Stem Cell Research

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STEP ONE Patient’s own cells are collected with a skin biopsy.

STEP TWO Harvested skin cells are reprogrammed into stem cells, which are then “guided” to act like neurons.

STEP THREE MRI imaging directs injection.

STEP FOUR Reprogrammed cells are injected into the brain.

JANUARY/FEBRUARY 202 1 . D ISCOVER 49THE BODY

Researchers test more therapies with novel techniques for a range of diseases. BY KENNETH MILLER

FOR MORE THAN TWO decades, experts have prophesied that stem cells will someday revolutionize

medicine. While adult stem cells have long been

used to treat a handful of blood and immune disorders, the excitement has centered on two more versatile variet- ies: embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), both of which can be transformed into any cell type in the body. Google “the promise of stem cells,” and you’ll get at least 200,000 hits, involving ailments ranging from diabetes to neurodegener- ative disorders. So far, however, no one has managed to translate that potential into a practical therapy.

In 2020, a string of breakthroughs suggested that the revolution may finally be near. The most dramatic news came in May, when the New England Journal of Medicine published the first case report from a study using custom- grown stem cells to treat Parkinson’s disease in humans. The debilitating condition, which affects 10 million people worldwide, primarily results from the loss of neurons that produce the neurotransmitter dopamine. Existing treatments have had limited success. Stem cell researchers aim to replace dying neurons with healthy ones grown in the lab — and the NEJM paper was the clearest sign yet that such efforts could pay off.

The authors — led by neurosurgeon Jeffrey Schweitzer at Massachusetts General Hospital and neurobiologist Kwang-Soo Kim at McLean Hospital — used what are known as autologous iPSCs. These are stem cells generated

from the recipient’s own mature cells, which greatly reduces the likelihood that immunosuppressants will be needed to prevent rejection. The team collected skin cells from a 69-year-old man and reprogrammed them into iPSCs. They then guided the stem cells to take on the characteristics of dopaminergic neurons, which they implanted into the patient’s putamen, a brain region implicated in Parkinson’s. Over a 24-month period, PET scans showed evidence that the new cells were functional. The man’s motor symptoms and quality-of-life scores improved, while his daily medication requirement decreased. He experienced no side effects or complications.

“This represents a milestone in ‘personalized medicine’ for Parkinson’s,” Kim wrote in a statement. It also represented a milestone for the patient — George “Doc” Lopez, a physician- turned-medical equipment entrepre- neur, whose financial contributions to Kim’s research helped make the surgery possible.

Once a record-breaking free-diver, Lopez had severe tremors and rigidity before the implant; he could barely rise from a chair. Afterward, he was able to return to swimming and diving, and to perform such mundane tasks as tying his shoes. “Parkinson’s had me under a death sentence,” he says. “[The therapy] has not only changed my life, it has literally saved my life.”

Kim cautions that a single case study is

only a beginning. Much more research, including full-scale, carefully controlled clinical trials, will be needed to establish the safety and efficacy of his team’s tech- nique. “Nonetheless,” he adds, “I believe this study is extremely encouraging and informative.” He and his colleagues plan to launch such a trial by the end of 2022. Meanwhile, other human studies using iPSCs or ESCs are planned or underway at a handful of medical centers around the globe.

A “BRIDGE” TO A NEW LIVER Stem cells also demonstrated lifesaving powers for a 6-day-old baby in Japan who received the world’s first successful transplant of custom-grown liver cells. The child (whose sex has not been made public) was born with a urea cycle disorder, a genetic condition in which the liver is missing an enzyme that helps break down nitrogen into urea. Without it, ammonia builds up in the blood- stream with potentially fatal results. A liver transplant is usually needed, but it can’t be performed until the child is several months old — which may be too late. Liver cells called hepatocytes can sometimes be transplanted as a “bridge

treatment,” but supplies are scarce in Japan due to low rates of organ donorship.

Doctors at the National Center for Child Health and Development used ESCs to grow hepa- tocytes, then injected 190 million of them into the baby’s liver. In May, the team reported that the transplanted

DAWN OF THE STEM CELL REVOLUTION?

