Cell scientists aim to rebuild hearts with reprogrammed tissue

Researchers in Oxford and California experiment with medical technology that could make transplants unnecessary

The Guardian, Alok Jha, science correspondent, Monday 28 January 2013

Embryonic cells under the microscope. Scientists on both sides of the Atlantic
 are working on ways of adapting cells to help repair damage from heart attack.
Photograph: Mauricio Lima/AFP/Getty Images

Every two minutes someone in the UK has a heart attack. Every six minutes, someone dies from heart failure. During an attack, the heart remodels itself and dilates around the site of the injury to try to compensate, but these repairs are rarely effective. If the attack does not kill you, heart failure later frequently will.

"No matter what other clinical interventions are available, heart transplantation is the only genuine cure for this," says Paul Riley, professor of regenerative medicine at Oxford University. "The problem is there is a dearth of heart donors."

Transplants have their own problems – successful operations require patients to remain on toxic, immune-suppressing drugs for life and their subsequent life expectancies are not usually longer than 20 years.

The solution, emerging from the laboratories of several groups of scientists around the world, is to work out how to rebuild damaged hearts. Their weapons of choice are reprogrammed stem cells.

These researchers have rejected the more traditional path of cell therapy that you may have read about over the past decade of hope around stem cells – the idea that stem cells could be used to create batches of functioning tissue (heart or brain or whatever else) for transplant into the damaged part of the body. Instead, these scientists are trying to understand what the chemical and genetic switches are that turn something into a heart cell or muscle cell. Using that information, they hope to programme cells at will, and help the body make repairs.

It is an exciting time for a technology that no one thought possible a few years ago. In 2007, Shinya Yamanaka showed it was possible to turn adult skin cells into embryonic-like stem cells, called induced pluripotent stem cells (iPSCs), using just a few chemical factors. His technique radically advanced stem cell biology, sweeping aside years of blockages due to the ethical objections about using stem cells from embryos. He won the Nobel prize in physiology or medicine for his work in October. Researchers have taken this a step further – directly turning one mature cell type to another without going through a stem cell phase.

And politicians are taking notice. At the Royal Society in November, in his first major speech on the Treasury's ambitions for science and technology, the chancellor, George Osborne, identified regenerative medicine as one of eight areas of technology in which he wanted the UK to become a world leader. Earlier last year, the Lords science and technology committee launched an inquiry into the potential of regenerative medicine in the UK – not only the science but what regulatory obstacles there might be to turning the knowledge into medical applications.

At Oxford, Riley has spent almost a year setting up a £2.5m lab, funded as part of the British Heart Foundation's Mending Broken Hearts appeal, to work out how to get heart muscle to repair itself. The idea is to expand the scope of the work that got Riley into the headlines last year after a high-profile paper published in the journal Nature in which he showed a means of repairing cells damaged during a heart attack in mice. That work involved in effect turning the clock back in a layer of cells on the outside of the heart, called the epicardium, making adult cells think they were embryos again and thereby restarting their ability to repair.

During the development of the embryo, the epicardium turns into the many types of cells seen in the heart and surrounding blood vessels. After the baby is born this layer of cells loses its ability to transform. By infusing the epicardium with the protein thymosin β4 (Tβ4), Riley's team found the once-dormant layer of cells was able to produce new, functioning heart cells. Overall, the treatment led to a 25% improvement in the mouse heart's ability to pump blood after a month compared with mice that had not received the treatment.

Riley says finding ways to replace damaged cells via transplantation, the dominant research idea for more than a decade, has faltered. Scientists have tried out a variety of adult stem cells – derived from areas such as bone marrow, muscle and fat – turned them into heart cells and transplanted them into animal models, which initially showed good results.

But those results could never be repeated in humans with the same degree of success. "In humans, moving into clinical trials, the actual benefit, from a meta-analysis just on bone-marrow-derived cells, is a meagre 3% improvement," he says. "That's barely detectable clinically and unfortunately isn't going to make a vast amount of difference to your overall quality of life."

The original impression from rodent studies was that the transplanted cells would become new muscle and contribute to improving damaged areas, but Riley says that idea has fallen out of favour. "All they do, if anything at all, is to secrete factors that will help the heart sustain the injury, rather than necessarily offer long-term regeneration."

That is where the reprogrammers get going. Find the chemical factors that will make a cell (a skin cell, say, or a piece of scar tissue) think it is in the womb, so it switches certain genes on and others off and becomes a new heart cell, and you can avoid the large-scale transplant altogether. All you need is an infusion of the right drugs and resident cells will do all the required repair work.

