Bugs as drugs – Innovating in the Microbiome space

Thank you! So much has happened over the past 17 years since I’ve been at the Sanger, not sure how far back we can go.

But before we continue, I must say that the focus here has to be the team at Microbiotica. I co-founded the company and helped hire the right people to run it, so it has been a massive team effort that delivered on the incredible work. The team had to innovate in a completely new area of medicine with novel bacteria, some of which still don’t even have names.

So, how did it all happen? I’ll take you through it all in a summarised way. Microbiotica was founded in 2016 but I’d been working on the scientific ideas behind the company for a long time before that. I recall we talked about it openly for a case study featuring Microbiotica a couple of years back.

“As a postdoc in 2007, I started a research programme here at Sanger on Clostridium difficile, a bacterium that causes colon infection. Back then, I was investigating the possibility of modulating the mouse microbiome by transplanting ‘good’ missing bacteria to treat a C. difficile infection. It worked and that was the basis for the research I did afterwards on developing live biotherapeutic products that is applicable in humans and for other diseases.”

Dr Trevor Lawley,
Group Leader in Parasites and Microbes programme, Wellcome Sanger Institute

That research showed clear potential that bacteria from the human gut microbiome could be turned into a drug. We often call this “bugs and drugs”. It was then, with tremendous help, support and advice from the translation team at Sanger, that Gordon Dougan, former head of the Parasites and Microbes Programme at the Sanger Institute, and I decided to turn this into a company so we could benefit patients. Our aim was to be able to progress this into the clinic, as we are doing today.

Four years after spinning out from the Sanger Institute, we were very much still in the discovery phase focused on identifying the important bacteria for the products we wanted to create. However, by 2020, we had refined our search and had found two drug candidates - one for ulcerative colitis and another for advanced melanoma.

At that point, we entered the manufacturing stage, which was another whole different challenge. Many of the bacteria we have in our products are newly discovered, so the team had to do everything from scratch, figure out how to grow them in optimum conditions, for example. During the manufacturing phase, the team also had to work closely with different regulators like the Federal Drug Administration (FDA) in the US, and make sure they understood what the product was about. We had to demonstrate that the product was safe and to understand what data was required to initiate clinical trials with these novel products.

We also started planning the clinical development. We have two beautifully designed studies that we think will help us answer the questions we set out to ask. Another learning curve for all of us. We are running two phase one, in-patient clinical trials in parallel, which I’ve continuously been told is very ambitious. And there have been many challenges there too. We have two distinct products. The first one, MB097, which - fun fact - is named after my favourite hockey player, Connor McDavid, captain of the Edmonton Oilers who wears number 97, is for treating advanced melanoma. And there is also MB310, which is the second product for treating patients with ulcerative colitis. Between both products, we’re working with 17 different species of bacteria identified from the gut of healthy people.

We believe our approach will be broadly applicable to a range of diseases, but we are initially focusing on melanoma and ulcerative colitis because the science made sense and these represent two diseases with a huge unmet clinical need. We have two products that could work, and with the early scientific research having happened at the Sanger Institute through a collaboration with the Cancer, Ageing and Somatic Mutation (CASM) programme - we realised these could be life saving drugs.

We saw that the microbiome was important to how cancer patients responded to a type of immunotherapy that blocks so called ‘checkpoint proteins.’ Checkpoint proteins tend to turn off our immune cells for various reasons; by blocking them, these drugs unlock the patient’s immune system’s ability to fight off cancer cells. Approximately 45 per cent of patients treated for advanced melanoma, a skin cancer that has spread through the patient’s body, had a positive clinical response after this type of immunotherapy. But what about the other 55 per cent? We looked at the microbiome profile of the patients that had not responded and found that they had certain groups of bugs that were missing from their gut microbiome compared to those who had responded well to the therapy.

“We hypothesised that the patient’s microbiome was helping the patients respond by influencing the status of their immune system. We cultured these bacteria and turned them into orally delivered drugs, and we’re now going back to treat the patients for whom immunotherapy had previously failed. We will give them our drug, MB097, for six months and see if they then respond positively to the immunotherapy.”

Dr Trevor Lawley,
Group Leader in the Parasites and Microbes programme, Wellcome Sanger Institute

We are now also exploring applicability to other cancers by incorporating machine learning to our analyses. We have preliminary evidence that shows that some of the bacteria we are working with could be useful in other types, such as lung cancer.

The other product, MB310 is for ulcerative colitis, a condition in which the colon and rectum become inflamed. It is a painful disease which can mean some of the patients need to have part of their colon removed. At the Sanger Institute, there’s been work focusing on the genes that make people prone to the disease, but the consensus is that a combination of susceptibility genes and the composition of the microbiome can lead to the disease.

So, we looked at fecal microbiota transplantation studies. It doesn’t sound nice, but that’s the science of poo! There was a paper in 2015 from a Canadian group that showed that you could transfer stool from a healthy donor into patients with ulcerative colitis and get a good response rate - the patients got a great benefit with minimal side effects. We created our drug following this body of evidence and now we have started testing it. We’re going to see if we can help patients recover from ulcerative colitis by restoring their microbiome so they can avoid having part of their bowels removed.

