Injecting molecules from a sea slug that received tail shocks into one that didn’t made the recipient animal behave more cautiously.
When molecular biology methods failed her, Sangeeta Bhatia turned to engineering and microfabrication to build a liver from scratch.
May 1, 2013|
ROBERT E. KLEIN/AP, ©HHMI.Liver cells are very finicky: once removed from the body, they begin to lose function within hours. This has made it difficult for biologists to build an artificial organ for patients whose livers have failed, or even to test new drugs on liver cells. So as a graduate student in Mehmet Toner’s lab at the Massachusetts Institute of Technology (MIT), Sangeeta Bhatia was given a single task—get liver cells to function outside the body.
To mimic the organization of liver cells in the body—long lines of cells stretched across sandwiched layers of extracellular matrix—in a dish, Bhatia first used chemistry to pattern the surface of glass with hydrophilic and hydrophobic molecules to force rat hepatocytes to line up neatly. Three years later, “it wasn’t really working,” recalls Bhatia.
Her boyfriend and future husband, Jagesh Shah, an MIT electrical-engineering student at the time, mentioned a microfabrication facility on campus that made patterned surfaces for computer chips. “I went over there and convinced them to let me into their facility,” says Bhatia. Using the computer-chip-manufacturing equipment, Bhatia patterned her surfaces with straight collagen lines etched onto glass slides as a physical structure to organize the cells. “That became one of the very earliest projects at MIT in this field called biomedical microelectromechanical systems, or Bio-MEMS, the interface of living cells and microfabrication,” she says.
Now director of the Laboratory for Multiscale Regenerative Technologies at MIT, Bhatia has her own patterning equipment, and has since built a complete, miniaturized ex vivo liver, used in drug testing applications and to study pathogens that infect the liver. She continues to pioneer advances at the intersection of biology and engineering, including the development of quantum dots to transport drugs to tumors and synthetic nanoparticles to detect disease.
But Bhatia’s achievements extend far beyond just academic publications: she is an advocate for women in engineering, a cofounder of two biotech companies, a mother of two, and a classically trained Indian dancer. Here, Bhatia admits to her love of grant writing, how she once begged for a job, and why she brought a microscope to her book club.
“Disproportionate attrition is something I’ve worked on my whole career—to try and improve the pipeline of women in engineering.”
Family influence. “I grew up in a family of Indian immigrants, and my parents were really involved in what I would be when I grew up. The only question was whether I would be a doctor, an engineer, or an entrepreneur. The joke in my family now is that ultimately I ended up becoming all three.”
The sign. When Bhatia was 16 years old, her father took her to visit a friend in bioengineering at MIT. “My dad brought me to see the lab, and it really captured my imagination. I grabbed onto the idea that instrumentation and devices could be useful for human health.” Bhatia attended Brown University, where she studied biomedical engineering. Serendipity struck during her junior year: “I was walking by a lab at the medical school and the sign on the door said ‘Artificial Organs.’ I thought that sounded cool, and I eventually got up the guts to knock on the door and beg them to let me intern for the summer. They did, and it became my field.”
Gap year. After graduating from Brown in 1990, Bhatia spent a year working at ICI Pharmaceuticals in Wilmington, Delaware, doing drug development. “Even though I liked tissue engineering at the time, I still had this notion that I was supposed to go into industry. So I worked in pharmaceuticals in what’s called formulation, which is basically converting medicinal chemistry to oral formulations—pill making. Within a month of arriving there, I knew it wasn’t for me. I needed to go immediately back to graduate school.”
Double the fun. Bhatia completed a PhD at MIT and an MD at Harvard Medical School, then did a postdoc with Toner at MIT, where she took her boyfriend’s advice and applied computer-chip fabrication technology to successfully pattern liver cells in a dish. “We got the cells to organize, but they still weren’t functioning in a way that they would be useful. So we went on to do co-cultures, where we added another cell type [to the liver cells], and that actually worked really well. My lab has been studying how that works, and why it works so well, for 20 years. We’ve made human versions and high-throughput versions that have been spun out to a company that sells microlivers to pharmaceutical companies for drug metabolism and toxicity screening.”
