mates honed the original designs to prevent more off-target edits in both RNA and DNA.

But for her final project, Rees turned away from base editing to improve a more traditional approach to genetic editing: homology-directed repair (HDR). In this method, when CRISPR cuts DNA, a pre-made replacement piece is sent in to patch the gap. “The really nice thing about that is you can make any mutation that you’d like,” Rees says.

Base editing is limited to converting a C:G base pair to a T:A or a T:A to a G:C; with HDR, all changes are possible. But, HDR relies on cellular division; most cells in an adult body no longer divide. So, while useful for science, Rees doubts the technique’s therapeutic future.

Rees’ future is not in doubt: In March, she joined Beam Therapeutics, Liu’s start-up. There, she’ll continue to hone CRISPR base editing alongside her former lab mate, Gaudelli.

Rees might spend up to 90 hours in the lab during an especially congested week. But she still manages to run in races from the mile all the way up to the marathon. She won the women’s division in the New Bedford Half Marathon, and came in first in her age group in the 3,000-meter race at the British Athletic Championships and the 10,000-meter at the James Joyce Ramble in Dedham, Massachusetts. She also broke the five-minute mile barrier, all within the last year of her PhD.

Clearly, clumsiness doesn’t slow her down. Rees may have knocked over countless boxes of pipettes, scattering the clear, clattering masses like hundreds of hollow toothpicks across the lab floor. But even if she can’t restrain her unwieldy elbows, she can still work to improve CRISPR’s dexterity and, one day, knock out some of our most trenchant genetic diseases.