Bhatia’s lab group works at the intersection of technology and medicine. Her research program has two main goals: engineering a lab-grown liver that can one day be implanted into patients, and using nanomaterials to design better ways to detect tumors and deliver therapeutics to cancer cells. Her group is attacking these problems—plus a few others—from several angles, integrating the tools of tissue engineering, materials science, and microfabrication.
On Fridays, the usually tranquil space of HHMI investigator Sangeeta Bhatia’s office at the Massachusetts Institute of Technology (MIT) gets a little crowded. The room fills with energy as her team gathers in two groups—liver researchers first, then the cancer team—and clusters, about 10 at a time, around a table better suited for 6. Her students and postdoctoral fellows have her full attention as they share new data and devise future experiments, jumping up occasionally to sketch out an idea on the room’s white board. “I love Fridays,” Bhatia says. “They’re nothing but science.”
How can members of a group that is simultaneously studying liver biology, tissue regeneration, and cancer, not to mention stem cells and infectious disease, find common ground? “Everyone here is working on something very, very different,” points out one member. But there is a constant exchange of ideas among the biologists, chemists, computer scientists, and engineers who gather in Bhatia’s office. All are eager to learn from one another, and they often make unexpected connections and come to creative solutions.
That’s because a collaborative nature is a prerequisite for joining Bhatia’s lab. It’s not enough for a job candidate to have the right scientific knowledge or technical skills: All members of the lab must weigh in on each potential member, and they look for people who will contribute to the amiable environment for which the lab is known. “We’ve turned away smart, ambitious people because we didn’t think they’d be good citizens,” Bhatia says.
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To keep her team motivated as they work to create better solutions for patients, Bhatia is intent on crafting a supportive and sustaining environment for herself and the members of her lab. Curiosity, innovation, and a drive to improve human health are prized. So too are time and energy to spend outside the lab. “I want this to be a happy little oasis, a place where everyone wants to come,” she says of the scientific community she oversees.
|See Sangeeta Bhatia on NOVA scienceNOW.|
As a student at MIT and Harvard Medical School, studying both bioengineering and medicine, Bhatia didn’t exactly dream about running an academic lab of her own. Her professors seemed harried, her labmates worked through the night, and the intensity and competitive atmosphere did not mirror the lifestyle she wanted. “When I looked up the pipeline,” she recalls, “I wanted to know whether there were people who were married, had kids … were normal.” And as an aspiring female engineer in the 1990s, Bhatia found few role models in academia.
Her parents, immigrants from India who placed a high value on education, had actively encouraged Bhatia’s curiosity and aptitude for science and math. “As a child of Indian immigrants, there’s sort of a limited menu of career choices,” she observes. “My dad used to ask me, ‘What are you going to be, a doctor, an engineer, or an entrepreneur?’” She was determined to become part of the new field of bioengineering by the time she was in high school, when her father brought her to a friend’s lab at MIT, where researchers were investigating ultrasound therapies for cancer. “I was really captivated by the idea that engineers could use instruments to impact human health,” Bhatia says. She wanted to do that, too. She just assumed she’d do it within the biotechnology industry.
Bhatia is quick to acknowledge that her career might have taken a different path. “But then someone reminded me that, as an academic, you can build the group in your image: You can make the culture one you want to live in.” Her graduate work devising a system to grow liver cells in the lab had fueled her curiosity and sparked countless ideas for new experiments. So straight out of medical school, she took a faculty position in the bioengineering department at the University of California, San Diego (UCSD). She set herself up to explore her lingering questions about the liver, added a new cancer focus to her research, and took care to surround herself with people who shared her values. “And I loved it,” she says.
