Hostility Towards Paid Trials Searching for Significant Effects

This popular science piece is characteristic of a prevalent and hostile view of the growing practice of patient-funded clinical trials. In this model the patient pays a sizable portion of the costs, which certainly makes it a lot easier to gather larger amounts of data, as the trial organizers don't have to seek the funding themselves. On the other hand, it tends to rule out the ability to carry out a blind trial in which not everyone actually gets the treatment, as well as other similar refinements. That is a problem if the goal is to search for and quantify marginal effects, but if the point is to discover or rule out large effects, I'd argue that control groups are not necessary. The control in that case is the established progression for patients who do not get the treatment, or who undergo existing, marginal treatments. We are at the stage in the development of medicine to treat aging in which marginal effects, such as those resulting from the use of metformin as a calorie restriction mimetic, should be discarded as uninteresting. Once at the stage of trying things in human studies, the research community should be filtering for significant effects, such as those obtained by clearance of senescent cells. Given the poor state of funding for aging research in general, methods that can pull in more resources to obtain more data should be applauded.

In the case of the approach being trialed here by Ambrosia, as mentioned earlier this year I think our expectations should be low, and the outcome I expect is for there to be no significant benefit. The only ethical question worthy of consideration is whether those involved then do the right thing: publish the data, shut up shop, and move on to the next project. Transfusions of young blood to old individuals are not producing benefits in mice, and there is reason to think that the beneficial outcomes observed in old mice due to parabiosis, the linking of circulatory systems between an old and a young individual, are due to factors or circumstances not replicated by periodic transfusion. It isn't difficult to imagine that beneficial outcomes require the youthful system reacting in a dynamic way to the presence of aged signals, for example, or - as suggested by some researchers recently - that it is nothing more than a consistently maintained dilution of problem signals in the aged environment.

Just off a winding highway along the Pacific coast in Monterey, California, is a private clinic where people can pay $8,000 to have their veins pumped with blood plasma from teenagers and young adults. Jesse Karmazin is the entrepreneur who made the practice possible, by launching a clinical trial on the potential of "young blood" through his startup Ambrosia. He says that within a month, most participants "see improvements" from the one-time infusion of a two-liter bagful of plasma, which is blood with the blood cells removed. Several scientists and clinicians say Karmazin's trial is so poorly designed it cannot hope to provide evidence about the effects of the transfusions. And some say the pay-to-participate study, with the potential to collect up to $4.8 million from as many as 600 participants, amounts to a scam. Ambrosia says it will enroll almost anyone over 35, and the fees of $8,000 per person could add up. But Karmazin rejects the idea he is out to generate profits. He says that money is needed to cover the cost of clinical procedures, laboratory tests, and the plasma.

What's certain is that it's based on some intriguing if inconclusive science. Karmazin says he was inspired by studies on mice that researchers had sewn together, with their veins conjoined, in a procedure called parabiosis. Over the last decade or so, such studies have offered provocative clues that certain hallmarks of aging can be reversed or accelerated when old mice get blood from young ones. Yet these studies have come to conflicting conclusions. Further, parabiosis experiments offer little insight into how Ambrosia's one-time transfusions will affect people. Despite such uncertainties, the potential of young blood to treat disease is being explored in a number of clinical trials.

In 2014, Stanford University neuroscientist Tony Wyss-Coray demonstrated that old mice had increased neuron growth and improved memory after about 10 infusions of blood from young mice. That prompted Wyss-Coray to launch a small company, Alkahest to test transfusions of plasma from young people in the treatment of Alzheimer's disease. Alkahest's clinical study is more conventional than Ambrosia's: it does not charge participants, it expects to enroll only 18 volunteers, and it is initially looking at how well the elderly can tolerate small doses of plasma. Like several other researchers and bioethicists, Wyss-Coray worries about the fact that Ambrosia's trial is funded by participants rather than investors. "People want to believe that young blood restores youth, even though we don't have evidence that it works in humans and we don't understand the mechanism of how mice look younger."

The formal goal of the Ambrosia study is to measure the effect of young plasma on about 100 biomarkers. Before the infusion, and one month after, all participants have their blood analyzed for biomarkers. But Irina Conboy, a professor at the University of California, Berkeley, thinks the biomarker results will be meaningless: for one thing, the study lacks a control arm with patients who don't get plasma. Blood biomarkers, she says, change for many reasons. She's also wary of Alkhest's study on Alzheimer's patients. Last year, she and colleagues found that older mice whose blood was partially replaced with younger blood saw few benefits. "Both studies are hurt by the same problem, and the problem is that there is no evidence to suggest that an infusion of plasma from young to old animals reverses aging."



This magazine is generally hostile to rejuvenation biotech research as is the Chief Editor Jason Pontin who launched a name calling attack on Aubrey last year on Facebook as some might recall. There are a few writers there who are more fair but in general I find the magazine hostile and filled with establishment flunkeys all too quick to respond in a kneejerk fashion to anything that deivates from their view of how science should be conducted.

I completely agree with Irina Conboy about this study though I think it will be practically meaningless and I am far more interested in her work on a blood filtering system that calibrates cytokines turning old blood back to young.

Posted by: Steve Hill at January 13th, 2017 9:01 AM

I think Alexander Masters did a good job outlining the issues (not all ethical) and solutions to paid clinical trials in his articles. A summary article was published on Medium in 2014:

Alexander did manage to raise 2 million USD to get an oncolytic virus into clinical trials for NET cancers.

I do think this approach may be applicable to regenerative medicine. But then it may not, getting rich individuals on cancer trials is fairly easy as they are going to die. On the other hand people already spend ridiculous sums of money on cosmetic surgery and treatments that don't do much at present[1]. You could tell rich individuals glucosepane or senescent cell removal might make their skin look more youthful. Maybe vanity will be an even bigger driver than mortality?

[1] Most plastic surgery just makes people look worse not better in my opinion.

Posted by: Jim at January 13th, 2017 11:17 PM
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