Part I: Lynne Maquat’s 40-Year-Voyage to Solve the Mysteries of Gene Expression

“Beam me up, Scotty!”

The famed Star Trek phrase sped through 17-year-old Lynne Maquat’s head while standing anxiously in front of her high school classmates in the spring of 1970. She was about to give a dreaded final presentation in a public speaking course, and prayed that she might be magically transported to the Starship Enterprise, or at least, that the right words would find their way from her brain to her lips.

Fast-forward to October 2017, and all eyes are on her again as she speaks before more than 200 doctors and scientists at one of the oldest and most prestigious medical lectures in the country.

There is no trace of the shy girl—the first in her family to attend college—as she flawlessly summarizes more than three decades of RNA biology research in 30 minutes, engaging the Harvey Society Lecture audience at Rockefeller University with her quick wit and humor. There is no fumbling for words as she effortlessly explains how solving the vast and complex mysteries of gene expression may one day help to cure nearly every disease on the planet.

Impeccably dressed—as is her trademark—in an elegant, custom-tailored ball gown, Maquat could be any graceful woman laughing and mingling over cognac at the post-lecture reception in New York City. But beneath her feminine, fashion-forward exterior is a gritty and determined iconoclast. She is living proof that doing things the hard way—defying doubts, exceeding expectations, and pushing boundaries—
is the right way, and the only way for her.

Poised on one of the newest and most promising frontiers of discovery, Lynne Maquat, PhD, is boldly going where few scientists have gone before.

“Lynne has always done things that seemed counter to doctrine, things so strange that you think they just couldn’t happen,” says her friend and colleague Gregory Petsko, PhD, professor of Neuroscience in the Brain and Mind Research Institute at Weill Cornell Medical College. “But she believes in what she’s doing and never gets discouraged. Her science is rigorous and deep, and you’re a damn fool if you don’t believe her.”

Years of meticulous focus led to Maquat’s discovery of nonsense-mediated mRNA decay (NMD), one of the most prominent surveillance systems in the body to protect against mistakes in gene expression that lead to disease. Maquat and other scientists are now working to gain a deeper understanding of the sophisticated mechanisms related to NMD, knowledge that is contributing to the development of new drug therapies for genetic disorders such as Fragile X syndrome, cystic fibrosis, and hundreds of others.

“Before Lynne, we really didn’t know how NMD worked,” says Joan A. Steitz, PhD, the Sterling Professor of Molecular Biophysics and Biochemistry at Yale University and an investigator at the Howard Hughes Medical Institute. “It was clear that this process was importantbut it was a huge, looming question in the field.”

Solving that looming question, and a litany of subsequent accomplishments as a researcher and mentor, place Maquat at a table with the most influential scientists in the world.

A member of the National Academy of Medicine (2017) and National Academy of Sciences (2011), she is the recipient of Canada’s Gairdner International Award (2015), the RNA Society Lifetime Achievement Award in Science (2017), and the Vanderbilt Prize in Biomedical Science (2017).

In February, she received the 2018 Wiley Prize in Biomedical Sciences, one of the highest international honors recognizing the work of researchers who improve the understanding of biological systems and processes, champion novel approaches, and challenge accepted thinking.

Indeed Maquat’s success flows from her courage to go against the grain of conventional wisdom and her willpower to “get back in the ring” any time the strength and validity of her science was questioned.

Now at the pinnacle of her career, she admits it’s not always pleasant to revisit her early years when she wasn’t as sure-footed as she is now in the highly competitive, male-dominated arena. But she acknowledges the lessons other aspiring scientists—men and women—might learn from her journey.

“I have given a very large chunk of my life to science, but science also saved me,” she says, adding that the solitary pursuit of answers—sometimes huddled over a microscope in a darkened laboratory until the wee hours of the morning—helped carry her through difficult chapters in her life. “There were hard times when it would have been easy to quit, but I never retreated. My salvation was always my work, not as an escape, but as a portal to a better place.”

Her work, she explains, not only enabled her to support herself financially, but also to make amazing discoveries, train young scientists now running labs all over the globe, and work toward desperately needed therapeutics for complex diseases.

“Today I can pretty much go anywhere in the world and have friends,” she says. “How wonderful is that? What’s most important to me now is staying devoted to my science, and giving back as much as I can.”

At age 65, the exceptionally youthful J. Lowell Orbison Distinguished Service Alumni Professor in the Department of Biochemistry and Biophysics, seems to be just warming up for the next stage of her career.

“She’s like the Energizer Bunny,” says Robert H. Singer, PhD, professor in the department of Anatomy and Structural Biology at Albert Einstein College of Medicine. “When other people bow out, she keeps going.”

While Maquat frequently treks to far-flung locales for speaking engagements, conferences, award ceremonies, and mentoring work, she calls Rochester home.

“Being a part of the larger University and city community and being able to interact with such highly accomplished people here, not only in science but in history, music, and art, is inspiring and so important to my perspective and vision,” she says. “When I have space in my brain to be perceptive, the best ideas come through.”

Making Strides

Whether crossing city streets, navigating hospital hallways, running her laboratory in Rochester or visiting others around the world, Lynne Maquat doesn’t “walk” anywhere—she strides.