She returned to MIT in 2005, moving with her family back to the Boston suburb where she grew up. Her Laboratory for Multiscale Regenerative Therapies is located on the sunny fourth floor of MIT’s new Koch Institute for Integrative Cancer Research. From her office, she can gesture toward many of the area labs her team is collaborating with to explore liver biology, cancer therapy, stem cells, and infectious disease. “Multiscale” means the group is working with both nanotechnologies and microtechnologies. Because of their small size, nanoparticles, so tiny that about 1,000 of them could fit across a human hair, behave differently than larger particles, and Bhatia’s team is exploiting their unique electromagnetic properties in its cancer research. The microtechnologies, such as the tools they use to produce their artificial livers, are still tiny but about 1,000 times larger than nanoparticles.
Bhatia has a strong instinct for matching her group’s interdisciplinary strengths to some of the most troublesome clinical problems. As a graduate student, she was so fascinated with the medical courses required for her Health Sciences and Technology program that she kept taking “just one more course,” until finally she decided to complete a medical degree. Now, as an “accidental doc,” she speaks fluently with clinicians about the challenges their patients face and the limitations of current technology.
“I love my science but I don’t think about it 24/7!”
In deciding what research to pursue and how to go about it, Bhatia is guided by a clear objective. “Sangeeta has always been someone who wanted to make an impact, to leave the world better than she found it,” says Christopher Chen, a graduate school classmate of Bhatia’s who is now a bioengineer at the University of Pennsylvania. They have remained close friends, and Bhatia calls him her “science buddy,” scheduling regular phone calls to consult about the rewards, frustrations, and nitty-gritty details of running a lab.
Chen recalls that during the clinical portion of their graduate training, he and Bhatia had a shared goal: to record each day in their notebooks “one really good idea” inspired by their interactions with patients. Although Bhatia was deeply into liver research by that time, “her ideas weren’t just about the liver,” Chen says. “They were about infectious disease, how to improve a surgical technique … all kinds of things. I think she would have made an impact no matter where she landed.”
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A Supportive Environment—for the Liver
Bhatia’s enthusiasm for her work is obvious as she speaks animatedly about the wonder of the liver, the organ she learned to love as a graduate student in the lab of tissue engineer Mehmet Toner at Massachusetts General Hospital. The pinkish-brown triangle carries out more than 500 functions in the human body, including removing toxins, generating energy, storing vitamins and minerals, and helping to regulate fats and sugars in the bloodstream. Before her graduate work, researchers faced challenges growing hepatocytes, the cells responsible for most of these functions, in the laboratory. Removed from a complete liver, the cells promptly died. In Toner’s lab, Bhatia found a way to stabilize them by mimicking the liver’s architecture.
In the body, hepatocytes are sandwiched between two layers of extracellular matrix and receive support from neighboring cells called stroma. Hepatocytes and stroma do not establish this structure on their own when placed in a dish, so Bhatia used microfabrication techniques to pattern tiny circular spots of collagen, a component of the extracellular matrix, onto the surface of a culture dish. She let hepatocytes establish themselves on the collagen dots and then added stromal cells. The cells thrived.
Grown in this way, the micropatterned co-cultures live for several weeks. Bhatia has refined the model since she and Toner first reported it in the Journal of Biomedical Materials Research in 1997, and today she and her collaborators are using it to explore what happens to liver cells as conditions such as drug exposure and viral infection progress. Rockefeller University virologist Charles Rice says that his lab used to rely on a cell line developed from cancerous hepatocytes, which poorly reflected the behavior of normal cells, to study the hepatitis C virus (HCV). When they infected the Bhatia lab’s co-cultures with HCV in 2010, they had a much more reliable model of the virus, which affects about 150 million people worldwide. The two labs have continued to work together to design a fluorescent indicator that lets them identify which hepatocytes have been infected with HCV, so they can trace early cellular events in viral infection and test the effects of potential therapies.
One challenge of the liver, Bhatia says, is that its extraordinary multitasking makes it virtually irreplaceable with anything but new liver cells. “When the liver fails, you support the person medically and put them on a transplant list,” she says. “Sadly, lots of patients die on that list.” Bhatia fully expects to change that—and her high expectations are infectious.
