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Patients' Skin Cells Turned Into Heart Muscle Cells to Repair Their Damaged Hearts

ScienceDaily (May 22, 2012) — For the first time scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue.

The research, which is published online May 22 in the European Heart Journal, opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients' immune systems rejecting the cells as "foreign." However, the researchers warn that there are a number of obstacles to overcome before it would be possible to use hiPSCs in humans in this way, and it could take at least five to ten years before clinical trials could start.

Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue.

Professor Lior Gepstein, Professor of Medicine (Cardiology) and Physiology at the Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology and Rambam Medical Center in Haifa, Israel, who led the research, said: "What is new and exciting about our research is that we have shown that it's possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young -- the equivalent to the stage of his heart cells when he was just born."

Ms Limor Zwi-Dantsis, who is a PhD student in the Sohnis Research Laboratory, Prof Gepstein and their colleagues took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or "transcription factors" (Sox2, Klf4 and Oct4), followed by a small molecule called valproic acid, to the cell nucleus. Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene.

"One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumours," explained Prof Gepstein. "This potential risk may stem from several reasons, including the oncogenic factor c-Myc, and the random integration into the cell's DNA of the virus that is used to carry the transcription factors -- a process known as insertional oncogenesis."

The researchers also used an alternative strategy that involved a virus that delivered reprogramming information to the cell nucleus but which was capable of being removed afterwards so as to avoid insertional oncogenesis.

The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together. "The tissue was behaving like a tiny microscopic cardiac tissue composed of approximately 1000 cells in each beating area," said Prof Gepstein.

Finally, the new tissue was transplanted into healthy rat hearts and the researchers found that the grafted tissue started to establish connections with the cells in the host tissue.

"In this study we have shown for the first time that it's possible to establish hiPSCs from heart failure patients -- who represent the target patient population for future cell therapy strategies using these cells -- and coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue," said Prof Gepstein.

"We hope that hiPSCs derived cardiomyocytes will not be rejected following transplantation into the same patients from which they were derived. Whether this will be the case or not is the focus of active investigation. One of the obstacles in dealing with this issue is that, at this stage, we can only transplant human cells into animal models and so we have to treat the animals with immunosuppressive drugs so the cells won't be rejected."

Much research has to be conducted before these results could be translated into treatment for heart failure patients in the clinic. "There are several obstacles to clinical translation," said Prof Gepstein. "These include: scaling up to derive a clinically relevant number of cells; developing transplantation strategies that will increase cell graft survival, maturation, integration and regenerative potential; developing safe procedures to eliminate the risks for causing cancer or problems with the heart's normal rhythm; further tests in animals; and large industry funding since it is likely to be a very expensive endeavour. I assume it will take at least five to ten years to clinical trials if one can overcome these problems."

Prof Gepstein and his colleagues will be carrying out further research into some of these areas, including evaluating using hiPSCs in cell therapy and tissue engineering strategies for repairing damaged hearts in various animal models, investigating inherited cardiac disorders, and drug development and testing.


Surgery. For the first time scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue. (Credit: © muratolmez / Fotolia)

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Rewritable DNA memory shown off

Rewritable DNA memory shown off

DNA artworkThe researchers say that biological systems are "one of the coolest places for computing"

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Researchers in the US have demonstrated a means to use short sections of DNA as rewritable data "bits" in living cells.

The technique uses two proteins adapted from viruses to "flip" the DNA bits.

Though it is at an early stage, the advance could help pave the way for computing and memory storage within biological systems.

A team reporting in Proceedings of the National Academy of Sciences say the tiny information storehouses may also be used to study cancer and aging.

The team, from Stanford University's bioengineering department, has been trying for three years to fine-tune the biological recipe they use to change the bits' value.

The bits comprise short sections of DNA that can, under the influence of two different proteins, be made to point in one of two directions within the chromosomes of the bacterium E. coli.

The data are then "read out" as the sections were designed to glow green or red when under illumination, depending on their orientation.

Integrase moleculeThe trick was to balance the effects of two competing proteins - integrase and excisionase

The two proteins, integrase and excisionase, were taken from a bacteriophage - a virus that infects bacteria. They are involved in the DNA modification process by which the DNA from a virus is incorporated into that of its host.

The trick was striking a balance between the two counteracting proteins in order to reliably switch the direction of the DNA section that acted as a bit.

After some 750 trials, the team struck on the right recipe of proteins, and now have their sights set on creating a full "byte" - eight bits - of DNA information that can be similarly manipulated.

The work is at the frontier of biological engineering, and senior author of the research Drew Endy said that applications of the approach are yet to come.

"I'm not even really concerned with the ways genetic data storage might be useful down the road, only in creating scalable and reliable biological bits as soon as possible," Dr Endy said.

"Then we'll put them in the hands of other scientists to show the world how they might be used."

As the DNA sections maintained their logical value even as the bacteria doubled 90 times, one clear application would be in using the DNA bits as "reporter" bits on the proliferation of cells, for example in cancerous tissue.

But longer-term integrations of these computational components to achieve computing within biological systems are also on the researchers' minds.

"One of the coolest places for computing is within biological systems," Dr Endy said.

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IBM researchers make 12-atom magnetic memory bit

Image of a bit stored in 12 atomsThe groups of atoms were built using a scanning tunneling microscope

Researchers have successfully stored a single data bit in only 12 atoms.

Currently it takes about a million atoms to store a bit on a modern hard-disk, the researchers from IBM say.

They believe this is the world's smallest magnetic memory bit.

According to the researchers, the technique opens up the possibility of producing much denser forms of magnetic computer memory than today's hard disk drives and solid state memory chips.

"Roughly every two years hard drives become denser," research lead author Sebastian Loth told the BBC.

