The Hard Cell

Roger Johnson first realized his heart was failing during a vacation in Spain five years ago, when his lungs filled with fluid and he struggled to breathe. The 57-year-old general practitioner swiftly flew home to Manchester, England, underwent a triple bypass, had a pacemaker installed and began taking a veritable pharmacopoeia of heart drugs. Today, he can’t walk more than a half-mile or work long in his garden. Unless he becomes eligible to join a transplant waiting list, modern medicine 404 Not Found

nginx/1.14.0 (Ubuntu) can do little more for him. Now 62 and retired, he’s taking part in a stem-cell clinical trial at the London Chest Hospital. “If it works, it’s probably the only treatment for somebody like myself,” he says.

In the hospital’s cardiac catheterization laboratory, cardiologist Anthony Mathur uses a probe to map the electrical activity in Johnson’s heart. Mathur finds 75% of it damaged, the consequence of earlier undetected heart attacks. Then he takes 10 syringes filled with either blood serum containing stem cells from Johnson’s own bone marrow or just blood serum — as part of the experiment, neither patient nor doctor knows which — and injects them directly into Johnson’s heart through a catheter threaded into the main artery in his left thigh.

Mathur hopes the $5.5 million, four-year study will help clarify whether stem cells from a patient’s own bone marrow can repair a failing heart. There’s much at stake in the outcome, and not just for the 300 chronic-heart-failure patients the trial will study or the two in 1,000 people who are diagnosed with the condition in developed countries every year and face a 37% risk of dying in the first year. The London trial is among the first large-scale efforts to determine whether stem cells — building blocks of the body that have the potential to become new cell types — will someday provide cures for debilitating diseases and disorders, including Alzheimer’s disease and arthritis. No single study is expected to establish that definitively, but Mathur’s is an important step in a multipronged approach encompassing basic science research and clinical trials, including work on human embryonic stem cells.

Europe has become an increasingly important base for that cutting-edge research, particularly as American and Asian efforts endure setbacks. The Bush Administration’s limit on the use of federal money for human embryonic stem-cell research in the U.S. since 2001 has reduced funding and deterred some scientists from undertaking the controversial work. A report in Nature Biotechnology in April found a widening gap in the rate at which U.S. and non-U.S. research teams have published articles about human embryonic stem-cell research in scientific journals since 2002, and concluded that the U.S. was “falling behind in the international race to make fundamental discoveries” in the field. Asian efforts are well funded, but haven’t escaped difficulties either. South Korean veterinary scientist Woo Suk Hwang, who cloned the first dog and claimed to have cloned the first human embryo, was discredited late last year after he confessed to falsifying many of his results.

Liberal laws and renewed funding, meanwhile, are pushing Europe toward the front of the field. The UK Stem Cell Foundation, a private charity, is raising $185 million for research in Britain, and the British government will match up to $18.5 million a year for 10 years. After loosening restrictions on human embryonic stem-cell research in 2004, Spain invested j150 million in a 32,000-sq-m research center in Valencia. The European Union has given a total of j11.9 million to 13 stem-cell research centers in eight countries over four years, and, in July, authorized an additional but unspecified sum from its j54.5 billion research budget for 2007-2013. That in turn has prompted municipal authorities in places like London and North Rhine Westphalia, Germany, to recruit managers to coordinate stem-cell research and development so their economies can benefit from potential breakthroughs in the estimated $56 billion market for stem-cell biology and applications. “Almost every major city is trying to set up stem-cell work,” says Una Chen, head of the Stem Cell Therapy Program at the University of Giessen in Germany. “It’s a boom.”

So, for example, scientists in Sweden are studying how stem cells might be used to treat Parkinson’s disease. A Belgian team is investigating whether they might be used to treat diabetes. Some researchers expect therapies for these diseases will require embryonic stem cells because of their potential to grow into all types of tissue, but many labs work with both cell types. “We’re not sure where the breakthroughs will come,” says David Macauley, chief executive of the UK Stem Cell Foundation. “Everybody expects it will come from embryonic stem cells, but the majority of stuff we are seeing is in the adult stem-cell camp.”Work on the heart is furthest along because it is a comparatively simple organ and easy to access with a catheter. Initial studies use adult stem cells from the patient’s bone marrow, which lack potential to become other cell types but don’t carry the political and ethical baggage of embryonic stem cells. And much is already known about them — bone marrow transplants have been routine treatment for leukemia since the 1970s.

Interest in using adult stem cells to repair the heart took off in 2001, after U.S. researchers reported that mice in which they had induced heart attacks recovered up to 37% of their lost heart function within seven to 11 days of having the cells directly injected into their hearts. In 2001, researchers at the Hospital of the Johann Wolfgang Goethe-University in Frankfurt tried the technique on 20 people, who recovered an average of 7% of left ventricular ejection fraction, a measure of the heart’s ability to empty itself. Though it sounds marginal, a 7% improvement may give some patients sufficient heart function. “The challenge of science is to improve on those numbers,” says Mathur.

Still, skeptics question whether trials like his are premature while stem cells’ mechanisms remain poorly understood. Some scientists theorize that either the cells or growth factors added to them enable new vessels to form in the heart, but no one is sure. “There is something to it, but you need much more bench work,” says Michael Marber, a professor at King’s College London who is skeptical of the trials. “What we need at the moment is to understand more of the basic biology.” The trials’ sponsors argue that such additional research could take years and delay new treatments. “Our understanding of many therapeutic interventions in the heart is provisional,” says John Martin, a professor at University College London, who is collaborating with Mathur in a related trial on patients immediately after heart attacks. “We still don’t understand how aspirin or beta-blockers work.”

So far at least, no harm has come to Mathur’s first 40 patients as a result of the procedure. Stem cells from a patient’s own bone marrow are unlikely to be rejected by their immune systems. But other studies suggest proceeding cautiously. Patients in France and Holland who had skeletal muscle tissue transplanted from their limbs to their hearts developed irregular heartbeats that required electric shocks to restore the rhythm to normal. At least two cases ended in death. Mice treated with stem cells have developed tumors, suggesting renegade cells can grow uncontrollably.

Experimental science usually proceeds by trial and error, and patients like Johnson accept its risks because their conditions carry a poor prognosis. “I have nothing to lose and I might benefit from it,” he says. After Mathur’s trial was launched, his hospital’s switchboard was inundated by 1,000 calls from would-be participants around the world. All the attention creates high expectations which, if unmet, can lead to disappointment. And there are obvious limits: patients with spinal cord damage who expect stem cells to enable them to walk someday, says Martin, are probably being unrealistic.

Progress toward stem-cell therapies is more likely to be incremental and selective. Look at Johnson: three months after his treatment, he says he feels about the same as he did before it, though it’s probably too early to know if the treatment has helped him. He has a check-up with Mathur at year end and will be monitored until 2010. By that time, it might be clear whether stem-cell research is a leap forward or a blind alley.