Alice Chen, who completed her Ph.D. in Bhatia’s lab in 2011, was taken aback when Bhatia asked her during their first meeting what she would do if she cured liver failure by the time she graduated. But suddenly, she recalls, it seemed possible. “She just always expected excellence,” Chen says. “Of course, we didn’t cure liver failure, but I’m really proud of what I was able to accomplish under her guidance.” Chen transformed the surface-bound liver cultures into three-dimensional “microlivers” by supporting the cells in a hydrogel matrix. The structures, which are about the size and shape of a contact lens, carry out normal liver functions when implanted in mice, according to their paper published in the Proceedings of the National Academy of Sciences in 2011. Chen hopes they will improve researchers’ ability to test potential drugs. Now, as a lead scientist at the California biotechnology company Auxogyn, Chen says when she is presented with a difficult or discouraging problem, she often finds herself thinking “What would Sangeeta do with this information?”
Scaling up the microlivers to take over function in the human body could take decades, Bhatia acknowledges. A lab-grown liver for transplant would probably need to be 10 to 30 percent the size of an adult liver, and there are a variety of hurdles to overcome. “We’re trying to work on all the major bottlenecks,” she says.
One of the biggest obstacles is obtaining enough cells, which do not multiply in the lab and must come from patients. Several researchers in her lab are exploring ways to accelerate the cells’ growth or direct the development of expandable progenitor cells. They’re also examining the role of the cells’ interactions with one another and with components of the extracellular matrix. In the meantime, Bhatia says, “We’re trying to mine our inventions for near-term applications.”
One of the most satisfying applications came last year when Hepregen, the company Bhatia cofounded with former student Salman Khetani in 2007, used the liver cultures to compare the effects of several compounds, including one that had been a candidate therapy for hepatitis C infection until it caused unexpected toxicity in a clinical trial. The drug had not caused liver toxicity when tested in animals before the trial’s launch, but when Hepregen tested it on human liver cells grown with Bhatia’s system, toxic effects were evident. Researchers found a closely related compound that could be administered to the liver cells without toxicity and began a new clinical trial. “That was really gratifying,” Bhatia says.
In her relentless quest for new opportunities, Bhatia used a sabbatical in 2008 to consult with public health experts and infectious disease specialists about how her lab might best make a difference in global health issues. She learned that the malaria pathogen Plasmodium vivax—less studied than its more virulent cousin Plasmodium falciparum—was particularly difficult to diagnose and treat because of its ability to lie dormant in the liver. After talking with malaria researcher Stephen Hoffman at the Maryland-based biotechnology company Sanaria, the researchers showed that P. vivax can grow inside the Bhatia lab’s liver cultures. Now Bhatia’s and Hoffman’s groups are working to re-create the pathogen’s elusive hypnozoite stage with hopes that they can use the model to screen potential antimalarial drugs.
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Alongside the liver studies, about half of Bhatia’s lab is devoted to developing nanotechnologies that improve cancer diagnosis and therapy. “The program has evolved in an opportunistic way,” Bhatia says. A conversation in 2000 with Sanford-Burnham Medical Research Institute biologist Erkki Ruoslahti triggered Bhatia’s first thinking about cancer technologies. Ruoslahti had been screening for molecules that would adhere to the lining of blood vessels that surround tumors and healthy tissues. Bhatia and Ruoslahti realized the peptides he identified could be used to target nanoparticles to those sites within the body, and the two teamed up to begin experiments with nanosized semiconductors known as quantum dots. They soon recruited UCSD materials scientist Michael Sailor to the project and the three began introducing new properties, such as a porous or biodegradable structure, into their nanoparticles.
Today, Bhatia’s cancer team is taking cues from biology to design more efficient nanoparticle systems. They are designing two-particle systems in which one particle finds the tumor and then acts as an antenna to attract a second particle designed for diagnostic detection or therapy delivery—not unlike how different cell types work together to signal and treat a microbial infection, Bhatia says. They also would like to engineer a system in which simple components can achieve complex behaviors when they come together in large numbers and are working on mimicking the kind of swarming behavior seen when birds flock and ants forage for food.
