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One of the world’s leading experts on cellular therapies for traumatic brain injury (TBI), Dr. Cox directs the Pediatric Surgical Translational Laboratories and Pediatric Program in Regenerative Medicine at the University of Texas Medical School at Houston, as well as the Pediatric Trauma Program at the University of Texas-Houston/Children’s Memorial Hermann Hospital in the Texas Medical Center. He is the author of over 120 scientific publications and 20 book chapters and has served on scientific study sections/review groups for the NIH, American Heart Association, Veterans Affairs MERIT Awards, Department of Defense and Congressionally Directed Medical Research Programs. I recently sat down with Dr. Cox to discuss his ongoing, landmark clinical trial examining the potential of adult stem cells to treat children with severe traumatic brain injuries.
 
What is the incidence of traumatic brain injury in children?
 
TBI is the leading cause of disability and death in children and adolescents in the U.S., with the age groups at highest risk being 0-4 and 15-19 years old. Every year, 564,000 children in the U.S. are seen in hospital emergency departments for TBI and released, while another 62,000 require hospitalization as a result of brain injuries. (Source: Brain Injury Association of America)
 
What is the traditional course of therapy for children with such severe injuries?
 
In broad terms, the standard of care in the treatment of severe traumatic brain injury hasn’t fundamentally changed over the past 30-40 years. For injuries of this type, most neurosurgeons focus on blood clots and trying to control the inflammation that causes swelling. Ostensibly, they’re trying to mitigate against “secondary brain injuries,” the cascade of events that occurs after the primary injury. This is critical to control as the brain is encased in a rigid, bony compartment and thus blood flow to the brain can become compromised causing irreversible brain damage beyond the initial event.
 
How are you approaching the treatment of children with severe brain injury?
 
We have an ongoing Phase 2b clinical trial sponsored by the National Institutes of Health (the National Institute of Neurological Diseases and Stroke) that uses the child’s own bone marrow derived mononuclear cells, which are infused intravenously within 48 hours after a severe traumatic brain injury. Normally, after a severe TBI, a child will lose about 10 percent of the white matter in their brain. So, utilizing specialized MRI scans, we’re measuring the preservation of specific structures in the brain, early after the injury and again at six months. This is a double blinded, randomized study that will ultimately include 50 patients, some of who will get a placebo instead of their own cells. After 20 patients have been enrolled, the DSMB will evaluate the progress and safety of the study — we are on patient number 13.
 
How severe are the conditions of the children?
 
Children enrolled to date in the study range between the ages of 5 and 17. Their brain injuries are very severe, some of the worst any family could ever have to face. These aren’t concussions, which are mild brain injuries. These children come to us in a coma. They are the victims of car accidents and falls and sporting accidents (bikes, etc.). Given the nature of these injuries and the great stress they place upon loved ones, we become very close with these families over time.
 
What do you think is the mechanism of action at work here?
 
Many people assume we’re drilling a hole in the brain and administering the cells directly. But the cells are actually given intravenously to the children. In pre-clinical and animal studies, we showed that the cells can modify the body’s immune response to the injury itself and stimulate an anti-inflammatory reaction, even in the brain.
 
It’s truly a fascinating treatment and one that reflects how connected our brains are to the rest of the human body — how we’re a complete, integrated system. Once these cells are taken from the child’s body and administered to them, they sequester in the spleen, where they produce a host of molecules/cells/growth factors in distant organs, which then go on to influence the injured brain, especially in regard to inflammation. Overall, the decreased inflammation translates to preservation of brain tissue — and that’s what we are measuring with MRI in the trials.
 
What is your hope for the outcome of this trial?
 
We hope to see similar results in the Phase 2 study to those in Phase 1, wherein a safety trial indicated structural brain preservation. In that study (published in the journal, Neurosurgery in 2011), we noted that there was no decrease in the brain volumes of children with severe brain injuries, treated with their own bone marrow derived cells. Normally, there is a loss of about 10 pecent of this tissue over 6-12 months post injury. That stabilization post treatment led us to design the second trial around the idea of preserving brain tissue rather than a global functional outcome.
 
You’re also doing clinical trials with adults that have suffered a severe TBI. Do you see any difference in the cellular effect between working with children and adults? Do the children’s brain tissue regenerate more quickly, for example?
 
That’s a good question and we don’t know the answer to these questions quite yet. We do know that younger bone marrow cells tend to have a greater effect and there is some data to suggest that bone marrow cells derived from females have more potent anti-inflammatory effects.
 
How did you get interested in the possibility of using adult stem cells to treat traumatic brain injuries?
 
I became interested in TBI because I direct the Pediatric Trauma Program at UTHealth and Children’s Memorial Hermann Hospital in Houston, Texas. Trauma is the leading cause of death for children. If you have a healthy, term infant, the most likely cause of death as a child is due to injury — not infection, cancer, heart disease, etc. We are an extremely busy Level 1 Trauma Center, and the most frustrating injury with the most devastating consequences is TBI. Over 90 percent of the deaths are due to head injury. So, to impact the primary killer of children requires a new approach. In 2001-2002 time-frame, we were following the pre-clinical studies going on in the area of cell therapy and now 12-13 years later, we are on the cusp of changing the way we approach this problem.