The process requires an understanding of how an embryo develops and what cues nature uses to grow all the body's cell types from just a sperm and an egg. This ability to regenerate does not quite stop at birth: injure a one-day-old mouse's heart, for example, and it will completely regenerate. Injure it again after a week and the heart will scar. "Within seven days, it goes from completely repairable to the adult wound-healing default position," says Riley. "We want to understand what happens during that window."

Many scientists believe the secrets of how to regenerate tissue are linked with an understanding of how to reverse the ageing process. Saul Villeda, of the University of California, San Francisco, presented work at the recent annual meeting of the Society for Neuroscience in New Orleans where he showed that blood from young mice reversed some of the effects of ageing in older mice, improving learning and memory to a level comparable with much younger animals. Older mice had an increased number of stem cells in their brains and there was a 20% increase in connections between brain cells.

Though his work is yet to be published in a peer-reviewed journal, Villeda speculated the young blood was likely to be working in the older mice by increasing levels of chemical factors that tend to decline as animals get older. Bring these back, he says, and "all of a sudden you have all of these plasticity and learning and memory-related genes that are coming back".

At the Gladstone Institute in California, Prof Deepak Srivastava has already transformed scar-forming cardiac cells in mice into beating heart cells, inside living animals, using a set of chemical factors. His results were published last April in Nature.

"We've redeployed nature's own toolkit in these cells to convert non-muscle cells that are in the heart into new muscle. More than half of the cells in the heart are not muscle [but] architectural cells called fibroblasts that are meant to support the muscle," he says.

"We had the idea that if we could somehow fool those cells into thinking that they should become muscle, then we have a vast reservoir of cells that already exist within the organ that might be able to be called upon to regenerate the heart from within."

He injected three chemical factors – called Gata4, Mef2c and Tbx5, collectively known as GMT – into the damaged region of a heart and, within a month, the non-beating cells that normally ended up becoming scar tissue had become functioning heart cells that had integrated with their neighbours. "The factors get taken up by the fibroblasts and the non-muscle population of cells and they initiate a genome-wide switch of the programme of the cells so that it now begins to activate thousands of muscle-specific genes and it turns off thousands of fibroblast genes."

Srivastava directs cardiovascular and stem cell research at Gladstone, the institute where Yamanaka carried out his Nobel-prize-winning work. Srivastava's direct reprogramming technique takes Yamanaka's work further because it allows scientists to turn one type of cell into another without having to go through a stem cell phase in between, thus reducing the risk that any future therapy might induce cancer.

The method has been proven to work, so far only in Petri dishes, for blood, liver and brain cells. "Ultimately, as we learn enough about each cell type, it's likely we might be able to make most cell types in the body with this direct reprogramming approach," he says.

The tough task for all these scientists – from those working specifically on the heart such as Riley to those working more generally on all cell types such as Srivastava – is to identify and catalogue the thousands of chemical factors that are at work in the various stages of cell development, and that are the keys to the transformation of one cell into another. Riley's team is working with Shoumo Bhattacharya at the BHF Centre for Cardiovascular Target Discovery at Oxford, led by Shoumo Bhattacharya, to screen thousands of small molecules in the lab that could, in combination or isolation, predict a certain type of cell behaviour in a living heart.

Meanwhile, the Gladstone team have started experimenting with their direct reprogramming technique in pigs, as a preclinical trial before trying it out in humans. "We're trying to do the same experiments we did in the heart in the pig's heart because it is very similar in size and physiology to human hearts. If it works there and it is safe, then we'd be ready for a human clinical trial," says Srivastava.

He has not entirely abandoned investigating cell transplantation, using muscle cells derived from embryonic stem cells. But he is clear which would make the simpler therapy.

"We're testing both head to head – let's say both works, then I think the direct reprogramming method will be a lot easier."

And the relative simplicity of direct reprogramming, discovered by Yamanaka just five years ago, still surprises him. "It's phenomenal," he says. "We never thought it would be this way."

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Quantum biology: Do weird physics effects abound in nature?

"The Quantum Factor" – Apr 10, 2011 (Kryon channeled by Lee Carroll) (Subjects: Galaxies, Universe, Intelligent design, Benevolent design, Aliens, Nikola Tesla (Quantum energy), Inter-Planetary Travel, DNA, Genes, Stem Cells, Cells, Rejuvenation, Shift of Human Consciousness, Spontaneous Remission, Religion, Dictators, Africa, China, Nuclear Power, Sustainable Development, Animals, Global Unity.. etc.) - (Text Version)

"..... Cell Division - a Static process ? 

