Stem cell advance
A field long on promise and short on healing was energized on Oct. 15, 2014, when The Lancet reported on the transplant of retinal cells into 18 people who were blind because cells had died in the center of the retina.
The study focused on safety, but the hints that the transplant worked fed a desperate hunger for progress on stem cells — the long-awaited “spare parts” that may someday revolutionize medicine. Getting the story precisely backwards, CNN headlined “Stem cells help nearly blind see”, then proceeded to explain that “Researchers say that human embryonic stem cells have restored the sight of several nearly blind patients — and that their latest study shows the cells are safe to use long-term.”
In fact, the experts we talked to were optimistic about the safety issue — a huge hurdle for stem cells — but less sanguine about the “getting the blind to see” aspect.
So, how much progress are we making in stem cells, in the clinic and the laboratory?
The clinic part is easy: The U.S. Food and Drug Administration has not approved any non-experimental transplant of cells derived from the most versatile stem cells. These are the embryonic stem cells (ESC) that sparked all the attention 16 years ago, when they were first isolated by Jamie Thomson at the University of Wisconsin-Madison.
The laboratory part is promising, but more complex.
Stem cells stem from what?
The cells replaced in the Lancet study, called retinal pigment epithelium, came from ESCs. The RPE provides essential metabolic support to photoreceptors — the cells that convert light into nerve impulses.
Patients in the Lancet study had either dry age-related macular degeneration (AMD) or Stargardt’s macular dystrophy, which affects younger people. In both diseases, the RPEs die, which kills the photoreceptors. The dying starts at the center of vision, causing blindness exactly where detailed vision is most needed.
Each patient received three RPE-cell injections to one eye.
The diseases chosen illustrate the type of condition most appropriate to early human tests of pluripotent stem cells, says William Murphy, co-director of the Stem Cell and Regenerative Medicine Center at UW-Madison. “You need a substantial, unsolved clinical problem like AMD, ALS (Lou Gehrig’s disease) or spinal cord injury.”
“The new study was important from the basis of safety,” says David Gamm, an associate professor of ophthalmology and visual sciences at UW-Madison, and an expert in retinal stem cell biology and cell-based therapies, “but I think it’s difficult to read too much into the efficacy data.”
The examiner and the patient both knew which eye was treated (“you can’t fake that,” Gamm says) and patients may try harder on vision tests with that eye after the transplant;
After repeated eye-chart testing, AMD patients may learn to use surviving retinal regions; and
The procedure replaced the RPE, not the photoreceptors. Because those light-sensitive cells in the center of vision are dead, the treatment at best could have “awoken photoreceptors on the edge of the lesion that are not dead but are not working because they don’t have the RPE,” Gamm explains.
Transplanting retinal cells may sound like a magic bullet, “But it’s not like putting a new carburetor into a car,” says Gamm. Eyes in advanced cases of both diseases are like “a beat-up engine. A lot of those not-so-subtle details were not discussed” in the article.
The study was more convincing on the safety issue, Gamm says, “but unfortunately that often does not get the attention it should get. The patients were followed for a median of 22 months, and nothing like the formation of tumors was seen, or cells getting to the wrong place. These are all important aspects of the study and were done well. I would flip the order of priority on the study to the safety aspect. That’s the part that will advance the field.”
But if the retinal cell transplant was the most impressive clinical trial to date, how much longer must we wait?
For people with untreatable disease, the 16 years since the discovery of human embryonic stem cells amounts to forever. But it’s fair to say that when ESCs were first isolated, they resembled a gang of trouble-prone youths more than a disciplined cadre of bio-workers.
Their unlimited capacity to form any cell type gave embryonic stem cells plenty of potential for mischief, so the first step in putting them to work was to decipher the biochemical cues that guide stem cells into useful occupations.
For comparison, how does the timeline stack up against monoclonal antibodies, identical molecules that trigger or block specific biological processes? Monoclonals were dubbed a “magic bullet” when they were discovered in the early 1980s, but “It took 20-plus years for first therapies,” says Derek Hei, director of Waisman Biomanufacturing at UW-Madison’s Waisman Center.
Today, Hei says, monoclonals have finally become “a mainstay of biotechnology,” used in treating cancer and autoimmune diseases like psoriasis and arthritis. “You can look for a similar timeline with cell therapy [derived from pluripotent stem cells].”
Even though biomedical technology has advanced rapidly since the 1980s, stem cells are “significantly more complex” than monoclonals, Hei says. “Cells can differentiate, integrate and replace dead cells, can secrete factors to help other cells survive, and it would not surprise me if it takes 30 years from the initial discovery, to where we have pluripotent stem cells becoming mainstream therapy.”
Nonetheless, Hei was pleased with the latest results. “You don’t really understand all the potential risks and technical issues until you start developing therapy. You will learn things in the first clinical trials that you can’t learn in animal studies.” It’s safe to assume that unanticipated problems will need to be solved, he adds.
The other uses
Even as Thomson’s epic 1998 discovery focused attention on the blockbuster potential of “spare body parts,” he and his colleagues already envisioned other jobs for the versatile stem cells.
