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IT STARTS slowly, with a faint discomfort that grows until it feels like a vice is tightening around your chest. The pain radiates to your left arm and shoulder, and to the back of your neck. You feel sick, dizzy and short of breath. When the pain passes, you wonder what on earth just happened. In one way you can consider yourself lucky: you have just survived a heart attack.

But your troubles are far from over. When the blood supply to part of your heart was blocked, the muscle cells there died. As the dead cells are replaced by scar tissue, more and more strain will be put on the rest of the heart, causing it to enlarge and slowly fail.

This is the fate of millions of people around the world. Yet if the dead area of their hearts could be replaced with new muscle tissue, their lives would be transformed. A few years ago, doctors thought they might have the answer. They hoped that damaged hearts could be fixed by extracting stem cells from people and injecting them into the heart.

The bad news is that this approach seems to do little good. But the work has not been in vain. It has led to a series of discoveries that promise to provide better ways of regenerating the heart.

Not so long ago, few researchers entertained any hopes of regenerating the heart. While some fish and amphibians can grow new muscle if their hearts are damaged, mammals cannot. Break a human heart, and its cells will stubbornly refuse to grow back again.

But what if you could grow new cells outside the body and get them to turn into new heart muscle? This idea really took off around 2000, when it was shown that stem cells in our bone marrow have the potential to turn into heart muscle cells. If you extracted these stem cells and injected them into the heart, the thinking went, they would turn into muscle and replace any damaged tissue. 鈥淭he field went through a phase of 鈥榟ave cells, will inject鈥�,鈥� says Rahul Aras, head of Juventas Therapeutics in Cleveland, Ohio.

While some early animal trials produced dramatic results, the results of human trials so far have been disappointing. Any improvements in heart function are usually slight, and some people developed an irregular heartbeat after certain types of cells were injected. Biologists certainly haven鈥檛 given up on the idea of repairing the heart with stem cells, though. Some are experimenting with different kinds, such as embryonic stem cells, for example. Others think it might not be necessary to inject any cells at all. Instead, they argue, if only we can discover the right signals, we could persuade the existing stem cells in our bodies to multiply, travel to the heart and repair it.

The hope is that the cells will work their way into the heart over days or weeks, which might be better than a massive one-off dose of stem cells. If it works, 鈥渋n situ stem cell therapy鈥� would have numerous other advantages over injecting cells. For starters, there would be no need to extract people鈥檚 bone marrow, which is a painful procedure, and no risk of the stem cells becoming infected or acquiring dangerous mutations when outside the body. It would also be much easier to scale up this approach to treat large numbers of people.

Doctors have long used drugs that stimulate the bone marrow to produce more blood stem cells. Building on this work, in 2009 Sara Rankin of Imperial College London and her colleagues showed that certain combinations of chemical factors make the bone marrow of mice release the kind of marrow stem cells that are capable of turning into muscle. The same chemical cocktail also releases endothelial progenitor cells, which help form new blood vessels and so might restore blood supply to the heart (). 鈥淲e think these cells are mobilised in the context of normal injury, but we want to enhance that effect,鈥� says Rankin.

The procedure releases a flood of stem cells into the blood within hours. It remains to be seen, however, whether this will significantly boost healing in people. Some reckon what really matters is getting stem cells to go where they are needed.

Marrow stem cells are known to bind to a protein called SDF-1, found on the surface of some other cells. So several companies, including Juventas Therapeutics, hope that getting cells in areas of tissue damage to produce SDF-1 will make stem cells remain in the area and repair the damage. 鈥淢obilised stem cells don鈥檛 know where to go,鈥� says Aras. 鈥淲e鈥檙e creating a beacon or a signal as to where the damage has occurred, so those circulating cells move to that target.鈥�

In a phase 1 trial, pieces of DNA containing the gene for the SDF-1 were injected into the hearts of 17 people with heart failure, resulting in the temporary production of SDF-1 in some heart cells. Last year, and had positive results, though this will of course have to be confirmed by larger studies.

In theory, the best results would come from combining these two approaches: getting the bone marrow to release more stem cells and getting more to stay in the heart where they are needed. But there is a twist in this tale. The whole idea behind this approach 鈥� that marrow-derived stem cells will form new heart muscle 鈥� now appears mistaken. 鈥淭he heart is a complex and highly organised tissue,鈥� says Brock Reeve of the Harvard Stem Cell Institute (and brother of actor Christopher Reeve). 鈥淓ven though people could create heart muscle cells in vitro, [stem cells] don鈥檛 organise into heart tissue that can beat at a certain rate when injected into the body.鈥�

Nevertheless, they do often seem to help. 鈥淎 lot of work has now shown that these stem cells can promote the repair of heart tissue following heart attack, but without becoming part of that tissue,鈥� says Rankin.

It is now thought that marrow-derived stem cells help by releasing signalling factors that in turn rally local cells to initiate repair, for instance by growing new blood vessels. Juventas Therapeutics says animal studies show that its treatment promotes the growth of blood vessels. While the beneficial effects of marrow cells are not enough to compensate for the billion or so muscle cells lost after a serious heart attack, it鈥檚 a start.

