Stephanie Culler
Designing microbiome therapeutics to help cure cancer
TEDxSanDiego 2018

It’s 2:00 AM and I’m all alone in the biology lab at CalTech. As I’m looking into the microscope, I can’t believe my eyes. After five years of failure and personal struggle, I had succeeded in the development of an engineered human cell.

This human cell contained a genetic circuit made of DNA that was programmable, much like the electronic circuits in computers. This circuit was wired to detect the onset of cancer. It could be wired to detect any signal. This cell could only detect proteins created by cancer. If it detected these proteins, it would express a death gene, essentially killing itself.

Up to this point, most genetic circuits could detect only few sets of inputs and required long development times. This circuit was modular and could be rapidly programmed to tap into a wide range of biological pathways in different types of cells.

This work went on to be published in Science Magazine. It was highlighted as one of the top breakthroughs of 2010. While this was an important scientific and persona achievement, it only partially fulfilled a promise that I made to my grandmothers who had passed away over 16 years prior. The promise was that I would do something about cancer.

However, as a young teenager I didn’t quite know the best way to fulfill this promise. In middle school, for my eighth-grade report, reflecting on my life up to that point, I had made the dedication to my family, my grandparents, and of course to the cure of cancer. In high school this promise led me to volunteer hundreds of hours at the local hospital, The American Red Cross, and American Cancer Society.

I realized through those efforts that I wanted to become a scientist, to help develop the next generation of cancer therapeutics. It was that desire and passion that brought me to CalTech where I performed my graduate work in the department of chemical engineering developing novel intelligent cancer therapeutics.

My research made me hungry to be an entrepreneur and to see my efforts translated into impactful products. I decided that industry was the path forward and that if I could be successful in developing groundbreaking technologies that I could do the same with my own company.

In the Summer of 2010, I joined a local company here in San Diego, Genomatica. Under the leadership of the systems biology department head, I helped pioneer new technologies for engineering microbes to turn sugar and other renewable feedstocks, like waste gas, into commodity chemicals that up to that point could only be produced from petroleum. Essentially, we made tiny microbial chemical factories.

We succeeded in developing, scaling, and commercializing the world’s first fermentation of a non-natural chemical, 1,4-butanediol, found in a variety of every day plastics. This was a major step forward for the chemical industry, as it eliminated the use of toxic chemicals and nonrenewable resources like oil. The developed technology was recognized with the Presidential Green Chemistry Award.

Over the years I had attended conferences and read a variety of publications. In the process, I began to learn more about the microbiome, this brand-new field about the microbes in and outside of our bodies. It wasn’t until 2015 that I had truly become interested and fascinated by the role of the gut microbiome and human health.

As I dug into the literature, I began to understand the meaning behind Hippocrates quote, behind Hippocrates saying from over 2,000 years ago, that all disease begins in the gut. That’s because the gut is the largest immune organ. The immune system is the body’s defense against infectious organism and other invaders. In fact, 80% of our immune cells exist in our gut.

Another important role of a healthy gut microbiome is to produce nutrients, vitamins, and bioactives that help promote normal immune function to prevent disease like cancer. They can become damaged or dysbiotic through the impact of diet, lifestyle, and antibiotic use, for example. Dysbiotic ones have been linked to a number of diseases, including autism, Parkinson’s disease, and diabetes. As such, one could think of the gut microbiome as the gatekeeper of the immune system.

What surprised me about my research was the realization that even though I was a scientist and a true expert on how microbes function, I had taken for granted an important role of the microbiome. For the general public, this topic is rarely even discussed.

What is the role of the microbiome in nutrition? That’s where the nutrients and bioactives that may have potent anti-cancer and anti-inflammatory properties are extracted from the vegetables and fruits that we eat.

But not all of us have the microbes responsible for this extraction. Even healthy people may be missing these microbes. Cancer patients and others with damaged microbiomes are far more likely to be missing them.

As I began to understand this fundamental role of the microbiome in nutrition, I remembered the poster that my grandmothers received over 20 years ago from the American Cancer Society when they were first diagnosed. It displayed fruits and vegetables that could reduce your risk of cancer, and possibly help you fight it.

