Dr. Arlene Sharpe's brilliant scientific career began with the humble lima bean.
In second grade, in Gary, Indiana, her science fair project showing the lima bean's stages of germination won a special note from the school principal. She still has it today, at age 65.
"I hope the germination of the lima bean will only be the first of many science studies for which you’ll receive a blue ribbon," it reads.
And so it has been.
Sharpe is now the chair of Harvard Medical School's new department of immunology. And she is a leading pioneer of the science behind immunotherapy, a wave of new cancer treatments that unleash the patient's own immune system to fight their disease. It is widely considered the most exciting cancer advance in decades.
But she began as a grade-school life science putterer, fascinated by how things grow and constantly concocting combinations of chemicals, trying to sprout seeds in glass aquariums in the family living room.
"They would mold over, over and over again," she recalls. "But I would keep trying. And my parents were saints. They tried to encourage me to grow things outside, to be honest. It was somewhat smelly at times."
She grew particularly curious about the workings of disease. Her mother was sick for most of her childhood.
"She died of leukemia when I was 15," Sharpe says. "There was not much that could be done at that point in time, and I didn’t understand why. And I wanted to learn how to do more to be able to help people, so no one would find themselves at the age of 15 in such a position."
She went to Harvard, where as an undergrad she worked in the lab of the renowned researcher Jack Strominger, exploring how penicillin kills bacteria.
"It was that 'aha moment' for me. I couldn’t believe they actually paid people to do this, because it was so much fun."Arlene Sharpe
"It was that 'aha moment' for me," she says. "I couldn’t believe they actually paid people to do this, because it was so much fun."
That was back in the ‘70s, but Strominger still remembers her fondly. "Arlene is one of my favorites," he says, "I think because she's such a modest person."
Another pivotal encounter for her scientific career — and personal life — came in German class, which met early in the morning.
Gordon Freeman, an undergrad a year ahead of her and working in a different biology lab, often slept through class and went to hit her up for their homework assignments. They started dating.
Years later, Sharpe was planning to leave Harvard for Yale Medical School. "So we were going to be apart," Freeman says. "And I wanted to make sure that we stayed together. So — um — I proposed."
And so was born what Freeman calls “the family business.” He's now a professor of medicine at the Dana-Farber Cancer Institute and Harvard. The “family business” was trying to understand the genes that control the immune system. Freeman would clone them, and Sharpe would use a tool that was new back then, called gene knockout, to eliminate them and see what they did.
"She made a big discovery," he says, "which was if you knocked out CTLA-4, the body’s defenses went haywire."
CTLA-4 is a superstar molecule in cancer immunotherapy. It’s often compared to a brake that keeps the immune system in check, and Sharpe showed that when you take off that brake, the immune system attacks.
Sharpe and Freeman did even more important work on another brake system known as the PD-1 pathway, which has led to immunotherapy drugs now being used against more than a dozen types of cancer. Sharpe helped figure out how a kind of a trigger could activate that brake.
"Scientifically, the understanding of these negative receptor molecules, these brakes in the immune system, was hugely important," says Manchester University immunology professor Daniel Davis, author of "The Beautiful Cure." "And medically, it became hugely important when it was realized that you could unleash the immune response against cancer."
Sharpe stresses that all the new PD-1 drugs — and more to come — owe their existence to basic science research.
"The PD-1 story is one that emphasizes the value of discovery, curiosity-driven research," she says. "This work did not start out to understand how to cure cancer. We were understanding how the immune system was regulated."
The PD-1 drugs work for only a minority of the patients who take them, but they’re a big piece of the current boom in immunotherapy. A PD-1 drug called Keytruda is helping some patients with advanced lung cancer — like Barry Nelson, a retiree from Boston’s West End.
"You know, I never say that I'm cured, I always say that I'm healed," he says. He has personally thanked Sharpe and Freeman for his reprieve, he says, "because my healing came from God, but he blessed them with the technology and the idea of how to put all this together so that it would bless other people all around the world."
So far, immunotherapy drugs block only those two known brakes — CTLA-4 and PD-1 — but this is only the beginning, says Manchester professor Davis.
"There are in fact many, many brakes on the immune system — there are something like 20 different brakes," he says. "And we can try switching them off each alone or each in combination, or in combination with other drugs. So I think that's why we are at the dawn of something much bigger than we've seen so far."
The latest Nobel Prize for medicine went to two scientists whose work helped lead to immunotherapy — but not to Sharpe and Freeman, even though they had won other prizes that are often precursors to the Nobel.
But there are plenty of other rewards. Sharpe says the biggest is the privilege of getting to do the science — and "that knowledge then can get translated to therapy to help people in many different kinds of diseases. So it doesn't get any better than that."
And she leads the couple of hundred members of the new immunology department at Harvard at a time when the field is sizzling. Connections to the immune system are turning up in all sorts of diseases, from Alzheimer’s to heart disease.
"Obesity. Chronic inflammation. What are the triggers of this? It's all coming to the immune system," she says.
"Our kids have, I hope, forgiven us for being obsessed scientists."Gordon Freeman (Sharpe's husband)
Humming with freezers and fridges and centrifuges, Sharpe's own lab of about 25 people focuses largely on how the activity of immune cells called T cells is ratcheted up and down.
For example, their work recently found that T cells are key to how our immune system weakens as we get older — which could lead to ways to keep it stronger.
Brief personal note here: I wanted to know how Sharpe had managed to balance raising a son and a daughter, now grown, with leadership positions in a field where 14-hour days are common. But I didn't want to ask her, because prominent women are so often asked about work-life balance, while men are not.
So — I asked her husband.
"We had very supportive parents," Freeman says. And "we started having kids when Arlene had just become an assistant professor. So we were making at least a reasonable income, and we were able to have child support."
Their workplaces were helpful too, Freeman says.
"And our kids have, I hope, forgiven us for being obsessed scientists," he says.
As Sharpe tells the story of her scientific career, it includes no discrimination or #MeToo moments. It's a litany of appreciation and gratitude for mentors like then-pathology chief Ramzi Cotran of Brigham and Women's Hospital: "Ramzi had so much confidence in me that it gave me confidence in myself," she says. And Rudolf Jaenisch at the Whitehead Institute: "He was incredibly supportive as my post-doctoral adviser, and I learned so much from him about tackling difficult scientific problems."
"There are a lot of really good, good male scientists as role models and mentors, and so that shouldn't get lost."Arlene Sharpe
"I think there's a cultural shift," she says about gender in science, "but you know, there are a lot of really good, good male scientists as role models and mentors, and so that shouldn't get lost."
Gender issues in science are complex, Sharpe says, but also simple. She likes to say that she has her personal family and her lab family, "and I think that's what it comes down to, is thinking about how you would want a family member treated and how you would like to be treated."
This weekend, Sharpe is set to be inducted into the National Academy of Sciences, one of the highest honors in American science.
With a laugh, she acknowledges, a self-evident truth: "I've come a long way from the lima beans."
This segment aired on April 26, 2019.