Liz Parrish is a CEO, humanitarian and patient zero in her own experiment. (Credit: BioViva) Elizabeth (Liz) Parrish is the CEO of BioViva, a biotechnology company that focuses on developing gene therapies, and other regenerative therapies, to intervene with human aging. Last September, Parrish added an interesting line to her job description: patient zero for two anti-aging therapies that the company is researching. Parrish is receiving two kinds of injections, which are administered outside the United States: a myostatin inhibitor, which is expected to prevent age-associated muscle loss; and a telomerase gene therapy, which is expected to lengthen telomeres, segments of DNA at the ends of chromosomes whose shortening is associated with aging and degenerative disease. The study will likely continue for many years. But last week, BioViva issued a press release describing an unexpected early result, offering a clue as to what the BioViva team might publish in the weeks or months to come. It will be unclear exactly what the BioViva researchers have found until the results do go through the rigorous process of scientific peer-review, but the un-reviewed BioViva report is raising some eyebrows. Telomeres of T-lymphocytes in blood samples taken from Parrish in September were 6.71 kilobases. That’s shorter than normal for Parrish’s age, but lymphocytes from the samples taken in March after six months of gene therapy measured 7.33 kb, according to BioViva.
In this illustration of a chromosome, the telomeres are highlighted in green. (Wikimedia) The company equates the reported 620-base increase to reversing the clock on Parrish’s chromosomes by twenty years. But there are numerous caveats noted by experts in genetics and laboratory medicine that were recently published by the non-profit group Genetics Expert News Service. For one thing, telomeres are being tested only in her T-lymphocytes, as opposed to all tissue types of her body, so even if the test result were evidence for de-aging of T-lymphocytes it doesn’t necessarily prove her entire body de-aged. “Long-lived T cells have shorter telomere lengths than newly generated naïve cells; and cells which have reached their maximum limit of cell divisions have shorter telomeres than any other cell type,” says Rita Effros, a professor of pathology and laboratory medicine at UCLA. “Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data.” Furthermore, notes Dr. Bradley Johnson, Associate Professor of Pathology and Lab Medicine at the University of Pennsylvania, “Telomere length measurements typically have low precision, with variation in measurements of around 10 percent, which is in the range of the reported telomere lengthening apparently experienced by Elizabeth Parrish.” These criticisms notwithstanding, Parrish serving as patient zero for a brand new treatment is a milestone in medicine, one that harkens back to the medical pioneers who regularly injected themselves with various new drugs over a century ago. Before BioViva's news broke, Discover’s Dr. David Warmflash interviewed Parrish about the therapies and her feelings about being the first test subject.
Discover: What would you say makes BioViva stand out from other biotech or gene therapy companies? Is it that you’re using yourself as a test subject?Liz Parrish: Yes, and number two is treating biological aging as a disease. Actually, that is probably number one. We’re going at the root cause of what makes most of the population sick. And then second, of course, we’re 100 percent behind the product. We’re using them. We are not just a research company. BioViva is about saving lives, and lessons from history suggest that the use of multiple experimental therapies at once may be the shortest route to saving lives. When AIDS research first began, we saw the use of many drugs which, when used in isolation, helped with one mechanism of the disease, but patients still died from another mechanism of the same disease. It was only when doctors combined those drugs into cocktails we saw the first real advances in combating AIDS.
Do you feel any connection, or do you see yourself as carrying on a tradition of the those early medical researchers from the late 19^th and early 20^th century who tested different drugs on themselves?
LP: Yes, I guess so in retrospect. We didn’t do it in the spirit of that. We did it because it had to be done, because we needed a test patient on the gene therapy, but I think it is in that spirit and I wish more people had that spirit. The U.S. is 5 percent of the world population. We take 75 percent of all prescription drugs and yet have the shortest lifespan of every industrialized country, so I wish more people would get behind their drugs and other therapies. I think it would prove that what they have is something that you would want to take. OK, so let’s talk about the therapies that you’re taking. Is there any concern the telomerase gene therapy could led to malignancy, to cancer, in any tissue?LP: Telomerase has never been hypothesized to be the sole cause of cancer. Not all cancers have telomerase upregulated in them. Cancer cells can develop daily in your body from a very young age. But isn’t a youthful immune system is what keeps full-blown cancer at bay? The confusion of longevity research with cancer research is a recurring misconception and implies correlations that have not been proven. There are two lines of research into telomerase: longevity and cancer. The two never intersect. In longevity research we do not find ourselves looking at increases in cancerous cells from telomerase induction, but rather a protection against cancer. In previous interviews with other people, you've alluded to the tragic story of Jesse Gelsinger, the 18-year-old boy who died in an early gene therapy clinical trial at the University of Pennsylvania in the 1990s. Ethically, of course there's a difference between Gelsinger and you; I've heard you say that this is worth risking your life for. But on top of the tragedy of Gelsinger losing his life, didn't it also set the whole field of gene therapy back several years? From that perspective, in the unlikely event that something goes terribly wrong in the experiment on you, do you worry what might happen to gene therapy research? Have you considered this a possible rationale for slowing down, maybe taking a more conservative approach?LP: Gene therapy has come a long way since the 1999 tragedy of Jesse Gelsinger. The relevant research did not stop [after the event], only the applications, and even then only temporarily. But the big game-changer now is that we have better delivery methods. Hundreds of people are partaking in gene therapies today and none have the issues we saw 16 years ago in Jesse Gelsinger. We also need to put this in perspective: almost 100,000 people already die of adverse drug reactions (ADEs) every year in the USA alone, while nobody has ever died from this latest generation of gene therapies. That being said, we at BioViva are very careful to ensure the safest possible outcome while still testing every limit. I would not have taken a gene therapy that would have likely killed the patient and nor would anybody at BioViva. I simply stated that all data are equally important, and that to that end I would accept any outcome, up to and including my own death, in order to move the science forward. We as a company, and I as a person did take a risk, but a risk we believe will change the world for the better and kick-start an industry with the best approach to curing disease and increasing healthy lifespan.
