Building a Better Way

Lego minifigures, like engineers, are disproportionately
 male. But Sangeeta Bhatia '90 has her own, custom-made in 2015 by Maia Weinstock '99. It's a fitting tribute to the engineer, physician, biotech entrepreneur, and mom who takes tiny pieces and puts them together in unexpected ways.

Bhatia does a lot of things a little differently. She has used microfabrication, the technology behind microchips, to grow human liver cells outside the body. This has allowed drug companies to test toxicity on these "micro livers" in the lab and to hope that they can someday manufacture whole human livers for transplant patients. She is a senior scientist at a top institution, but instead of spending nights and weekends at the lab, she insists on balance so that, for example, Wednesdays are "Mommy Day" spent with her kids.

Her very presence in the field of bioengineering as an engaging, stylish woman of color is de facto doing things differently. "Many people still have this image of an engineer as a kind of nerdy guy, interested in taking things apart," Bhatia said in an October 2015 speech at Brown celebrating the groundbreaking of the new engineering building (it just opened this fall). "Someone who stays up all night playing video games and eating Doritos, with very few social skills. Right?"

Bhatia, a petite figure in a sleeveless top and capri pants, her toenails a chic shade of blue, is not that guy. She took a gap year after Brown in which she backpacked and taught aerobics. She does classical Indian dance to relax—she thinks that's what caught the attention of Brown's admission office—and, with husband Jagesh Shah, a professor at Harvard, she runs her kids' elementary school science fair. She's literally a soccer mom—Shah coaches their daughters' teams. But take heart, mere mortals. "My car is a mess; it smells like a dead animal right now," she admitted to Nova ScienceNOW when they profiled her in 2009. "I don't cook. At all."

What she does do, with the team she's assembled at her lab at MIT, is figure out which sequences of amino acids can get into a tumor, then put them on synthetic materials that are way smaller than the diameter of a human hair, and use that to detect cancer. They've managed to grow the dormant version of malaria in a dish so drugs can be tested in vitro before being tested in humans. They've also prototyped breathalyzer and urine tests for cancer.

Bhatia has been elected to the National Academy of Sciences and the National Academy of Inventors, and she was one of the youngest women ever elected to the National Academy of Engineering. She's won prestigious national prizes and awards, including the Lemelson-MIT Prize, known as the "Oscar for inventors." In addition to having her own lab, the Laboratory for Multiscale Regenerative Technologies, she recently launched The Marble Center for Cancer Nanomedicine at MIT. The prize for cleanest car in the Boston area can probably wait.

The door to her future was in the Biomed Center
Bhatia, who was born and raised in Boston, got interested in bioengineering at Brown when, in order to get to her human physiology lab, she had to walk past a door in the Biomed Center that was labeled "artificial organs." That sounded cool to her, so one day she knocked on the door. "I begged them to let me intern," she says. She spent the summer working on using electricity-producing plastics (piezoelectrics) to enhance nerve regeneration and became hooked on the field that is now called tissue engineering. After Brown and that post-undergrad gap year, in which she also worked for a pharmaceutical company pressing pills ("it was really boring"), she started grad school at MIT.

Her parents approved. Bhatia's father was an engineer, and her mother was one of the first women in India to earn an MBA. They considered three careers acceptable: doctor, engineer, or entrepreneur. So when Bhatia said she wanted to pursue a PhD because bioengineering bosses seemed to have them, her father, who felt PhDs are often impractical, asked, "When are you going to start a company?"

It took a few years. In 2008 she launched Hepregen to bring the artificial liver technology to the commercial market, and she started Glympse Bio in 2015 to commercialize the urine-test diagnostics, with investment from her Brown roommate, longtime friend, and venture capitalist Theresia Gouw '90. "We are scheduled to start, we hope, our first clinical trials next year," Bhatia says, "It's like having another child."