This poster was on the door of my parents’ refrigerator for many years and it was engrained in my memory. Broccoli, the anti-cancer posterchild was featured. In fact, you need gut microbes to extract the anti-cancer metabolites from cooked broccoli.

I wondered if my grandmothers with cancer were missing those gut microbes. Was it even possible for them to reap the benefits of eating a healthy diet? Was the focus on eating the right foods flawed? It was becoming clear to me why Hippocrates said, “Let thy food by thy medicine.”

Over the years this department head and I worked on many projects together. We ultimately realized that our knowledge and experience with microbes could be leveraged for developing microbiome therapeutics to repair damaged ones, so in the Summer of 2017 we founded Persephone Biome.

I was inspired by the important function of gut microbes in producing anti-cancer and anti-inflammatory compounds from the food that we eat. I wondered if the engineering and systems biology skills that I had developed throughout my career could be used for the prevention and treatment of disease. Could we develop microbiome therapeutics to give back those missing gut microbes and functions to cancer patients and others struggling with disease?

The microbiome is not only involved in human health, it also impacts how well medicines work. In fact, the microbiome impacts the efficacy of over 50 FDA approved drugs. The microbiome can modify the chemical features of these drugs or influence how the immune system responds. These include drugs like pain relievers we take every day to more complex chemotherapy drugs.

One class of cancer drugs recently shown to be influenced by the microbiome are immuno-oncology drugs, also known as checkpoint inhibitors. These are relatively new cancer drugs. Cancerous tumors normally evade the immune system through a variety of mechanisms. Checkpoint inhibitors are groundbreaking drugs that essentially remove the blindfold off of the immune system, allow it to recognize, attack, and kill cancer cells.

These can be a cure for some patients. We can actually say there are cures for cancer. Examples include blockbuster drugs which you may have heard of, Yervoy, Opdivo, and Keytruda. However, these drugs are effective in less than 30% of cancer patients in which they are used.

Earlier this year, three high impact publications in Science Magazine demonstrated the gut microbes influence and modulate the efficacy of checkpoint inhibitors. These studies used next generation genome sequencing technologies to identify the bacteria in the gut microbiomes of these patients.

It was shown for cancer patients that respond, they have diverse microbiomes, they have lots of different kinds of microbes, diverse in function. Unfortunately, for the 70% of cancer patients that don’t respond, they have severely damaged microbiomes with limited kinds of bacteria, which results in limited function.

At Persephone Biome we are discovering the gut microbes and how they function for patient response. We use this knowledge to create microbiome therapeutics, to give back those missing gut microbes and functions to patients. We want to help all cancer patients, but most importantly to convert non-responders to becoming responders. Could we go from 30% potential cures to 50%, 70%, or higher?

To find out, we isolated gut bacteria from healthy individuals. We put together rational groups of gut bacteria that we believed would improve a patient’s immune response to checkpoint inhibitor therapy.

We evaluated our therapeutic in a preclinical colon cancer mouse model.

Shown here is tumor size. In the absence of drug. In the presence of our microbial therapeutic. Checkpoint inhibitor alone. Checkpoint inhibitor with our microbial therapeutic. You can see the substantial reduction in tumor size.

With this groundbreaking data in hand, we’ve begun the development journey towards clinical trials and aim to be in the clinic by the end of next year.

How can we positively influence our microbiome? First, prebiotics feed the microbes already in our gut. Prebiotics are typically nondigestible fiber compounds. Foods such as cereals, bran, legumes, bananas, onion, and garlic are good sources of prebiotics. Bear in mind that eating a diet rich in fruits and vegetables can also help you keep your prebiotic intake up.

Probiotics are live microbes and can also be beneficial for gut health. Naturally fermented foods such as kefir, yogurt, tempeh, kimchi, and sauerkraut contain the highest amount of active live microbes.

Unlike our own genome, which is mostly fixed from birth, the microbiome can be modified by our diet, overall lifestyle, and microbial therapeutics. We can all take charge of this amazing gatekeeper of our immune system and use it to prevent and fight disease. We can all be active participants when it comes to gut health.

Thank you.