From spare parts to delaying old age—the promise and future of stem cell research

Since their first therapeutic human use in 1957, when Seattle physician and future Nobel laureate E. Donnall Thomas, M.D., attempted a bone marrow transplant to treat leukemia, stem cells—those miraculous collections of cytoplasm and nuclei capable of an astonishing amount of cellular transformation—have offered to medical researchers, doctors, and the public alike the prospect of curing intractable diseases and crafting a storehouse of spare parts to remedy all manner of tissue damage.

In 2006, buoyed by a combination of $10 million from the State of Connecticut and $80 million in university funds, Yale created its own Stem Cell Center (YSCC) at the School of Medicine and recruited Haifan Lin, Ph.D., a rising superstar in the research community, to lead the fledgling effort.

“Ten years ago, we began the center with a vision for what we might be able to do with stem cells, both in terms of medical applications and helping resolve the mystery of life,” says Lin. “I’m happy to tell you that quite a lot has been achieved on both fronts.”

More than 89 research groups from 23 departments are gathered under the YSCC umbrella, and their interests run the gamut from deciphering the fundamentals of stem cell biology to developing the best ways of using the cells to treat some of the worst human scourges, cancer and heart disease among them. Working with the highest of high-tech tools in laboratories dedicated to genomics as well as to growing, imaging, and manipulating what Lin calls “the mother of all cells,” scientists here are beginning to see these investments pay off. They now have the ability to make custom-tailored tissues and organs that, because they’re made from an individual’s own stem cells, are transplantable with much less risk of the body’s immune system attacking them and causing rejection.

“YSCC researchers have pioneered this approach to repair children’s broken hearts,” says Lin, highlighting work by Christopher K. Breuer, M.D., and Toshiharu Shinoka, M.D., who developed techniques in which stem cells harvested from the bone marrow of children born with heart ventricular or atrial defects could be reprogrammed to transform into new, fully functional blood vessels that were then used to repair the heart defects. (The two doctors now head the Tissue Engineering Program at Nationwide Children’s Hospital in Columbus, Ohio.)

This isn’t science fiction anymore

The first successful operation using such stem cell-engineered cardiac tissues took place five years ago at Yale-New Haven Hospital, and offshoots of the techniques are under investigation to develop other replacement parts, from sections of the brain to new lungs. “This isn’t science fiction anymore,” says Lin, noting that 400,000 people die each year from lung disease because, to a large degree, “there aren’t enough donors.”

Much of this progress, however, would never have been possible were it not for a fundamental breakthrough announced at the time the YSCC opened for business. In 2006, Japanese researchers demonstrated that such ordinary adult mouse cells as skin cells could be reprogrammed to become nearly as malleable as embryonic stem cells, and the same possibility was shown in human adult cells the following year. This discovery allowed researchers to work with stem cells that had not come from aborted fetuses, thereby avoiding the fierce ethical and moral debates. The ability to now use induced pluripotent stem cells—iPSCs, for short—however, has given Yale scientists an almost limitless supply of raw material for applied and equally critical basic investigations.

Reprogramming adult cells

The ability to reprogram an adult cell so that it functions like an embryonic one is “incredibly cool,” says Diane S. Krause, M.D., Ph.D., the YSCC’s associate director who works with bone marrow-derived stem cells to understand their involvement in the development of certain kinds of leukemia and how such cells might be used in therapies against cancer.

Krause, a professor of laboratory medicine, cell biology, and pathology, explains that while iPSCs have yet to make a jump into a hospital setting, there are at least a couple of scenarios—gene therapy and organ repair—on the horizon. In advanced cases of sickle-cell anemia, for example, doctors attempt to treat the condition with a bone marrow transplant that comes from a close relative of the sufferer. A cure is possible, says Krause, “but the patient is also very much at risk for graft-versus-host disease, which is serious and can be fatal. So what if you could take the patient’s own stem cells, correct the genetic defect that we know causes the disease, then induce them to make fixed copies that we could now transplant back? With such an autologous transplant, there would be little risk of graft-versus-host disease.”

In the case of a heart attack, adult stem cells from the organ could be induced to become, say, muscle cells that can be transplanted to regenerate new functional cardiac tissue instead of the scarring that now typically results when an infarct leads to oxygen deprivation and tissue death.

Another area in which stem cells could prove important involves the liver, particularly in the case of accidental or deliberate acetaminophen overdoses, which can kill enough cells to prove fatal. “The liver is actually really good at regenerating,” says Krause, “but there are some patients who have a transient problem with liver regeneration, and if they could just get enough cells to function until their own liver restores itself, they would be able to survive long term.”

An autologous transplant of iPSCs reprogrammed to become liver stem cells could, in theory at least, keep a patient alive long enough to enable the damaged organ to regain its functionality. All this, of course, is a promise for the future. “We know perfectly well that we can use iPSCs to treat acute liver failure,” says Krause. “But we don’t know how to make the cells become functional lymphocytes, how to get enough of them, and how to make sure they’re safe.”

The importance of basic research

That, says Lin, is where fundamental research comes in. “We realized early on that we didn’t fully understand the inner workings of stem cells, and without the knowledge of the molecules that make them tick and make them quiet, we would never be able to harness their power and come up with rationally designed therapies,” says Lin. “We’d just be guessing.”

Lin received his bachelor’s degree at Fudan University in 1982 in his native China, and a doctorate at Cornell in 1990. Starting in 1994 at the Duke University Medical School, Lin focused on a bold but risky research area: the vast stretch of the genome known as “junk DNA.” A small percentage of the human genome—some 26,000 genes—is known to make messenger RNA molecules that help code for proteins, says the researcher. “The rest was considered useless,” Lin explained, “but that turned out to be more because of technological limitations than reality. We just weren’t able to find where the genes were and how they might affect development in model species and in humans, so we dismissed them as unimportant.”

With improvements in molecular tools, including such revolutionary technologies as DNA deep sequencing, a gene-editing method known as CRISPR, and others being used and developed in the YSCC core laboratories, Lin and others discovered that this viewpoint was akin to saying that since most humans lived in cities, the countryside no longer mattered. It turned out that this so-called noncoding stretch of the genome mattered plenty. “Junk DNA is making millions of little RNAs that are very important for determining the fate of stem cells—for turning them on and off at the right time,” Lin explains.

Learn to hit the start button effectively, and the result can be a supply of spare parts. Learn to hit the stop button, and the result might be the medical equivalent of the Holy Grail: an effective cure for cancer. “Studying stem cells is not only important in regenerative medicine,” says Lin. “We believe that the fundamental insights we’re discovering will turn out to be crucial in creating a kind of personalized medicine that can treat malignancies.”

Current cancer treatment, of course, is brutal, since it can’t discriminate between actively dividing normal cells and their out-of-control counterparts. But Lin is working with some of his fundamental RNA insights on stem cell reprogramming and control to find medications and techniques to better diagnose and conquer breast cancer. Preliminary results from his lab suggest that the rogue cells responsible for metastatic disease can be stopped from migrating, and over the next decade, Lin feels that such studies may lead to the rational design of “very targeted, much less harmful” therapies.

Stem cell research may point to something even more astounding. “We are on the verge of learning how to protect the genome from being damaged, and this might enable us to figure out how to extend a healthy life for a longer time,” says Lin, suggesting that “old age” may, sometime in the not-too-distant future, need to be redefined. “We’re very excited about the progress we’ve made and the prospects of what’s to come. The whole field is undergoing evolutionary change, and Yale is an integral part of it.”