Using a very small sample size in a medical experiment is almost a sure way to evoke outrage and criticism in the scientific community. But what about using just one subject?
The criticism may be out of proportion with respect to the response that you might receive otherwise, all other factors of the research being equal. On the other hand, there can be good science value in a single-subject study. Earlier this year, for instance, astronaut Scott Kelly returned to Earth, after nearly a year in space. During his time on the International Space Station (ISS), prior to leaving, and after returning, he and his Earth-bound, former astronaut twin brother Mark provided hundreds of samples of urine, blood, and DNA. Their body systems have been measured in every which way and researchers are analyzing the data, hoping to learn more about how the space environment affects the body.
Experiments involving one or two humans are the not the standard way of doing things in medical science. They don't allow for randomized control trials (RCTs) characterized by some patients getting a treatment, others getting a placebo (sham treatment) and neither the patients nor the researchers known who got what. But there are unusual circumstances when a single patient study is all that can be done, at least for the moment. Those circumstances include studies on the ISS, where having just one pair of astronaut twins is pretty unusual.
They also include research situations that entail potential risk to a subject's health, so the human who acts as a guinea pig needs to be extremely brave. That latter category harkens back to many research physicians of the late 19th and early 20th centuries, who would test drugs on themselves, a famous example being William Stewart Halsted. He is considered to be the father of modern surgery, but he's also remembered for having cocaine and morphine addiction --an affection that he developed as a result of testing those on himself before daring to try them on any patient.
Elizabeth (Liz) Parrish, CEO of the Seattle-based biotech company BioViva is not a physician nor a scientist, but seven months ago she decided to take a risk similar to that taken by Halstead and other medical pioneers of his era. Parrish is a healthy woman in her mid forties, but last September she become her company's patient zero for two gene therapies, one for a myostatin inhibitor that is supposed to reverse muscle loss, the other for telomerase that is supposed to de-age chromosomes by lengthening telomeres—bits of gene-less DNA at the ends of each chromosome that get shorter each time cells divide to produce new generations. If the telomeres get too short then actual genes start to get snipped, and so the length of telomeres is considered to be one aspect of cellular aging.
Telomerase gene therapy
Two and a half weeks ago, BioViva issued a press release announcing that telomeres in T-lymphocytes sampled from Parish's blood prior to beginning the treatment in September had been unusually short for a woman of Parish's age, but that samples taken six months later had just been analyzed and showed telomeres being 620 base pairs longer than in the September measurement. In March, a few weeks prior to the BioViva press release, this writer interviewed Parrish on behalf of Discover Magazine, and asked her several questions, some which anticipated potential criticism by the science community of studying just one test subject and one particular type of body cell --criticism that was mirrored in statements by specialists in laboratory medicine published on April 27 by the non-profit organization Genetics Expert News Service (GENeS).
There are several important technical issues that could explain the apparent telomere lengthening reported for Elizabeth Parrish." explained Dr. Rita Effros, Professor of Pathology & Laboratory Medicine at UCLA. "A change in the proportion of cell types within the peripheral blood could be due to a number of factors: immunological encounters over the year; environmental/lifestyle effects such as exercise, which affects the trafficking of immune cells from blood to certain organs; or even hormonal status (i.e., the time of the month)....A second issue with the data is that the telomere length measurements were performed in different experiments. The proper way to compare different time points for telomere lengths would be to cryopreserve (freeze) the two samples, and run the telomere length measurements side-by-side under identical experimental conditions.
To be sure, the above criticism is based on simply what is stated in the BioViva press release. The discussion really won't move forward until the BioViva data are peer reviewed and published in a scientific journal.
“It’s hard to assess how accurate the results are without knowing details of how the measurements were performed," said Dr. Bradley Johnson, Associate Professor, Pathology and Lab Medicine, at the University of Pennsylvania.
Although the usual way to do things is to wait until after the paper is reviewed and scheduled for publication, and then issue a press release, it's quite possible that peer review is going on right now and that BioViva decided to release some information on the early side merely to whet our appetites. Going by what Parrish revealed in the Discover interview, BioViva is taking a non-standard approach to research that includes more than using Parrish as patient zero. They're bypassing the highly regulated FDA process that allows clinical research in the United States with emphasis on proving safety before efficacy. They're doing this by administering the gene therapy to Parrish overseas, and if you're thinking that this puts Parrish's health at risk, you are correct. However, she's well aware of it and she expressed her reasons in the Discover interview:
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?
That sounds rational, but the counterpoint is that to make real clinical advances one must go through the process of the FDA, or the health regulatory agencies of other countries. This is the approach of another telomerase gene therapy company, Telocyte, whose president, Dr. Michael Fossel also has supplied me with some perspective
"We at Telocyte intend to pursue the same basic goal [as BioViva] via FDA human trials. We wish Liz the best and understand her urge for haste, but we believe we can achieve a good deal more by ensuring credibility in FDA sanctioned trials," Fossel told me recently, then added point that simplified notions that came up both in my Discover interview and on the GENeS critique, namely that, "Incidentally, there are severe problems in interpreting telomere data from peripheral leukocytes."
Yes, that is is a major point that will be raise in the peer review process. It's a potential reason for BioViva to consider slowing down, but not a reason to divert from moving forward.
David Warmflash is an astrobiologist, physician and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.