In 2019, clinically-studied probiotic specialist Seed Health launched a partner company known as Luca Biologics focused on women’s health. Based on 15 years of academic vaginal microbiome research, LUCA’s pipeline targets urinary tract infections (UTI), bacterial vaginosis and preterm birth. The company’s first drug candidate targets UTIs and will enter a Phase 1b trial this year.
The company’s chief scientist, Dr. Jacques Ravel, led research recently published in Genome Biology that shed light on vaginal microbe composition and its functions.
We recently spoke with Dr. Ravel to learn more about that research and Luca Biologics’ pipeline.
Drug Discovery & Development: What initially inspired you to focus on microbial ecology?
Ravel: My Ph.D. was in microbial ecology at the University of Maryland, and my postdoc at Johns Hopkins University focused on natural product chemistry. While doing the postdoc, I taught myself bioinformatics, mining the genome for natural product pathways. After my postdoc, I joined the faculty at The Institute for Genomic Research (TIGR), which Craig Venter and Claire Fraser founded in 1990. The institute sequenced the first microbial genome in 1995.
Jacques Ravel. Image courtesy of Luca Biologics.
I joined in 2002 and started doing a lot of microbial genomics. That was a boom phase in microbial genomics. Every bacterium had to have its genome sequenced.
At that time, I started shifting my research toward ecology. I wanted to understand communities of microbes using the technology that we had available at TIGR, which was mostly sequencing-based.
We started doing metagenomic sequencing of microbial communities. The first paper that we published was on the gut. The gut is so complex that we spent half a million dollars and didn’t really have much to show for it.
I felt like it would be better to have a less complex system. And that’s when I met my collaborator, Larry Forney of the University of Idaho. He had already done some work on the vaginal microbiome — mostly from a microbiology perspective. I brought in the genomics, and then we merged our research.
That is how I got into the vaginal microbiome, women’s health and sexually transmitted infections.
It’s been almost 20 years that I’ve been doing this work.
Drug Discovery & Development: Can you share more on the topic of the diversity of the microbiome and its role in your research?
Ravel: The basis of Luca Biologics is the discovery of unseen diversity in what we believe to be the low-diversity community of the vaginal microbiome. Healthy communities of bacteria are characterized by low diversity because one species dominates — Lactobacillus.
But, ecologically, it makes zero sense to have one species dominate without genetic diversity within that species. Within that community dominated by one species, every member of that species is not clonal — it’s not identical to the other. There’s diversity.
It’s similar to how humans have colonized the earth, but we are all different. Each of us has very tiny genetic differences, and that diversity manifests through different phenotypes, whether it’s our appearance or what we contribute to society.
Microbes in the vaginal microbiome are the same. Even though one species dominates a community, many strains work together towards one goal, which is establishing and maintaining that community and the stability of the community. If one clone disappears, another might take over because there is a redundancy of functions.
We’ve discovered this microecology, which is what we are leveraging to develop better products for modulating the vaginal microbiome.
Drug Discovery & Development: Can you say more about what led to the founding of Luca Biologics?
Ravel: I met Raja Dhir, the co-CEO of Seed Health, which was founded in 2015 when I was on sabbatical in Paris. We just really clicked, and it was a great collaboration.
I always wanted to found a company to leverage my work, but the big challenge is that I’m a scientist. I don’t know anything about business. I don’t know anything about how to start a company. Raja had all of that business experience and is also a scientist.
Seed Health is a company, but it is also a foundry. They support startup companies financially.
We incorporated in 2019, and we are about to go into a clinical trial.
Drug Discovery & Development: What can you say about your first clinical trial?
Ravel: To us, the most important thing is going through the regulatory process. We don’t want to put a product on a shelf to sell with broad claims that is not substantiated by science. So that’s why Luca is going through that meticulous and expensive process to get FDA approval.
The first indication that we were going after is UTI for women. We are bringing a new approach to treatment.
One of the big challenges in treating UTIs is that there’s basically only one tool — antibiotics.
The efficient ones have enormous side effects that are not pleasant.
UTI in itself is not a pleasant disease. It’s often recurrent. It plagues the quality of life for many, many women.
About 10 million women experience UTIs every year.
That means using antibiotics, and then if the infection comes back, you use more antibiotics, and the bacteria become more resistant, and you switch antibiotics. It’s a constant battle.
Women who have been suffering from UTIs will tell you that it’s horrible.
We are bringing a different approach to treating UTIs. We are building a tool to prevent its recurrence.
