Reversing brain death: Far-fetched or feasible?

From gene editing to human head transplantation, the limits of medical science are being pushed further than ever. And now, researchers have turned their attention to another extraordinary mission: reversing brain death.

Though it sounds similar to the makings of fiction, scientists have received approval for the first ever trial that aims to restore neuronal activity in humans who have been declared brain dead.

The proof-of-concept study - which forms a part of the Reanima Project - is the brainchild of two life sciences companies: Bioquark, Inc., based in the United States, and Revita Life Sciences, based in India.

Due to begin later this year, the trial will recruit 20 individuals who have suffered brain death as a result of traumatic brain injury (TBI), but whose bodies are biologically alive as a result of cardiopulmonary and trophic support - a model referred to as a "living cadaver."

To participate in the trial, each subject must be aged between 15 and 65 years, be unwilling for organ donation, and have written consent from a legally acceptable representative.

Researchers - including Bioquark CEO Ira Pastor - will test a variety of techniques that previous studies have demonstrated to possess neuroregenerative properties, and these will be combined with devices that have been shown to stimulate the central nervous system of coma patients.

Using this "combinatorial approach," the researchers hope to move subjects from a brain dead state into a coma state, effectively bringing them back to life.

Unsurprisingly, the proposal has been met with much criticism. Last year, an article published in the journal Critical Care - penned by researchers Ariane Lewis and Arthur Caplan of the New York University Langone Medical Center in New York City - claimed that the trial has "no scientific foundation" and "borders on quackery."

Pastor's response to such criticism? "A hundred years ago they said the same things about cardiopulmonary resuscitation and organ transplantation - now look how far we've come."

We take a closer look at the science behind Pastor and team's project and ask, "Is it really feasible to bring someone back from the dead?"

What is brain death?

Defined as the "irreversible loss of all functions of the brain, including the brainstem," brain death occurs as a result of brain injury. This may occur through TBI, stroke, or the loss of blood flow or oxygen to the brain.

Brain death is defined as the complete, irreversible loss of all brain function.

Brain death is a legal definition of death; once brain function ceases, the body is no longer able to perform activities that are crucial for our survival, such as breathing, regulation of heartbeat, and swallowing.

To declare a person as brain dead, a physician must confirm a complete absence of brain reflexes - such as pupillary response to light and facial muscle movement - and the inability to breathe without ventilatory support. Other tests may also be required to confirm brain death.

Brain death should not be confused with coma. While a person in a coma is unconscious, parts of their brain are still functioning, and there is a possibility that their condition may improve.

Patients who are brain dead, however, are considered to have a complete loss of brain function, and there is no way to overturn this - yet.

Pastor and team believe that their controversial trial represents the first step toward the regeneration of neurons and the restoration of neuronal functioning in humans. In essence, they believe that they could one day achieve what most people perceive to be unachievable: restoring life to the clinically dead.

Attempting to reverse the irreversible

The clinical trial will involve a four-step approach. The spinal cords of the brain dead subjects will be injected with stem cells, which are cells that have the ability to differentiate into other cell types, including neurons.

"The stem cells - minimally manipulated, autologous, adult stem cells derived and expanded from patient fat and/or peripheral blood - will serve as some new 'bricks' in the regenerative process," Pastor explained to Medical News Today.

Subjects will also be injected with a peptide called BQ-A - derived from ooplasms, the cytoplasm of an egg, or oocyte - which Pastor told us will act as the "blue print" and "mortar" in the regenerative process.

Researchers plan to use a four-step approach to restore neuronal activity in clinically dead subjects.

As well as aiding neuronal growth, Pastor explained that the peptides will help to reprogram and recondition the surrounding tissue at the location where stem cells are injected, and they will also help to target and destroy components of dead tissue.

Once these steps are complete, median nerve stimulation techniques and transcranial laser therapy will be applied to each subject for 15 days, with the aim of spurring connections between the newly formed neurons.

"In short, it is our contention that there will be no 'single magic bullet' for success and any traditional single drug approach would be fairly futile. Hence why we are employing this type of 'combinatorial' approach," Pastor told MNT.

After the procedure, each subject will be continuously monitored in the intensive care unit. In particular, the researchers will monitor the patients' brain activity, pulse, blood pressure, respiration changes, and oxygen saturation.

"Our main hope is that this trial will show us that the 'gray zone' between deep coma and irreversible coma is indeed just that - 'gray,' and that, with the tools of 21st century regenerative medicine, that there are possibilities to push that transition in the opposite direction to save lives, as well as begin a new chapter in the treatment of the wide range of consciousness disorders - coma, persistent vegetative state, locked-in syndrome, etc.," said Pastor.

"Secondarily," he added, "we hope the trial will answer certain 'deeper' issues about the human mind."

A look at the evidence

Individually, each of the four techniques that Pastor and team plan to use in their trial have shown promise for improving brain functioning. Research indicates that stem cell therapy and transcranial laser therapy may help to repair brain damage.

