Scientists in Dr. David Gamm’s lab at UW-Madison can coax stem cells to grow into three-dimensional retinas in a dish and show that the tissue responds to light.
But putting the cells into the damaged eyes of people with blinding disorders, in a manner that improves vision, could be a much greater challenge.
“We know the spare part is right, but we’re trying to put it into an engine that may or may not accept that part,” Gamm said.
Gamm is one of about 100 faculty researchers using stem cells to model diseases, screen drugs or develop cell therapies at the university, where James Thomson gained international attention 20 years ago this week by announcing he was the first scientist to grow human embryonic stem cells outside of the body.
In the two decades since Thomson’s discovery set off an ethical debate and raised the hopes of patients with a wide range of diseases, stem cell science has shifted from a hot flame to a slow burn. Biological achievements continue to bubble up, but it’s not clear if or when transformative treatments might be served.
In 2007, Thomson and Japanese researcher Shinya Yamanaka developed induced pluripotent stem cells — or iPS cells, skin or blood cells reprogrammed to their embryonic state — which eased concerns about destroying embryos to produce stem cells.
Many scientists at UW-Madison and other institutions have guided blank-slate embryonic stem cells or iPS cells to become specialized cells of the brain, heart, pancreas and other organs.
Some of the cells carry mutations that cause disease, enabling a better understanding of what goes awry than animal models can provide. Others are used to test experimental drugs for side effects. Still others are being prepared as potential replacements for patients with Parkinson’s disease, heart failure, diabetes or other conditions, whose cells are damaged or have died.
Eyes are ‘leading the way’
A leading candidate for stem cell therapies is blindness caused by disorders such as retinitis pigmentosa and macular degeneration.
Injecting an experimental treatment into a blind eye carries a relatively low risk, said Gamm, a pediatric ophthalmologist. Eyes are encapsulated, so wayward cells likely wouldn’t travel to other parts of the body. If something goes wrong, an eye can be removed. Doctors wanting to see how transplanted cells are behaving can dilate the pupils and look — no MRI or PET scan required.
“The eye is leading the way,” said Gamm, who noted that many of the human trials of stem cell therapies taking place today are treatments for vision disorders.
One of Thomson’s original embryonic stem cell lines has been used by California-based Asterias Biotherapeutics to create an experimental therapy for spinal cord injury. An initial clinical trial found the injection to be safe, with some patients seeing improved motor function, the company said in July.
An experimental treatment for graft versus host disease, a complication of bone marrow transplants, last year became the first cell therapy developed at UW-Madison from stem cells to undergo a clinical trial. The study, in England, by the Australian company Cynata Therapeutics, used blood cells derived from iPS cells by Igor Slukvin, a UW-Madison pathologist.
Gamm hopes to start a clinical trial for vision loss in 2021, with UW Hospital a likely site. In public talks and interviews, he is eager to explain the science and careful to manage expectations.
In doing both, he becomes Metaphor Man. Raised in Michigan, he likes to talk engines. The spare part he’s developing is the retina — specifically, retina cells called photoreceptors, which include rods that detect black-and-white images and cones that capture color.
Photoreceptors are like spark plugs, Gamm said. In people with vision loss, they could reignite sight. But, he asks, will they work if the engine is rusted?
Layers of retina
The retina, a membrane at the back of the eye, is an “elegant layer cake,” Gamm said.
Photoreceptors begin the process of seeing, and transmit signals to bipolar cells and ganglion cells, which relay messages to the optic nerve. Beneath the photoreceptors is the retinal pigment epithelium, or RPE, another tier of cells that nourish photoreceptors and remove their waste.
While photoreceptors play the lead role, RPE cells are a vital supporting actor. “They are the Batman and Robin of vision,” Gamm said.
Retinitis pigmentosa, a group of genetic disorders that wipe out peripheral and night vision, typically beginning in childhood, primarily attacks photoreceptors. Macular degeneration, which destroys central vision, usually in advanced age, primarily affects RPE cells. But when those cells die, so do photoreceptors.
Only a few treatments exist for the conditions, including a gene therapy approved last year for a rare form of retinitis pigmentosa and injections that can treat bleeding in macular degeneration.
For people with severe vision loss, prosthetics are available. One, by the California company Second Sight, sends signals from a camera imbedded in special glasses to a chip implanted atop the retina, stimulating ganglion cells to allow the brain to perceive crude shapes.
BrainPort, by the Middleton company Wicab, bypasses the eye altogether. It translates digital information from a video camera into stimulation patterns on the user’s tongue. Patients learn to interpret the tongue signals as a form of vision.
Such devices can provide a rough semblance of sight, but restoring photoreceptors or RPE cells through cell therapy could produce a more natural type of vision, Gamm said.
RPE cells derived from embryonic stem cells or iPS cells have been transplanted into patients with macular degeneration in several trials, including one by Massachusetts-based Advanced Cell Technology, now part of Astellas Pharma of Japan. That trial, in 2012, found no apparent complications and an increase in retinal pigmentation, suggesting the transplanted cells survived.
