Regenerative Medicine
How politics, spectacle, and misinformation are drowning out the field’s most promising advancements
In 1954, Dr. Joseph Murray and Dr. David Hume performed the first successful human organ transplant at Brigham Hospital in Boston. For years, the main barrier to transplantation had been the human immune system, which recognizes foreign tissue and uses white blood cells to attack and destroy it. To overcome this obstacle, the surgeons transplanted a kidney from a healthy donor to his genetically identical twin. The recipient of the kidney did not reject the organ, and he lived for eight years after the surgery. Dr. Murray later won the Nobel Prize in Physiology or Medicine for the pioneering procedure.
But for many years following this procedure, very few organ transplants between unrelated donor/recipient pairs were performed. Early anti-rejection drugs were not very effective, had many harsh side effects, and increased morbidity. Then, in 1983, the FDA approved the immunosuppressive drug Cyclosporine for organ transplant recipients. It performed better than earlier experimental immunosuppressive drugs with fewer side effects. Once Cyclosporine was proven to work safely and effectively, the shortage of organ donors became the limiting factor of organ transplantation. In response to this shortage, Congress passed several pieces of legislation to expand organ donation; the most significant of these established the Organ Procurement and Transplantation Network (OPTN) in 1984. The goal of the network was to improve the organ matching process, increase the number of organ donors, and create a national organ registry. While these efforts have done a lot to help organ transplantation in the United States, there is still a substantial shortage of organ donors. Today, over 122,000 people are in need of a lifesaving organ transplant, and this number continues to grow every year.
In response to this problem, scientists and physicians have worked together to pioneer the field of regenerative medicine. Leaders in the field claim that a patient’s own stem cells could one day be used to regenerate entire organs, reducing the need for organ donors and toxic, expensive immunosuppressive drugs. While these claims may give hope to millions of people with currently untreatable diseases, many challenges remain.
Scientists have been studying animal stem cells for decades; geneticist Martin Evans and embryologist Matthew Kaufman discovered how to procure embryonic stem cells from mouse embryos in 1981. In 1998, a research team led by developmental biologist James Thomson isolated stem cells from human embryos. In their seminal paper published in Science that year, the authors predicted that human embryonic stem cells could one day be used in transplantation medicine to prevent or treat diseases like Parkinson’ disease and juvenile-onset diabetes.
The embryos used in Thomson’s studies were originally created for in vitro fertilization; since the process often creates more embryos than needed, the spare embryos (which would otherwise be destroyed) are often donated for stem cell research with the informed consent of the mother. Many pro-life groups were quick to speak out against using human embryos for stem cell research. The Catholic Church has been one of the most outspoken; former Pope John Paul II stated that “the killing of innocent human creatures, even if carried out to help others, constitutes an absolutely unacceptable act.” This statement and pressure from other pro-life groups led to many pieces of legislation in the late 1990s and early 2000s that restricted stem cell research in the United States. In 2009, President Obama issued an executive order that removed many of these restrictions from federal stem cell research programs, and instructed the NIH to revise stem cell-related funding guidelines. While this executive order ensured the continuation of stem cell research for several years, there is no guarantee that President Obama’s decision will not be reversed by a future administration. In the absence of federal restrictions, many legislators are actively working to ban embryonic stem cell research in their states. In March 2015, the Oklahoma House voted 80–13 in favor of legislation that would make it a felony to conduct embryonic stem cell research in the state. Fortunately, some progress has been made that may limit the negative impacts of such legislation.
In 2007, Japanese researchers demonstrated that human somatic cells could be converted into induced pluripotent stem cells by transducing four specific genes that code for transcription factors. Like embryonic stem cells, induced pluripotent stem cells can differentiate into virtually any type of human cell, which makes them potentially useful in regenerative medicine. But converting somatic cells into induced pluripotent stem cells has proven to be very challenging. In early experiments, the rate at which targeted somatic cells were converted to induced pluripotent stem cells was extremely low: between 0.01% and 0.1%. This, and the fact that induced pluripotent cells divide less rapidly than embryonic stem cells, makes it difficult to generate induced pluripotent stem cells in quantities large enough for clinical use. The introduction of transcription factors in the conversion process also makes induced pluripotent stem cells more likely than embryonic stem cells to mutate and cause tumors if inserted into a patient for therapy.
