Special report: The future of medicine - to increase the body's healing capacity

In recent years, considerable progress has been made in replacing damaged heart tissue and rebuilding muscles. On top of that, researchers are in the early stages of developing new nerve cells. Some of the innovations can emerge from the laboratory as medical treatment in a few years, others in a few decades, and it is possible that some of them will even fail in the end. Here are some of the most promising innovations.

The liver is a unique organ among the large organs of the human body because it has a wonderful ability to recover from injury. A person can lose a significant part of his liver in an accident or surgery, but as long as at least a quarter of the liver remains intact and relatively free of scars, it can regenerate itself and return to its original size and full activity. Unfortunately, such self-recovery ability does not characterize other body parts. A salamander can regrow its tail, but a human cannot regrow an amputated leg or regenerate areas of the brain lost in Alzheimer's disease. For this to be possible, humans need help, and this is the promise of a new and developing field of research: tissue regeneration medicine.

Stem cells, which are progenitor cells capable of producing a variety of tissues, play an important role in the new field. Scientists are learning how to mix a mixture of sugar, protein and fiber molecules to create an environment where stem cells will develop into replacement tissue. As the following articles show, considerable progress has been made in replacing damaged heart tissue and rebuilding muscle. On top of that, researchers are in the early stages of developing new nerve cells. Some of the innovations can emerge from the laboratory as medical treatment in a few years, others in a few decades, and it is possible that some of them will even fail in the end. Here are some of the most promising innovations.

With a whole heart / Faris Jaber

Stem cells may change the way doctors treat heart failure

In early 2009, Mike Jones bought a newspaper in a store in Louisville, Kentucky and read about a local doctor who wanted to try something unprecedented: to heal a diseased heart using stem cells that would be produced from the patient himself and grown in culture. Stem cells are immature cells with the ability to regenerate tissues. Jones, who was 65 at the time, suffered from congestive heart failure, meaning his heart was not pumping blood efficiently. He contacted the doctor, Roberto Bolli of the University of Louisville, and in July of that year Jones was the first person in the world to receive a transfusion of his own cardiac stem cells.

Before the treatment, Jones could barely walk up the stairs. Today he is strong enough to trim wood for the fireplace and clear fallen tree trunks in his 36-dunam estate. The amount of blood that the heart ejects from the chambers of the heart in each contraction, or its "ejection segment", increased from 20% to 40% in the two years after the experiment. This is a lower percentage than the normal value (which is 50% to 70%), but it is still a dramatic improvement.

Since then, the condition of hundreds of other patients who suffered cardiac damage and doctors injected them with stem cells extracted from their own hearts or bone marrow as well as stem cells from foreign donors has similarly improved. Researchers believe that the stem cells build new tissue and encourage other cells to divide. But many important questions remained unanswered. Scientists have not yet discovered which of the different types of stem cells works best and how exactly to prepare the cells for treatment, but new knowledge is being acquired quickly. "I believe that we are at the threshold of one of the greatest medical revolutions of our generation," says Boley. "We still have to learn how to use these cells properly, but it's already real. In the future we will produce our own stem cells, grow them and keep them in the freezer until we need them."

repair the pump

In the last forty years, scientists have seen the heart as a powerful but vulnerable living pump. Since the adult heart does not seem to be able to regenerate its cells, the researchers concluded that any cell death weakens it irreparably. However, from time to time scientists observed under the microscope adult heart cells that had divided. Carbon dating of preserved heart tissues verified the hypothesis that the adult heart replaces its cells during life, although the rate of replacement is slower than that of the intestines and skin. Biologists now estimate that the heart replaces 5 percent or more than 4-XNUMX billion cardiac muscle cells each year. Researchers also discovered that the new cells are created by the division of mature heart cells and stem cells in the heart.

These local stem cells allow the heart to repair itself with small repairs. After a heart attack, for example, cardiac stem cells mature into new heart cells and encourage existing cells to divide. But this self-repair lasts only a week or two, too short a time to replace the billion-plus cells that are damaged in a typical heart attack. The result is a large area of ​​inelastic scar tissue. Just as a bulge forms in the damaged area of ​​a car tire, so the heart swells in the area of ​​the scar. The heart, which was previously an elliptical and efficient organ, becomes a weak and ineffective pump.