In particular, bone-marrow-derived stem cells may stimulate division of stem-cell-like cells already living in the heart. Until recently, such resident cells were thought to be rare, if they existed at all. Now it is clear that rather than being born with all the heart cells we will ever have, there is an ongoing slow replacement of heart cells throughout life. The current estimate is that 1 per cent of heart cells are replaced each year in a 25 year old, but this percentage falls as we age. 鈥淭he human heart isn鈥檛 as static as we thought it was,鈥� says Paul Riley of the Oxford Stem Cell Institute in the UK. Over the past decade, researchers have begun to identify the heart stem cells responsible for this renewal. Some groups now hope to treat patients by extracting heart stem cells, growing large numbers in the lab and injecting them back into individuals鈥� hearts. The first small human trials produced encouraging results ().

While heart stem cells may prove more effective than bone marrow cells, getting hold of them is riskier. One trial used heart stem cells extracted from a small piece of heart tissue taken during bypass surgery. If we could identify the correct chemical cues, though, it might not be necessary to extract heart stem cells. 鈥淲e just need to tap into the mechanisms by which these cells are turned over 鈥� and drive it forward,鈥� says Riley.

He and his colleagues recently identified a population of stem cells in the epicardium, the outermost layer of the tissue that surrounds the heart muscle. These cells can turn into new heart muscle cells following a heart attack ().

Even better, Riley discovered a way of activating these cells directly. He found that a chemical called thymosin beta 4, which was already known to promote the development of blood vessels in an embryo鈥檚 heart, could also trigger the growth of new blood vessels and heart muscle in adult mice. 鈥淭hat鈥檚 critical, because for the repair of damage following a heart attack you need to replace both the blood vessels and also the muscle that鈥檚 lost,鈥� says Riley.

Unfortunately, the effect of thymosin beta 4 is relatively weak in adults, so it is no miracle cure. Nonetheless, Riley鈥檚 work is an important proof of principle. It shows that it is indeed possible to use chemical factors to boost the healing power of the heart. His team is now searching for molecules with a stronger effect.

鈥淭he work proves chemical factors can boost the healing power of the heart鈥�

Even more striking evidence comes from Hesham Sadek of Southwestern University in Dallas, Texas. Last year, he did a rather gruesome experiment. A day after birth, he anaesthetised a baby mouse and placed it on ice until it stopped breathing and its heart stopped beating.

Then he chopped off the bottom 15 per cent of its heart, exposing the chambers inside. Within minutes, a scab formed over the wound, sealing the chambers from the outside. As the animal was slowly warmed, it began to return to life.

What happened next astounded biologists. Over the coming weeks the scab began to disappear and in its place grew new heart muscle. Just three weeks after its tip was amputated, the mouse鈥檚 heart had completely regenerated itself (). 鈥淚t looked completely normal 鈥� indistinguishable from a normal heart,鈥� says Sadek.

This was not the only surprise. The missing heart muscle was replaced not by stem cells, but by existing beating heart cells that were somehow being triggered to divide. 鈥淲e found that they divide very avidly in the newborn heart, but then something happens and this ability to divide is shut off, so in the adult heart that slow turnover of cells is carried out by a stem cell population,鈥� says Sadek. 鈥淭he million-dollar question is what prompted these cells to start dividing?鈥�

Regenerative powers

Already they have some clues. Tiny pieces of RNA called microRNAs play a big role in controlling the activity of cells, and by looking at what happens in the heart during the early days of a mouse鈥檚 life, Sadek and his collaborators have identified a group of microRNAs that regulate the division of heart muscle cells. Blocking members of this miR-15 family in newborn mice boosted heart muscle cell division (). The team is now looking at what happens when miR-15 is blocked in adult muscle cells, but Sadek will not discuss the results prior to publication.

Even if the hearts of mice can be made to regenerate, there is no guarantee that the same is true of humans. However, Sadek says that he was contacted by several heart surgeons in the wake of his paper, who told him that infants bounce back from major heart surgery if it is done within three months of their birth, but do not do nearly so well if operated on later. This suggests the human heart also possesses similar regenerative powers early in life.

鈥淭he fact that this happens indicates that maybe we can push this further,鈥� says Sadek, who hopes to track the fate of cells in babies undergoing heart surgery in the near future. 鈥淭he mental block we had that the mammalian heart doesn鈥檛 regenerate is gone.鈥�

鈥淭he mental block we had that the mammalian heart doesn鈥檛 regenerate is gone鈥�

All these discoveries are leading to a major shift in thinking. There is still a long way to go before this approach starts helping people with heart disease, but in theory at least, treatments based on stimulating the heart to repair itself should be safer and cheaper than injecting stem cells. In the long run, they have the potential to help far more people.

And the heart could be just the start. If it can regenerate itself, why not other organs like the brain? If these studies have shown us anything, it鈥檚 that the mammalian body has many tricks up its sleeve. We shouldn鈥檛 underestimate its ability to surprise us.