Bhatia's work producing artificial livers started in her second year at MIT, when she joined the lab of Mehmet Toner, a biomedical engineer who was trying to develop a device that would use human liver cells to process the blood of patients with liver failure. Bhatia set out to figure out how to get liver cells to grow outside the body. She tried and failed for two years. Then she had a breakthrough.

In the body, liver cells don't just grow on their own, Bhatia explains. They grow in a particular structure—a community, she calls it—with connective tissue cells. But just throwing both types of cells into a petri dish didn't work. Instead, Bhatia hit on the idea of creating the right structure for these cells by using microfabrication techniques designed to create computer chips. Instead of putting tiny circuits on a chip, she etched a glass culture dish with the geometric configuration in which liver cells grow in the body. Success: the liver cells, organized in the right way and supported by connective tissue cells, could live for several weeks outside the body. Today, pharmaceutical companies around the world use Bhatia's micro livers, grown from human liver cells, to test whether or not their drugs are toxic to humans before they try them on actual people.

While Bhatia worked in Toner's lab, she started taking the year's worth of medical school classes at Harvard that her biomedical engineering program required. Fascinated, she added even more med school classes. Then after she finished up her bioengineering PhD, she transferred into Harvard Medical School as a third-year med student—a foray into one of her other parentally approved career paths. But she still threw her hat in the ring for academic gigs and later that year accepted a junior professor position at UC San Diego. So in 1999, her fourth year of medical school, she multitasked, working at both a hospital ("for inspiration") and a research lab ("where my heart is"). The combination remains crucial for her work, Bhatia says. "Over my career, I have always looked to the clinic to recognize what the real unmet medical needs are," she explains.

In 2005, after six years in San Diego, Bhatia returned with Shah and their first daughter to Boston to accept a professorship at MIT.

How to build a kinder, gentler top academic lab
When Bhatia was in grad school she looked "up the pipeline" to the lives of research scientists and engineers, and she didn't like what she saw. When she popped into the lab one Saturday night at 3 am, her colleagues were still working. When she thought about her future, she says, "I realized I didn't want to be there every Saturday night." So when she set up her own lab at MIT, she prioritized excellence but she had other key concerns.

As with the liver cells she studies, she feels people thrive best in a community and with support. For her own sake and to enhance the success of her lab, Bhatia makes it a priority to hire people who aren't just great at what they do but can also get along well with others. Like some high-tech entrepreneurs, she encourages them to both work hard and live a balanced life—and to spend 20 percent of their work time "tinkering" on creative projects that may or may not pan out. (The breathalyzer test for cancer came out of one of these "submarine" projects, so called because they're hidden from Bhatia unless they succeed.) Bhatia's lab manager, Lian-Ee Ch'ng, says the lab, a warren-like series of rooms on the fourth floor of MIT's Koch Institute for Integrative Cancer Research, feels very different from others she has worked in. "Sangeeta has a very personal touch," Ch'ng says.

Thirty people work in Bhatia's lab, including a research director, scientists, and the grad students. It looks like any top facility, with row after row of workstations and separate rooms for incubators, specialized microscopes, ultra-low-temperature freezers, and massive tanks of liquid nitrogen. They have a 3-D printer and, perhaps the most high-tech piece of equipment in the lab, Ch'ng says, the Pannoramic 250, a high-speed, five-color slide scanner that produces beautiful digital images of the cells on a microscope slide.

It looks like a place built for workaholics, where it would be easy to keep your head down and your focus on yourself. But Bhatia doesn't allow it. She sets a tone of collegiality, Ch'ng says, which really makes a difference: "People talk to each other."

There's an inherent tension, Bhatia admits, in bringing together excellent, ambitious people and also prioritizing work-life balance, community, and citizenship. "They're not all exactly the same thing," she says. But this combination of priorities may be an important reason why the Bhatia lab has a staff that's about half female. "I have an orientation that attracts young moms," she says. Her male staff members who have kids are probably able to be better dads, too.

