In his UW-Madison lab, Su-Chun Zhang discovered a likely cause of ALS, the deadly neurological disorder also known as Lou Gehrig’s disease, after turning skin cells from ALS patients into stem cells.
A protein error in cellular structures called neurofilaments, which transport chemicals that allow muscles to move, leads to paralysis in at least some forms of ALS, Zhang found. The company he started, BrainXell, is using a federal grant to screen compounds that might be developed into drugs to fix the error.
“If we know what’s going on at the early steps of the disease process, we can potentially devise a means to intervene,” Zhang said.
To make iPS cells, scientists reprogram skin or blood cells back to their embryonic state. No embryos are destroyed, or even used, as is required to get embryonic stem cells.
James Thomson, the UW-Madison researcher who captured international attention by first isolating human embryonic stem cells, in 1998, reported his creation of iPS cells in the journal Science on Nov. 20, 2007. On the same day, the same feat was proclaimed in the journal Cell by Shinya Yamanaka, a Japanese researcher who went on to share the Nobel Prize in 2012 for the work, as he had done it first in mice.
The discovery of iPS cells — which, like embryonic stem cells, can be coaxed into many cell types, from heart to kidney to brain — ushered in a new era in biology and regenerative medicine.
Not only did iPS cells remove the ethical and political controversy surrounding the destruction of embryos to obtain stem cells. They also offered the potential to devise cell therapies for Parkinson’s disease, heart disease, diabetes, spinal cord injury and other conditions from a patient’s own cells, which could overcome the risk of immune rejection.
A decade after the discovery of iPS cells, progress is mixed. Clinical trials of experimental therapies using the cells have barely begun, but the cells are proving useful in other ways.
They’re allowing researchers like Zhang to make discoveries by studying disease models in a dish, considered better than animal models in many respects. They’re also letting pharmaceutical companies screen potential drugs for side effects, many of them using iPS cell lines made by Cellular Dynamics International, a Madison company founded by Thomson.
“People who want a cure for X, Y and Z disease are going to be disappointed with the 10 years of progress,” said Dr. Tim Kamp, a UW-Madison cardiologist and co-director of the university’s Stem Cell and Regenerative Medicine Center. “But from a realistic standpoint, I think things have progressed fairly well.”
Billions of cells
Biomedical engineers like William Murphy, the other co-director of the stem cell center on campus, are using iPS cells to create “organoids,” or “tissue chips,” three-dimensional clusters of cells that mimic human brains, livers, blood vessels and other tissues in lab dishes.
In work funded by the U.S. Environmental Protection Agency, Murphy and his colleagues are using organoids to screen chemicals for toxicity, as the health effects of many chemicals on the market today are unknown.
Meanwhile, Murphy is hopeful enough about cell therapies from iPS cells that he’s working on methods to grow a lot of them efficiently. In September, the National Science Foundation awarded $20 million to UW-Madison and other universities, including the Georgia Institute of Technology, to improve cell production through an Engineering Research Center for Cell Manufacturing Technologies.
“How do we generate billions of cells in a way that’s reasonably low cost and highly effective and safe, while maintaining their function?” Murphy said.
Cellular Dynamics, or CDI, already produces billions of cells per year, directing iPS cells into 14 types of cells sold and used in research worldwide, said Kaz Hirao, CEO.
The company, started in 2004 and acquired by Fujifilm in 2015, plans to apply to the U.S. Food and Drug Administration to start clinical trials of cell therapies for Parkinson’s in 2019 and heart disease by 2020, Hirao said.
CDI is also developing immunotherapy for cancer, similar to the unprecedented chimeric antigen receptor, or CAR, T cell therapies approved by the FDA in August and October. Those expensive treatments use a patient’s own cells, while CDI is looking at an off-the-shelf preparation using banks of cells from other people.
“The reason is very simple,” Hirao said. “We can make a more cost-effective therapy.”
Another CDI project aims to restore vision to people with age-related macular degeneration or a disease called retinitis pigmentosa.
Opsis Therapeutics, a joint venture started last year between CDI and Dr. David Gamm, director of UW-Madison’s McPherson Eye Research Institute, hopes to start a clinical trial within three years.
In the first reported clinical trial involving iPS cells, in 2014, a Japanese woman received retinal cells derived from her own iPS cells. She fared well, but safety concerns stopped the study.
This year, a Japanese man got the same treatment, but with iPS cells from another person. The National Eye Institute in the U.S. plans to apply next year to start a study involving retinal cells derived from iPS cells, grown using a protocol developed by CDI and Opsis.
Those efforts and others involve supportive tissue in the eye, called retinal pigment epithelium cells. Gamm is focusing instead on what he calls the star of the vision show: photoreceptors, which detect light.
“They’re what’s lost; they’re the key element,” he said. “But they’re also more difficult to make, and to get to function in the diseased eye.”
Gamm said, “It’s great that we’re at this position where we’re now thinking of how best to install the cells, because we actually have the spare parts now, which 10 years ago we didn’t have. But it’s still a large hurdle to overcome.”
Kamp, the cardiologist, is part of an $8.6 million, seven-year National Institutes of Health grant to test 3-D “heart patches” of heart muscle cells, grown from iPS cells, in pigs.
The cells are made at UW-Madison, then sent to Duke University in North Carolina, where they are fashioned in patches. The patches are shipped to the University of Alabama, where they are delivered into pigs after heart attacks.
Human trials could be next. But challenges remain, including immune rejection from the pigs and getting the patches to sync up to the pig hearts, mechanically and electrically.
“It’s not like plugging a USB drive into your computer, and it just hooks up fine,” Kamp said.
Thomson, who in 2011 won the Albany Medical Center Prize in Medicine and Biomedical Research, sometimes called “America’s Nobel,” is using iPS cells to develop blood vessels that could someday be used in bypass surgeries for cardiovascular disease.
The blood vessels of many patients aren’t suitable for use as bypasses, doctors say. Thomson and others at the university are trying to create artery “banks” from the iPS cells of universally compatible donors, through an $8 million NIH grant.
For Zhang, a neuroscientist, iPS cells are helping him better understand — and develop potential treatments for — ALS and a related condition called spinal muscular atrophy, along with Parkinson’s and spinal cord injury.
He is pursuing spinal cord injury not only as a scientist, but also as a patient.
After a bicycle accident in 2014 injured his spinal cord, Zhang was able to regain the ability to walk. But he struggles to use his hands to write or hold chopsticks, has digestive complications and feels pain in all of his limbs, which causes trouble sleeping.
“It’s horrible,” he said. “You feel like your legs are on fire all of the time, and you simply want to chop your legs off.”
He plans to spend much of this winter in Singapore, because warm weather reduces the pain. But his dedication to creating cell therapies in his Madison lab has only intensified, he said.
“It should be possible,” he said. “I am actually very hopeful.”