"The obvious question to ask is how long can we keep going. And the fundamental physical limit is the world of atoms.

"The approach that we used is to jump to the very end, check if we can store information in one atom, and if not one atom, how many do we need?" he said.

Below 12 atoms the researchers found that the bits randomly lost information, owing to quantum effects.

A bit can have a value of 0 or 1 and is the most basic form of information in computation.

"We kept building larger structures until we emerged out of the quantum mechanical into the classical data storage regime and we reached this limit at 12 atoms."

“Start Quote

As a scientist [I] would totally dig having a scanning tunnelling microscope in every household”

Sebastian LothResearch lead author

The groups of atoms, which were kept at very low temperatures, were arranged using a scanning tunnelling microscope. Researchers were subsequently able to form a byte made of eight of the 12-atom bits.

Central to the research has been the use of materials with different magnetic properties.

The magnetic fields of bits made from conventional ferromagnetic materials can affect neighbouring bits if they are packed too closely together.

"In conventional magnetic data storage the information is stored in ferromagnetic material," said Dr Loth, who is now based at the Center for Free-Electron Laser Science in Germany.

"That adds up to a big magnetic field that can interfere with neighbours. That's a big problem for further miniaturisation."

Other scientists thought that was an interesting result.

"Current magnetic memory architectures are fundamentally limited in how small they can go," Dr Will Branford, of Imperial College London, told the BBC.

"This work shows that in principle data can be stored much more densely using antiferromagnetic bits."

But the move from the lab to the production may be some time away.

"Even though I as a scientist would totally dig having a scanning tunnelling microscope in every household, I agree it's a very experimental tool," Dr Loth said.

Dr Loth believes that by increasing the number of atoms to between 150 to 200 the bits can be made stable at room temperature. That opens up the possibility of more practical applications.

"This is now a technological challenge to find out about new manufacturing techniques," he said.

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Evolution seen in 'synthetic DNA'

Artwork of RNA transcriptionMolecules called polymerases help to faithfully copy the genetic information stored in single strands of DNA

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Researchers have succeeded in mimicking the chemistry of life in synthetic versions of DNA and RNA molecules.

The work shows that DNA and its chemical cousin RNA are not unique in their ability to encode information and to pass it on through heredity.

The work, reported in Science, is promising for future "synthetic biology" and biotechnology efforts.

It also hints at the idea that if life exists elsewhere, it could be bound by evolution but not by similar chemistry.

In fact, one reason to mimic the functions of DNA and RNA - which helps cells to manufacture proteins - is to determine how they came about at the dawn of life on Earth; many scientists believe that RNA arose first but was preceded by a simpler molecule that performed the same function.

However, it has remained unclear if any other molecule can participate in the same unzipping and copying processes that give DNA and RNA their ability to pass on the information they carry in the sequences of their nucleobases - the five chemical group "letters" from which the the two molecules' genetic information is composed.

'No Goldilocks'

“Start Quote

There is nothing 'Goldilocks' about DNA and RNA - there is no overwhelming functional imperative for genetic systems or biology to be based on them”

Philipp HolligerMedical Research Council

The classic double-helix structure of DNA is like a twisted ladder, where the steps are made from paired nucleobases (RNA is typically a single helix).

Philipp Holliger of the UK Medical Research Council's Laboratory of Molecular Biology and a team of colleagues created six different DNA- and RNA-like molecules - xeno-nucleic acids, or XNAs - by replacing not the nucleobases but the sugar groups that make up the sides of the ladder.

"There's a lot of chemisty that seeks to build alternative nucleic acids, and people have been modifying the bases, the sugars and the backbone, but what we were focusing on was the type of nucleic acid or polymers that would retain the ability to communicate with the natural DNA," Dr Holliger explained in an interview for the Science podcast.

Because the nucleobases themselves were the same as those of DNA and RNA, the resulting molecules were able to join with their natural counterparts.

The effect is similar to work recently published in Nature Chemistry, showing that another sugar-substituted DNA analogue could be made to pair up with DNA itself.

But the crucial point in creating a full "synthetic genetics" is a set of nucleic acids like DNA and RNA that can not only carry genetic information, but would also allow it to be changed and passed on - evolution and heredity.

That requires a set of helper molecules called polymerases, which, once DNA or RNA "unzip" and expose their genetic information, help create new DNA molecules from those instructions.

Artwork of Pfu DNA polymeraseThe work's key advance is the "polymerase" molecules that guide the copying process

Dr Holliger and his colleagues have developed polymerases that efficiently transcribe the code of their synthetic DNA to natural DNA and then from that back to another synthetic DNA.

The process of evolution was encouraged in the lab; one of their DNA analogues was designed to cling to a particular protein or RNA target, those that failed to do so were washed away.

As successive copies of those that stuck were made, variations in the genetic code - and the resulting structure the molecules took on - led to ever more tightly attached XNAs.

"We've been able to show that both heredity - information storage and propagation - and evolution, which are really two hallmarks of life, can be reproduced and implemented in alternative polymers other than DNA and RNA," Dr Holliger explained.

"There is nothing 'Goldilocks' about DNA and RNA - there is no overwhelming functional imperative for genetic systems or biology to be based on these two nucleic acids."

In an accompanying article in Science, Gerald Joyce of the Scripps Research Institute wrote that "the work heralds the era of synthetic genetics, with implications for exobiology (life elsewhere in the Universe), biotechnology, and understanding of life itself".

But the work does not yet represent a full synthetic genetics platform, he pointed out. For that, a self-replicating system that does not require the DNA intermediary must be developed.

With that in hand, "construction of genetic systems based on alternative chemical platforms may ultimately lead to the synthesis of novel forms of life".

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