Two to tango. “There was a seminal paper in the 1980s where a French investigator named Christiane Guguen-Guillouzo added another cell type she isolated from the liver to liver cells, and these random co-cultures would transiently rescue the liver cell phenotype [from dedifferentiation]. But when I was a grad student we didn’t have those cells—the support cells we had were from Howard Green and Jeffrey Morgan, then at MGH [Massachusetts General Hospital]. They were growing these feeder cells, a subclone of fibroblasts that make a lot of keratinocyte growth factors, and they just happened to be the only cells I had available to try the co-culture experiment. But after looking at many, many mesenchymally derived cell types—all of which boost liver-cell function to some degree—to date, the best cell line that we’ve ever found is still the subclone from Morgan and Green. Recently, in a set of new papers, this obscure cell type has turned out to be at the center of the co-culture world.”
Infectious idea. “We realized, somewhere along the way, that having an ex vivo model of the human liver had a lot of fundamental applications. In the lab, we’ve gotten heavily into infectious diseases. It turns out there is a whole host of pathogens that specifically infect hepatocytes—and only human hepatocytes—so there are no rodent models of these organisms, which include hepatitis C (HCV), hepatitis B, and the liver stages of human malaria. In 2010, we published a persistent HCV infection model of our human microlivers with Charles Rice at Rockefeller University, and we’re about to publish a malaria model of them as well.”
Artificial liver at last? In 1999, Bhatia took a job as an assistant professor at the University of California, San Diego, but she kept her connections at MIT. There, Jennifer Elisseeff, a friend working in Robert Langer’s lab, had been developing a technology for encapsulating cartilage cells in a polymeric hydrogel material. “She was trying to make cartilage, so she would mix this prepolymer solution, still a viscous liquid, with cells and inject it under the skin. When light shines on it, it hardens in place as the polymers crosslink. I had gotten it into my head that we could do organ printing for livers using this kind of material. We started an initiative in our lab that works on 3-D liver tissue engineering to make an implantable liver. We’ve gotten liver cells to live in this material, and had a PNAS paper last year where we grew human livers in mice. Now we’re trying to make them bigger by vascularizing them, working with Christopher Chen at the University of Pennsylvania to move toward [implanting them in] patients.”
Phage phishing. “In the early 2000s, a postdoc candidate applied to my lab named Warren Chan, who later became a professor at the University of Toronto, and he was really interested in using quantum dots [nanoparticles that have size-dependent light emission] in biology. I had his CV sitting in my inbox when I got introduced to Erkki Ruoslahti, a luminary who codiscovered fibronectin and its binding motif RGD. When I met Erkki, he had pioneered a technique of in vivo phage display in the mid-1990s, where he was taking phage libraries and injecting them into disease-model mice. Then he would fish out the phage that would home in on different tissues, and identify the peptide sequences that conveyed the homing. He and I together wondered if you could make these sequences synthetically and put them on a nanoparticle that could then home in on tumors. I hired Warren, who was a quantum-dot maker, and in 2002 we published what we believe was the first phage-derived peptide-targeted nanomaterial paper [in PNAS]. That cancer nanotechnology effort grew into half my group, so now half the lab does liver and half the lab does cancer.”
The power of pee. Bhatia has cofounded two biotech companies and is ramping up to launch a third. “It’s related to a paper we just published in Nature Biotechnology. We take these same peptides that home in on disease sites, but once there, they respond to proteases in the disease environment and give off a synthetic signal to detect a disease—a synthetic biomarker. We’ve designed the sensors so they get accumulated in the urine, so it’s basically a urine test—a noninvasive urinary detection of diseases [such as cancer and other complex disorders].”