"I think Sangeeta's a wonderful role model for women," then-grad student Geoffrey Von Maltzahn told Nova. "But she's a terrific role model for anybody. One of the hardest things in life is to make a clear distinction between how much time you're going to dedicate to your work and how much time you're going to dedicate to your family and your friends. She's able to manage that with a sense of ease that I think is inspirational, independent of whether you're a man or a woman."

However, when Bhatia started working from home on Wednesdays so that she could pick up her daughters from school, she felt it was professionally risky. So at first she called it "working off campus." Now, everyone knows it's "Mommy Wednesday." She makes a point of modeling work-life balance to show that it can be done without sacrificing success.

She's also purposely using her visibility as a top scientist to be a role model for women in engineering. "There are not a lot of engineers that look like me, still." Yet when she first got to Brown, she didn't see what all the "diversity" fuss was about. "I looked around the classroom and thought that there were plenty of women."

Then, when she was a senior, she and her friend Theresia Gouw looked around again, and there were many fewer women—only seven in a class of 100. "We realized that we had just witnessed the so-called disproportionate attrition, the leaky pipeline."

Bhatia started reading about the subtle bias and the feeling of "not belonging" that discourages many women from pursuing the field. She and Gouw surveyed the other women who stayed in engineering and found that "every one of them had had mentors or parents who encouraged them."

As a newcomer to MIT, and as one of the few women engineering graduate students, Bhatia got a clear taste of that "not belonging" feeling when a thermodynamics professor asked her, on the first day, if she was in the right class. At first, Bhatia says she did what she could to downplay her femininity, wearing pants and not much makeup, trying to disappear. But later, she realized she had to be visible to make a difference and help patch up that leaky pipeline. So she makes a point of speaking openly and specifically about being a woman engineer.

Bhatia thinks her attitude stems from the orientation towards public service she got in college. "I think that's very Brown," she says. "Not just noticing, but taking action." But she says that her commitment to gender and other types of diversity also happens to be good business. "Just look at the metrics," she points out. "Quality of ideas, return on investment, time to profitability, every objective metric has shown to be improved with diversity."

Though living a balanced life was important to Bhatia, she feared the consequences on her career. "I said to myself, 'This is a tradeoff I'm willing to make. If it means I'm not at the top of my field, that's absolutely a decision I'm making with my eyes open.'"

Instead, she found that her choice to have a life outside the lab had the opposite effect: it helped her excel. "You have to find a way to sustain your energy and your creative spirit," she says. As many workplace productivity studies have shown, having downtime increases productivity, and Bhatia is no exception to this rule. "I feel like if I worked the way that I thought I was supposed to, I actually think I wouldn't be as productive. For me it's helpful to come in and out of those worlds."

The tiniest tools 
on earth
Bhatia's still working with livers, but microfabrication is now old technology. Much of her current work uses nanotechnology: "You make materials so tiny that they can circulate in the body," she explains.

It's with these insanely small tools that Bhatia set out to find better ways to diagnose and treat cancer. While still at UC San Diego, she began collaborating with renowned cancer researcher Erkki Ruoslahti, who had figured out how to engineer viruses so they'd home in on tumors. Bhatia replicated that, not with viruses but with materials, such as quantum dots (qdots), little semiconductor crystals that are more than ten thousand times smaller than the width of a strand of human hair.

Bhatia coated qdots with peptide sequences that would allow them to enter tumor cells. Then she injected the qdots into mice that had cancer. Sure enough, the qdots homed in on the tumors. In 2002, Bhatia and Ruoslahti published a paper on their findings. "A lot of people say it was one of the first of its kind in what later became this field of nanomedicine," Bhatia says.

The urine test for cancer was an outgrowth of that work—and a happy accident. In the Bhatia lab, they were trying to make "smart contrast agents," materials that would light up in tumors and thus show up on an MRI. "That was when the students noticed that whenever the animals were tumor-bearing, the bladder would light up," Bhatia says. "Then we realized we didn't need an MRI at all, that we had created this kind of urine diagnostic." All they had to do was create a paper test to detect the biomarker that appeared in the urine and voilà, an inexpensive and relatively noninvasive test for cancer.

