Though met with the inevitable zombie jokes — in part because the human research subjects are officially categorized as “living cadavers” — a new reanimation study of brain death has many compelling and hopeful aspects to its principal investigator in India and biotech sponsor in the U.S.
“As someone who started my career in orthopedic traumatology and who has ventured into neurology, spinal cord injury, and regenerative medicine due to the related overlap between the disciplines, this represents a unique opportunity to explore interventions in the most serious of central nervous system [CNS] indications: brain death,” says Himanshu Bansal, MD, who is conducting the research at Anupam Hospital in Rudrapur, India.
In an email interview with IRB Advisor, Bansal says he is in the process of recruiting 20 human subjects from area hospitals between the ages of 15 and 65 that have been declared brain dead from a traumatic brain injury having diffuse axonal injury — one of the most common and devastating brain traumas — on MRI. The living cadavers must not be indicated for organ donation, have no cranial implants, and cannot be pregnant.
“Patients will be recruited through neuro-intensivists and through family introductions at regional ICUs in the northern India area,” he says. “We have created a special long-term acute care unit at the Anupam facility where the patients recruited for the study will be transported and placed.”
Sponsored by Bioquark Inc. in Philadelphia, the study is registered with the National Institutes of Health as a clinical trial but it has IRB approval only to be conducted in India. The study will use a variety of interventions from stem cells, biologics, laser therapy, and nerve stimulation to see if there are any favorable signs for brain regeneration. There is no expectation that any patient will be brought back from brain death in this initial research.
“There have been a lot of zombie jokes, but we’re not near that at this point in time,” says Ira S. Pastor, BS, MBA, Bioquark CEO and director of the affiliated ReAnima Project. “We do not anticipate any reanimation event in terms of someone jumping up and walking around the ICU.”
Quest for Fire
Instead, the investigators are looking for the stir of a spark — any signs of neurogenic or vasculargenic activity that could mean formation of new neurons or blood vessels where there was no pre-existing activity in the brain stem.
“We are sort of taking a step with this living cadaver model to merge together biologic tools that have been used in neuroregenerative medicine and some of the same tools that are basically used in the ICU to try to wake up coma patients,” Pastor says.
The study is registered on ClinicalTrials.gov as a “Non-randomized, Open-labeled, Interventional, Single Group, Proof of Concept Study With Multi-modality Approach in Cases of Brain Death Due to Traumatic Brain Injury Having Diffuse Axonal Injury.” (http://1.usa.gov/25JIxNi)
The primary outcome measure is reversal of brain death as noted in clinical examination or by electroencephalogram (EEG) test to detect electrical activity of the brain. The time frame is six weeks, and of course the patients will have to be kept on life support to allow the study to proceed over that period. As approved by an IRB in India, informed consent must come from family members of the research subject. Depending on the results, some families may be asked if they would like to continue into a second phase of the trial.
“The IRB was quite open to the study design and ethical dynamics surrounding such research, [allowing] informed consent to be supplied by family members,” Bansal says. “Families that have contacted us to date realize and understand that this is much more of an early stage, exploratory research endeavor at this point. It is not easy to recruit for, but we are not promising miracles as a result of this first study. This is a basic open label design and all patients will be given the same set of interventions.”
Secondary outcome measures include analysis of cerebrospinal fluid for color consistency, cell counts, and microbial evaluation to signify any signs of aseptic or bacterial meningitis, pulse, O2 saturation, blood pressure, and respiration changes.
The study has been questioned for the perception of exploiting some regulatory loophole between the living and the dead. It certainly raises questions about the boundary between the two and invites contemplation of some utterly unknown aspects of consciousness. You cannot work with living cadavers in research that involves harvesting organs, but other than that it is an essentially new, unregulated frontier in both the U.S. and India, Pastor says.
Long-range, this line of research holds great promise for a variety of devastating conditions, Bansal says.
“This area has been quite off the radar for most pharma companies and healthcare institutions,” he says. “[This research] could potentially effect change that can apply to millions of patients with other disorders of consciousness, brain injuries as well as chronic degenerative conditions of the CNS.”
Salamanders and ‘Terminal Lucidity’
There are existing examples in nature that have regenerative powers unavailable to humans. For instance, the salamander can regenerate whole limbs and brain matter.
“We as a company are making the bet that [human] memory and mind will be recoverable,” Pastor says. “We base that assessment on many things, not the least of which is the fact that non-human species that go through complete brain regeneration can be trained to do something, and have their brains destroyed, only for the memories of the mind to come back. We are really trying to mimic what happens, for example, when you cut out a brain of a salamander, how it reforms from the remaining tissue in the spinal column.”
We may think of the human brain as a static organ, but we are able to maintain function and memories over years while “burning up a 100,000 neurons in the course of day,” he says. “Then there are many conditions we don’t have answers to.”
Those include the bizarre but documented phenomenon of “terminal lucidity,” in which people with severe Alzheimer’s and other degenerative brain conditions astonish their caregivers by becoming completely coherent and communicative for a brief period before they die.
“We also cannot explain why we see consciousness in children who are born without a cortex,” Pastor says. “There have been cases in the literature in the past few decades of very young children who have been considered brain dead that have recovered. These are controversial and they never had a [documented] prognosis, but they show that when there is still an active neurogenic piece persisting, like in an infant, things aren’t as black and white as they seem.”