Recent advancements have significantly reduced mutation risks and have improved the efficiency of somatic-to-stem cell conversion, but embryonic stem cells remain the gold standard in terms of differentiation ability, and are thus the most widely applicable for disease research, drug discovery, and regenerative medicine. As long as embryonic stem cells offer benefits that induced pluripotent stem cells do not, members of the science community ought to continue to be vigilant in their fight for funding and legal support of embryonic stem cell research.
The medical applications of stem cells have been known for decades, well before they were isolated from human embryos. Since 1968, hematopoietic (blood-generating) stem cells derived from bone marrow have been used to restore blood cells destroyed during the treatment of certain cancers, like leukemia and lymphoma. This is currently the only widely practiced form of stem cell therapy. These stem cells can also be found in umbilical cord blood, but since very few people have their umbilical cord blood preserved at birth, stem cells must usually be extracted from the bones of a healthy donor that is immunologically matched to the recipient. As such, this form of stem cell therapy faces many of the same problems as organ transplantation, like donor shortages and harsh immunosuppressive drugs.
Despite the dearth of clinical stem cell applications currently in use, the National Institutes of Health believes that stem cells still have a lot of potential, stating that researching them could lead to “new treatments and possible cures for many debilitating diseases and injuries, including Parkinson’s disease, diabetes, heart disease, multiple sclerosis, burns and spinal cord injuries.” They go one step further to say that stem cell use in regenerative medicine “empowers scientists to grow tissues and organs in the laboratory and safely implant them when the body cannot heal itself” and “has the potential to solve the problem of the shortage of organs available through donation.”
Some of these optimistic predictions have proven to be true; several stem cell therapies are now out of the lab and undergoing clinical trials, including Prochymal for Crohn’s disease, MyoCell for improving cardiac function after severe heart attack-related heart damage, and ELAD for liver failure. Clinical implementation of these stem cell therapies may be only years, if not months, away. In the last few years, many simple tissues have been bioengineered with biocompatible materials, seeded with stem cells, and inserted into patients. In 2013 at the Children’s Hospital in Illinois, a 2½-year-old girl born without a trachea became the first patient to receive a bioengineered trachea in the United States. Regenerative medicine specialist Dr. Paolo Macchiarini worked with a team of researchers to create the trachea by bathing a tube of biodegradable plastic fibers with the young girl’s own stem cells and implanting it without the use of harsh immunosuppressive drugs.
Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, has also utilized stem cells to bioengineer simple organs. Recently, he has been investigating the potential of 3D bioprinting, which involves stocking a three-dimensional printer with human stem cells to “print” tissue that can be used to repair damaged or diseased organs. Dr. Atala has become a celebrity of sorts in the regenerative medicine and 3D bioprinting fields. He has made dozens of press appearances and has given multiple TED talks on the subjects; in his 2011 talk “Printing a Human Kidney,” he spoke about the potential of regenerative medicine while an on-stage 3D bioprinter constructed what appeared to be an exact replica of a human kidney. At the end of his presentation, he revealed the finished product in his hands — as if it were ready to be placed into a patient that afternoon — to the audience’s thunderous applause.