Stem cell therapy provides the heart with an enormous amount of its own repair cells. Animal studies show that some of the injected cells mature into mature cells, but the majority die within a few days. Before they die, the cells secrete a mixture of proteins that encourage healthy heart cells to multiply, as well as enzymes that break down the collagen fibers in the scar tissue, making way for new heart muscle cells.

So far, researchers have completed only a few and limited studies in humans. Boley and his colleagues removed a small piece of heart tissue from 23 patients with heart damage or failure, including Jones. The researchers cultivated small gardens of heart cells in petri dishes and sifted the stem cells with the help of the protein c-kit, which is used as a specific marker of stem cells. Then they allowed the stem cells to make millions of copies of themselves.

After that, 16 patients received a million cardiac stem cells through a catheter inserted into the cardiac artery, and 7 patients received standard treatment (mainly beta blockers and diuretics). Four months later, the ejection fraction of the patients who received stem cells improved from 30.3% on average to 38.5% on average, while there was no improvement in the patients who received standard treatment (minimal change from 30.1% to 30.2%). One year after the treatment, the average weight of the scar tissue in patients who received stem cells decreased by 30%.

In a similar experiment, Eduardo Marvan from the Cedars-Sinai Heart Institute in Los Angeles and his colleagues treated 17 patients using their own stem cells and 8 patients with standard treatment. Marvan and his team used remote-controlled forceps to pinch and remove a small grain of heart tissue for growing it in the laboratory. Unlike Boley, who extracted mainly "true" stem cells that expressed the c-kit protein from his cell cultures, Marvan produced a diverse mixture of cells, some of which had a more limited ability to differentiate. Patients who received the standard treatment did not show a statistically significant change in the size of the scar tissue or healthy heart tissue, while among patients treated with stem cells there was a 42% decrease in the size of the scar and an increase of 13 grams in the healthy heart tissue over one year, although their ejection fraction did not improve at all .

Other researchers have tried to treat heart failure with cells called mesenchymal stem cells, which originate from the bone marrow. These cells are of interest because their chance of becoming cancerous is less than that of other stem cells. These stem cells secrete growth factors that encourage nearby cells to reproduce, and they can also become heart muscle cells under the right conditions. The results of the studies so far are inconsistent: the condition of some patients clearly improved, while in others almost no positive changes were observed.

Joshua Harr of the University of Miami wondered if heart patients would be able to take in stem cells from a donor's bone marrow, or if they would reject them as foreign cells. Harr injected 15 patients with the stem cells from their own bone marrow, and 15 others injected cells from donors. Thirteen months later, no one rejected the transplanted cells, and the scar tissue shrank by more than a third in both groups. For older patients, stem cells from young donors may be more successful than autologous stem cells, because young cells have not yet undergone significant wear and tear.

"Until now, we didn't have a way to remove the scar that forms after a heart attack," Hare says. "Reducing the scarring and replacing the scar with new tissue are the breakthrough we've been waiting for. I believe it will change the treatment of heart failure."

Glue as a panacea / Christine Gorman

Regrowth of muscles, tendons and even organs may be possible with the help of glue produced by the body itself

For years, biologists were so focused on the mechanisms of cell activity that they almost completely ignored the "glue" that holds the cells together in the human body or other animals. From the moment researchers began to study the intercellular substance, called the extracellular matrix, they realized how dynamic it is. It is not enough that the neglected tissue provides the biological scaffolding necessary to maintain the tissues and organs and prevent them from disintegrating into a viscous puddle, but it also sends out chemical signals that, among other things, help the body to heal.

These insights have prompted researchers to now develop a new approach to tissue engineering in which the regenerative powers of our natural scaffolds play the leading role. The idea is to produce an extracellular matrix from animals, such as pigs, and implant it in patients suffering from severe internal damage (after, of course, neutralizing the components of the patients' immune system so that they do not provoke a destructive attack against the implanted material). The new scaffolds are supposed to distribute molecules that will attract semi-specialized stem cells from other areas of the body to fulfill the various roles and differentiate exactly into the type of tissue that should be in place. In the end, the transplanted scaffold will also be replaced with human proteins and fibers and thus the memory of the farm animals from which it was produced will disappear.

