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Stem cell scientists take hope from first human trials but see long road ahead
Sarah Boseley, health editor
guardian.co.uk, Monday 4 June
Much hangs on outcome of first human trials amid funding difficulties, political opposition and public suspicion
Marcus Hilton sits in front of the TV and stares at the Sky News headlines scrolling along the bottom of the screen. If he moves his head about he can find the little patch of vision in his right eye where letters jump from a tiny size to suddenly bigger. It is a small but crucial difference for Hilton, and it represents a huge scientific achievement.
Hilton has the distinction of being the first person in the UK to receive a transplant of human embryonic stem cells. He has Stargardt's disease, a condition that destroys the central vision of the eyes at an early age. His view of the world is limited to what the rest of us catch on the edge of our field of vision. He was diagnosed when he was about 10, after various pairs of glasses did no good at all. Now 34, he recalls: "I could never see the blackboard. I was blagging my way through school native wit.".
Scientists hope that stem cells may restore the sight of people like Hilton and the many millions of older people suffering from macular degeneration, the most common cause of blindness. Hilton is part of the world's first trial using retinal pigment epithelium (RPE) made from stem cells derived originally from embryos left over from fertility treatment.
That makes the treatment controversial for some people, particularly in the US where Advanced Cell Technology (ACT), the company that has produced the RPE cells and is running the trial, is based. "I've had a few bizarre emails from crazy Americans," says Hilton. "And some crackers Americans saying great things as well one from a share-buying group."
Hilton, from West Yorkshire, was treated in January at Moorfields eye hospital in London, where Prof James Bainbridge injected 50,000 RPE cells a tiny amount into the space under the retina of his right eye. The first trial in humans of such experimental treatment is a safety trial to make sure, following successful animal tests, that there are no damaging effects.
Caution is the watchword. Hilton was the third person in the world to have the treatment, after two in the US. This is not the first stem cell experiment in people, however. That was an attempt by Geron, an even more adventurous California biotech company, to heal paralysis. Its dreams of enabling people such as the late Superman actor Christopher Reeve to walk again were dashed when in November last year the company announced that the difficult economic climate had made it too hard to raise the money needed to continue with its trial, which had not reported any improvement in the four patients enrolled.
The Geron treatment, like ACT's, was only supposed to be a safety trial, so the fact that nobody pulled themselves to their feet and made tentative steps across the room should not have been a setback. But there are enormous financial risks in backing these expensive projects and it is not surprising that ACT's chief scientific officer, Dr Robert Lanza, is enthusiastic about the improvements reported by patients with advanced eye disease in their trial so far.
One woman with Stargardt's went from being able to discern only hand movements to counting fingers. She can also read more letters on a chart. "One of them can now read her watch and go to the mall alone," says Lanza. "It is very hopeful. I think if we are seeing this with a small number of cells at the very advanced stage, imagine what we could do with those young children who are going blind at the age of six to 10 sometimes."
There was much tongue-clicking from the scientific establishment when Geron announced it would put its money into cancer rather than stem cells. "Making Superman walk would have been great for business but was an ambitious target for a serious problem and maybe not the best start scientifically or clinically for stem cell therapies," Prof Alison Murdoch, of Newcastle University, said at the time. John Martin, professor of cardiovascular medicine at UCL, called it "an intrinsically flawed study" and said: "The first trials of stem cell that will give an answer are our own in the heart."
Unlike some other stem cell scientists, Prof Pete Coffey, of the Institute of Ophthalmology at University College London, pays tribute to Geron, which he says was "without doubt the torchbearer", doing regulatory groundwork with the Food and Drug Administration (FDA) in the US that has eased the way for others. But it was an expensive gamble for a biotech company that was always vulnerable to market fluctuations. "These organisations are burning money. They really do live hand to mouth," he says. Coffey says there were signs of improvement in the spinal patients, albeit unreported. "But Geron had trials going on in cancer and in stem cells. It was fairly clear the stem cell path, particularly for spinal injuries, was going to be a long path."
The eye, however, is a different matter. For one thing, it is safer. "If those cells go wrong in the eye, it is not going to kill you," he says. And the eye is "immune privileged": it will tolerate a graft of human tissue in this case stem cells without the immune system mounting an all-out attack and causing rejection. Most transplant patients are on immuno-suppressant drugs for life, to stop their body rejecting the heart or kidney. Hilton is taking the drugs as a precaution and hates the side effects, but hopes he will be able to stop.
Trials and troubles
Coffey, director of the London project to cure blindness, is developing his own stem cell therapy for age-related macular degeneration, which affects about a quarter of the over-60s in the UK. His therapy is subtly different from that of ACT which, he says, has understandably focused on patients who may produce the best early results. "As a business and a biotech, they have been very sensible," he says. Coffey's backers are the Californian Institute of Regenerative Medicine, the Medical Research Council and drug company Pfizer but, he says, "I'm not seeing it as a race." ACT's work has helped them a little.
A great deal hangs on the outcome of these first human trials. Hostility to scientists "playing God" by engineering spare parts for ailing people from embryonic cells is not concentrated merely among rightwing evangelicals in the US. Opponents scored a potentially significant victory in October last year when the European court of justice ruled that procedures involving stem cells could not be patented. The decision was clarification of a case brought in Germany by Greenpeace against Oliver Brόstle, a scientist who sought a patent for inventing a way to turn embryonic stem cells into brain cells. The judgment said the process was an immoral "industrial" use of human embryos.
