Personalized medicine isn’t all about our DNA. Researchers are increasingly looking past the information encoded on our genes to find answers to how individual variation contributes to complex disease; epigenomics, transcriptomics and proteomics are proving their worth in the lab and clinic.
But things get really interesting once you forget about human cells altogether.
Companies like the Cambridge-based Microbiotica are much more interested in the bacterial cells that live inside us; our microbiome.
Harnessing the Human Microbiome
Microbiotica’s research goes in two directions, says Mike Romanos, Microbiotica’s co-founder and CEO. “One is using the latest technology to make next generation therapeutic products, or medicines, comprising bacteria themselves, for various diseases. The other is using that same technology to understand the bacteria associated with our response to other medicines.”
Most of the medicines we take have to at some point reckon with our gastrointestinal (GI) tract. The GI tract is, Romanos says, really under the control of our gut bacteria (unsurprising, given that there are roughly 39 trillion bacteria in there). “Indirectly, the composition of the bacteria in our gut controls autoimmune disorders, tumor rejection, brain function, metabolism and cardiovascular function,” says Romanos.
Given the vast size of our microbiome, it has remained chronically understudied, Romanos says, “In the past, the community believed that many gut bacteria were not culturable outside the intestine.” This means that only a limited amount of our microbiome has been properly sequenced. Whilst the brain is often considered the greatest mystery of biology, there has been a similar-sized knowledge void sitting in our gut the whole time.
Culturing the Unculturable
What then, has emboldened Microbiotica to harness bacteria for medical purposes? The answer lies with the work of the company’s Chief Scientific Officer, Trevor Lawley. A group leader at the Wellcome Sanger Institute near Cambridge, Lawley has focused his research on the notorious pathogen Clostridium difficile. He has helped develop tools including the Human Pan-Microbe Communities (HPMC) database, a curated, searchable store of over 1800 gastrointestinal microbiome samples, and a novel workflow for culturing bacteria based on shotgun sequencing and the broad-range bacteriological medium, YCFA. This workflow’s results were published in 2016 and in one fell swoop, archived 90 species from the Human Microbiome Project’s ‘most wanted’ list of previously uncultured and unsequenced microbes. Armed with these tools, Lawley’s work is now propelling Microbiotica. This means the company can pack quite the punch, says Romanos: “We have the most powerful library for microbiome analysis in the world, and it will become by far the biggest collection of the world's microbiomes, which allows us to get the speediest and highest precision in understanding what species are relevant, even at a very large clinical trial scale.”
This technology has led to a much publicized $534 million collaboration between Microbiotica and Genentech, the Roche-owned biotech giant. This represents that company’s first foray into the microbiome, an exciting sign for the industry, says Romanos, “Genentech are characterized by having a tremendously high scientific reputation in the industry. Although they're part of Roche, they've been kept separate, and they have this sort of innovative, entrepreneurial spirit, even though they're quite big.” The collaboration involves using Microbiotica’s tech to both create bacteria-based medicine and use microbiome information to predict drug responses to diseases.
Aiming at IBD
The collaboration’s first project targets the group of complex and chronic conditions broadly termed Inflammatory Bowel Disease, “Genentech’s primary motivation is to understand microbiome signatures of drug response in their pipeline of IBD medicines. That means which bacteria in the patients predict a positive response to the medicines, and which ones predict a negative response to the medicines. We're talking here about quite advanced clinical trials with many, many patients globally,” says Romanos.
Microbiotica also bring an informatics toolkit to assist with this analysis. “Because it's such a complex thing, the microbiome, you have different bacteria which can perform the same function. We use artificial intelligence to work out what those signatures are, and it may be that those signatures comprise alternates. From those signatures, Genentech will potentially get diagnostics which will tell them where to use their medicines, and where not to use them, and also bacteria that could be used as adjuvant medicines.”
Making Medicine with Microbes
The Genentech collaboration also aims to use the bacteria identified by Microbiotica’s workflow as medicines themselves. The pioneer area for this research, says Romanos, is in combating C. difficile, that old foe of Lawley’s: “In the US, 30,000 people die every year from recurrent C. difficile infection. We know that it can become antibiotic resistant and it costs the economy a vast amount every year in hospital treatment. The premier therapy now, around the world, for recurrent C. difficile, is fecal microbiota transplantation, or FMT.”
As might be expected, Romanos says this business of moving feces from person to person is a messy business, and despite its widely recognized success in treating refractory cases of C. difficile infection, the therapeutic mechanism behind FMT is still poorly understood. Microbiotica’s insight was once again based off of Lawley’s research: he showed in a 2012 paper that there was no need to transplant whole feces when treating C. difficile in mice. Instead, transplanting selected bacteria from the feces, identified using sequencing analysis, does the job just as well. Romanos suggests the bacteria could be delivered through an orally-given capsule (a massive plus to patients used to more invasive methods), and he hopes it could hit clinics as early as 2020.
C. difficile represents only Microbiotica’s first target for its microbial medicine. Romanos says the company has plans to move into targeting IBD with their successor to FMT. “It's been shown now that FMT cures ulcerative colitis (a type of IBD) in about 30% of cases. Only a few trials have been done with fecal transplantation, but the guy who did the best one, in Australia, approached us. We're now collaborating with his group, using their samples to analyze which bacteria transferred from the fecal transplant will effect the cure, using our technology. That will be our next product, defining the bacteria that have already been shown to work in a fecal transplantation study of ulcerative colitis.”
The Biggest Fish
Microbiotica’s next move after that, says Romanos, is to take aim at the biggest fish in the pharmaceutical sea: immuno-oncology. This field targets the processes that stop our immune cells from destroying cancer on their own. Drugs in the field include Merck’s Keytruda, an antibody that targets the PD-1 receptor, allowing the immune system to recognize more cancer cells. Merck made $3.809 billion from Keytruda in 2017 alone. This is big business. Microbiotica’s role, says Romanos, could be to make sure that the right drugs are being used in the right patients: “Immuno-oncology is curing people of cancer for the first time ever, and yet the response of that medicine is dependent on the gut bacteria. I think most people believe that now. If you have the right gut bacteria, your immune system will respond and reject the tumor. If you don't, it doesn't. If you have the wrong bacteria, you'll get serious side effects.”
The Stage is Set
It's an exciting time for microbial therapeutics. Even in the UK, which Romanos says has lagged behind other countries in the field, Aberdeen-based 4D Pharma has set up a collaboration with Merck to determine the potential role of microbes in Keytruda therapy. Romanos believe that Microbiotica’s location in Cambridge can provide them the academic and financial strength to compete in what is sure to become a competitive market. He mentions the influence of the Sanger as being key, alongside collaborations with colleagues in Addenbrooke’s Hospital in the Cambridge Biomedical Campus and investment from Cambridge Innovation Capital, which gave Microbiotica a seed fund of £8 million just eighteen months before the half billion rolled in from Genentech (not a bad return on investment).
The stage is set for the microbiome to take a central role in personalized medical initiatives as it is finally recognized alongside other omics as a major determinant of our health. Romanos believes that Microbiotica’s toolkit will ultimately help research drill down to answer basic questions about diseases: “When we're able to map, at scale, all the bacteria in many different people associated with a disease, then I think we're going to start learning more, and we'll get to the mechanisms as well.”