Researchers are turning this vision into reality at an astonishingly fast pace. Less than ten years ago, surgeons began using an extracellular matrix to repair an abdominal hernia (hernia), caused by areas of weakness in the muscles and supporting tissue that surround the intestines. Today they are trying to grow tendons inside the body, and in the not too distant future they hope to make regeneration of major muscle groups and even organs a daily procedure. Not surprisingly, the US Department of Defense, which has developed a grim expertise in treating wounded soldiers whose faces, arms or legs have been pierced by explosive charges in Iraq or Afghanistan, has invested tens of millions of dollars in many of these studies.

Scarring vs. Regeneration

One of the researchers who is in a particularly successful position to advance the field is Stephen Badylak, deputy director of the McGowan Institute for Tissue Regenerative Medicine at the University of Pittsburgh. Badylak began his career as a veterinarian, then completed a doctorate in pathology and finally a medical degree. "It's not the most practical way to learn," he says, "unless you're willing to incur massive tuition debt."

Badilak believes that the extracellular matrix will have an advantage in the future, especially in the treatment of bomb victims. The mammalian body, he says, is limited in the ways it is able to respond to injury. Small wounds, like a paper cut, disappear after inflammatory cells flood the area, fight infection and remove damaged tissue. A short time later there is complete regeneration of normal skin (not scarred). Soldiers hit by bombs, on the other hand, may lose 20% to 80% of the mass of a particular muscle group. In such severe cases, the researchers say, the body cannot restore the tissue, and the gap that opens is filled with compressed scar tissue, which although connects the remaining tissue parts, but also results in a loss of activity. In these cases, the best option may be amputating the limb and fitting a prosthesis that will provide a greater range of motion.

Badilak and his colleagues are now using the extracellular matrix to treat 80 such patients, who have severe muscle injuries that occurred at least six months before starting treatment. After a strict regimen of physical therapy, designed to ensure that the body has regenerated as much muscle as possible on its own, the surgeons reopen the old wounds, remove the resulting scar tissue, insert the biological scaffold and connect it to the adjacent healthy tissue.

The initial results are promising, says the veterinarian-physician-tissue engineer. Biopsies of muscles that have undergone such treatment show biochemical changes similar to those seen by researchers when they developed the method in animals. If all goes well, Badylak hopes to publish findings from the first five patients in the summer of 2013.

A sweet solution for organ replacement / Kathryn Harmon

To build large organs that function properly, scientists must find a way to weave blood vessels into them

The audience of listeners and viewers of TED talks is used to being surprised by technological innovations, but Anthony Attala's talk from the Wake Forest Institute for Tissue Regenerative Medicine surprised even them. Behind Atala, hidden from the eyes of the audience at the beginning of the lecture, stood all kinds of vials and nozzles humming with mysterious activity. Then, about two-thirds of the way through the lecture, the camera focused on the innards of the machine and showed how it made a back-and-forth weaving motion, placing living cells grown in lab culture layer by layer across a central surface, according to precise XNUMXD digital instructions. The process, known as XNUMXD printing, simulates the operation of inkjet printers, except that instead of ink, the printer uses a solution of living cells. At the end of Atala's so-called "printing" process, layer by layer, a life-sized kidney made of human cells, just like a personal XNUMXD printer can produce, say, a spare part for a coffee machine.

A quick and direct way to produce organs is a welcome development for more than 105,000 Americans waiting for organ donations. But the programmed kidney presented by Atala two years ago was not suitable for transplantation. It lacked two crucial components: active blood vessels and tubes for collecting the urine. Without them or other internal channels, the cells in the inner layers of large organs such as the kidney cannot receive necessary oxygen and nutrients, or eliminate toxic waste materials, and are doomed to a rapid death. Scientists tried to print such hollow structures into the organ, layer by layer, by leaving empty areas in the appropriate places in each layer, but this method created channels that could collapse and collapse under the pressure created by the blood flowing from the heart.

A team of scientists from the University of Pennsylvania and the Massachusetts Institute of Technology (MIT) offered a sweet solution to the problem. Instead of printing the organ and all its internal tubes at once, they print a template of the tubes from soluble sugar and then build the appropriate layers of cells around the template. Then the pattern is washed out, leaving behind a solid structure of passages resistant to changes in the body's blood pressure.