"We think it's a platform technology," says Bhatia, who is investigating the use of this type of diagnostic with other diseases, including liver disease, which could help patients avoid expensive and invasive biopsies. The test works great in mice, so their biggest hurdle is to work with the FDA so that it can be tested on people.

The "blue-sky" goal
One of Bhatia's dreams is to create a functioning human liver made outside the body that can be implanted into it. That goal is still far away, but it's getting closer. In June, she published a paper that explained her group's successful attempt to grow working livers in mice.

Building on her micro liver technology, they used a 3-D printer to produce tiny liver "seeds" that they populated with a community of liver cells and helper cells. The configuration, they thought, would allow the cells to respond to regeneration cues—the liver being one of the only organs in the body that can regenerate.

They implanted these seeds in mice with failing livers—and the lab-created livers grew 50 times larger in the mice's bodies. They also looked a lot like real livers and performed liver functions. Making a liver for a human obviously requires many more cells than making one for a mouse, though.

"We think you probably need about 10 billion cells to get up to clinically relevant tissue, which is a lot and too many to print practically in a reasonable amount of time," Bhatia says. "We have a long way to go."

In the meantime, they have found another use for the micro livers: testing malaria drugs. "There's a really elusive dormant form of vivax malaria that can hide out in a liver," Bhatia explains. The only drug that's been known to clear this dormant form of the disease is primaquine, which has been around since World War II. But it can cause blood damage in patients, and some strains of the dormant malaria have developed resistance to it. "There's been a big push for new drugs since 2008, when the World Health Organization announced a new malaria eradication campaign," Bhatia says.

What Bhatia's team has been able to do is grow this dormant strain of malaria in their micro livers, allowing drugs to be tested against it. "Now we're trying to molecularly describe it, which has never been done," she says.

The malaria work came about because a lab member, graduate student Nil Gural, wanted to work on the untreatable form of the disease. "When she came, we had never grown [the dormant strain] before. We had no access to it." Gural, who is originally from Turkey, said she was willing to live in Bangkok for a while to get it going.

Gural has now been working on this for a couple of years, going back and forth from Boston to Bangkok. The work is going really well, Bhatia says. The lab is working with Medicine for Malaria Ventures, the organization that is coordinating the effort to develop new drugs that will work on the dormant stage of the disease. Given that there are about 212 million malaria cases that cause nearly half a million deaths each year, according to the World Health Organization, it's research that has great potential for positive impact.

Bhatia says her commitment to malaria work comes out of her entrepreneurial instincts as shaped by Brown. "My professional work has started out in what I would say is a very high-tech place," she says, "and that's growing 3-D livers. That's probably going to be an expensive solution for patients with liver failure. The same thing for our cancer work. We're working on really, really, really cutting-edge but still expensive ideas."

Expensive ideas are, of course, where the profit lies for an entrepreneur. But Bhatia says Brown taught her to look beyond profit to ask, "What can you do to make the world a better place?" For Bhatia, that's finding global health applications for her work, such as taking the micro livers and using them to help eradicate malaria, or using the nanotechnology the lab comes up with to create inexpensive paper-based diagnostic urine tests for lung, colon, and ovarian cancers, allowing patients to be tested and even treated right on the spot, including in remote areas of developing countries where follow-up can be next to impossible. That's still a dream, but as she said in her Spring 2017 TED Talk, "We already have this working in mice."

Half of Bhatia's staff crowds into her office every Friday—it switches back and forth between the cancer and liver groups. It's a medium-sized office with a desk, a small table, and a small couch. Behind her desk is a large framed print of something that looks like a lush white flower in full bloom. It's actually a genetically engineered colony of yeast. Her Lego figure is perched on a window sash, and below it an unusual clock keeps the time. Six metal figures in the clock itself appear to hoist a seventh who hangs below, though every time the seventh figure gets almost to the top, it falls down again. Her husband gave it to her as a present when she got tenure. "What he said was, 'Look at all these people helping you climb. You're leading a team and they're helping you achieve your vision."

