A FEW months ago, Evelyn Hilton was able to ditch the walking stick she had relied on since 2014 and stand on her own two feet again. Meanwhile, Sonia Olea Coontz felt her right arm “wake up” after more than six months of it being totally paralysed and was able to walk more easily. Both had taken part in clinical trials in which stem cells were injected into their brains at the site of an earlier stroke.
This was no “Lazarus effect”; the patients didn’t wake from surgery and leap dramatically from their beds, totally cured. Yet the results were a major step forward in efforts to heal damaged brains, and could lead to such treatments becoming widely available within just a few years.
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It is undoubtedly an exciting time for stem cell medicine. Stem cells, the blank slate from which the body can build any type of cell it needs, are proving themselves capable of doing what was once thought impossible: healing broken brains. Yet having followed the progress of cell therapies since the 1980s, it seems to me that this technology is just the beginning of a wave of even more exciting potential treatments. They would involve persuading the diseased brain to replace its lost cells without the need for a transplant: a true regenerative medicine of the brain.
Brain injuries present the body with a unique problem. While most other tissues can repair themselves when damaged, the adult brain, with the exception of two small regions, cannot make new neurons from scratch. There is a short window of time after injury when the brain attempts to clear away debris and reroute its connections to regain some of the lost function. Some drugs, if given within a few hours, can stop the damage from becoming too severe. Even so, the fact that dead neurons can’t be replaced can mean that the damage done leads to lifelong disability.
The idea of restoring brain function by transplanting new cells into people’s brains predates the possibility of stem cell medicine. In the 1980s, two Swedish people with Parkinson’s disease were given brain grafts of dopamine-producing cells from the adrenal glands. The cells lost in Parkinson’s disease use dopamine as a neurotransmitter, and although the adrenal glands are located far from the brain, above the kidneys, they too make dopamine. The idea was that if dopamine was needed, perhaps it wouldn’t matter what kinds of cells were providing it. Initial results from animal studies looked encouraging, but and the approach was soon abandoned.
“The adult brain cannot normally make new neurons from scratch”
Other researchers tried using dopamine-producing nerve cell precursors taken from aborted fetuses. The approach was controversial, but because the implanted cells were closer to what is lost in Parkinson’s, patients seemed to fare better.
Almost 100 people have had these kinds of transplants in trials over the past two decades, and follow-up studies show that in many cases the cells are alive and the . It seemed to be the breakthrough we had been waiting for in the treatment of neurodegeneration, and the future looked bright. I remember predicting at the time that cell therapies would be widely available within five years.
That didn’t happen, for several reasons. First, when larger trials were done including a control group who had the surgery but had no cells injected, it turned out that, overall, fetal cells performed no better than placebo. What’s more, the older, more severely affected patients got the least benefit from the surgery. The treatment also proved logistically, as well as ethically, difficult. Each transplant required material from three or four aborted fetuses, meaning that many people would never be comfortable with the procedure. It was also clearly never going to be possible on any practical scale.
Similarly, efforts to genetically engineer the enzymes needed to produce dopamine into various other cell types have yet to succeed, despite several decades of experimentation and animal studies. All in all, by the early 1990s, it looked as if replacing brain cells with a rough approximation of what had been lost just wasn’t going to work.
Fortunately, stem cells were just starting to show promise in the lab, and this changed the game. Symptoms of Parkinson’s disease may well be alleviated if a few hundred thousand dopamine-producing neurons could be replaced. But stem cells, with their ability to generate various cell types, held the potential to fix many more kinds of brain damage. Brain tissue is composed of many different kinds of cells, including neurons, support cells, connective tissue and blood vessels. The earlier attempts at cell replacement had shown it was possible to squirt cells into an injured brain without causing further damage. The question now was whether stem cells could get in there and rebuild the complex structure of what had been lost.
Again, animal studies looked promising. Rats injected with stem cells following a stroke recovered sensation and movement to a degree rarely seen before. On closer inspection, though, there was a surprise. The reason it worked wasn’t because dead and dying cells had been replaced with shiny new ones, although this did happen to some extent. Even when stem cells remained in their immature state and didn’t differentiate at all, they still contributed to recovery. In many cases, the implanted cells didn’t even survive for more than a few weeks, but still the animals showed significant recovery.
What seems to be happening is that stem cells release growth factors and other chemicals that stimulate the brain to heal itself, potentially . Some of these chemicals may also boost the immune system, reducing inflammation and helping to stimulate blood vessel growth – all crucial if a newly mended bit of brain is going to thrive. In fact it could even be that this plays a more important part in brain fixing than cell replacement.
“Patients have a hole drilled in their skull and a slurry of cells is gently squeezed in”
So far, though, no one knows for sure what the stem cells are doing in the brain, and this has led some to argue that even if it works, we should hang back from using it on patients. Some researchers think it would be unethical to proceed; others think it would be unethical not to.
