Needless to say, improvements in medical technology and medical care are nothing less than astounding. While in the past the cause and effective treatment of a broad range of diseases eluded even the best medical researchers, progress now seems to occur almost daily. Yet even though there has been huge progress, surprises still abound.
One of the best examples is in what has come to be referred to as the microbiome. These are the trillions of bacteria that live within, as well as on the skin of, every human, as well as other animals. In my last post, I discussed how medical researchers have concluded that bacteria in the vaginal canal appears to provide protection to the baby against obesity and allergies. The evidence of this is that children born via Caesarian section tend to have a greater risk of obesity, the reason being because the C-section children weren't exposed to beneficial bacteria in the birth canal.
Not only are there a significant number of important bacteria and other organisms in each of us, scientists are finding incredible genetic diversity therein. In fact, it's hypothesized that the genetic information contained in the typical human microbiome is 150 times the genetic data in the typical human genome alone! Realizing the potential, the US National Institutes of Health has established a Human Microbiome Project, likely modeled on the hugely successful Human Genome Project.
Long before anyone knew there was something called the human genome, it was understood that the gut contains some beneficial things. As far back as 1700 years ago, Chinese doctors – at least what they called doctors at the time – concocted what was euphemistically referred to as "yellow soup". It was taken from a healthy individual and given to someone with diarrhea. While it sounds disgusting, apparently it worked! Independently of the Chinese, other "doctors" discovered that camel dung could effectively treat dysentery in humans.
The point of these three examples – the two treatments for dysentery/diarrhea and the apparent value of vaginal fluid in preventing obesity – is that microbiomes of healthy humans and other animals appear to provide significant health benefits. When you couple these with the fact that there is such incredible genetic diversity in the human microbiome, it suggests that drug companies ought to look very closely at the human gut, and maybe even those of other animals, to find solutions to many maladies.
My wife, a nurse, always like to say that buried somewhere in the Amazonian rainforest is the cure for cancer. Maybe so, but maybe it's much closer than that, as close even as the human gut.
Makes sense, if we can just overcome our natural negative reaction to the "yuck" aspect of this. A number of companies are investigating the possibilities. The field has gotten so hot that a French venture capital firm, called Seventure, is focusing on microbiome related investments.
One strategy goes by the name FMTS. Some PR person deserves a big bonus for that, because FMTS is an acronym for fecal microbial transplants. Sounds pretty awful, unless you happen to suffer from something called Clostridium difficile, or C. diff, a bug that causes very serious, even life threatening, diarrhea. One novel way to address C. diff is using FMTS. A company in Roseville, Minnesota called Rebiotix is developing a FMTS that is a standardized liquid suspension of healthy gut bacteria. Another company called Seres Therapeutics, based in Cambridge, Massachusetts, is developing a FMTS for C. Difficile and also ulcerative colitis.
Diarrhea is certainly an unpleasant affliction, but for most people it is a temporary problem. A potentially more serious problem is tooth decay. Nearly everyone has suffered this, and flinches at the thought of seeing a dentist to have cavities filled. A possible solution is under evaluation by C3J Therapeutics, a company based in Marina del Rey, California. C3J's strategy is to identify "good" bacteria from one part of the microbiome to create what is called an antimicrobial peptide aimed at Streptococcus mutans, the bug in our mouths that's believed to cause cavities.
Sometimes the cause of a health problem is that something important is missing, such as certain enzymes. If the proper enzymes can be inserted, the problem may clear up. To deal with this, another approach is to harness the power of certain viruses that occur naturally in the body and put them to work doing something else. Blue Turtle Bio in San Francisco, and Synlogic
in Cambridge, Massachusetts, are trying to get bacteria in the body to transport things like enzymes.
As previously noted, scientists have identified a link between obesity, allergies, and the microbiome. How about autism? In fact, at least one company – Second Genome (www.secondgenome.com) in San Francisco – to see if there is in fact such a link. If the link is confirmed, that would suggest the possibility of harnessing the power of a healthy microbiome to resolve the problem.