"I was like, that's nice, but once you get tenure"—the figure plummets to the bottom again as if to illustrate her point—"you climb the next ladder."

Fifteen people assemble in this space that would comfortably seat half as many. "They sit on the floor and the table," Bhatia says. "We keep saying maybe we should move to the conference room but I think they like the intimacy of barreling into my office for 90 minutes." The group uses the time to talk about early results of experiments and to "cross-fertilize."

"I'm continually reinforcing that," Bhatia says. "Otherwise they don't talk to each other." Science is a lot of failure, she adds. "You have to think of all different ways to keep your team energized and excited and engaged. The best way is if they're constantly learning."

Bhatia has improved and perhaps saved many lives already, thanks to the drugs that now are not tested in humans if they are toxic to micro livers. An off-the-shelf liver or a urine test for cancer or liver disease could also be lifesaving.

But when asked what she's proudest of, she says it's her students, because she gets to be what she calls a "multiplier." She trains her grad students and post-docs in a way of working and a way of thinking, and then they go out into the world. "I feel like they've all gone on to do really interesting things," Bhatia says. "One of them is a venture capitalist and serial entrepreneur. He built a bunch of companies. Some of them are professors training their own students. There's a lot of them out there. It's the most amazing thing to feel like you've played a role in that."

- by Louise Sloan '88
This article appears in the November/December 2017 issue of the Brown Alumni Magazine.

Photo: Geordie Wood

Be Recognized for Who You Are

Sangeeta Bhatia '90 may not have had many role models to look up to as a woman engineer, but that doesn't mean she didn't learn a lot of lessons along the way. Here's some of her advice for people from any group that has been historically underrepresented in the field.

STAY CONFIDENT. Being one of the only women or people of color in your field is difficult. Keep focused on your strengths. Bhatia says she struggled with "imposter syndrome." "There's this feeling that you don't belong, and you're always second guessing yourself. That does diminish with time."

TAKE THAT MEETING. With famous scientists or engineers, Bhatia learned to ask questions or strike up a conversation about the person's most recent paper. The collaboration that led to one of her most important breakthroughs was a result of following up on a colleague's offer of an introduction. Worst case, making connections can make a dull meeting more interesting. "Okay, I'm at a conference," she'd tell herself; "Who are the people I want to meet? What the heck? Let's meet them."

SPEAK UP EARLY ON. In business meetings, Bhatia says, often "I was the only woman, only engineer, only person of color." And she looked young. "One thing I quickly realized was that I needed to make a comment or ask an insightful question pretty early in the convening of a group." It wasn't her personal style to do this, but, she realized, "there are times where you've got a group of really high-powered people together, and you're there for an hour, and nobody knows who you are. You have something important to add. You have to make it clear early in the conversation why you're at the table."

IDENTIFY MENTORS. When Bhatia and Theresia Gouw '90 were seniors and looked into what made some women stay in engineering while so many others left, they found that what the women who'd stayed all had in common was mentors—whether that was a professor, parents, or a family friend. Bhatia concedes it's hard to force these relationships. It's clear that her mentors came not just through luck but also through her own efforts in cultivating relationships with key people around her and following up on any advice and opportunities.

STUDY SUCCESS. Identify your weaknesses and look around at who is doing that thing well. Bhatia says she was comfortable expressing her ideas one-on-one, and as a professor she also became comfortable speaking to a lecture hall. But groups of between 10 and 30 people in faculty meetings or on advisory boards felt awkward to her. "I started studying it and looking at who is really effective in this setting. How have they managed to be effective? At what points are they choosing to speak up? What offline work have they done to grease this conversation so that by the time they speak up, they're able to carry the room? I made kind of a project of it, trying to figure it out, because I realized I wasn't actually naturally good at that."

BE YOUR OWN BOSS. "This is something Theresia has taught me, which is that one of the answers to diversity is to create your own organization, put yourself at the top, make the culture that you want it to be."