Scientists seeking to combat the nation’s No. 1 killer have discovered why experiments using cell transplants to repair damage from a heart attack wind up backfiring and causing life-threatening arrhythmias.
“I don’t think this is science fiction that’s decades or centuries away,” said Michael Laflamme, a professor at the University of Toronto and senior scientist at the University Health Network. “It’s happening already.” Laflamme, who was not an author on the paper, praised the researchers for finding “a viable path” toward overcoming the dangerous irregular heartbeats. That path uses cutting-edge gene editing to replace dead heart cells with new ones engineered to reduce arrhythmias.
In a typical heart attack, the organ loses about one quarter of its 4 billion cells, said Charles Murry, who led the study and directs the Institute for Stem Cell and Regenerative Medicine at the University of Washington.
Even when we are fortunate enough to survive a heart attack, we’re thwarted by our own biology. The human heart is able to regenerate at birth, but loses the capacity soon after for reasons that aren’t fully understood.
Lacking the power to regenerate, the heart instead replaces dead tissue with a stiff scar that makes it harder for the organ to pump. As a result, the flow of oxygen to the heart slows, starting a deadly cycle that climaxes when “the heart cannot adapt to meet the circulatory demands of the body,” Murry said.
The team at the University of Washington created special cardiomyocytes — heart muscle cells — with four altered genes and implanted millions of them in Yucatan minipigs, hairless animals that weigh about 110 to 120 pounds. The MEDUSA cells, named after a character from Greek mythology, attached themselves to the pig heart, beat in sync with existing cells and cut arrhythmias by 95 percent. The arrhythmias that did occur were over much faster.
Researchers have long pursued cell transplantation as a possible treatment for heart disease, which kills about 700,000 Americans each year, accounting for one of every five deaths.
“My mother died of heart disease,” Murry said. “I use as a benchmark, ‘Would I have put these in my mother?’ ” Asked if the new cells met his standard, he said, “Knowing how they perform in the pig heart, yes. I would have put them in my mother.”
Identifying the culprit
The University of Washington team discovered that cardiomyocyte injections cause arrhythmias because the cells are immature, so they fail to harmonize with the heart’s electrical system and force the organ to beat too quickly.
To address these flaws, the scientists started with human embryonic stem cells, which have the potential to become any of the 200 different cell types in the body. Researchers conducted experiments to determine the genes most likely to play a role in the arrhythmias.
They altered different combinations of those genes in stem cells, which they then grew into heart muscle cells. The scientists tested the combinations to determine which caused the fewest irregular heartbeats. The best combination ― subtracting three genes and adding one ― minimized arrhythmias, though it did not get rid of them entirely.
“It’s an important contribution to the field to have identified the culprit in the arrhythmias,” said Wolfram-Hubertus Zimmermann, director of the Institute of Pharmacology and Toxicology at University Medical Center in Göttingen, Germany. “It’s clearly notable that the previously observed massive arrhythmias were not seen, but the problem is not fully solved yet.”
Murry said his lab is probably two years away from testing cell injections in a clinical trial.
Researchers at Stanford Hospital in Palo Alto, Calif., and in Germany, Japan and China have already launched clinical trials of different cell treatments aimed at repairing damage to the heart. Some involve injecting cardiomyocytes into the heart wall, others require suturing patches made from cells directly onto the heart.
The main advantage to injecting heart muscle cells is that the procedure would not require open-heart surgery. A patch would. The main advantage to the patch is that more of the transplanted cells survive, said Nenad Bursac, a professor of biomedical engineering at Duke University, whose lab has done extensive work with patches.
Injected cells die at a greater rate because they’re detached and unable to receive survival signals from neighboring cells. Also, when the cells are first implanted into the wall of the heart, they start off without an oxygen-delivering blood supply.
Economic head winds
Serious obstacles must be overcome before Murry’s technique could be used in people. Even the greatly reduced number of arrhythmias could still prove fatal for a patient recovering from a heart attack.
Moreover, the five pigs implanted with MEDUSA cells had not sustained heart attacks. The injected cells, as a result, had less chance of causing irregular heartbeats and were not required to repair damaged tissue. Also, some researchers not involved in the study expressed concern that too much editing of the genes in heart cells poses a risk of triggering cancer, or interfering with the vital functions the cells perform.
“Because we went through all of these gene edits, the question we’re now answering is, ‘What if we compromised the cells too much?’ ” said Silvia Marchiano, a postdoctoral fellow in Murry’s lab who worked on the project for five years.
One of the genes edited out in MEDUSA cells ― SLC8A1 ― “can impact the ability of heart cells to contract,” said Timothy Kamp, director of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin at Madison. Still, he added, “I think the concept of editing these genes is powerful. Perhaps a simpler combination [of edits] may work.”
Kamp said that the ideal solution would involve developing an off-the-shelf line of cells that could be used by a wide group of patients, but without requiring them to take immune suppression medications. The medications are needed to stop the body’s immune system from identifying injected cells as foreign and attacking them.
“The arrhythmias are one of the key roadblocks. The investigators conducted an important study but will need to test more animals to show these genetically modified cells do not cause irregular rhythms and can improve heart function,” said Joseph Wu, director of the Stanford Cardiovascular Institute.
Wu is leading a clinical trial in which nine to 18 heart-attack patients will receive a catheter injection of heart muscle cells; these have been grown from human embryonic stem cells and have not undergone gene editing. Patients will be given a drug to prevent the life-threatening arrhythmias.
Scientists have learned to reprogram a patient’s own cells, avoiding the controversy surrounding embryonic stem cells and eliminating the threat of rejection by the immune system. But Wu and his colleagues are not using that technique for the clinical trial. Creating reprogrammed cells would take months longer and cost far more money, Wu said.
No matter the approach, the challenges involved in heart regeneration are not just scientific, but also economic. Studies involving large animals must come before clinical trials, and they are costly.
Sana Biotechnology, the company at which Murry was a senior vice president, cut its Cardiac Cell Therapy program in December. The company’s stock had plunged, he said. (Murry no longer works at Sana Biotechnology.)
“What does this say about financial obstacles?” Murry said in an email. “It says the market is terrible right now and it’s hard to raise money. Scientifically, we’ve got this. Our program is better than ever, and we’ve made new breakthroughs since the MEDUSA discovery.”