An inspiring dessert

Jordan Miller (one of the project's lead scientists and a postdoctoral fellow at the University of Pennsylvania) came up with the idea in two stages. One, when he looked at the display of corpses and organs in the "Body Worlds" exhibition, he saw that the corpse preparers demonstrated the lace-like structure of blood vessels in a large organ by injecting silicone into the vascular system and massaging and removing all organic tissue remnants.

Miller hypothesized that it would be possible to create a synthetic template that would serve as a basis for building the internal blood vessels. But the chemicals required to melt the silicone are toxic to the living cells that are supposed to coat the mold. The way around the shiny problem at the same time he was served in a luxury restaurant a trellis-like dessert made of hard sugar. Why not make a mold of blood vessels or other cavities from sugar, which can be washed off with water?

Miller and his colleagues adapted an open-source 100D printer called Rep-Rap to use a carefully tailored mixture of sugars to print fibers of various diameters, from a millimeter to XNUMX microns.

The team used these fibers to create an idealized version of a blood vessel network and coated the skeleton with cell-friendly polymers to prevent the sugar from dissolving too quickly. Then the scientists wrapped the entire structure in a mixture of extracellular fluid and endothelial cells of the type that line blood vessels. In the end they washed the sugar off with water and were left with stable blood vessels made from living cells.

Then came the cells' turn. Just like in the body, the cells began to reshape the blood vessels in which they found themselves, strengthening the entire structure and even forming tiny capillaries at the ends of the larger blood vessels. By allowing the cells to finish the work of completing the details, says Christopher Chen, director of the Tissue Manufacturing Laboratory at the University of Pennsylvania, "we are freed from completely designing the structure." The body can make the subtle repairs in an almost perfect organ, and bring it to full function.

To date, Chen, Miller and their colleagues have created cubes of liver tissue with blood vessel templates made of sugar and implanted them in rats to demonstrate that they integrate with the existing vascular system. These lumps of tissue cannot take the place of whole organs, but one can see how adding liver, kidney or pancreas cells to a fully developed system of blood vessels could one day lead to XNUMXD printing of large organs.

Replanting the brain forests / Ferris Jaber

Neurodegenerative disorders destroy the brain, but doctors hope to one day replace the lost cells

The nerve cells in the human brain branch and grow alongside other nerve cells, around and above them just like trees in a tangled forest. Scientists used to think that every nerve cell that withers and dies due to injury or disease is gone forever because the brain cannot replace it with another. However, since the 90s, most neuroscientists believe that the adult brain cultivates small gardens of stem cells that can become mature neurons.

Researchers are still trying to learn how often these stem cells become new nerve cells and how efficiently the differentiated cells survive and join the existing neural circuits in the brain. There is evidence that the neural stem cells in the brain help a little in self-healing of the brain, such as replacing a small group of nerve cells damaged in a stroke. But such minimal self-healing does not restore the millions of nerve cells that perish in a stroke, traumatic brain injury, or degenerative brain diseases such as Alzheimer's and Parkinson's.

Twenty years ago, brain surgeons tried to overcome the brain's limited ability to regenerate by transplanting slices of fetal brain into a patient's brain to replace dead nerve cells with new ones. The results in those clinical trials were disappointing, but some surgeons now believe they have found a way to make the treatment safer and more reliable. Instead of relying on embryonic tissue, scientists can grow millions of young nerve cells from stem cells in the lab and inject them directly into the patient's brain. Although few expect the treatment to be widely used in less than ten or twenty years, first studies towards the goal have already begun.

The most promising research so far has focused on Parkinson's disease, which seems to respond particularly well to the transplant. Parkinson's disease affects about 10 million people worldwide (including XNUMX million in the US). The disease is mainly caused by the death of nerve cells that secrete dopamine in the area of ​​the midbrain known as the "black substance" (substantia nigra), which has an important role, among other things, in controlling movement. Symptoms often include tremors, stiffness and difficulty walking.