The Myth of the Scholar
Despite her focus and drive, she is not interested in perpetuating “the myth of the scholar,” Bhatia says. “You don’t have to think about science 24/7. I love my science, but I don’t think about it 24/7!”
Her students aren’t entirely convinced. “She’s very devoted to her iPhone,” they say. “If you email her at 1 a.m., you might hear back right away.” But they know those emails come late because Bhatia stays off the computer in the evenings until after her daughters’ 9:00 bedtime.
“When they’re awake, it’s all about them,” she says. The girls’ soccer games and dance recitals (Bollywood is the current favorite) sometimes trump discussions of experimental design. And on Wednesdays, Bhatia works from home so she can be waiting at the school when the afternoon bell rings. “Earlier in my career, I used to tell people I was working ‘off-campus,’” she says. “Now everyone knows Wednesdays are Mommy Day.”
She and her husband Jagesh Shah, a systems biologist at Harvard Medical School, are instilling in their daughters the same curiosity about the world that shapes their lives. “They love science,” she says delightedly, perhaps in part due to the home experiments the four conduct together. The girls are also regular guests at the annual outreach event for middle school girls organized by MIT’s Society of Women Engineers. Bhatia and a handful of classmates launched the program, which they called Keys to Empowering Youth (KEYs), when she was a graduate student.
“This age group had been identified as the pinch-point in the pipeline, where girls begin to lose interest and drop out of math and science,” she says. “So we wanted to bring them in so they could experience the ‘gee-whiz’ aspects of a high-tech lab that they’d never be exposed to in the classroom.”
Now she is the KEYs faculty advisor and hosts an event in her lab each year. This year’s session had a glitzy Lady Gaga theme, and each girl went home with a sparkly hydrogel they’d made by entrapping glitter in a prepolymer solution. Bhatia’s hopeful that the exposure to female engineers will help keep the girls inspired and engaged as they advance in their education. “Plus,” she says, “I just love that my five-year-old knows the word ‘hydrogel.’”
She’s similarly pleased with her trainees, who say her mentorship offers rigorous and well-rounded preparation for their future endeavors. Gabe Kwong, a postdoctoral researcher who is developing a diagnostic urine test for tumor-derived proteins, points out that with no two people working on the same project, “you’re very quickly expected to become the leader in your own subfield.”
But apart from discussions of data and experiments, lab members find Bhatia always makes time for counseling about careers and personal decisions as well. “I keep expecting that level of involvement to diminish, but it never does,” says fifth-year graduate student Meghan Shan.
“I’m really proud of my students,” Bhatia says. “They’ve gone on to do really varied things.” Many are running their own academic labs, she says. Others are entrepreneurs, launching companies to develop stem cell therapies, nutrition technologies, or reproductive technologies. One student is working to help introduce a biotechnology sector in his native Portugal. Another has become one of the only women on the faculty of her department at the Indian Institutes of Technology.
Bhatia’s unfaltering support for women in engineering is motivated both by her own experience and by hard data. Early in her career, Bhatia says, she was hyperaware that she was usually the only woman in the groups of engineers she encountered. “In the beginning, I felt really fragmented,” she says. “I used to overthink everything.” As one of only two female students in her graduate program, she says, she used to puzzle over whether she should wear skirts to class, or if she’d be better off downplaying her femininity.
Confident and self-assured now, Bhatia laughs at the memory. But studies have shown that until women in academia make up about 30 percent of their field, they continue to face a “chilly climate,” she says. Female engineers have not yet reached that critical mass. “The key is to not get complacent,” Bhatia says. “The data show that unless you keep actively working on diversity, you can rapidly lose the gains made by the hard work of so many.”
Bhatia, who in 2006 founded the first diversity committee for the Society of Biomedical Engineers, still often finds herself the only woman in the room—or the only M.D., the only non-Caucasian, or the only mom. “But I don’t think about that anymore,” she says. “Once you have a set of accomplishments that you’re proud of, the rest of it kind of falls away. Now I have a very coherent sense of my identity. I have a vision that I’m excited about and an amazing team to drive it.”