Dangerous drop-off. “At Brown, one thing that would influence me for many years was noticing how many of my women classmates would drop out over the course of our 4-year curriculum. That kind of disproportionate attrition is something I’ve worked on my whole career—to try and improve the pipeline of women in engineering. The start of the decline is in the middle-school years [ages 11 to 13]. When I was a grad student, I helped to start an outreach program to get middle-school girls excited about engineering and science, which is still at MIT and has seen about 2,000 girls to date.”
Lasting impression. “There’s something that happens in Cambridge, and in this field in general, that I call ‘intellectual flexing.’ Scholars get together and try to establish their credibility, like ‘My last Nature paper this and my Science paper that.’ But that’s not my style. It actually turned me off of science when I was training. But I had to learn to get comfortable with intellectual flexing, especially when I look younger than everyone in the room. I try to make a thoughtful comment at the right moment so that people know to take me seriously. I will say there is an upside to looking young, and being female and Indian, in science. Once I get folks to take me seriously, I feel that they often remember me.”
Tenure tip. Bhatia has two daughters, ages 6 and 9. “One important thing for me, a benefit that I know not all women are able to have, was that I was promoted pretty young, so I had both my kids post-tenure. I decided to work from home one day a week, and we call this ‘Mommy Day.’ I’ve been home most every Wednesday since. I take my girls to school and pick them up at 3. On the rare occasion that I am out of town or have to work, they complain because it’s their day. That’s the kind of thing, though, that might be hard to feel you can do if you don’t have the security of tenure.”
“Grant writing for me is a super creative process—a moment to indulge in your ideas and tell a story.”
Working mom. “I have a ton of help. My parents are in town, my husband is incredibly supportive, I have a babysitter who’s like part of the family and an administrator who runs my life at work. I don’t cook. My advice is to realize you can’t do everything yourself. For me, I want to be present and awake when my daughters are awake, but that means when they go to bed, I’m back on the computer at 9:30 p.m. But that’s fine, because that’s what I’m passionate about.”
Desk of her own. “I actually love academic desk work. Grant writing for me is a super creative process—a moment to indulge in your ideas with your students and colleagues and pull them together and tell a story. It would be nice, though, if they all got funded.”
Beach living. “When I got the offer to work at UCSD, to my husband’s credit, he said, ‘Let’s try it out. We’ll live near the beach and get a convertible.’ We just went out there and made it an adventure. We didn’t get the convertible, which he still complains about, but we lived three blocks from the beach, and walked there every morning.”
Family tradition. “Growing up, I was a classical Indian dancer. I even had a formal professional dance debut, an Arangetram—a performance that is sort of the equivalent of a Bat Mitzvah or a sweet 16, with everyone you know there. Dancing was a big part of my life. I don’t perform anymore, but my two little daughters just started.”
Books, booze, and HeLa. “The last book we read when I hosted book club was The Immortal Life of Henrietta Lacks. As a treat, I brought home some fixed HeLa cells and my friends looked at them under the microscope. It was great—along with lots of wine and snacks, of course.”
Stuck at the fair. This year, Bhatia and husband Jagesh Shah, a systems biologist at Harvard, organized their daughters’ school science fair. “Our kindergartener did a project on surface tension, our fourth grader did a project on carbonation, and the two of us ran the fair. We’ve been joking now that we’ll probably be doing this for the next 6 years. There’s no escaping now.”
• With Mehmet Toner at MIT, engineered a co-culture system to support liver cells ex vivo
• Built microlivers-on-a-chip, used to test liver drugs and model hepatitis and malaria infections
• In 2002, with Erkki Ruoslahti and Warren Chan, pioneered a technique using quantum-dot probes
for tumor targeting
• In 2011, grew human liver tissue in mice, an important step toward developing an artificial liver for
• Helped start an outreach program to encourage middle-school girls to go into science and engineering,
which has served over 2,000 students