In the early 80s, scientists extracted immature brain tissue from rat embryos and transplanted it into the substantia nigra of rats whose dopamine-secreting neurons had previously been eliminated to simulate Parkinson's. Although the transplanted neurons survived, they failed to form a functional neural circuit. Normally, when the brain develops in the womb, the nerve cells in the substantia nigra send branches to another area of ​​the brain called the striatum, where they secrete the neurotransmitter dopamine to communicate with nerve cells in the striatum. The distance between the substantia nigra and the striatum in adult brains, even in adult rat brains, is considerably greater than in fetal brains. In the early experiments, the nerve cells were not able to bridge the gap. In the following experiments, the researchers tried, instead, to transplant the immature nerve cells directly into the striatum. This transplant seems to be working. The neurons survived, entwined themselves into existing neural circuits and began to secrete dopamine.

In subsequent experiments on rodents and monkeys, such implants returned the dopamine level to almost the normal level and improved motor function: the animals trembled less and improved their grip on objects. The researchers hypothesized that the treatment is beneficial not only because of the dopamine secreted by the transplanted nerve cells, but also because they secrete growth factors that protect and nourish the dopamine receptor cells in the striatum. Since the transplanted neurons are living cells that constantly produce, secrete and absorb neurotransmitters, they can maintain the balance of dopamine levels in the brains of Parkinson's patients more effectively than drug therapy such as taking L-dopa.

In the early 90s, fetal brain tissue was transplanted into four Parkinson's patients in Sweden in a groundbreaking experiment that paved the way for two large clinical trials in 40 and 34 patients funded by the American Institutes of Health (NIH). In both experiments, the fetal tissues were implanted in half of the people, and the other half underwent a sham operation. The results were discouraging. There was no benefit in the treated groups compared to the control groups, except for the benefit in the condition of some patients less than 60 years old in one of the trials.

While many researchers considered these experiments a complete failure, others doubted the data and decided to try again for several reasons. First, it is extremely difficult to standardize fetal tissue implants because patients often receive tissue samples of different qualities and from different donors. Second, Anders Björklund of Lund University and other researchers argued that the experimenters expected premature improvement. The transplanted nerve cells are far from mature, and it probably takes several years for them to integrate into the brain. In a study that followed the transplanted patients in one of the experiments and was funded by the NIH, it was found that two and four years after the transplants there was an improvement in some of them.

Lorenz Stader of the Memorial Sloan-Kettering Cancer Center focused on another way to replace the cells lost in Parkinson's, which solves the regulation problem. He exposed embryonic stem cells in the lab to a series of substances that mimic the type of chemical signals the cells were supposed to receive in the fetal brain. These signals push the cells towards a certain stage of development corresponding to two months in the womb. This stage takes place after the last cell division, but before the cells grow long or branched processes. Because Stader carefully monitors the growth and development of the cells in the laboratory, he can create millions of young, nearly identical nerve cells suitable for transplantation. Injection of embryonic stem cells that have not undergone any differentiation into the brain or any other organ increases the risk of creating tumors because the stem cells may grow out of control. So far Stader has published promising results of experiments in rats and monkeys: in both of these types of animals an improvement in movement control is seen. He hopes to begin human clinical trials within three to four years.

"This study deals with a much broader issue," says Björklund. "Parkinson's disease is an appropriate touchstone for testing this type of treatment. If this stem cell treatment method is beneficial for Parkinson's patients, it will open up the possibility to treat a wider variety of damages and diseases of the central nervous system."

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in brief

The emerging field of tissue regenerative medicine may one day revolutionize the treatment of heart disease and neurodegenerative diseases, solve the shortage of organ donations and completely regenerate muscles, tendons and other damaged tissues.

The key to success, as the researchers are learning, is to provide the body with a sort of starter kit made of a variety of proteins, fibers or cells, or to clone additional copies of semi-specialized stem cells that are already present in the adult patient. Then the body is allowed to do its thing.

The help from the outside allows the body to regrow tissues of types or in amounts that are not normally possible for it. Such self-healing therapies have already helped some heart disease patients to some extent and helped surgeons repair damaged muscles.

Repairing the heart

When semi-specialized stem cells are extracted from a diseased heart, they are helped to make millions of copies of themselves and then injected back into the heart. The process allows the heart to break down scar tissue and grow new muscle cells.

Brain growth

To replace dead brain cells due to degenerative disorders of the nervous system, such as Parkinson's disease, some researchers are trying to transplant fetal brain tissue and inject young nerve cells grown in the lab from stem cells.