[Junk Sciences] Is reviving brain dead patients with stem cells a scientific breakthrough or just another Dr. Frankenstein Monster fantasy?

I am sure that everyone heard about that clickbait headlines that run over on social media, with viral posts and videos proposed by a company named “Bioquark” (US) in association with another company named “Revita Life Sciences” (India). Among some websites that have reported that information, I decided to share the article posted by Futurism earlier this week:
http://futurism.com/brain-dead-brought-back-life-thanks-new-biotech-experiments/

Of course, my first reaction was surprise and shock. Surprised because no one came as far to make a claim on resurrecting dead people.  Oh well, not surprised if you look at fictions they only time I heard people resurrecting dead were with various methods including electrical energy (Frankenstein’s Monster), trioxin 245 (Return of the living dead), cybernetic implants (Robocop) or some classified scientific methods codenamed “Lazarus project” (Mass Effect 2).
Because with extraordinary claims comes extraordinary proof and evidence. Usually this does not end up very well and usually ends up flat like an underbaked souffle. Just see the epilogue of Theranos and remind yourself to never sell the bears hide before killing it.

What is being “brain dead”?

Brain death is defined according to the Merck Manual by “a loss of function of the entire cerebrum and brain stem, resulting in coma, no spontaneous respiration, and loss of all brain stem reflexes. Spinal reflexes, including deep tendon, plantar flexion, and withdrawal reflexes, may remain. Recovery does not occur.”  (source: http://www.merckmanuals.com/professional/neurologic-disorders/coma-and-impaired-consciousness/brain-death).
This definition is very important as it is inclusive of both absence of cortical function as well as vegetative functions emanating from the brain stem. Brain stem is an important nervous structure that controls all the vegetative functions including control of the respiration, bowel movements, blood pressure, pH and smooth muscles activity. When a patient in such condition, this is a point of no-return. There is virtually no chances patient recover. The patient seems alive because the patient is on respiratory aid and still has the heart beating. The heart will keep pumping as long it is properly perfused with oxygen and nutrient.
One test to assess the brain status of a patient in comatose stage is to assess its ability to breath by its own. This is what we refer the apnea test. The human body is designed that it will by survival reflex induces breathing even when we force apnea. In these patients, the loss of brain stem viability will fail to induce this respiratory reflex.
In the case of this news, we will have to look at the application packet submitted to the NIH clinicaltrials.gov portal that can be consulted here.

According to the application, the companies have in their inclusion criteria:
Individuals declared Brain dead from a traumatic brain injury having diffuse axonal injury on MRI Not willing for organ donation
Written informed consent from the legally acceptable representative of the patient

This is an important criteria for ethical standpoint, because these volunteers fall into the uniform anatomical gift act (http://www.uniformlaws.org/shared/docs/anatomical_gift/uaga_final_aug09.pdf).

Because they can considered as anatomical gift, there is little or no of the ethical issues commonly raised with living and healthy patients, that require absolutely an institutional review board (IRB).
In the press release, the company  or companies as it involves Bioquark and Revita Life Sciences claim they receive approvals from the Institutional Review Boards and by the National Institute of Health to perform their experiments on volunteers that donated their bodies to science and that refused to sign as potential organ donors.
It is also important to note this trial will be performed outside the United States, especially held into the Anupam Hospital, Rudrapur City, Uttrakarand State in India (based on the email address of the collaborator listed on the trial).
This is an important issue to raise, as we have these trials performed in India. India has currently a fairly laziest policy in terms of ethics in biomedical research as raised recently by an article in the World Health Organization (WHO) referenced here: http://www.who.int/bulletin/volumes/86/8/08-010808/en/.

Although running experiment on clinical dead persons is by itself not an ethical violation as long as the body is utilized and treated following medical and ethical consideration, we cannot however fully guarantee that these donors and their relatives have provided their consent into a fully informed and without any financial incentives.

What is the science behind the trial?

The second issue that I have with this study is the science behind it. In their application, the authors listed the outcomes as the following:

Primary Outcome Measures:

  • Reversal of brain death as noted in clinical examination or EEG [ Time Frame: 15 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • Cerebrospinal fluid (CSF) analysis of color consistency, cell counts, and microbial evaluation [ Time Frame: 15 days ] [ Designated as safety issue: Yes ]
    To signify any signs of aseptic or bacterial meningitis
  • MRI analysis to analyze any changes in meninges [ Time Frame: 15 days ] [ Designated as safety issue: Yes ]
    To signify any signs of aseptic or bacterial meningitis
  • Pulse [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • O2 saturation [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Blood Pressure [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • Respiration changes [ Time Frame: 15 days ] [ Designated as safety issue: No ]

