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Data Mining the Microbiome Toward a Cure for Inflammatory Disease, by Peter DiLaura of Second Genome


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Wait, we take antibiotics through our food supply?!

If you take the roughly last 70 years of Western society, we have changed the way that we are colonized. Kids delivered via C-section have a different bacterial community than those delivered vaginally. We have also changed our nutritional sources: breast-fed infants have a different microbiome than formula-fed infants, and a high fat diet produces a different microbiome than a low fat diet.

When you take antibiotics, which we do all the time both through medicine and through our food supply, there is a huge impact on the microbiome. We are just now discovering that these changes are having a pretty profound effect on our health and wellness.

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Second Genome is particularly focused on barriers and barrier function.

In gut inflammation, in diseases like inflammatory bowel disease (which includes Crohn’s and ulcerative colitis), the barrier that normally separates microbiome from host is damaged, and bacteria are setting off a danger signal to the host. This drives inflammation, which then has a number of downstream effects.

There are a few key elements that are required to harness microbiome science for drug discovery.

First, the field has moved forward because of the very significant advances in sequencing technology. Most of us are familiar with the Human Genome Project, which was driven by the National Institutes of Health [NIH] and others, close to twenty years ago. This was a massive undertaking costing billions of dollars to sequence the human genome. Today, the capability to do that work costs a few thousand dollars, it can happen very quickly, and it can happen with an incredibly high degree of fidelity and accuracy.

This increase in sequencing technology, which has been faster than Moore’s Law, allows us to take a biological sample and understand the genomics of that biological sample. Taking a skin swab, a fecal sample, or a biopsy from inside the intestine, we can look at the bacterial community. At Second Genome, we have built a platform that allows us to sequence the microbiome in a number of different settings, and we have analyzed thousands of samples from patients across multiple disease settings; and we have generated terabytes of data from these experiments that we then can crunch.

The second big component of our capabilities is our computational biology infrastructure that allows us to take these massive data sets and analyze these data in a way that allows us to look at differential signals. What is the microbiome doing when diseased that it is not doing when healthy? How is the host expression – that is what is going on at a cellular level in the host – changing in response? We can integrate these data sets and analyze them and separate signal from noise in ways that were not computationally possible or affordable just a couple of years ago. So the next step of this analysis is that we crunch these big data, and then we develop novel hypotheses about disease understanding.

Third, after we have used our data analytics to generate hypotheses, we then have to test these hypotheses. We then move to the lab, where our teams of microbiologists and immunologists are running tests in relevant biological systems to validate our hypotheses. Initially, we perform these tests in vitro or in disease models to see if we can drive the relevant effect. And ultimately, after extensive work to characterize the potential drug, we run clinical trials in human subjects, first in healthy subjects to make sure that the drug is safe, and then in people who have the disease to establish that the drug is going to be efficacious. That is how we go from a set of microbiome samples that captures the biology that is important to understand, all the way through to a drug that will provide a meaningful treatment for patients.

Human health is not exclusively human.

It is not just things encoded in our human DNA that matter, but it is also this commensal bacterial community that we are carrying around. In many ways, we are one giant petri dish where we are cultivating this bacterial community that does great things for us, which we need to nurture.

Being thoughtful when one takes antibiotics is really important. Antibiotics are truly a miracle drug and have saved countless people and extended human life expectancy in a very meaningful way, but we have to be stewards of our use of antibiotics so that we do not endanger our microbial communities.

We often forget that a huge portion of antibiotic usage in North America goes into our food supply; when possible, buying chicken and beef that are raised antibiotic free is something that we do for our family because it has been demonstrated that even food level doses of antibiotics can have an effect on our microbiome.

And when our young children pick up something off the floor in our house and put it in their mouth, as long as they are not going to choke on it, we do not worry about it too much. They are probably picking up bacteria that is contributing to a healthier ecology. Like most things in life, more diversity is better – people that have more complex microbiomes are generally healthier.

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Probiotics as a dietary supplement will not hurt; however, for most probiotics that are available, the health value is not supported by the strong claims that exist when something has been evaluated in a rigorous clinical environment. So you know they are not going to do any harm, but it is unlikely that they are going to have a hugely beneficial effect directly on a specific disease.

How the CEO of Second Genome spends his time:

I generally try to focus on three primary questions. First, are we executing on the right strategy? Have there been any external things that require that we refine our approach? Second: do I have the right team in place? Is the team that we have assembled the right set of capabilities and personalities that will allow us to execute successfully on the strategy? And third: Do we have resources aligned where we need to invest to enable the strategy and the people to do the right things?

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