Furthermore, studies have shown that median nerve stimulation can help to awaken comatose patients, while transcranial laser therapy has been found to improve recovery from neurodegenerative disease.

But are such studies enough to suggest that, when combined, these techniques can revive patients who have been declared brain dead? Some researchers have their doubts.

Is reversing brain death realistic?

"By definition, DNC [death by neurological criteria] requires irreversible cessation of all functions of the entire brain, including the brainstem. As such, the proposal that DNC could be reversible is self-contradictory," Caplan and Lewis wrote in their article last year.

Echoing Caplan and Lewis's comments, Dr. Dean Burnett, a neuroscientist at the Centre for Medical Education at Cardiff University in the United Kingdom, told The Telegraph, "While there have been numerous demonstrations in recent years that the human brain and nervous system may not be as fixed and irreparable as is typically assumed, the idea that brain death could be easily reversed seems very far-fetched, given our current abilities and understanding of neuroscience."

Some researchers say that the idea of reversing brain death is 'far-fetched.'

Responding to such denunciation, Pastor told MNT that there have been numerous reports of spontaneous brain death reversal in scientific literature in recent years. He pointed us toward the case of a 10-month-old boy who, after being declared clinically brain dead, began breathing 15 hours later.

"Although controversial, hotly debated, and resulting in poor prognoses, we believe such cases highlight that things are not always black or white in this area of severe disorders of consciousness, and provide important clues for further investigation," said Pastor.

Pastor and team are far from surprised by the criticism their project has received. "[...] being something that has never been attempted and at the very far end of the disorders of consciousness spectrum, it seems a 'very far-fetched' project to many - although not to all - and this is indeed true."

"However, the 'very far-fetched' criticism is one we have anticipated from the neuroscience community, and frankly it has been quite fun when we sit down to explain our ideas and convert these folks to the 'Wow. That is still far-fetched but you may be on the right path to get it done, eventually.'"

The issue of ethics

Other concerns that researchers have raised about the trial are of an ethical nature. Following on from their comments that brain death reversal has "no scientific foundation," Lewis and Caplan wrote, "The suggestion that DNC could be reversed provides families of brain dead patients a cruel, false hope for recovery. This is especially so for families that believe in reincarnation."

Pastor strongly refutes this claim and says that it could be argued that even approved medications are offering "false hope."

Critics say that the trial is offering 'false hope' to the families of brain dead patients.

"Why? Because we know that based on the inclusion/exclusion criteria of our registrational clinical trials - combined with the fact that, in 2017, we incorporate next to zero pharmacogenomic or, more importantly, toxicogenomic information in our study designs - that all of the 'disease output-targeted' drugs that eventually make it to the market will only work in a small percentage of their target population," Pastor told MNT.

"This is a widely acknowledged, but largely unspoken truth from the pharmaceutical industry - we are not offering false hope - it is just hope."

Another ethical concern involves the neurological state of trial subjects. The aim of the trial is to shift patients from a brain dead state into a state of minimal consciousness, or a coma. Some critics claim that reverting a patient to such a state is immoral.

"Aside from being in a sense a bit flattering, [this] translates to that we may succeed in transitioning a brain dead subject into a coma subject and, in doing so, we will have a) given the subject a poor quality of life, and b) added new costs to the healthcare system," Pastor told MNT.

"We find this critique ludicrous - [...] you can debate forever whether a dead person has a better quality of life than a coma patient - but to think that if we succeed at such a monumental scientific transition, that we would actually then stop, and not try to continue on with patients through the disorders of consciousness spectrum to an eventual state of wakefulness, is just silly," he added.

"And in a system that spends $7 trillion annually, we think that a few coma patients would not add significantly to additional burden."

'Brain death will be solved before cancer'

There is no doubt that Pastor and team's proposal is eccentric; in these modern times, when we have yet to find a cure for cancer, reversing brain death seems an impossible feat.

But Pastor strongly believes that such an achievement may not be as far away as many people believe. Talking to MNT, he noted that cancer and many other diseases are often caused by "multiple biological processes that interact in complex networks."

"Brain death - not to simplify it by any means - by comparison has only one ultimate, quite well defined end regulatory state, making it much easier for us to develop, target, or modify our methods towards a successful outcome," he said.

"Let's just say we believe that this first 'level' of brain death [...] will be solved long before cancer ever is."

Ira Pastor

If this first phase of the Reanima Project is successful, Pastor said that the team will then attempt to restore independent breathing and heartbeat to each patient. "Yielding a subject that is no longer technically dead anymore, the next step is continue on with patients through the disorders of consciousness spectrum, to an eventual state of wakefulness," he added.

Pastor and team hope that by this time next year, they will have conquered the first step toward making a seemingly impossible feat possible: bringing the dead back to life.