Engineering the Human Chemical Plant

Sangeeta Bhatia, SM ‘93, PhD ‘97, designs devices that let her examine the natural environment of liver cells.

Sangeeta Bhatia often finds herself the only engineer in a roomful of clinicians, or the only physician in a roomful of engineers. A biomedical engineer who is also a Harvard Medical School-educated physician, Bhatia, SM ‘93, PhD ‘97, employs microscale technology to help find novel solutions to problems in biology and medicine. Few researchers manage to bridge the gap between medicine and engineering single-handedly. Bhatia does.

“I’m a technophile, and I love a clever, elegant solution,” says Bhatia, who has a joint appointment to the Harvard-MIT Division of Health Sciences and Technology and the Department of Electrical Engineering and Computer Science. “But the other pressure in me is that I was trained as a physician to improve human health and understand human disease. I’m a scientist, too, and I want to understand a problem deeply.”

Bhatia designs artificial devices on the size scale of cells–with features measured in micrometers–that allow her to study and manipulate cell behavior more precisely than was previously possible. Her lab focuses on liver cells, probing their natural environment to better understand how they function. Her work is both fundamental and practical and combines artificial materials with living cells to help solve real problems in medicine, such as artificially engineering liver tissue and finding better ways to screen drugs for liver toxicity.

Though trained as a physician, Bhatia has chosen to devote herself full time to bioengineering research, first at the University of California, San Diego, and now at MIT, to which she returned in 2005 to lead the Laboratory for Multiscale Regenerative Technologies. Bhatia began studying the liver as a PhD student in medical engineering at HST, when she worked in the laboratory of Mehmet Toner at Massachusetts General Hospital. “Over the years, I just fell in love with this particular tissue and trying to understand it,” she says. The liver is a football-sized chemical plant responsible for several critical tasks, such as metabolism and bile secretion. With more than 17,000 people in the U.S. waiting for liver transplants, surgeons recognize that there is a critical need for alternative ways of replacing liver tissue.

Toner’s lab was working on manipulating liver cells so that they could be housed in external devices to help patients with liver failure in the same way that dialysis machines help those with kidney failure. But the cells of the liver are very difficult to keep in culture; when taken out of their native environment, they quickly cease to function. They must be grown, arranged, and kept stable on an artificial platform. “If you’re trying to make a cartridge of these cells, and they’re not working very well, then you don’t have a prayer of sustaining your patient,” says Bhatia.

Bhatia continues to hunt for better ways to culture liver cells outside of the body. She studies and manipulates cells with devices constructed on the cellular scale. The enabling technology is not new; engineers have used photolithography for decades to etch tiny patterns in surfaces when laying down circuits in computer microchips. But the same techniques have only recently been applied to biology, and Bhatia’s knowledge of both fields has put her at the forefront of their synthesis. The purpose of the tools that Bhatia develops is what she terms “deconstructing the environment around the cell.” Liver cells range in size from about 10 to 50 micrometers, and their function is largely controlled by their environment. “Ten to a hundred microns is technology that was invented in the ’80s,” Bhatia says. “But if we apply it cleverly to biology, we can control that environment, and people have not done that before.”

Little research has been done on the microenvironment of the cell. Most current knowledge of cell biology comes from studying large populations of cells grown in petri dishes. But that’s much like trying to deduce the habits of a single person based on a bird’s-eye view of New York City. Just as Manhattan can change from rugged to ritzy in a single block, the environment surrounding cells in a live organ can change in the space of micrometers. Understanding that environment is a problem central to the development of cell-based therapies–both those that seek to incorporate cells into artificial devices or engineered tissue and direct therapies using stem cells.

For example, liver cells survive better outside the body if they have as neighbors cells from connective tissue. Bhatia’s lab has been testing specific patterns of cell placement on microfabricated surfaces and has found that certain arrangements of the two types of cells are more stable than others. The researchers are trying to determine what liver cells get from their neighbors: Physical contact? A chemical signal? “We are interested in the dynamics of the cell-cell interaction,” Bhatia says. To help solve this puzzle, postdoctoral fellow Elliot Hui recently developed a device consisting of two tiny interlocking combs that hold cells; with it, the researchers can test how the cells change when they are brought together or held just a few micrometers apart.

These discoveries can help scientists learn the conditions necessary to grow liver cells in devices and, ultimately, to create an artificial liver from cultured cells. Joseph Vacanti, a Harvard Medical School surgeon at Massachusetts General Hospital, is working toward creating artificial organs, including artificial livers. “It remains one of the more challenging problems in the field of tissue engineering,” Vacanti says. “What distinguishes Dr. Bhatia is her ability to successfully combine technologies to help us understand how liver cells work and how to control their function.” Bhatia is also applying some of the same thinking to stem cells, which could potentially be coaxed to become any kind of cell–including liver cells–with the right environmental cues.

Tissue engineering is just one of the clinical applications of Bhatia’s work. Along the way, she realized that the techniques she had developed for studying liver cells could prove equally valuable in screening drugs for liver toxicity. Even the most promising drug can be thwarted if it becomes toxic as it is broken down in the liver. Microtechnology offers a way to array liver cells on patterned surfaces and quickly test the effects of multiple chemicals. The potential of Bhatia’s work to change medicine has garnered her awards such as a five-year Packard Fellowship for promising young scientists and engineers, and Technology Review named her to the 2003 TR100 list of top young innovators. Bhatia’s lab has also won attention for its research in nanotechnology; she and colleagues have worked on harnessing the properties of nanoscale particles to target and treat cancer cells.

Jennifer Elisseeff, PhD ‘99, a fellow HST graduate (and TR100 honoree) and a bioengineer at Johns Hopkins University, says, “What I really like about [Bhatia’s] work is that it sort of defines what we think of as biomedical engineering.” Elisseeff, who focuses on developing new biomaterials from which to construct artificial tissue, adds that Bhatia “develops new devices to study biological problems that have a direct medical application. That’s what we should strive for.” Beyond its immediate uses, Bhatia’s work is drawing attention for a more fundamental reason: it blurs the boundaries between living and artificial systems, which may have far-reaching implications for how we treat disease.

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