Let me take you to the cellular division process. We've said this before, but you need to hear this to understand how it works. A cell is ready to divide. The Human body is designed to rejuvenate... all tissue. You've been told that there's some tissue that does not rejuvenate, but that is incorrect. It all rejuvenates at different speeds at different times and in different ways. It rejuvenates. So now you know that the Human body is designed to live a long time. Unfortunately, the energy that you have created on this planet and what you've gone through, has beat it up. You don't live much more than 80 years. That was not the design.

The Biblical personalities were sometimes prophets and sometimes masters and sometimes just there... and lived for hundreds of years. Did they really? Or perhaps this is that just a metaphor? Did they get that right in the Bible without a error in transcription? I'm going to tell you the truth. It's very accurate. Thousands of years ago you lived a very long time, Lemurian. If you knew your lifespan, you'd gasp. But not anymore. Instructions have been given over time to DNA, literally, by the energy of the planet... en energy that you have created through consciousness.

A cell divides. Right before it divides, it needs the blueprint to clone itself. The blueprint is available from the stem cell. The stem cell gets its information from the quantum part of the DNA, which has never changed since you were born. It's remained static, since nothing has ever changed it... and the fact that you don't believe it's changeable and have just accepted aging. There's not a conscious effort to do anything with it, and it just lays there like it always did.

The diving cell "talks" to the stem cell and says, "Do the same thing you always did? Change anything?" And the stem cell talks to the cell that is dividing, saying, "Make another one just the same." Then you rejuvenate just like the last one, accepting everything you received when you were born. ..."

"Recalibration of Knowledge" – Jan 14, 2012 (Kryon channelled by Lee Carroll) - (Subjects: Channelling, God-Creator, Benevolent Design, New Energy, Shift of Human Consciousness, (Old) Souls, Reincarnation, Gaia, Old Energies (Africa,Terrorists, Cuba, Iran, North Korea, Venezuela ... ), Weather, Rejuvenation, Akash, Nicolas Tesla / Einstein, Cold Fusion, Magnetics, Lemuria, Atomic Structure (Electrons, Particles, Polarity, Self Balancing, Magnetism, Higgs Boson), Entanglement, "Life is necessary for a Universe to exist and not the other way around", DNA, Humans (Baby getting ready, First Breath, Stem Cells, Embryonic Stem Cells, Rejuvenation), Global Unity, ... etc.) - (Text Version)

”… There are several things that are going to happen in mainstream science. First, you're going to find some secrets of DNA and they're going to be embryonic. Start watching scientists discover the embryonic cells and the magic within them. You already know that unusual stem cells exist in the placenta. You also know that the pre-programmed adult stem cells are still there in the body. But what about the DNA of the unborn? (Intellectuals, please keep reading, for to stop now will create unrest.) Second, your work today Yawee, will represent "the perfect template" without using what you did in Lemuria. That's why you're the Human who will do this. It's an extension of why you came here, and is perfect for 2012 and beyond.

These embryonic cells of the unborn are untouchable by society, and they might as well be on Mars, for no science is going to try to use these cells in a 3D manner, which is all you know how to do at this point. If they try, it won't work anyway. There are quantum processes you are learning about that are not only non-invasive, but actually helpful and that can transfer attributes from one biological cell to another and from one Human to another. Think "wireless" [Kryon human again]. What you thought would take wires over 1,000 miles long is now done with satellites. It's an analogy that shows you that you are moving into totally new understandings of the transfer of energy. Let's discuss the mother in that temple for a moment. …”


"... I want to define life for you - not biological life, but spiritual life. So for all those intellectuals, just hold on, for many won't like this. Spiritual life, as measured by Spirit, is when a Human has free choice. When is that? It's when they take their first breath. Not in utero. There will be those who will say, "That's wrong, that's wrong. The soul in the woman's body is alive!" Just wait. I'm talking about spiritually. That which Spirit sees, and it's when you come from the other side of the veil and take your first breath.

A child with the mother has no free choice. That child is linked to the choice of the mother until it is born. It is, indeed, a soul in preparation for free choice, and there are many attributes that are spiritual that we have discussed before about how that soul reacts. But now I'm discussing life with polarity [duality], free choice.

But let's discuss that "child inside" for a moment, for there is a process I want you to know about. I want to talk about 240 days into the pregnancy. At about that time, the child has perfect DNA. It hasn't taken its first breath. The DNA hasn't measured the energy of the planet yet, since it is contained. Did you realize that? Inside the womb is a perfect child. The child's DNA has all the attributes of the Akash and also the parent, but it's different in a way you have not been told. The DNA is 100% as designed.

The quantum instructions within the DNA are all talking to the biology of the child,, getting ready for the first breath. ..."