Antibiotics, antivirals and other drugs have helped countless people, but for some, they can also cause liver damage. There’s no way to tell who’s susceptible until after it happens, and until recently, scientists trying to develop ways to find out sooner faced significant obstacles.
For one thing, taking liver cells from a person for research isn’t ethically permissible. And the livers of mice and rats aren’t exactly the same as those in humans.
Now three professors at the University of Connecticut School of Pharmacy are working to get around those problems using stem cells that can be turned into liver cells. Researchers Urs A. Boelsterli, Theodore Rasmussen, and Winfried Krueger hope to figure out why drugs cause liver damage in some people, which could potentially lead to a way to tell who is, and isn’t, at risk from certain certain drugs.
Their work is one of 20 stem cell research projects awarded state funding this week. Overall, the Stem Cell Research Advisory Committee awarded $9.8 million in grants, the latest round of funding in the state’s 10-year, $100 million commitment to the work. This week’s grant awards mark the fifth round of funding; since 2006, the committee has awarded more than $60 million. The money comes from the state’s tobacco settlement fund.
This year’s grant recipients also include nine projects by researchers at the UConn Health Center, nine at Yale University and one at Wesleyan University. The grants will fund work on topics including heart defects related to Down syndrome, treatment of cartilage damage and a risk factor for schizophrenia.
One grant, for $1.29 million, went to Chondrogenics, Inc., a start-up company that grew out of the work of Caroline Dealy, a professor at the UConn Health Center who is studying ways to create cartilage using stem cells. The goal is to develop cartilage that could be used replace damaged cartilage in patients with osteoarthritis.
“These awards signal Connecticut’s commitment to stem cell research and the life sciences sector,” Gov. Dannel P. Malloy said in a statement released by his office. “Connecticut continues to conduct some of the finest stem cell research in the country, and these awardees further demonstrate Connecticut’s promise as a leader in bioscience.”
For their work, Rasmussen, Boelsterli and Krueger were awarded a three-year grant for $1.29 million.
Most people are able to tolerate medications without liver damage, but Boelsterli said that many of the drugs that can cause liver problems are so widely used that even a small percentage of patients with adverse effects amounts to a lot of people.
The question he wants to answer: “Why are certain individuals predisposed to developing this toxicity and the vast majority is not susceptible?”
Figuring out what causes some people to get liver damage could lead to the development of predictive tests to identify people at risk before they are prescribed medication.
Boelsterli had been studying drug-induced liver toxicity for years when he and his colleagues learned about techniques involving stem cells. In them, he said, they saw great potential.
Stem cells are considered particularly promising because they have the potential to turn into any type of cell. Scientists can use them to study what causes cells to develop in certain ways, how diseases develop, and to create new cells like neurons or human liver cells that would otherwise be difficult to get in large quantities–or at all–for research.
“You can’t go to a patient, you can’t say ‘we’d like to have a brain biopsy, please, so we can study what’s going on,'” Rasmussen said. “In general, you can’t get these invasive biopsies from patients just to study disease mechanisms.”
While human embryonic stem cells have provoked controversy, the stem cells Rasmussen, Boelsterli and Krueger will use are known as induced pluripotent stem cells, or iPS cells, which don’t involve embryos.
Instead, they are created from cells that have already differentiated. By introducing certain genes to them, scientists can turn them into stem cells that are not differentiated and have the potential to become any type of cell. Then researchers can coax them to become a certain type of cell. Rasmussen’s lab will start with skin cells from patients who have had drug-induced liver injuries, and from those who haven’t, and end up with liver cells.
One advantage of iPS cells is that they retain the genetic characteristics of the person they came from, so iPS cells derived from the skin cells of a person with a genetic disease that get turned into liver cells would be expected to exhibit the characteristics of the liver of a person with that disease.
Then, Boelsterli said, researchers will look at how the cells function, comparing those from patients with drug-induced liver injuries to those from patients without them.
They will also expose the cells to drugs known to cause adverse effects to see how the cells react, comparing those from patients with liver damage to those who did not get it.
Krueger, meanwhile, is interested in whether there is a genetic basis for drug-induced liver injury. Exploring that will involve exposing the cells to particular drugs and determining whether certain genes are expressed more or less than they otherwise would be. Krueger said the literature is divided on whether there is a genetic link to the drug reactions.
“Obviously, something has to change in response to the drug,” he said, and the researchers hope to determine what it is.
Boelsterli and Rasmussen stressed that the project represents a collaboration between researchers with different interests and expertise. Rasmussen specializes in stem cells, while Boelsterli has an expertise in liver toxicity and Krueger is an expert in genetics.
“None of us could do it by ourselves,” Boelsterli said.
Rasmussen said that in addition to potential advances in science and the benefits to people’s lives they can create, research at universities in the state can foster biotechnology companies and the jobs they create.
“It’s got to happen somewehere, so why not here?” he said.