All opinions are my own and do not necessarily reflect those of Novo Nordisk.
A few days ago the New York Times ran a nice article discussing a recent test of whether fecal transplants can be done using a pill format delivery system. The research, reported (and free, no less!) in the Journal of the American Medical Association, was peformed by physicians at Massachusetts General Hospital who had formulated human feces in an encapsulated pill format to see if that would be effective as a kind of fecal transplant. Fecal transplants appear to overcome infections by Clostridium difficile in patients. However, the conventional method for providing a fecal transplant is to deliver a liquid slurry either nasopharyngeally or via an enema-like procedure, neither of which is easily scalable. Also, yuck.
The current work, in which 14 of 20 patients responded to initial treatments using the poop pills, and an additional 4 responded the second time around, provided a proof of concept that a frozen, pill format delivery system may be a workable alternative to the current standard.
But as I was reading this article, I was struck by another thought. Are we missing a great opportunity for research into the interplay between the microbiome and human physiology?
Human subject biomedical research is tricky in many ways but let me call out two.
First, the human population is incredibly diverse, both in a genetic sense–that is, our differences in DNA–and in our environmental exposures. This means data from experiments with humans are always noisier than corresponding experiments with, for example, mice. Laboratory mice are, for practical purposes, genetically identical. They also live in very controlled environmental conditions. Same types of cages, same type of bedding, food, etc. For humans, it’s often difficult to set up a well controlled system or environment for a given experiment. The clinical studies done by the pharmaceuticals companies are the gold standard in controlled human testing for biomedical interventions. A gold standard, by the way, that actually has some drawbacks in terms of translation of experimental findings to the broad population.
Second, there are ethical and moral issues whenever working with humans or human materials. One of the key points is consent. From an ethical standpoint, people should have the opportunity to give consent or at least foreknowledge when involved in experiments. The recent debates about Facebook’s and OKCupid’s experiments on their users in part centered around the question of consent: was the disclosure of data usage policies in the terms and conditions (that almost no one reads through sufficient) to qualify as consenting people for these kinds of behavioral experiments? For biological experiments, there isn’t any debate; consent is necessary, and getting it is one of the most time-consuming, important, and expensive parts of any research protocol.
Getting back to the treatment in question, people across the US are obtaining fecal transplants. These treatments are in what we might call “Research” mode, in that there has not yet been an FDA approved device or pharmaceutical for this approach. Which means there were and are consents involved. And the situation also involves essentially replacing a person’s intestinal gut microflora with a defined, or at least definable, new population.
Do you see where I’m going with this?
There has been a lot of hype about the gut microbiome and the effect it may have on our health. And there have been some really neat experiments in mice (for example here) demonstrating an effect of microbiota transfer on mouse biological function. However, doing similar experiments is humans is generally unethical.
In this case, however, the patients undergoing fecal transplants are consented for the treatment and I believe it’s an ethical situation because the primary purpose of the transplant is to cure. Further, while not as well controlled as a mouse study or even a standard clinical trial, fecal transplantation does at least involve the controlled perturbation of the human system, and this in turn strengthens evidence for cause and effect. The opportunity then is to add an element of data gathering onto the existing framework for fecal transplants, to help us understand, in a real situation, how the microbiome affects us and how we function. To be clear, I’m not advocating trying to provide different designed microbiota samples to patients, only what they would be getting as part of normal C. difficile treatment. Just studying this baseline would be quite interesting in and of itself.
What would this involve? Certainly microbiome samples before and after the transplant. Preferably many times before and after to establish a baseline. Genome sequencing of the individual would be good, to look for genetic determinants of microbiome interactions. Blood samples could be taken periodically, to analyze blood-borne proteins and metabolites, and also to profile the blood transcriptome. One can think of a variety of measures, some more invasive than others, that would allow an understanding of the effect of a new microbiome on an individual’s health.
And for a control group? There are two. Neither group is perfect, but perhaps by comparing the fecal transplant patients to healthy individuals as well as to individuals who have successful antibiotic treatment of their C. difficile infections, putative specific changes to human health metrics due to microbiota populations can be identified.
Another possible control group is the collection of individuals who undergo a standard colonoscopy. This procedure leads, in the preparatory stage, to a rather large scale depletion of the gut microbiome.
I think this could be an overall interesting experimental setup, and is especially attractive as the consenting process is already in place. It takes advantage of an existing situation–fecal transplants for medical treatment purposes–and looks for a way to leverage that situation to try and get more out of it than originally planned. To create a new efficiency.
That’s really the point I’m trying to make. This idea embodies a couple of threads about understanding human health. We know that animal models only take us so far in understanding human biology and we need to do more studying of humans directly. A recent piece by David Shaywitz at Forbes makes this point, that we have to capture as much human phenotypic data as possible to get the biggest impacts on human health.
And so, in order to make progress as quickly as possible, we need to leverage existing systems and processes to derive as much information as we can. There’s this term I’ve heard in museums, “Found Art.” It refers to the use of everyday objects that are found and re-imagined into a different format or context as a work of art. I think we need to be more proactive about doing “Found Research.” The current Big Data craze is in part a manifestation of “Found Research.” Big Data analytics take existing datasets that were created for one purpose and mine those datasets for additional insights.
These kinds of add-on experiments would add costs, to be sure. But a really large cost in any study is the identification and consenting of a cohort of patients. That’s already happening with fecal transplants. Eventually we might get to a point where many individuals sign off on a portable consent for broad based phenotypic research, such as is being pioneered now by Sage Bionetworks and others for genomic data. Such a consented individual would be able to sign up for a research study much more quickly and easily than is currently the case; the burden would be on the research organization to honor the terms of the portable consent. However, for now, individuals consent on a per study, rather than a per individual, basis is the norm, and that underscores the importance of getting everything possible from existing studies. It’s a driving force behind the movement towards clinical trial data transparency.
Last year Robert Plenge, Edward Skolnick, and David Altshuler wrote a review in Nature Reviews Drug Discovery about how genetic studies help identify “experiments of nature” that can be leveraged to improve drug development. I think fecal transplants and other medical procedures fall into a similar category and should be similarly appreciated as another potential source of value for biomedical research.