One of the big things is that the gut is believed to be the reservoir for UTIs because E. coli lives in the gut. But the problem is that the urethra is pretty far from the rectum, and organisms don’t just jump from the rectum to the urethra. There’s an intermediate reservoir here, which is the vagina. We see E. coli all the time in a vagina. They don’t have to be in very high abundance, but they will colonize and then expand in the urethra.
So there’s a barrier there that’s not optimal in many women. And so the idea is to modulate the composition of the microbiota to restore that barrier, so even if E. coli comes from the gut, it’s just not going to survive in that environment, and they won’t colonize the urethra.
That’s part of the approach that we are using. We’re reconstructing this microecology. It would be a microbiome-based product in many ways. Many players work together to maintain that stable ecosystem.
We’re expanding into a different formulation for bacterial vaginosis, and attached to this is also the prevention of preterm birth.
Drug Discovery & Development: Can you say more about the problems associated with the widespread use of antibiotics to treat UTIs?
Ravel: Antibiotics work, but often we don’t think about their impact.
For example, I also study chlamydial infections. The antibiotic therapy that cures chlamydia wipes out the only protection a woman has against chlamydia.
So we get rid of chlamydia, but we expose a woman to reinfection by chlamydia because we basically eliminate the vaginal microbiome. Almost every organism is sensitive to azithromycin, the primary drug you give for UTIs. It is often given at such a high dose — 1 g — that it just wipes out everything, so reinfection is common.
That’s just not acceptable.
Again, stopping recurrence involves reestablishing this barrier that should not have been destroyed with antibiotics. And then, after that, the idea is to be antibiotic sparing because you don’t have a recurrence.
Drug Discovery & Development: Can you provide a synopsis of the research recently published in Genome Biology?
Ravel: There’s been a lot of discussion in the microbiome field related to bacteria that are present in low abundance are important. And in many ways, it’s really hard conceptually to understand this.
In that paper, we looked at the presence of bacteria, what they do and how much they contribute to the community as a whole.
We found that it is true that bacteria that are present in lower abundance contribute a lot and play an important role in the function of that community.
In terms of diagnostics and new targets, it’s very important to understand who those bacterial players are. So we highlighted some of those.
If you think about the microbiome as a field, more than 10 years after the initiation of the Human Microbiome Project, almost all studies have been extremely descriptive and associative.
A paper might conclude that the presence of a type of bacteria is associated with a certain symptom or disease. The bigger problem with this is that when you say this to people, they immediately think, ‘Oh, this bacteria causes this disease or this symptom — even though it’s a simple association.’ But in those studies, you differentiate between cause or effect. Did the disease change the microbiome, or did the change in the microbiome lead to the disease? By looking at an association, we cannot establish that relationship.
What a lot of people are doing in the microbiome space is based on these associations. For example, scientists saw fusobacterium on colon cancer, so there’s an idea that the bacteria cause colon cancer. That’s been the dogma since discovering the bacterium in colon cancer.
In the paper in Genome Biology, we look over time at what those microbes are doing. We used strong bioinformatics and combined metagenomic data with descriptive, functional and transcriptomics data from a microbial perspective. Then, we turned that into functional roles for those different microbes in different phenotypes.
We found something that will be very useful to the future in terms of what is protective in the vaginal environment. We discovered is that lactobacillus in the vagina, unlike the gut, the food for bacteria comes from the host. The host provides the food. And what we find is that in a vagina, we know that there’s a layer of mucus produced by the cervix that just flows down from the cervix, and it protects the epithelium. Human cells don’t like to be touched by bacteria. Almost every cell responds to bacteria — even good ones.
Mucus provides this buffer to that reaction. The way those non-lactobacillus bacteria — this diverse community — can create problems by using the glycan, the sugar associated with mucus, to access the epithelium, the cells. And then the cells can react.
Some bacteria produce cytolysin, a pore-forming toxin that lies in the epithelium. But on the other hand, we found that lactobacillus is completely unable to use the sugars present on the mucus. No enzyme is expressed that could use those sugars. That is really good because what it’s doing is that it’s surviving on the top, and it’s not eliminating that protective layer. It uses glycogen present in the epithelial cells that are consistently shed to grow. So it’s using the reject product of the host, which sheds cells because they regenerate that vaginal epithelium constantly. So it uses those resources as opposed to the protective layers — mucus.
That was very important because nobody understood which nutrients bacteria were using in the vaginal microbiome.
If you think about what they use, you can now support their growth by providing what they use. And if you know what other bacteria use, you can inhibit the enzymes related to the sugars or enzymes they use.
So we gained a much clearer understanding of that ecology. That will help us develop better drugs, better products and better bacteria in the future.