The headlines have been coming all year from some of the biggest names in cancer drug discovery and development — from Merck, Bristol-Myers Squibb and AstraZeneca. And just last month, data from Roche’s advanced bladder cancer study lit up the international medical community, pointing toward what could be the first major breakthrough in over 30 years for this dangerous cancer.
 
The big story here, of course, and the hope for cancer patients everywhere, is immunotherapy. Also known as biological therapy, or biotherapy, immunotherapies use the patient’s own immune system to fight cancer, either by stimulating the immune system to attack cancer cells or by providing a patient with the biological tools it needs to fight cancer. Merck’s Keytruda, for example, is a humanized monoclonal antibody that blocks, or inhibits, PD-1, a protein that prevents the body’s immune system from attacking melanoma cells, offering a boost to the patient’s immune system. Roche’s new antibody, MPDL3280A, works in a similar way for bladder cancer patients, exposing tumors to an immune system that is hard-wired to destroy them.
 
For both advanced bladder cancer and melanoma patients, chemotherapy has offered the primary treatment weapon for well over 50 years. Born from the seeds of WWII research, when scientists discovered changes to the bone marrow of Navy personnel exposed to mustard gas — and the pioneering work of Dr. Sidney Farber — chemotherapy is wonderfully efficient at wiping out cancer cells. But, as patients and doctors will tell you, the toxic compounds utilized in this procedure destroy healthy cells in abundance, leading to serious side effects and putting severe strains on the immune system.
 
And this is one of the great promises for cancer immunotherapies — this new modality might ultimately reduce the incidence of chemotherapy altogether, making cancer treatment far less burdensome on patients and families, while offering better treatment outcomes.
 
Of course, every medical breakthrough brings a host of commercial challenges, and Nature’s astute May 2013 story on the immunotherapy trend highlights cost concerns; after all, many of these therapies will be used as part of multi-drug cocktails, pushing the price tag of cancer treatment ever higher.
 
I certainly agree that it’s vital to reduce the costs of drug discovery and development, making cancer drugs more affordable for patients. However, I’m also hopeful that, over time, the rise of immunotherapies could help cut the costs of cancer treatment. While some immunotherapies will be used in combination with chemotherapy, or immediately afterward, clinical success may point toward a day when they are used in lieu of chemotherapy altogether — and this will have big implications for the financial burdens associated with side-effects. For patients, today’s chemotherapy regimens require the use of a wide array of costly medications to help control the impact of side effects, whether nausea, infections, diarrhea, pain or fatigue. And while it’s true that even immunotherapies are not side-effect free, they pale in comparison to traditional chemotherapy and, by fortifying immune systems, bring the promise of creating healthier bodies that beat back the disease, and mitigate side effects, biologically.

Bob Hariri, M.D., Ph.D., is the vice chairman of Human Longevity Inc. (HLI), a genomics and cell-therapy diagnostics and therapeutics company he co-founded in 2013 with Craig Venter and Peter Diamandis, which is focused on extending the healthy, high-performance human lifespan. Utilizing technological advancements in genomics, bioinformatics, computing and cell therapy, HLI plans to develop therapeutic solutions to some of the most complex yet actionable diseases, such as cancer, heart disease and dementia. A recipient of the Thomas Alva Edison Award in 2007 and 2011, the former CEO of Celgene Cellular Therapeutics, and one of the pioneers of the global cell-therapy industry, Bob recently sat down with me to discuss his current work on the frontiers of aging and cellular science.
 
You’ve formed one of the most provocative and promising companies working in the cellular sciences. How did you get together with Craig Venter and Peter Diamandis of the X PRIZE?
 
I am very fortunate to have two remarkable visionary friends in Craig and Peter. I have admired the work that Craig has done in the broad landscape of genomics and synthetic biology and have always been inspired by his pioneering approach as an entrepreneur. Peter is one of my closest friends, and I have marveled at how he has, virtually single-handedly, reinvented incentivized competition, catalyzing a new generation of cutting-edge businesses. The three of us realized that we shared many common passions, among which was a desire to impact human health and society by exploring aging as a targetable disease. All of us have ventured, failed and succeeded by seeking to answer scientific questions based in real-world experience and offering solutions. We all took paths that were challenged, in some cases ridiculed and rejected, by established scientific institutions. In part that’s because invention without relevance or context has less impact than true innovation. We all saw aging as an opportunity to innovate, not as an obstacle to human progress and prosperity.
 
What is the mission for Human Longevity?
 
Our mission is to extend the healthy lifespan by developing high-resolution diagnostics and stem-cell-based therapies. The tools we will develop are designed to attack the sources of premature death at the genomic and molecular level that are also linked and can be used to preserve and enhance cognitive function, physical capacity and overall vitality.
 
