(7c) Drugging the Human Microbiome

My essay describes the suggestion for a new form of pharmaceutic treatment, directly targeting the microbes in the human gut with small molecule drugs. I elaborate on my view of the current state of the art, the scientific and my personal motivation for a resulting unmet medical need, as well as my personal qualification and desire to become instrumental in a solution, using a specific example that originates from my current research in George Whitesides’ laboratory.

Western medicine has a long tradition of identifying causes and mechanisms, and of attempting to cure diseases rationally. In molecular medicine, even when a condition is treated symptomatically, the regulations of most developed nations require that a drug is defined by an active pharmaceutical ingredient: a precisely specified molecular entity, whose interactions with the human body lead to an improvement in health. This mode of operation has transformed our society in the last 100 years: it has completely eradicated some plaguing epidemics, has helped to improve our longevity by directly tackling issues of public and private health, and it has created a general notion of safety in the application of medicine by providing an assessment of probable adverse effects. As such, our system of drugging human conditions can unequivocally be described as very good, and suitable for the treatment of malfunction in almost all of the body’s organs and tissues.

Notable exceptions to that list are the human gut, and the brain. These centrally important functional units remain poorly understood from a pharmaceutical perspective (here, I specifically and completely abandon the discussion of differences in understanding of the physiological and molecular function of these two entities). That notwithstanding, other schools of medicine, such as traditional Chinese medicine, connect and re-focus many unhealthy conditions to a dysfunction of the gastrointestinal tract, and have successfully treated these for a long time with drug formulations, that might appear crude and unsophisticated by our standards. Personally, such a dichotomy directly provokes to question the paradigms of western medicine. What are we obviously missing, and not even making up for with our high technical and scientific esteem?

For the treatment of diseases connected to the gut—may these connections be known, or yet unknown—I am convinced that a major factor of neglect lies in the symbiotic effects of commensal microorganisms with the human host. This field, simply subsumed in the term ‘the microbiome’ or ‘microbiome research’, has gained tremendous attention in the last decade. Researchers have finally elucidated, using scientifically accepted methods, commonly known effects of nutrition on human health, thereby sometimes overthrowing long-lasting beliefs. It has become increasingly clear that we cannot ignore the function of microbes in the gut, nor can we treat the human and the prokaryotic cells as separate entities in their role as essential elements for maintaining a healthy host. It is the co-habitation, that needs to be investigated: its beneficial effects need to be understood, and any meaningful deviation from these optimum states have to be analyzed to eventually treat the symbiosis of organisms to restore normal function.

Tackling this challenge, medicine will need new diagnostic tools: methods to analyze the human microbiome non-destructively, and preferably non-invasively to generate more data from healthy subjects. We will require more knowledge of the symbiosis of multiple species with human cells, and their dynamic variation and adaptation to a changing environment, especially when the conditions transition from a healthy to an unhealthy state. To my best knowledge, many of these aspects and problems are being investigated by the most talented researchers around the globe. Still, I believe that many of these efforts are merely directed at improving or altering the existing strategy of drugging human cells.

Here, I propose to shift that paradigm, and target drugs at the microbes themselves to elicit a specific response, which in turn will lead to a beneficial effect in the co-culture of commensal organisms *and* human cells. I argue that although prokaryotes are immensely less complex than the human body, their intricate network of biochemical reactions still allows for many ways to achieve homeostasis, with a variety of molecular inputs and outputs, thereby generating a therapeutic opportunity. Moreover, since the scientific prowess of western medicine regularly culminates in the development of extremely specific drugs, that only marginally deviate from their intended action in the complex environment of humans, it should clearly be possible to generate such molecules for a microbial target. In short, once direct, molecular links between a commensal microorganism and the human gut are established, drugging the former to beneficially increase that interaction should be possible, hence ultimately benefiting the latter. Most importantly, such a therapeutic effect might not be achievable by a direct treatment of human cells.

My interests in this idea stem partly stem from my enabling experience as a bio-organic and a biochemical engineer, and partly from my insatiable desire to improve human health by fundamental measures. Personally, I find the advent of antibiotics, or the impact of air bags in cars on life expectancy, much more *impressive* than, for instance, the gradual extension of an undesirable state in the treatment of late-stage cancer. This statement should by no means devaluate the medical achievement of the latter, and by no means morally question its justification; I believe that the universal and equal valuation of life is a defining aspect of humanity. Any business that caters to that ideal has a righteous purpose.

Technically, I have always been fascinated by nature’s ability to control interactions in highly complex environments. My scientific career started with an education in organic synthesis, soon to move on to biocatalysis, and the design of small molecule inhibitors. This combination gave me the opportunity to learn the methods and the objectives of how to tweak the structure of natural compounds, or de novo design artificial ones, that undergo a specific interaction with the much larger, and much more complex entities found in most biomolecules. Additionally, in my training in biotechnology and molecular biology, I found endless fascination in the function on living systems: how they form and organize, how they adapt to extraneous influence, and how they use small molecules to communicate in symbiotic fashion, or employ them with overwhelming efficiency to outcompete others.

That is particularly true for microorganisms. Their lack of higher function—judged by the standards of humans, or more generally, highly developed forms of life—is juxtaposed to their astonishing speed in adaptation and ability to endure hostile surroundings with minimum requirements for nutrition. This simplicity in cultivation has enabled their use in technology for millennia. I thus argue that the otherwise almost prohibitively complex task of studying the effects of drugs on an organism (in higher organisms) should be a tractable problem in microbes. To me it seems almost wasteful to ignore the potential of such a system, except for the design of those economically challenged drugs that simply kill malicious prokaryotes.

The following stage—the investigation and biomedical engineering of the symbiosis of commensal bacteria in the human gut—admittedly and most probably presents a multitude of challenges similar to the ones encountered with human-targeted drugs. Nevertheless, the decimation of uncertainty and reduction of possible trajectories of events can logically only lead to a higher chance of success, provided that the physiological interaction has been ascertained. Even failing that, the acceleration of testing cycles enables faster learning.

Specifically, by designing a small molecule drug or a combination thereof, I propose to alter the output of small-chain fatty acids in commensal bacteria in the human gut. In a collaboration with biologists and physicians at the Broad Institute of MIT and Harvard, and cell biologists at Washington University at St. Louis, we have recently shown that some short-chain fatty acids suppress inflammation in epithelial cells in intestinal crypts. These compounds originate from microbial fermentation of indigestible, dietary fibers by commensal bacteria. As such, the physiological response is a relayed effect to nutrition, which is unlikely to happen in a hypothetically sterile setting (in absence of the human microbiome).

I am convinced that this example of a beneficial symbiosis could serve as a suitable point of entry for the general approach outlined in this essay. It would make use of an array of existing expertise and technologies familiar to the field of drug development, but also open up new paths of collaboration and widen the horizon by directly including microbiologists in drug design, without limiting them to killing microbes—surely a refreshing argument.

Teaching Interests: Biochemistry, (bio)organic chemistry, bioengineering, biocatalysis, enzymology, quantitative analytical chemistry, thermodynamics, separation science.