What do you think about the idea that, the potential of the studies on you notwithstanding, you’re just one datum, so what will we really know? LP: Yes, absolutely. That’s true, but N=1 from one human is worth 10,000 mice, but of course every human’s body is different and people are going to respond differently. And of course the FDA since the 1970s has passed almost 50 drugs through the system to the market that it pulled later, despite going through gold standard testing. So that’s why we have to start now and see what happens. No matter what safety and efficacy you have, if you can have N=10,000, you’re probably going to have some adverse effects down the road. Whether it’s directly related to the gene therapy or to something else in the patient’s life, it may take years to determine, so it’s very important to start now with gene therapy. Currently, over 100,000 people die of aging related diseases, so at what point do we realize that life is risky and that taking a chance may be our best bet? Which tissues are they using to monitor your telomere length, given that telomeres vary between tissues? Generally, in telomere studies, lymphocytes are used, because they're easy to access, but what factors went into deciding which tissues to use in you both for monitoring and targeting the therapy.LP: We are using lymphocyte testing at this time, as it is the most advanced and well understood way to test telomere length today. I also understand that to carry the therapeutic gene through your blood and into your cells, BioViva is using what’s called an AAV vector, which has the advantage of delivering the genetic payload so that it ends up as an episome (free floating gene), rather than being integrated into a chromosome. Is this a safety measure, to minimize the risk of mutagenesis and oncogenic transformation? Is there any possible negative to that, such as decreased duration of the effects?LP: We are not necessarily trying to integrate the gene, as studies have not proven the benefit of doing so. We are trying to create an episome in the nucleus, which will code for the target protein. Integration is still an important discussion because past delivery methods, which we avoid due to them creating integrational mutagenesis (integrating into the chromosome in random areas that caused the cell to become unstable). We want to separate our method from that older method. Our delivery method does not cause integrational mutagenesis, and when it does integrate, it does so into a safe harbor site on chromosome 19 where cancer is not an outcome.
Are there concerns among your team that treatment for slowing or reversing aging of healthy tissues could also prevent elimination of malignant or premalignant cells?LP: Cancer cells can appear in people of any age, but the proliferation of cancer cells owes more to a decrease in immune system capability than an increase in telomerase activity. Not all cancers involve telomerase production, and a peer-reviewed paper in 2012 showed that old mice saw no increase in cancer with telomerase induction. Telomerase induction may actually be our first line of defense against cancer, because a youthful immune system regularly rids the body of cancerous cells. The mechanism of telomerase could restore cells epigenetically to a youthful state exhibiting fewer aging gene biomarkers. An example would be turning off the genes that turn on as we age such as P53, a tumor-associated gene. If you were to develop a common type of cancer, how would we know if it's from the gene therapy, or because you would have gotten it anyway?LP: If I was to be diagnosed with cancer, we could have that cancer sequenced to see if it had an extra copy of the target gene [from the gene therapy]. So, you're getting telomerase gene therapy as well as a myostatin inhibitor. Was there any discussion about the merits of giving you two experimental therapies at the same time? Imagine it's the year 2096, you're 120 plus, looking and feeling exactly as you do today and you have the blood chemistry of a 25 year-old. How would we know which therapy did it?LP: Such an amazing outcome, if it happened, would necessarily be due to both those two therapies or more. We believe that these two types of therapy are synergistic, and will benefit each other in ways that will maximize outcome. One gene therapy is hypothesized to create better signaling with stem cells. The other creates stem cells that can potentially divide indefinitely, as stem cell depletion is a risk for older people. These benefits, combined with the protection against frailty or sarcopenia (loss of muscle tissue) with a myostatin inhibitor, and the more youthful epigenetics of a cell with telomerase induction, makes this combined therapy very powerful.