Can you tell me what the day-in, day-out working relationship with Craig and Peter is like? How do you collaborate?
 
For me, it is both a privilege and a humbling experience being part of a team with Craig and Peter. The raw genius of my two partners is staggering. What makes it all the more exciting is the depth and breadth of their interests, passions and personalities. We are very much alike. We are close friends, and we are optimists and hard workers. And all of us are more interested in getting things done than in taking credit for something. We work well together because we don’t see scientific failure or being wrong as setbacks but as teachable events. As a team, we are all very comfortable with risk and that makes the work environment at HLI the hottest show in town.
 
Can stem cells prevent aging and even turn back the clock?
 
We believe that stem cells that are functioning well can play an important role in extending health and improving physical and cognitive performance and cosmetic vitality. Our work in stem cells has shown that if you can identify and measure individual variation for specific markers of disease at particular ages, you can identify the factors that predict the variability in how cells change over the lifespan. Then, using the information derived by interrogation of the genomics, proteomics and metabolomics, we can tailor treatments to how individuals get sick and improve their health.
 
You have an innovative business model that will tap the power of the world’s most comprehensive database on human genotypes and phenotypes. Can you tell me how this data will be applied?
 
We are not simply a data company. Some press accounts claim that we are engaging in “big science” and will compete with other institutes that are creating their own sequencing centers.
 
We recognize that most discoveries are the result of small groups taking completely novel approaches and sharing their findings. Instead, we are going to generate the most comprehensive and complete human genotype, microbiome, and phenotype database, identify the most creative people and give them the freedom to make their own affiliations.
 
Will HLI commercialize therapy products for aging? What is the game plan for the years ahead?
 
In order to develop the tools designed to attack the sources of premature death at the genomic and molecular level that are also linked and can be used to preserve and enhance cognitive function, physical capacity and overall vitality, we need data. So our goal over the next year is to accumulate the largest genomics data set. Our goal is to sequence over 1 million full human genomes, microbiomes, MRI body-image scans, metabolomes, etc. We will commercialize therapies for diseases that are associated with the biological and molecular breakdown associated with aging. And we will develop a preventive healthcare model that will take baseline measures of stem-cell function, monitor that in real time and correct any drift from optimal activity with stem-cell therapy.
 
Do you plan to commercialize therapies outside the confines of the traditional drug-discovery and -development model?
 
I have always said that placental stem cells were the platform for developing products and personalized medicine outside of the one-receptor/one-target/one-drug model.
 
When I started Anthrogenesis (which became Celgene Cellular Therapeutics in 2003), I wanted to show that the placenta was not just the best source of stem and progenitor cells and biomaterials, but that the unique biology of the organ was the source of tremendous therapeutic potential. We’ve shown that placental cells and the extracellular-matrix scaffolding biomaterials can be produced in such quantities and consistency that doctors could use them the same way they prescribe small molecules or biologic agents. HLI will be able to program stem cells to both modulate and stimulate cell functions to treat disease and extend healthy aging.
 
In what areas do you expect to make the first breakthroughs?
 
I can’t predict what HLI will commercialize first. We will follow the science. That said, we believe that we’ve just scratched the surface of what the combination of digitized DNA and biological data and stem cells can do for the human condition.
 
Longevity is a red-hot field in medicine, and many companies are jumping into the mix. How do you feel about Google’s Calico venture? Are they competition for you?
 
We are thrilled and excited that a remarkable company like Google has invested so actively in biomedicine and see Calico as part of what will be a rapidly expanding enterprise of age management or wellness. I hope there are many more companies who participate in helping people live longer, healthier lives.
 
Can you tell me about the partnership between HLI and Celgene? What do you hope to accomplish?
 
HLI just signed an agreement with Celgene Cellular Therapeutics (CCT) to license, develop, and co-promote one of Celgene’s proprietary placental-cell population, PSC-100, in age-related clinical indications.
 
We have the opportunity to explore a variety of applications for this unique cell population, including sarcopenia, a condition associated with aging characterized by degenerative loss of skeletal muscle mass, quality, and strength. Celgene has also made an equity investment in HLI.
 
If you had a crystal ball, what does the future hold for cellular therapies and aging? What do you think the field looks like 20 years from now?
 
I believe stem-cell innovations will have a quantum impact on the kind of people we can be. Throughout our short history on this planet, our progress can be measured by our ability to thrive. By this, I don’t just mean the fact that we will live longer and live better or that, as a result, we will spend less on health care. Rather, I believe the technological and physical evolution of our species will increase the capacity to share, and to be more flexible, inventive and determined in the face of uncertainty.
 
These citizens of this new way of life will be known as “the regeneration generation.”
 
The regeneration generation will be able to tackle challenges and pursue endeavors consistent with the speed by which new paths are discovered and imagined. Living longer at a time when the supply of ideas and inventions increase more quickly will exponentially increase the opportunity to pursue many more possibilities.