The presentation was certainly dazzling, but also very misleading. Dr. Atala had not created anything close to a functional human kidney; it was simply a kidney-shaped biocompatible lattice stocked with human cells. Since it did not contain any of the kidney’s complex inner structures, it could not have completed any of the organ’s functions. In the recording of the video later posted online, TED added a disclaimer to inform the viewer that the printed kidney was merely an early experimental prototype “years away from functional and clinical use,” something that Dr. Atala conveniently left out of his presentation. Yet his seemingly miraculous demonstration defined the field of regenerative medicine in the media; dozens of articles were written about the feat, including one by The Independent entitled “Surgeon creates new kidney on TED stage.” The article (which has since been retracted) praises Dr. Atala for his ability to print “a real kidney using a machine that eliminates the need for donors when it comes to organ transplants.” As other labs have experimented with the technology, the 3D bioprinting hype has continued to grow.
3D bioprinting has certainly progressed in ability and sophistication in recent years, and it has been used with much success for a variety of medical applications, including customizable prosthetics and joint replacements. Even simple tissues like bone and cartilage have been successfully 3D bioprinted and transplanted. But the NIH’s belief that regenerative medicine could completely solve the problem of organ shortages is quite far-reaching. Printing complex organs and getting them to integrate with the body’s blood supply is likely decades away from reality. Today’s 3D bioprinters simply do not have the precision required to generate the varied and intricate patterns that allow organs to carry out necessary metabolic and circulatory functions.
The biggest challenge of organ regeneration is replicating the human vascular system, which supplies the nutrients and oxygen that organs need to survive. Organs contain a network of long, thin capillaries arranged so that every organ cell is no more than a few micrometers away from blood supply. These complex vascular networks are exceptionally difficult to print, but without them, cells starve of nutrients and oxygen, and have no means to excrete waste, resulting in their death and the death of the organ. Even if 3D bioprinters become sophisticated enough to print completely vascularized organs, the process would likely never be feasible for emergency organ transplants because of the time required for production. For example, even when constructing a simple heart valve, bioprinted cells require several weeks of incubation to grow and strengthen in order to function and withstand the high pressures of the human circulatory system. An entire organ would presumably take even longer to print and develop.
But despite what media hype may have led some to believe, regenerative medicine is not limited to just the problem-ridden process of 3D bioprinting. In 2012, a research team from the Massachusetts General Hospital in Boston demonstrated a much more feasible technique called recellularization that may both ameliorate the shortage of compatible donors and eliminate the need for harsh immunosuppressive drugs – two of the largest problems of organ transplantation. The researchers used an organic detergent to remove the cells from cadaveric rat kidneys, while retaining important extracellular matrix components. They then replenished these extracellular matrices with stem cells and neonatal kidney cells from the rat that was to receive the transplant. Within days, the cells differentiated into the correct types required for specific regions of the kidney. When these “regenerated” kidneys were transplanted into living rats, they integrated with the rats’ circulatory systems and successfully mimicked kidney function by filtering blood and discharging urine. Since the kidneys were free of the cadaveric rat’s cells, there was no need for immunosuppressive drugs, and little risk of organ rejection.
The research team hopes to try this recellularization technique with human kidneys soon. This method of organ regeneration requires organ donors, so it doesn’t have quite the appeal of 3D bioprinting. But since the process doesn’t require creating a complex vascular system from scratch, it is much more feasible, and still eliminates the need for donor immunocompatibility. This means that a patient in need of an organ transplant could receive one from virtually anyone of similar body size, which would greatly expedite the organ matching progress, and prevent thousands of unmatched donor organs from being discarded every year.
It is very easy to be seduced by ideas as exciting as printing out new human organs. While 3D bioprinting may appear to be an elegant solution to the organ shortage problem on paper or on a TED talk stage, the future of regenerative medicine may lie in a more feasible (albeit less glamorous) process like recellularization. It sometimes pays off to invest in technologies with little chance of success, but we must remember to realistically assess medical innovations’ current limitations while optimistically recognizing their future potential. If time, money, and energy are allocated to ideas with a chance of practical results in the near future, regenerative medicine has the potential to drastically improve the quality of life for the 122,000 Americans currently in need of an organ transplant, and for the millions of others suffering from degenerative diseases.
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