Her slender 5’11” frame is in constant motion even while meeting in her always-open-door office as she chews on a piece of gum, peers over her glasses at data, pecks away at her standing computer keyboard, or rolls her chair across the floor to grab a folder from a teetering pile on her desk. Her physical energy is surpassed only by her quick mind, which you can almost hear whirring like hummingbird wings as she dives from one topic to the next.

She runs a relatively small lab for a scientist who has produced a football-field- sized list of 130 publications, 23 book chapters, and too-many-to-count editorials and presentations. She’s trained more than 50 post-doctoral fellows, undergraduate and graduate students who now work at institutions such as the National Cancer Institute, University of Texas Health Science Center, Pasteur Institute in Lille, France, A*STAR Institute of Medical Biology in Singapore, and the University of Geneva in Switzerland.

It’s an impressive resume for any scientist, let alone a woman who was told in grammar school that she wasn’t college material.

“If you had told me when I was younger that one day I would be giving the Harvey Society Lecture, first of all, I wouldn’t have known what it was, and second of all, I wouldn’t have believed you,” she says.

What’s a Scientist?

Growing up in the pastoral town of Easton, Conn., Maquat’s mother was a registered nurse and operating room supervisor, and her father an industrial mechanical engineer trained under the G.I. Bill. Her first inkling of an interest in science was apparent in her love of the outdoors, and her ability to recall the names of native birds, plants, and trees. In school however, she gravitated more toward the arts. She liked English and writing, became fluent in Spanish, and played piano and clarinet.

“I didn’t have the foggiest notion of what a scientist was,” she says.

Though she was a strong student on paper, her intellect was often overshadowed by her shyness around her peers and her teachers. “I would clam up when my fourth-grade teacher called on me, because I was afraid of her,” recalls Maquat.

Later, that same teacher told her mother that Maquat didn’t have what it takes to go to college, and should put it out of her mind.

“I often tell that story to high school students as a reminder to never allow themselves to be defined or held back by anyone,” she says.

Indeed, Maquat’s grades spoke for themselves, and she enrolled at the University of Connecticut-Storrs in 1970. It was there, studying under biochemist Stuart Heywood, PhD, that she was drawn to the beauty and mystery of science.

She was fascinated by the subject matter of Heywood’s Cell Biology course, and his studies of protein synthesis in embryonic chick muscles. When the course ended after her sophomore year, she desperately wanted to work in Heywood’s lab, but wasn’t sure if it was allowed.

“Finally I asked him—I think while looking down at my shoes—Um, can I work in a lab?’ He replied, A lab?’ and I eventually squeaked out, Wellyour lab?’ To my shock and surprise, he said, Sure!’”

From there, any self-doubt began to take a back seat to her hunger for knowledge while working long hours in Heywood’s lab. She was in awe of what was already known about the steps of eukaryotic protein synthesis and the experiments that could uncover new effectors of mRNA translation.

Completing her research thesis in cell biology, Maquat graduated magna cum laude in Biology, packed a small suitcase and boarded a flight to start grad school in Biochemistry at the University of Wisconsin-Madison in 1974.

With no car and very few belongings, she was shocked and thrilled to learn the university would cover her tuition and pay her a $4,000 stipend.

“If you aren’t following in the footsteps of someone who’s been involved in academics at this level, you have no idea what grad school actually involves,” she says. “I couldn’t believe they were going to pay me to learn and conduct researchto do what I loved to do.”

She was thrown for a loop however, when she didn’t get a spot in the lab of her choice. Instead of studying RNA in human cells, she landed in a lab focused on RNA in E. coli. But the lab’s principal investigator, William Reznikoff, PhD, persuaded her to stick it out.

While not the same as human cells, bacteria have a redeeming quality—they grow very fast. Maquat learned to use bacteria for many purposes, a process that helped her develop a level of technical precision she would call upon again and again in her career.

Reznikoff’s lab also gave her an opportunity that most others at the time did not.

“I’m old enough to have entered graduate school at a time when there were very few female faculty,” she says. “And the men in many scientific circles made no secret of the fact that they thought women did not belong there. That was the reality of the day.”

Reznikoff—whose wife Cathy was a scientist and daughter Sarah is now a university mathematician—was an exception. He welcomed female grad students into his lab where they received equal respect and training as their male colleagues.

“The culture of Bill’s lab was definitely unusual for the times, and it was always one of encouragement, regardless of your gender,” says Maquat.

With Reznikoff’s guidance, Maquat earned her PhD in four-and-a-half years, and in 1979, chose to study RNA in human diseases as an NIH post-doctoral fellow in Wisconsin’s McArdle Laboratory for Cancer Research.

There, her advisor Jeffrey Ross, MD, now professor emeritus of Oncology at Wisconsin, was working on human hemoglobin gene expression. It was in Ross’ lab that Maquat began to focus on beta⁰ thalassemia, a group of inherited disorders that reduce the body’s production of hemoglobin. Low levels of hemoglobin lead to a shortage of mature red blood cells and a lack of oxygen in the body, which can cause severe anemia, bone deformity, an enlarged spleen, slowed growth, heart problems, and other issues.

Like any young post-doc, Maquat had no idea where her investigations would lead.

“We just went where the research took us,” she says.

In 1980, the research took her to Jerusalem, Israel, to analyze bone marrow aspirates from four Kurdish-Jewish children with thalassemia major (Cooley’s Anemia). Looking out at the tarmac before her first flight overseas, she was completely unaware that this trip would shape the trajectory of her science and career.