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STEM CELL RESEARCHERS AIM TO REPLACE DYING NEURONS WITH HEALTHY ONES GROWN IN THE LAB.

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cells had kept blood ammonia levels normal for six months, until the child received a liver transplant from its father.

FIXING FAILING HEARTS Some of this year’s news was more controversial. In January, a team led by Osaka University surgeon Yoshiki Sawa reported having carried out the first successful transplant of iPSC-derived cardiomyocytes — heart muscle cells — in a human patient. The recipient, who had cardiac-muscle dam- age from a blocked artery, was implanted with a biodegrad- able sheet holding 100 million of the cells as part of a small clinical trial. The researchers, who used allogenic iPSCs derived from a donor’s cells, planned to monitor the patient over the next year and eventu- ally try the procedure on nine more participants.

In May, however, a Chinese surgeon disputed that Sawa was first to perform such a transplant. Wang Dongjin of Nanjing Drum Tower Hospital told the journal Nature that his team had implanted two

men with cardiomyocytes derived from allogenic iPSCs a full year earlier. One patient, a 55-year-old electrician, said that before the surgery, he was constantly tired and out of breath; now, he could take a walk, use stairs and sleep for an entire night. 

Aside from which team won the race, both experiments leave big question marks. Although animal studies have shown promising results for iPSC-derived cardiomyocytes, Sawa doesn’t think implanted cells integrate with a recipi- ent’s heart tissue. Instead, he speculates, they may stimulate healing by releasing growth factors. If that’s the case, Sawa’s critics say, it would be safer to identify those regenerative proteins and administer them in a less risky way, like injection.

Wang’s experiment was muddied by the fact that both patients received heart bypass surgery along with their new cells. As University of Washington pathologist Charles Murry noted in Nature, “If you do two things to somebody and they get better, you can’t say which one caused it.” D

Doctors used embryonic stem cells, or ESCs, (left) to grow custom-made liver cells. Dopaminergic neurons (right), can be derived from induced pluripotent stem cells, or iPSCs.

A NEW TECHNIQUE has finally opened up one of the final frontiers of gene editing: the mitochondria. These are the mini- organs that power our cells and have a

little bit of genetic information of their own. Until now, the gene-editing tool CRISPR didn’t

work inside this part of the cell; CRISPR uses guide RNA to find its target, but RNA can’t get inside the mitochondria. Other gene-editing methods have relied on simply chopping apart mtDNA — the mitochondria’s DNA — rather than editing it. With this new tool, chemical biologist David Liu of the Broad Institute, Harvard University, and Howard Hughes Medical Institute has found a way to actually change the mitochondrial genome.

The new editing tool begins with a bacterial toxin known as DddA, discovered by microbiologist Marcos de Moraes at the University of Washington School of Medicine. The toxin kicks off a reaction that turns one nucleotide — the building blocks of DNA — into another. When done randomly, the change can be deadly for a cell. But the researchers were able to harness this ability to make targeted gene edits.

The end result is “quite a Rube Goldberg-like protein,” Liu says. The gene editor has many protein parts, including one that delivers the editor inside the mitochondria, one that indicates which gene to target and one that helps increase the efficiency of the edits. And there’s the toxin itself, which edits the nucleotide.

Key to the process was finding a way to deactivate the toxin while it passes through the cell, to make sure it doesn’t do any unintended harm. The team achieved this by splitting the toxin in half; once inside the mitochondria, the two parts reform at the site of the intended gene edit in a process pioneered by Beverly Mok, a graduate student in Liu’s lab.

The gene editor currently has a few limitations. For example, it only works on specific nucleotides. Liu says his lab is studying other toxins that might expand the editor’s capabilities. He also hopes to improve the efficiency rate of the edits, which is about 50 percent at best. Current limitations aside, the tool’s precise edits will allow scientists to study mitochondrial diseases in the lab like never before — and perhaps one day even cure them. D

There’s a mini second genome inside your cells, but no one could figure out how to edit it — until now. BY NATHANIEL SCHARPING

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EDITING THE MITOCHONDRIA