Setting up Microbiotica has been really rewarding, especially now that we're a clinical stage company. It feels incredibly exciting to start seeing our products tested in the clinic. Through it all, I’ve kept learning. Business Development is not my area of expertise - but I’ve had the opportunity to learn through all the phases of drug discovery and development, from how to develop a drug, to designing clinical trials and how to approach manufacturing and regulators. The Sanger Institute is a big piece of the company as well - it’s a bench to bedside story.

I still serve as the Chief Scientific Officer of Microbiotica and also maintain my Faculty position at Sanger. For my Sanger role I invest a lot of my time into training students and providing opportunities for their career development. So, I feel privileged to Chair the Sanger International Fellows programme working closely with Alice Mann from the Academics Programme team.

It’s a brilliant scheme focused on enabling scientists from low and middle income countries with access to genomics, training and mentorship. I’m so proud of what all the International Fellows are achieving, they are such a force - incredibly motivated individuals with commitment, and a huge knowledge of the local and regional issues affecting their communities in different parts of the world.

The International Fellows scheme was started by Gordon Dougan in 2012, when he was still Head of the Parasites and Microbes programme. It was then coordinated by other colleagues, Marcus Lee and Nick Thomson and it’s now part of my remit.

Our goal is to raise the profile of the International Fellows programme. It offers so many opportunities for both the fellows and for us: mentorship, grant collaborations, team development, networking and access to large scale technology and expertise. Members of the scheme can nominate students to attend our Master’s programme, which many do and then continue at the Sanger Institute throughout their PhD. It’s a great way to attract new talent and create diversity in Sanger science.

This year we’ve announced six new fellows and bid farewell to three, but the collaborations and projects they have started with us will continue to thrive. Claire Chewapreecha, from the Mahidol Oxford Tropical Medicine Research Unit in Thailand, is doing incredible work on a neglected tropical disease called melioidosis and has even presented a novel diagnostic test for the disease, which could save thousands of lives. Another example, Daniela Robles is focusing her work on a type of skin cancer, acral melanoma, which has no current treatments, but is a common form of cancer in Mexico. Very much needed research with a lot of regional impact.

“The International Fellows scheme is a shared project for the Faculty at Sanger, and we now have fellows representing different scientific programmes within the Institute, which shows how we’re broadening collaborations internally too. My goal now is to grow the scheme - how can we fund more projects and more fellows? Let’s see what the future holds.”

Dr Trevor Lawley,
Group Leader in the Parasites and Microbes programme, Wellcome Sanger Institute

Yes, we're recruiting 7,000 mother-baby pairs. This is a project led by the University of Liverpool and us at the Sanger Institute. The big question we want to answer is - how does breastfeeding impact a child’s microbiome and how does that, in turn, condition their growth, development and disease resistance throughout their life?

The idea is to analyse poo samples from the babies until they are two years old to look at the evolution of the microbes in their guts. Parallel to that, we’ll be analysing the breast milk, which we know provides growing babies with nutrients as well as good bacteria from their mothers. Being part of a large, longitudinal study means we will have enough data on all of these things to study the links between these factors and the early life microbiome.

The project is currently recruiting participants locally and it’ll be a total of 7,000 volunteers, mother-baby pairs. The study will be linked to anonymised electronic health records as the children grow and we’ll be able to monitor their health long term.

There are so many questions we hope to get answers to, including how does early life affect our health later in life? It’s an exciting project as it is the first one of its kind in terms of the research - looking into the microbiome of the babies and analysing the microbes in the milk. Plus its relationship not only with physical diseases but with mental health too, and the scale of the project, in terms of people recruited and number of years it’ll encompass.

I am - if you look at the microbiome, it can tell us so much. But it can tell us even more if we analyse it during early life. There are children, as we see in a global collaboration we’re part of, the Childhood Acute Illness and Nutrition Network (CHAIN), that even when they get the right nutrients, they can’t absorb them. That’s all down to their microbiome - it didn’t have the healthy bacteria in soon enough and now they’re missing crucial bugs. This is true for allergies or other conditions, like asthma, and we think we might be able to link it to mental health too.

I truly believe that by improving our gut microbiome in the early stages we will be able to improve health in the long term. The science we’re discovering seems to back this. This is where we can have an impact and that’s why this work is so exciting. We can look at curing diseases and recovering from cancer, but this research looks at prevention - how can we prevent those diseases in the first place?

My focus has always been on impact - how can I have the biggest impact in people’s lives with my research? The microbiome is such an interesting space. There’s a whole ecosystem of bugs living within us, each a different world, with their synergies, environments and ways of working together. Throughout my career, I’ve always tried to spot the opportunities to bring my work closer to improving people’s lives. It’s what I hope Microbiotica will attain, and what I hope our research and efforts in expanding microbiome research to underrepresented areas of the globe will help us achieve too.