Gamm is aiming higher: He wants to transplant Batman. “Photoreceptors are where it’s at,” he said.
‘Golden Cheerios’ and ‘pod people’
When Gamm, 50, came to Madison in 2000, he intended to stay three years. After growing up in Grand Rapids, Michigan, he majored in biology at the University of Michigan-Ann Arbor. He stayed at that campus to get his medical degree and a Ph.D. in neurosciences.
He planned to join the faculty at Michigan but figured he should get experience elsewhere. For the clinical training required after medical school, he came to UW-Madison.
As his residency ended, Marsha Mailick, then director of UW-Madison’s Waisman Center, altered Gamm’s plans when she offered him access to a lab. The center, next to UW Hospital, focuses on developmental disorders and neurodegenerative diseases, including vision disorders, and has a cadre of stem cell researchers.
Gamm decided to stay in Madison, where he could perform surgeries, treat children at an eye disorders clinic and study stem cells — with the goal of treating blindness — on the same campus as Thomson, the pioneer.
Gamm and his wife, Marilyn, settled down in Waunakee, where she is a teaching assistant at Arboretum Elementary School. They have three children: Emily, 23, a nurse in St. Paul, Minnesota; Anna, 21, a history major at UW-Madison; and Joe, 18, a senior at Waunakee High School.
In 2009, Gamm’s lab announced its first breakthrough, in the Proceedings of the National Academy of Sciences: growing early-stage retina cells from embryonic stem cells and iPS cells. Gamm patented the technology through the Wisconsin Alumni Research Foundation.
Two years later, in the journal Stem Cells, Gamm and others in his lab showed they could create three-dimensional retina tissue including photoreceptors and RPE cells. Gamm calls the hollow balls “golden Cheerios.”
The team later demonstrated that the cells respond to light and assemble roughly as they would in a developing fetus. Microscopic images show light-catching segments reaching out with what look like long stalks and oval heads. Gamm calls them “pod people.”
Working with campus engineers Shaoqin “Sarah” Gong and Zhenqiang “Jack” Ma, the lab developed a miniature biodegradable scaffold upon which photoreceptors could be delivered into the eye. Through WARF, they are pursuing a patent on that technology.
In 2016, Gamm started Opsis Therapeutics, a subsidiary of Cellular Dynamics International, the Madison stem cell company founded by Thomson that is now part of Fujifilm.
For its first clinical trial, Opsis plans to transplant photoreceptors derived from iPS cells into patients with retinitis pigmentosa, Gamm said. A study of photoreceptors and RPE cells for macular degeneration could follow.
Progress might be incremental
At 6 feet 6 inches tall, Gamm exudes a determination characterized by graduating first in his medical school class and being named chief resident at UW-Madison. He converses quickly and expansively, as if he’s worried he’ll leave out an important point before the clock runs out.
“I can hardly say ‘hello’ in 20 minutes,” he joked last year at a public talk after the moderator asked him to keep his presentation to that amount of time.
He seems to stumble upon analogies, embracing them as a way to help non-scientists understand the intricacies of his lab.
Even though his photoreceptors are grown under controlled conditions in a dish, they may be more adaptable to transplantation in blind patients than would be cells from a deceased donor who never had a vision problem, he said. They’re more used to harsh environments, like a boy raised by wolves, he said.
“If you take a city boy and stick him in the Amazon, he’s going to die,” Gamm said. “But if he’s raised in the Amazon, maybe he’s not going to play the piano, but he can survive in that harsher environment.”
As for thinking of the eye as a car engine, Gamm said people with retinitis pigmentosa need new spark plugs and those with advanced macular degeneration need spark plugs and a new cylinder head.
But if the engine has gone too long without those parts, it may have seized up and rusted. Replacing the entire engine is beyond the scope of the stem cell therapies being developed today, he said.
Given the scientific challenges, Gamm is troubled by what he calls rogue clinics, including some in the Milwaukee area and the Fox Cities, that offer unproven stem-cell therapies.
Such clinics — most of them for-profit enterprises that charge significant fees — often remove fat or blood from patients and inject part of it into various body parts, saying the stem cells within can help repair injury or illness.
The Food and Drug Administration has started to crack down on the clinics, seeking court injunctions this year against one in California and one in Florida, where some patients went blind after receiving injections to treat macular degeneration. Last month, the Federal Trade Commission filed a complaint against two other California clinics for making overreaching marketing claims for treatments costing up to $15,000.
“In the best-case scenario, you’re being separated from a lot of money,” Gamm said. “In the worst-case scenario, you’re putting yourself or your child or loved one in harm’s way.”
If stem-cell therapies are eventually approved, the first ones might offer only incremental improvements to patients, Gamm said.
They could be like the clunky computers of the 1960s, a far cry from today’s smart phones. Or like the Wright Brothers’ inaugural flight in 1903, which led to Charles Lindbergh’s trans-Atlantic journey 24 years later and routine global travel today.
“You can’t really expect to go from blindness to reading The New York Times,” Gamm said.