Microbes—exploiting our usually helpful and sometimes prickly partners

Can we get by with fewer antibiotics and better strategies that eliminate the bad actors and help our microbial friends?

Maryn McKeena has posted a thought-provoking and noteworthy report about the threat of pathogens that are largely resistant to contemporary antibiotics. A feature story in the Atlantic, by McKeena, also highlighted the relationship between agricultural use of antibiotics and the industry’s contribution to the emergence of resistant human pathogens.

Here, I’m going comment on the intersection between the microbes “out there,” and ones “inside” of us, and see if I can tie them together in a way that might produce for commentary.

The story of microbes that both invade and help becomes interesting when we sit back and consider that we have a shared and often totally dependent history of co-existence with many kinds of microbes; what biologists call a “commensal relationship.”

Almost all people who have stayed awake through high school biology discover—often with some degree of horror—that we subsist ourselves off a very clever and dynamic community of microbes that inhabit our gut, oral cavity, and a few other cavities, crevices, and interstices I’ll leave to your imagination. Without our gut microbial factories, doing what they do, we suffer, or at a minimum, we have a hard time doing what we do.

From the eco-biologist perspective, and putting aside our own conceit about our grandness as humans, we are, in some coldly analytical view a sentient bag that holds a happy community of bacteria in a commensal feast along the twenty feet or so of our digestive track.

Joshua Lederberg, a Nobel Laureate, and man who spent a good bit of time considering how humans and microbes get along, termed the whole arrangement “the Microbiome.” The term has stuck and the science of studying our give-and-take relationship with microbes has expanded, first as knowledge, and more recently as strategies to put that knowledge to work. Be patient, there really is a connection between this story and the threat of super-pathogens.

First, consider the scale of this “biome.” We are carrying around organisms that if counted run into the exponents of 10 to 15. Focusing just on the gut, where a lot of the action is, we carry about a glass full (8 oz.) of microbial hitchhikers, but in terms of numbers these individuals out-number our own cells by a factor of ten-to-one. The name-list is incomplete, but some of the nastiest bugs that have caused us disease, over the eons, congenially settled just below our stomach. They have holstered the laser swords in favor of dining on what’s left of our Cafe Latte or that cheeseburger with fries. There’s clues that these microbes were once pathogens, and changed sides, but when and how is not clearly established. Our own genome is replete with fragments of retrovirus DNA. As Lederberg has written, “…[we are] carrying around 500 different kinds of integrated retroviruses in our genomes that are a testimony to a history of experience with the [earlier] relatives of HIV. After millions of years, the ancient viruses we encountered now perform indispensable defense functions for the host.”

So, we can conclude that there is some sort of mutuality, some Yin-yang arrangement between humans and microbes; sometimes they get us, sometimes they cooperate. Sometimes there’s mischief lurking in the huge populations of bacteria residing in the human gut.

To now circle back to human infectious diseases, when this happy equilibrium is disturbed, when the bacteria get somewhere they’re not supposed to be, or interact outside the dining room of our gut, bad things start to happen: they can re-acquire nasty weapons they’ve been hanging onto just in case things don’t go well. A good example is when antibiotics get into our food supply and provide “selective pressure” on common organisms that are also outside their circuit, say E-coli of tainted hamburger fame. The list of misplaced and angry pathogens, and the associated diseases, is too long and dreary to report here.

To make the intersection I promised, consider the other part of the Microbiome that is not about infections. Instead it’s about chronic disease like diabetes. Disordered or dis-regulated Microbiomes are thought to affect the severity, if not the incidence, of Diabetes and other diseases heretofore magically lumped under “autoimmune disorders.” Also, to the hopes and expectations of the significantly overweight post-modern human, a rational approach to the Microbiome might just get rid of those love-handles.

So, I’m suggesting that the microbe, inside us or outside us, has the capacity for harmless commensal behavior or lethality; health or disease. What’s needed is some science to detect the bad actors and some engineering to design the goodness back when needed.

As a first line of defense, we need to detect pathogens quickly. To eliminate the really bad actors, we need to pick up our game. In the practice of managing clinical infectious diseases, we are still struggling with a simple military concept: tactical intelligence gathering. With a few exceptions the methods every clinician uses are tied to the tried-and-true “culture and sensitivity.” This approach goes back the Pasteurs and test-tubes with cotton stoppers. The patient supplies an appropriate sample from whatever ails them, and the material is incubated in growth media. Note here, you have to optimistic that the sample contains the pathogen. Over the years clever people have found ways to accelerate the identification, and to some extent the “phenotype,” or specifically, the antibiotic susceptibility of the organism being cultured. But all this is just “optimization” what is the venerable “culture and sensitivity study.” “Culture,” whether it’s your beer or your bread, is about a fixed amount of time until enough of the microbes are around that you can go to the next step. You can warm them up and give them the right nutrients, but cell division takes time. Over the last decade there have been a number of steps taken to hurry the process along by using antibody labeling or DNA fragment exam, but the majority of clinical labs can’t get a report to a clinician in less than about 36-hours and that’s often a best-guess report.

