CAMBRIDGE, Mass.—The estimated 200 million people worldwide who suffer from hepatitis C, an infectious disease affecting the liver, may soon benefit from new tests and treatments made possible by a recent discovery by researchers at the Massachusetts Institute of Technology (MIT) and Rockefeller University.
Until now, hepatitis C patients have been limited in their choice of treatments, which are also not always effective, because these treatments must be tested in liver cells, which unfortunately tend to lose their liver functions when removed from the body. Previously, researchers have been able to induce cancerous liver cells to survive and reproduce outside the body, but those cells are not sufficient for studying hepatitis C because their responses to infection are different from those of normal liver cells.
Now, a research team led by Dr. Sangeeta N. Bhatia, a professor of health sciences, technology, electrical engineering and computer science at MIT, has published a study describing how they have successfully grown hepatitis C virus in otherwise healthy liver cells in the laboratory. The study, published Jan. 25 in the Proceedings of the National Academy of Sciences, describes the researchers' ability to maintain liver cells for four to six weeks by precisely arranging them on a specially patterned plate. The cells can be infected with hepatitis C for two to three weeks, giving researchers the chance to study the cells' responses to different drugs.
"Cancerous cells are not the natural host for HCV and do not have an intact innate immune response," Bhatia says. "We know this is important therapeutically since interferon, which boosts innate immunity, is the only proven clinical treatment. These are primary hepatocytes that come from consented donor organs that are deemed unacceptable for transplantation and are then purified and frozen. We thaw the cells, organize them by micropatterning on a spotted surface and surround them with supportive neighboring cells. This tissue architecture supports their function in culture and allows them to express many of the receptors and host factors required for HCV entry and replication."
The researchers used healthy liver cells that had been cryogenically preserved and grew them on special plates with micropatterns that direct the cells where to grow. The liver cells were strategically interspersed with other cells called fibroblasts that support the growth of liver tissue.
"If you just put cells on a surface in an unorganized way, they lose their function very quickly," says Bhatia. "If you specify which cells sit next to each other, you can extend the lifetime of the cells and help them maintain their function."
Bhatia says other disease areas may benefit from this advance.
"We believe the liver stages of malaria can be modeled similarly, and we are working with the [Bill & Melinda] Gates Foundation to explore this," she says. "In addition, hepatitis B virus and Dengue might be amenable to this approach. We do not know yet if these will behave similarly to HCV."
The researchers note that the strain of hepatitis C they used was derived from a Japanese patient with fulminant hepatitis, the only strain ever successfully grown in a laboratory environment. The researchers hope to modify the system so they can grow additional strains, such as those more common in North America, which would allow for more thorough drug testing.
Ultimately, the research team believes it has developed "a novel, high-throughput assay for both entry inhibitors and replication inhibitors for at least one genotype of HCV," Bhatia says.
"The commercial opportunity will be determined in the fullness of time," she adds.
The study, "Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures," had many sponsors: the Greenberg Medical Research Institute, the Ellison Medical Foundation, the Starr Foundation, the Ronald A. Shellow Memorial Fund, the Richard Salomon Family Foundation, the Howard Hughes Medical Institute and the National Institutes of Health (NIH) through a NIH Roadmap for Medical Research grant.
Until now, hepatitis C patients have been limited in their choice of treatments, which are also not always effective, because these treatments must be tested in liver cells, which unfortunately tend to lose their liver functions when removed from the body. Previously, researchers have been able to induce cancerous liver cells to survive and reproduce outside the body, but those cells are not sufficient for studying hepatitis C because their responses to infection are different from those of normal liver cells.
Now, a research team led by Dr. Sangeeta N. Bhatia, a professor of health sciences, technology, electrical engineering and computer science at MIT, has published a study describing how they have successfully grown hepatitis C virus in otherwise healthy liver cells in the laboratory. The study, published Jan. 25 in the Proceedings of the National Academy of Sciences, describes the researchers' ability to maintain liver cells for four to six weeks by precisely arranging them on a specially patterned plate. The cells can be infected with hepatitis C for two to three weeks, giving researchers the chance to study the cells' responses to different drugs.
"Cancerous cells are not the natural host for HCV and do not have an intact innate immune response," Bhatia says. "We know this is important therapeutically since interferon, which boosts innate immunity, is the only proven clinical treatment. These are primary hepatocytes that come from consented donor organs that are deemed unacceptable for transplantation and are then purified and frozen. We thaw the cells, organize them by micropatterning on a spotted surface and surround them with supportive neighboring cells. This tissue architecture supports their function in culture and allows them to express many of the receptors and host factors required for HCV entry and replication."
The researchers used healthy liver cells that had been cryogenically preserved and grew them on special plates with micropatterns that direct the cells where to grow. The liver cells were strategically interspersed with other cells called fibroblasts that support the growth of liver tissue.
"If you just put cells on a surface in an unorganized way, they lose their function very quickly," says Bhatia. "If you specify which cells sit next to each other, you can extend the lifetime of the cells and help them maintain their function."
Bhatia says other disease areas may benefit from this advance.
"We believe the liver stages of malaria can be modeled similarly, and we are working with the [Bill & Melinda] Gates Foundation to explore this," she says. "In addition, hepatitis B virus and Dengue might be amenable to this approach. We do not know yet if these will behave similarly to HCV."
The researchers note that the strain of hepatitis C they used was derived from a Japanese patient with fulminant hepatitis, the only strain ever successfully grown in a laboratory environment. The researchers hope to modify the system so they can grow additional strains, such as those more common in North America, which would allow for more thorough drug testing.
Ultimately, the research team believes it has developed "a novel, high-throughput assay for both entry inhibitors and replication inhibitors for at least one genotype of HCV," Bhatia says.
"The commercial opportunity will be determined in the fullness of time," she adds.
The study, "Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures," had many sponsors: the Greenberg Medical Research Institute, the Ellison Medical Foundation, the Starr Foundation, the Ronald A. Shellow Memorial Fund, the Richard Salomon Family Foundation, the Howard Hughes Medical Institute and the National Institutes of Health (NIH) through a NIH Roadmap for Medical Research grant.