There may even be a link between the microbiome and cancer. At least there is the hope that the human microbiome can be harnessed to develop new oncologic drugs. Perhaps the most exciting new develop in the treatment of cancer is immunotherapy. This approach may be much more effective than traditional chemotherapy. However, patients respond differently to immunotherapy, some very positively but some not so. Interestingly, recent research, published in Science, shows that human gut microbes can influence how the patient responds to immunotherapy. One of the studies found that when patients were being treated with immunotherapies designed to block PD-1 and PD-L1 proteins, patients who were receiving antibiotics for unrelated issues responded less well to the immunotherapy treatment. In other words, the antibiotics somehow had a deleterious impact. The study also found that patients who had greater concentrations of a bacterium called Clostridiales responded better than those with higher concentrations of Bacteroidales. A second study showed that people who received antibiotics to treat infections shortly before or after starting immunotherapy did not respond as well to PD-1-blocking therapies. The researchers — led by cancer immunologist Laurence Zitvogel and cancer biologist Guido Kroemer, both of the Gustave Roussy Cancer Campus in Villejuif, France — also found that the presence of the bacterium Akkermansia muciniphila in both humans and mice was linked to better responses to immunotherapy.
These studies appear to suggest two things. First, the presence or absence of certain types of bacteria in the microbiome can influence the effectiveness of other treatments. Second, the use of antibiotics, even ones unrelated to the primary treatment, can negatively affect treatment.
Given that the microbiome seems to play an important role in human health, we may be witnessing a giant game of "unintended consequences". As previously noted, bacteria in the gut may perform a range of regulatory functions. Consider, however, what we've been doing over the past 60+ years. Since the accidental discovery of penicillin in the 1920's, we've revolutionized healthcare through antibiotics. Countless millions of lives have been saved because of antibiotics. Where people routinely died from the sudden onset of an infection, the risk of that has dramatically decreased.
Antibiotics kill bacteria, usually very effectively. We've, however, come to the realization that there are both good bacteria and bad bacteria, but antibiotics generally can't discriminate. So while we've deployed a range of antibiotics against the bad bacteria, those very same antibiotics have also killed lots of good bacteria, setting up a whole bunch of unintended consequences.
We've probably already dramatically altered our human microbiomes in lots of unexpected ways. If the microbiome plays that big a role in human health, we may have already inflicted a lot of collateral damage. There's already evidence that there have been lots of unintended consequences to the heavy use of antibiotics over the past 60+ years. An excellent example of this is a CDC study that found that 71% of severe C. Difficile infections in children, ones that caused severe diarrhea, were traceable to improper use of antibiotics.
There's an old saying, when the only tool you have in your toolbox is a hammer, every problem looks like a nail. To a certain extent, maybe we've come to think of antibiotics as the only tool in arsenal, so too many problems have been "solved" with them. If that's the case, then in a strange way, maybe it's actually beneficial that we're seeking increased antibiotic resistance, and more antibiotics rendered ineffective.
Well, in the short term, it's clearly not good. In the longer term, however, it suggests that rather than try to develop the next generation of antibiotics, maybe we should focus our attention elsewhere. That "elsewhere" could be the microbiome. In other words, focus attention on how a healthy microbiome defends against disease. The incredible amount of genetic material in the typical microbiome represents the result of millions of years of evolution. If we gain a better understanding of how the healthy microbiome works, we'll gain more and more clues on how it can be harnessed to deal with disease. Please understand, I'm not suggesting that we abandon antibiotics on a wholesale basis. Far from it. Instead, we need to avoid treating antibiotics as the "universal tool" in our toolbox and search for other approaches.
Yes, the cures to cancer and other diseases may well rest in the wilds of the Amazon, and other remote places, but those very same cures may reside just below our collective waistlines, too.
