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.

High Expectations

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.

Cancer

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.

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