Testing new drugs on a variety of human cells in a dish “is the immediate application” for stem cells, says Su-Chun Zhang, a professor of neuroscience at UW-Madison. Since the discovery of induced pluripotent stem cells (iPSCs) in 2007, researchers can grow cells from patients with various diseases, adds Zhang, a world expert on developing neural cells from stem cells. Having millions of cells, each carrying the donor’s disease, enables use of “high-throughput” screening to test thousands of potential drugs in robotic equipment.
William Murphy, a biomedical engineer at UW-Madison, says “Industry has been ramping up screening,” especially now that they can buy ready-made offspring of iPSCs. “I don’t think iPSCs or ESCs have replaced the current drug-discovery system, broadly, but in particular areas, there are quite a lot of pilot studies to try understand” how to screen drugs against diseased stem cells.
Further technological development is needed to ease high-throughput screening, Zhang says. “We need ways to handle the cells in a uniform way, to put the chemical on, and do this as simply as possible.” If it works, rapid screening of highly specialized cells “could be quite dramatic, can potentially shorten the process of discovery and increase the likelihood of success for a new drug.”
ALS is a fatal degeneration of the motor nerves that signal muscles to contract, and Zhang has already begun screening for a drug to stop an aberrant protein that he recently discovered as a root of ALS.
But he says researchers could benefit from a more sophisticated model-in-a-dish. Since the nerves do not operate in isolation, an ideal model would include nerve cells joined to muscle cells. “That is currently not available, due to complexity,” Zhang says. For one thing, when a nerve cell in a dish signals “contract!” to a muscle cell, the contraction can cause them to jump right out of the dish. “We are still trying to figure out a way to build such a system,” Zhang says, “but we are not there yet.
Making life easy for the robots, he adds, is a “pure technology issue.”
All of which is to say that pluripotent stem cells are a work in progress, especially in in terms of the ultimate pay-off: treating disease by replacing broken parts. Here are some critical areas for improvement:
Getting absolute control. “We know [controlling] differentiation is a challenge going forward for all applications,” says Murphy. “We have to specify, standardize the target cell for transplanting; have to know what is going in. Standardization will be an ongoing area of focus for the next five to 10 years. It’s a move from scientific discovery to engineering.”
Cell maturity: How much is enough? Some situations require that mature cells be transplanted, says Murphy, who explains that partly developed pancreatic cells would not release insulin. But to replace cartilage in osteoarthritis, a slightly immature cartilage-forming cell is better, since very mature cells don’t make that essential friction reducer. Immaturity is also valuable for neural-cell transplants, says Zhang. “If you move a mature cell, it will die. A young neuron in a hospitable location will connect to the right place. If it projects to the wrong place, that creates problems.”
Getting to maturity. Even fully differentiated cells derived from pluripotent stem cells may perform like fetal cells, not adult ones. Heart muscle cells, for example, can have the pulse and pumping force of a fetal heart. “We have to find ways to rapidly mature cells so they mimic the properties of an adult,” Murphy says. “It’s a giant challenge facing the field, how to get a maturation process that typically takes years and do it in days or weeks in a dish. The kitchen sink is being thrown at this problem.”
Getting realistic. Cells don’t live in isolation and flat dishes of a single cell type are gross simplifications of a real organ. Therefore, researchers are developing “organoids” that fuse multiple cell types to screen drugs and model diseases. Gamm has generated in-dish combinations of the eye’s retinal pigment epithelium and photoreceptor cells, and Murphy is developing a simple simulation of brain tissue. By recreating a disease in a dish, he says, “We can start testing the mechanism of disease progression, and compounds that influence the disease, but there are no simple technologies yet that can form organoids that are amenable to high-throughput screening.”
On the bright side
Finally, we return our story to its roots — a study of the safety of transplanting cells to treat age-related macular degeneration. As we neared publication, Cellular Dynamics Inc., received a $1.2 million grant from the National Institutes of Health to grow retinal cells for AMD transplant experiments scheduled for 2017 or ’18.
Another source of optimism is the growing recognition that developing cells heed chemical signals from their neighbors. “If you want to create a tissue structure in a dish, you might think the cells would have to be individually placed using external manipulation,” says Murphy, “but it turns out for some applications, cells have the capability” to find their proper location.
“If you provide them with the right surrounding conditions, stem-cell self-assembly can build complex structures, tissues, even organs,” says Murphy. “I don’t think anyone would have anticipated that, but it’s tremendously useful.”
Bringing stem cells to the clinic has been a long struggle, but Murphy admits to “cautious enthusiasm. There remains a great deal of potential for treatment, but there are real technical and regulatory hurdles that have to be passed.”
Stem cell products transplanted into the retina may or may not have restored vision in the recent study, says ophthalmologist Gamm, but the study was still a watershed. “You have taken cells derived from embryonic stem cells and put them into the retina, and did not hurt anybody; that’s good. It’s possible there may have been a limited positive effect on vision, and there was no negative. This was major, very positive.”
– David J. Tenenbaum
Kevin Barrett, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David J. Tenenbaum, feature writer
- Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy… Steven D Schwartz et al, The Lancet, Published online October 15, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61376-3 ↩
- Stem Cell and Regenerative Medicine Center at UW-Madison ↩
- The ALS Association advocacy homepage, trumpeting support for ALS research. ↩
- The ethical, legal and political minefield of stem cell research ↩
- Nasal cells allow paralyzed man to walk again ↩
- Stem cell research trends ↩