The idea of resurrection the clinical dead and the reality of the experiment is way different and definitely less eye-catching and sensationalized. The paradigm consist of implementing stem cells inside the brain and assess the presence of a re-establishemnt of an electrical activity as measured by an EEG.
Several studies has documented protocols to differentiate human pluripotent stem cells (including embryonic and induced pluripotent stem cells) into neurons capable of physiological activity, in other terms of capable to general an action potential or in other words electrical activity.
The first issue I have in this case, where, when and what of stem cells will be used are never mentioned, either on the press release or on Bioquark Inc. presentation slide.
The second issue I have is about the credentials of the investigators, Dr. Himanshu Bansal. By submitting a query on Pubmed with the keyword “Bansal H Stem“, we have only four results listed with two directly relevant studies published in the Journal of Stem Cells. Such journal is published by Nova Science Publishers, a predatory publisher as reported by Scholarly Open Access. Add to it there is no Thomson-Reuters ISI impact factor listed raise the question is this journal is legitimate or will publish anything as long as you give them a valid credit card number. Remember the adage “garbage in, garbage out

Things are even more murky when you visit Dr. Himanshu Bansal webpage and the tab about his stem cell results. For information, this is a screenshot of the page:
BansalStemCell

This is fairly impressive yet highly questionable when someone boast such claims without linking to the literature, considering that until now there is NO FDA approval for stem cell treatment.

If it looks like a quack and sounds like a quack

Now things are getting suddenly sour and fishy. The more we dive in and the more things are looking. Now one criteria I consider important for assessing a reliability of a startup biotech is its portfolio and if not the quality of the data presented. This is not looking good either.
Unfortunately, Bioquark has little to show and have rather laconic statements, no published studies, no data demonstrating the activity of their drug candidates nothing. For my standpoint, I am always skeptical when I see a biotech company making a living on cosmetic and beauty products, as seen on their page:
BioquarkCosmetics.png

This is raising already some issues about the company credential, I am not even talking about Revita Life Sciences. Both company have such a horrible web design but also looks a lot like websites I commonly label as “quackery”, especially the second website. Having on the frontage treatment like “Naturopathy, Bioactive Molecules, Laser Stimulation, Ayurveda….”. If it sounds like a quack and looks like a quack…..

Now, if you pay attention to the Slideshare, the quality of the data is simply horrible and just look like a botched data. One thing that particularly caught my eye was this slide:
BQA_Melanoma

The gold standard in cancer research using mouse models is the xenograft model in which you inject sub-cutaneously human cancer cell line and follow the growth of the tumor like in this study.
f1-large1

In their study, rationale of injection of tumor in the paw is never mentioned, not even mentioning the questionable quality of the pictures, with the identification number changing over time in terms of quality. Indeed the paw seems to display an edema as shown in an another study. Edema is a swelling of connective tissue due to various reasons. In that case, I question whether the authors injected some vital dye (Trypan blue or Evan’s blue) into the paw with a volume enough to induce an edema and allow it to resorb over time, as seen in a study found online.
If I was an investor at this point, I would run away from this project.

Conclusion
To conclude on this breaking news that has its weight of clickbait, I sincerely raise questions and skepticism on that study that boast to revigorate patients that are clinically dead. There are a lots of smoke screen, an outcome that is very limited with very or little significance in terms of science. Here are my major concerns about that experiment:
1. 
There are no data from preclinical studies done in animal models to support the information proposed for the clinical studies. This is contradicting the common scientific process in which we transition from the bench to the bedsides.
2. The outcome measured as proposed in the NIH application package is much less extraordinary that the claim posted on mainstream media. That is fine but really raises the relevance of this study. Stem cells may be able to survive and differentiate in the brain parenchyma to an extent they can generate electrical activity measurable by EEG. However, there is virtually no chances these cells will provide an axon rewiring capable to result in functional activity. So no zombies.
3. There is a lot of smoke screen in terms of the experimental paradigms. We don’t know which stem cells will be used, where such stem cells will be implanted and how they will address the outcomes beyond the EEG. It sounds impressive in terms of science but once we think on how this advance our current knowledge, we are dropping short. We are ending up with a similar outcome than Dr. Frankenstein monster: it sounds very impressive and defying but the relevance of the monster was virtually none.
4. Finally, the public data and the lack of credentials of both companies and the investigators in terms of experimental data, peer-reviewed studies quality and records and the tendency of both companies to rely on healthcare products if not on alternative medicine as a source of revenue is sincerely raising questions on the ability of these companies to deliver. In particular, some claims of therapeutical success of Dr. Bansal on treating neurological diseases using stem cells are highly questionable as there is until now no evidence or approval by the FDA for any stem cell treatment beyond bone marrow stem cell transplants for patients suffering from leukemia.

 

 

 

 

 

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