Nothing is as certain as death. Yet humans have come up with ways to push it further and further. The heart stops beating? Do CPR. The lungs fail? Use a mechanical ventilator. These techniques have saved the lives of millions. There is a point of no return, however: when the brain dies.
One company, Philadelphia-based Bioquark Inc., thinks it may be possible to push back on even that last step. Bioquark plans to launch a study to use stem cells and a slew of other therapies to bring a glimmer of life back to the dead brains of newly deceased patients.
The idea led to hundreds of chilling headlines and has met serious backlash from scientists and ethicists alike. While Bioquark’s proposed study may trigger ethical and practical concerns, experts do say advances in stem cell research and medical technologies mean someday brain injury could be reversible. Maybe (and that’s a big maybe) brain death won’t be the end of life.
“I agree stem cell technology in the neurosciences has tremendous potential, but we have to study it in a way that makes sense,” said Dr. Diana Greene-Chandos, assistant professor of neurosurgery and neurology at Ohio State University Wexner Medical Center. What doesn’t make sense, she says, is to apply stem cell research in complex human brains—very damaged ones—before animal studies have gotten far enough.
That’s why Bioquark’s proposed study, slated to take place in South America sometime this year, has caused such uproar in the science community. The team plans to administer therapies to 20 brain-dead subjects with the hope of stirring up electrical activity in the brain. The idea is to deliver stem cells to the brain and coax them to grow into new brain cells, or neurons, with the help of a nurturing peptide cocktail, electrical nerve stimulation, and laser therapy.
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“We are employing this [combined] approach, using tools that by themselves have been employed extensively, but never in such an integrated process,” said Bioquark CEO Ira Pastor.
One critique is that such a study could give false hope to families who may have a poor understanding of the severity and irreversibility of brain death, and confuse it with coma or vegetative state. “There are a lot of gray areas in medicine. And we should all keep an open mind. But we need to make sure we are not misguiding our patients,” said Dr. Neha Dangayach, attending physician in the neurosurgical intensive care Unit at New York’s Mount Sinai Hospital.
Pastor’s response to the criticism? The public is catching up to the idea of brain death. He’s also clarified that full resurrection is not the company’s intended goal—at least not yet. “We are not claiming the ability to erase death. We are working on a very small window, a gray zone between reversible coma and death,” he said.
Ethics aside, critics say there are practical problems with the plan. There is insufficient evidence behind Bioquark’s approach, they argue, and the way the study is planned does not sound realistic.
When the brain dies, inflammation and swelling run amok, the connections between neurons disintegrate, arteries collapse, and blood flow shuts down. “Once someone is brain-dead, you can keep them on the ventilator but it’s very hard to keep the organs from shutting down and the heart beating for more than a few days,” said neurologist Richard Senelick. “Nature is going to run its course.”
So, many scientists say Bioquark’s study may be a quixotic quest—on par with cryogenic brain preservation and head transplants. They may sound good in theory but are so impractical that they have little chance of success. Nevertheless, experts agree the quest does raise serious questions that deserve answers. Just what would it take to save a brain? Perhaps resurrecting dead brains is not in the realm of possibility…but what is?
Brain death and the cell ‘suicide switch’
There is an immense reward in pursuing brain regeneration. If it pans out, it could potentially save the lives of those who are injured in an accident or, more commonly, suffer extreme brain damage following a cardiac arrest or stroke. Every year in the United States, about 350,000 people experience an out-of-hospital cardiac arrest, according to the American Heart Association. Only about 10 percent survive with good neurologic function. Another 130,000 people die of stroke annually.
To appreciate the challenge of saving the brain, first look at what it takes to kill it. It was long thought that death occurs when the heart stops. Now we know that death actually happens in the brain—and not in one single moment, but several steps. A patient lying in a coma in an intensive care unit may appear peaceful, but findings from biochemical studies paint a much different scene in his brain: fireworks at the cellular level.
When neurons encounter a traumatic event, like lack of blood flow after cardiac arrest, they go into a frenzy. Some cells die during the initial blackout. Others struggle to survive in the complex cascade of secondary injury mechanisms, triggered by the stress of being deprived of oxygen. Neurotransmitters spill out of neurons in high concentrations. Free radicals pile up, burning holes in brain cell membranes. The pierced cells respond to the attack by producing more inflammation, damaging other cells.
Eventually, the stress response triggers apoptosis, or the process of programmed cell death. In other words, the cell’s “suicide switch” gets turned on. The cells die one by one until the brain ceases to function.
That’s brain death: the complete and irreversible loss of function of the brain. Doctors determine brain death by checking whether the patient's pupils react to light, whether he responds to pain, and if his body tries to breathe or has retained any other vital function of the brainstem, the part most resilient to injury.
“We have strict tests, because it’s a very serious question—the question of distinguishing life from death,” Dangayach said.
For brain damage at a much smaller scale, however, the situation could be manageable. Cutting-edge therapies are focused on this possibility.
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More neurons in a pill?
Stem cells have brought an exciting potential opportunity to the grim area of treating brain injury. Currently, there’s no FDA-approved stem cell-based therapy for brain problems, and experts suggest staying away from any clinic that offers such therapies. But that doesn’t stop researchers from being excited about the possibilities. Unlike in other parts of the body, cells lost in the brain are gone forever. Could stem cells replace them?
“That's a reasonable thing to ask,” neurologist Dr. Ariane Lewis of New York University said. Lewis is a strong critic of Bioquark’s approach, saying that the study “borders on quackery,” but she thinks stem cell research is promising for stroke recovery. “We have little evidence right now, and this is not a commonly employed therapy, but it’s a research question.”
Two regions in the adult brain contain stem cells that can give rise to new neurons, suggesting the brain has a built-in capacity to repair itself. Some of these cells can migrate long distances and reach the injury site.
In some injuries, the brain produces biological factors that stimulate stem cells. Researchers are working to identify those factors—with the aim of someday translating the findings into new drugs to boost a patient's own stem cells.
“If we can identify factors that stimulate these cells we could directly repair [the brain],” said Dr. Steven Kernie, chief of pediatric critical care medicine at New York Presbyterian Hospital, who is working on this research.
Other teams have been working on turning different types of brain cells into neurons. A team at Penn State University developed a cocktail of molecules that can convert glial cells, a type of brain cell, into functioning neurons in mice. The cocktail of molecules could be packaged into drug pills, the researchers said, perhaps one day taken by patients to regenerate neurons.
Another option: transplant new neurons into the brain. In a 2016 study, scientists successfully transplanted young neurons into damaged brains of mice. A real-life injury in the human brain is a much messier situation than a clear-cut lesion made in the lab. But eventually, such advances may translate into techniques to repair stroke damage.
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For diseases like Parkinson’s, in which a particular population of neurons is lost—as opposed to widespread indiscriminate damage—there have been several clinical trials with many more slated. Scientists in Australia are using brain cells of pigs as a substitute for lost neurons. Later this year, a Chinese clinical trial will implant young neurons derived from human embryonic stem cells into brains of Parkinson’s patients. And five more groups are planning similar trials over the next two years, Nature reported.
Approaches taken in Parkinson’s trials may be the most biologically plausible, Kernie said. If these trials are successful, they may pave the way for more widespread application of stem cells for treating brain diseases. “It’s not proven yet that it will work, but it’s something that's on the horizon.”
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