Scientists such as Prof Austin Smith, head of the Wellcome Trust Centre for Stem Cell Research at Cambridge University, were immensely frustrated that they were not allowed to offer evidence and explanation to the senior judges involved in the final stages of the case. "There was nothing we could do. We were not allowed to contact them directly and governments and the European commission are not allowed to lobby them. They are like gods on high who make this decision. They are not scientists," he says.
The consequences of the ruling for stem cell science could be dire, say Smith and others, because it will cause those companies and investors currently willing to put money into an already highly speculative venture to back away. More than 100 existing patents have been wiped out by this "scientifically ill-informed" judgment, says Smith. "The real problem is that these patents are wiped out in Europe but not in North America or Asia, which is where the big markets are. It means that existing or new companies are going to base their R&D [research and development] activities in North America or Asia because they have no protection in Europe. It is rather incomprehensible why the European court of justice would seek to put Europe at such a disadvantage."
Coffey's trial can go ahead, he says, but "if it is successful, the issue then will be how do we develop a commercialised, viable, therapeutic model?". And ACT, he says, is now at a disadvantage because its patents are not protected in Europe. Whether it is venture capitalists thinking of providing funds to individuals, or big companies such as Pfizer, "this is another area of uncertainty and that is the last thing they want in a challenging field."
Smith, on his way to Brussels to try to convince politicians of the importance of stem cell work, is aware of the need to fight back against a tide of suspicion. He talks of "a bizarre alliance in the European parliament of people like Greenpeace with Catholic conservative parties". He is concerned about an anti-science attitude. "It becomes quite irrational," he says. "There are still strong views out there that European funding should be stopped. There have been meetings in the European parliament presenting that viewpoint. They sell these fake stories of cord blood cells curing all diseases, but the politicians have no way of knowing this is distorting the evidence."
Beautiful but unworkable
Smith is not one of those who thinks that a more recent advance, induced pluripotent stem cells (IPS), which does not involve using embryos, will solve all the ethical and medical problems. These are cells from the skin or another part of the patient's own body, which can be tricked into becoming the kidney, brain cells or heart muscle he or she needs without being rejected as foreign by their immune system. It is "a beautiful but unworkable idea", says Smith. "The cost of generating these kinds of therapies for an individual is completely unrealistic. At the present time we have no model of how that could be done. It is so expensive."
Human embryonic stem cells, however, are potentially affordable. They offer a sort of off-the-peg alternative. "You can treat many people with one batch of cells. That makes it somehow conceivable that it could be economically viable for the healthcare system." Indeed, ACT's Lanza says they have enough RPE to treat everybody on the planet. "So the real use of IPS cells is to make them from diseased patients and use them in the lab to develop drugs," says Smith.
To an excitable public and to patients hoping for cures, it may seem that the talk has been going on for a long time and there ought to be treatments on the shelves pretty soon. In fact, experts say, the field has moved at a spectacular speed.
"To go from what was zero back in 1989 when the first human embryonic stem cell was derived and not even for human use to human trials is immensely fast," says Coffey.
But even now, says Smith, scientists are talking about going back to the drawing board. "We know now that we need more basic research because the human cells we have at the moment whether embryonic cells or IPS cells are not, as some people thought in the past, the same as the true embryonic stem cells that we have from mice."
Mice embryonic stem cells, which have been used in so much early stage research, appear to be slower than human embryonic cells to divide and differentiate. Basically, the human cells taken from a blastocyst (a five- or six-day embryo) have already moved on to the next stage, where equivalent mouse cells have not. That makes it hard to produce standardised cells that will all, for instance, make exactly the same nerve cells. There have been some partial successes but, says Smith, "we don't have a human cell either from an embryo or re-programmed that is held at this ground state." Taking cells at an earlier moment in the blastocyst development won't work, he says. "It is not the starting point that is important. The biology is subtly different between rodents and primates."
It will be years before there are treatments made from stem cells on the shelves. Smith says it is serendipitous that RPE cells can be made for eyes although it "could have a fantastic outcome". Within four to five years, there could be trials of human embryonic stem cells in diabetes and Parkinson's disease, he says.
Marcus Hilton will not for long be the only person in Britain to have undergone a human embryonic stem cell transplant, but he may be one of a small and select band for quite some time.
Stem cell targets
Parkinson's disease The disease kills neurons that produce dopamine, the chemical in the brain that conveys messages controlling body movements. Embryonic stem cells could be turned into dopamine-producing neurons. Early experiments in mice and rats have been encouraging. There were also earlier experiments involving the transplant of foetal neurons into the human brain. But while some patients have seen major improvements, others have not and there have been adverse side effects.
Type 1 diabetes This is usually diagnosed in childhood and is caused by the body's own immune system attacking the pancreatic beta cells, stopping them producing insulin. Patients have to monitor their blood sugar levels and inject insulin daily. Research in mice has shown it is possible to develop immature beta cells from embryonic stem cells and transplant them into the pancreas, where they mature and produce insulin. The concern is that the cells, which need to divide again and mature once transplanted, could form tumours.
Chronic liver disease The liver is the only organ in the body that can regenerate. Cells called hepatocytes divide and make copies of themselves, but in cirrhosis patients the liver is too badly scarred for repair to continue. Scientists think embryonic stem cells could be used to make hepatocytes, but the work is at an early stage.
Hearts Scientists in Israel recently announced they had succeeded in turning so-called induced pluripotent cells (adult cells that have been genetically reprogrammed to adopt an embryonic stem cell-like state) made from the patient's own skin into heart muscle in the lab. Scientists hope they may be able to help people who have suffered heart failure, sometimes caused by a heart attack, in which the heart cannot pump enough blood round the body. Their only option at the moment is a transplant or mechanical help.
First treatment in 2007. Pioneering ever since.
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