Now, here’s the conundrum: the clinical course of an acutely-infected person—to include death—can move faster than we can get “intelligence.” That’s bad news.

If we are looking for a definitive, no kidding, answer to identity of the microbe and it’s range of possible behaviors in the face of antibiotics, we need to look at the whole genome. Everything the organism—any organism—can do is coded in its DNA (or RNA). Until recently, that was not possible. There are two hurdles: a) isolating the right DNA from a cluster of “other DNA,” and b) matching the gene sequences to the known (and ideally prospective) DNA segments that code for resistance.

In the past, sequencing a microbe’s DNA was certainly time consuming and there was no real database for analyzing a sequence for markers of resistance.

In the last few years, science and computer-assisted informatics (bioinformatics) has stepped up to the plate. There are a number of technologies now aspiring to give the clinician data faster than the pathogen can do damage, and even monitor the pathogen’s response to an antibiotic. It’s all about speeding up the sequencing and the analytics—think smarter and faster than the pathogen can grow or deploy defenses, very much like a military campaign. An example—note, not THE solution, but an example—is the approach taken by researchers at the Broad Institute in Cambridge, MA: they search out microbial RNA which is basically a signal of the pathogen’s activity in the body and that includes a its strategy for defense against antibiotics (yes, a microbe has a strategy, but not a brain). Trick, course, is finding, concentrating, and analyzing this RNA. But, the advantage of this technique is that samples taken over the course of an infection will reveal whether a microbe has the capacity to resist and antibiotic, and, in turn, whether the therapeutic strategy needs to be altered. The end-game is making a therapeutic decision faster than the pathogen can mount a defense. Other technologies are coming along that increase the pace and accuracy of sequencing and data analytics. Pull on the this intellectual thread long enough and it’s possible to envision a future where antibiotic resistant pathogens face increasingly “smart” antibiotic therapies.

But, there’s always a “devil in the details” and the ability to detect and classify microbial pathogens is of no use unless we develop increasingly sophisticated approaches to combating them.

First, the economic realities are that pharmaceutical companies are not well “incentivized” to invest in new antibiotics that are used in episodic diseases; far better to invent a new drug for a chronic condition that requires daily use of medication.

Second, there’s probably a finite limit to the number of new chemicals that can be discovered, put through FDA certification, that will attack the microbe directly. Often the nifty chemical approach turns out to be toxic to the patient.

Over the last two decades scientists have increasingly “gone orthogonal” by devising clever strategies that don’t rely just on chemicals attacking bacterial structures or processes. Immunomodulators, drugs that up-regulate the patient’s immune system have been advanced, as are other strategies that seek a broader, systemic approach that is less likely to lead to a tit-for-tat battle with the microbe.

Now, this is where my tale turns back toward the Microbiome. Since this our resident tenants, or gut bacterial friends in particular, seem to have a multiform impact on our health and disease, why not bring them in as collaborators to fight the bad guys.

With funding from DARPA, a Bost0n-based firm, Ginkgo Bioworks, has be working on engineering Probiotic solutions for dangerous microbes at their source, which, as in the case of Cholera and other infectious diseases, is… out gut.

What’s really cool about this, beyond a very nice video presentation in Ginkgo’s website, is that it goes right at the source of populations of pathogenic bacteria. It’s also not exactly your run-of-the-mill “probiotics” retail product. This is real, data-driven, science, not as Ginkgo puts in their marketing material, “a bunch of people putzing around in the lab.” It’s also not anecdotal as is most of the popular probiotic (little “p” is deliberate, here) products.

It’s no surprise, then, when I noted with something of an arched eyebrow, that the “West Coastie” investor/tech accelerator, Y-Combinator, has invested in this firm.

Of course, the same strategies that create probiotics that are specifically targeted at eliminating, or managing, dangerous pathogens is also the same strategy the might be used for identifying and correcting microbial populations that produce chronic systemic diseases like Rheumatoid Arthritis or Diabetes.

And THAT is the really cool part about what Ginkgo is doing—a single scientific endeavor that has multiple applications for the health care market. That adds credence to their assertion that they are, in fact, a foundry.

So, the story does, after too much narrative, go full circle. We are what we eat, and hopefully, the microbes that help us digest our food and balance our Yin with our Yang, will stay along as white-hats in the search for health and prosperity.

Rob Carnes is co-founder of Redwood Innovation Partners, and otherwise a physician, writer, story-teller, rancher, and owner of a smart horse.