Whatever the rights and wrongs of that argument, clinical trials are under way. In the past two years, two companies – , and SanBio in Mountain View, California – have reported on their phase 1 clinical trials using stem cells to improve disability following stroke. Both have reported good safety data, and intriguingly, the first glimpse of efficacy.
In the ReNeuron trial, on which I acted as a consultant, fetal stem cells were processed using a technique that allows a single neural stem cell to generate enough cells to treat hundreds of patients. The SanBio technology starts with a different kind of stem cell, derived from bone marrow, but engineered in such a way that it maintains its stem cell characteristics.
Once the cells have been prepared, the technique for getting them into the brain is remarkably crude. Under anaesthetic, patients have a hole drilled in their skull, and using brain imaging to guide the surgeon to the site of injury, a slurry of cells is gently squeezed in. Remarkably, this procedure has proven relatively safe and easy, and most patients in the trial were able to go home within a day or two. Some reported temporary headaches, and some had local bleeding or fluid accumulation. One patient had a seizure, probably associated with the surgery, but neither trial revealed safety issues attributable to the cells.
Not all of the patients had the dramatic improvements that Hilton or Coontz experienced, but the majority showed significant improvement in control over their limbs, or had other life-changing improvements such as the loss of a tremor. And despite the cells themselves only lasting a month or so after the injections, the improvements seem to linger way past the six months after which stroke patients are usually told to expect no more change. “It’s two and a half years on from when I had the stroke and I am still having improvement,” says Hilton. “It’s slow, but it’s still happening. I don’t regret getting it done at all.”
Even small changes can have a big effect. Being able to move a limb or just a thumb can mean the difference between being able to take the top off a bottle yourself and needing to ask for help.
These successes have set the stage for larger clinical trials. SanBio is recruiting patients for phase 2 trials. The , reported in December 2016, look broadly promising, with the final results expected in 2017. If successful, these trials could herald a stem cell treatment for stroke within five years, although larger controlled trials would still be required before the treatment could be licensed by regulators. Other researchers are trying to introduce the cells sooner after the stroke to limit the damage rather than repair it, although it is too early to say whether this approach will prove superior.
Critics point out that even if this turns into a successful treatment, it won’t be the cell-replacement therapy originally envisaged, and some argue that we should hold off until we can deliver on that promise. That reality, however, may not be too far behind.
A key step towards this goal came in 2006, when Shinya Yamanaka of Kyoto University in Japan discovered a way to wind back the clock of adult cells to a point normally encountered only at the start of development, when embryonic cells have the potential to become any kind of cell in the body. The from cells derived from adult connective tissue won him the 2012 Nobel prize in medicine.
It is difficult to exaggerate the impact of Yamanaka’s discovery on stem cell research. After that it was possible to start with essentially any human cell – blood, skin, hair – and reprogram it into a stem cell. This discovery immediately alleviated the ethical and logistical pressure on deriving stem cells from human embryos, and Yamanaka’s iPS cells quickly became the cell of choice for regenerative medicine applications.
Although still a little way behind, therapies based on iPS cells are approaching clinical trials, and are increasingly seen as the future of cell transplants. What’s more, unlike the current technologies, these iPS cells can actually build new tissue from scratch.
The logical next step would be to hop directly from one cell type to another, without going via stem cells. Better still would be to do it directly at the site of injury. Both of these would have seemed crazy a decade ago, but now look like distinct possibilities (see diagram). In 2010, Marius Wernig at Stanford University in California and his colleagues showed that it is possible to tweak the activity of just three genes to , a cell type found in connective tissue, into a fully functioning neuron. In 2014, Magdalena Götz at the Munich Center for Neurosciences – Brain and Mind in Germany, and her colleagues demonstrated not only that is it possible to convert support cells in the brain into neurons, by changing the activity of just two genes, but that it . The trick here is that some of these support cells have hidden stem cell potential. The right combination of factors coaxes these properties to show themselves, giving the brain an opportunity to carry out repairs.
“The right combination of factors gives the brain the chance to repair itself”
The key then will be specificity. Neurons come in many different types, more than we can even count accurately. If you want to replace what was lost, you need the right type for the job; as the Parkinson’s experiments showed in the 1980s, not just any old cell will do. Can we come up with precisely the right recipe to generate a specific neuronal type?
It is a way off yet, but work in this direction is looking promising. Andrew Yoo and his team at Washington University in St Louis, Missouri, have been studying what it takes to generate a very specific neuronal type: the . They have shown that this finely directed fate switch is indeed feasible. We must assume that something similar will prove possible for other cell types. If we can just discover each cell’s particular code, then the regenerative possibilities are enormous.
It has taken more than the five years I originally anticipated, but I believe we are heading for a future where fixing broken brains may become a reality.
This article appeared in print under the headline “Mending minds”
