Can our bodies heal themselves?

Self-repairing organs might be the cure for heart disease

By Pawan Naidu

The term heart disease makes people uncomfortable, because of the bleak realities of damage to the organ responsible for blood circulation. Heart disease is the leading cause of death in the world and little that can be done to treat it. Even though some bodies reject transplants, they do work, but there are not enough donated hearts to go around. And unlike skin and liver cells, heart muscles duplicate themselves only rarely.

There was hope stem cells could be the cure for heart disease, but unfortunately, treatments haven’t shown any noticeable improvement. In the past few years biologist have been exploring a new method to battle cardiovascular disorders. What would your reaction be if I told you scientists believe they can make our bodies heal themselves by switching the identities of our cells?

After scientists discovered how a featureless cluster of identical cells can become the rich diversity of parts that comprise the human body, they assumed that adult cells were stuck with their fates.

Embryonic stem cells are derived from embryos that develop from eggs that have been fertilized and then donated for research purposes with the informed consent of the donors. Once embryonic stem cells, capable of becoming any type of tissue, had become, for example, a skin cell, there seemed to be no turning back. This belief changed in 2006.

Shinya Yamanaka, then at Kyoto University in Japan, discovered cells can be reverted back and reprogrammed. He changed adult mouse cells back into a stem-cell-like state by inserting a cocktail of proteins called transcription factors. These work by changing which of the cells’ genes are emphasized, switching the cells to a “pluripotent” state in which they are able to transform into any tissue in the body. A year later, Yamanaka repeated the experiment successfully with human cells, a breakthrough that earned him a share of the Nobel prize for medicine in 2012 along with Sir John B. Gurdon.

Yamanaka’s successful use of pluripotent stem (iPS) cells promises a new era of medicine. They provide a means to skip over the ethical concern of acquiring stem cells from discarded embryos. They also offered an abundant source of therapeutic cells that the immune system shouldn’t reject because they can be grown from the transplant patients themselves. The hope is that cells, tissues and perhaps entire organs can soon be grown in the lab from a patient’s cells, before being transplanted back to repair injury the damaged organs.

However, this method is still theoretical and there is skepticism. More than a decade after Yamanaka’s discovery, iPS cells have yet to deliver. Only a handful of stem-cell therapies have been approved by the US Food and Drug Administration, for several blood disorders, including leukemia, and skin growth after burns and all of those are making use of embryonic stem cells, not iPS cells.

“No cell-based therapy is close to being approved for heart disease,” Roberto Bolli, a cardiologist at the University of Louisville in Kentucky, wrote. “A rising tide of skepticism has bedeviled the field, leading some critics even to question whether clinical studies should continue.”

The skepticism is understandable, and there are legitimate concerns that need to be addressed. There are questions how closely these cells resemble stem cells, therefore people question how versatile and safe they are.

These questions prompted, Deepak Srivastava at the Gladstone Institutes in San Francisco, to explore an alternative approach that doesn’t involve lab-grown cells. The idea is to exploit the plasticity of cells like never before by transforming them inside the body rather than reverting to a pluripotent state first. This has to be done directly as iPS cells made inside animals have a tendency to turn cancerous.

Srivastava was the first to perform this manipulation on heart cells, when he and his colleagues used just three transcription factors to transform mouse heart fibroblasts, which make up some of the fabric of the organ, to beating heart muscle cells.

“Initially there was great skepticism that a small group of [transcription] factors could switch cell fate,” Srivastava said after the successful experiment.

Later, his team went further by getting those cells to beat in a coordinated fashion, just as in a real cardiac muscle. In 2013, he was able to successfully do the same thing with human cells.

We shouldn’t get too excited because Srivastava and his colleagues did this with cells grown in a Petri dish. To avoid complications that arise with transplants, the cells need to be made inside the body.

A team led by Douglas Melton at the Harvard Stem Cell Institute transformed ordinary pancreatic cells in mice into insulin-producing cells, which are destroyed by the immune system in people with type 1 diabetes. An encouraging sign of the principle working is that the converted cells produced insulin.

It isn’t so easy for heart muscle cells though, says Srivastava, because they need to coordinate their pulsing activity with the rest of the heart. In 2012, his team managed to reprogram mouse heart fibroblasts into muscle cells in a live mouse with three transcription factors. The mice had suffered a heart attack, producing scar tissue that impaired cardiac function. But a couple of months after the treatment, their hearts had begun to recover. Some of the scar tissue had been converted into beating heart muscle cells and the organ’s ability to pump blood had improved.

Surprisingly, the three proteins that did the trick here don’t work on cells in a dish, which suggests that surrounding tissues in the body can make in vivo, making cells inside a living organism, reprogramming more effective.

It is not entirely clear why, but Sheng Ding at the Gladstone Institutes, suspects it could be due to cells that surround the ones being altered supplying chemical or mechanical signals that help the process along. That, he says, is the kind of advantage conferred by the tissue regeneration that occurs naturally in animals such as salamanders, which can regenerate entire limbs.

There seems to be no fundamental reason why this reprogramming process can’t work in humans too and not just for heart disease. The questions now are how and when that will happen. Ultimately, like any experimental medicine, there are lots of boxes to tick, such as proven consistent successful in humans and by “turning off” the production of proteins while the cells are being manipulated, before we can test this new direction in cell reprogramming in humans, and plenty of potential pitfalls.

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