Tackling the microbiome from the ground up

On any given day, Laura Keller jokes that she is either a chemist or a biologist: it depends on which experiments are working well when you ask. In reality, Keller integrates both disciplines in her research studying microbes that live in the gut — called the microbiome.

As both a student in the Chemical and Systems Biology graduate program and a trainee in ChEM-H’s Chemistry/Biology Interface (CBI) Training Program, Keller works in the lab of Matthew Bogyo, where chemical techniques provide a fresh approach to understanding biological problems. Keller employs her undergraduate degree in biochemistry in her own research exploring common molecules that exploit vulnerabilities in harmful gut bacteria to develop better ways of fighting disease.

Keller says the CBI program crystallized the idea she had of combining chemistry and biology to better understand disease. “When I was applying to graduate school, I was working in the Alzheimer’s field. There were all these commonalities among different neurodegenerative diseases, but many therapeutics weren't working,” she says. “It was like: we need a reset, a new way to understand what's going on in these diseases. I was looking for how I could fuse chemical intuition with practical applications in biology to help human health.”

Keller spoke with ChEM-H about her current projects, what ChEM-H means to her, and how she’s grown as a scientist since starting her graduate career five years ago.

So, are you a chemist or a biologist?

That is something I ask myself every day at this point. My background is in neurobiology, and I wanted to develop more chemistry and chemical biology tools when I came here. In the lab, I have done chemistry, chemical biology, microbiology, biochemistry… My goal for my training is to be a chemical biologist, or a biologist who can have conversations with chemists and has enough understanding of what is possible in chemistry. It’s being able to connect all those different threads and have that lightbulb go off.

What is the central premise of your research?

Everyone knows what an antibiotic is, you take an antibiotic when you have an infection. So, antibiotics are really great at killing the bacteria that cause infection, but you also wipe out all of your good bacteria, and you get multi-drug-resistant bacteria if you don't use them well.

By that, I mean you are taking antibiotics unnecessarily or not completing the full course, because then you are exposing the bacteria to antibiotics unnecessarily and selecting for bacteria that are slightly more resistant to the antibiotics. It’s both on an individual level of taking the full prescription and using antibiotics responsibly, and on the systemic level of thinking about how we prescribe people these antibiotics.

With a lot of diseases of the gut microbiome, like inflammatory bowel diseases (IBD), you need to maybe only kill a couple of the bacteria, or just make their lives harder so that the good bacteria can take over. My research focuses on trying to understand how to kill just the bacteria that are prevalent in these gut diseases. Instead of trying to understand a complex system, we look at individual bacteria that are important and go from the ground up, working backwards. That way, when we're trying to develop drugs for IBD or other infections, we can go after targets that are unique to the bad bacteria and hopefully won't also kill the good bacteria. We’re trying to not view all bacteria the same. Some are good, and we want to leave them alone. Let them be! 

How does your project fit in to ChEM-H?

I was inspired by a 2019 conference in Montréal called “Microbiome: Chemical Mechanisms and Biological Consequences,” which I attended with funding from CBI. It was really cool to attend this conference when I was starting this project and get a sense of what the field is doing, the skill set that my lab has, and the resources that we have at Stanford through collaborations with great, renowned labs that are well-established in the microbiome field.

There's so much data out there showing correlations between different bacteria and different diseases. It’s really blossomed over the past decade or so. Still, there aren't a lot of great ways to understand how to target specific bacteria or specific chemical pathways to cure a disease. My project stems from that: how can we use chemical tools to better understand the gut microbiome? What can we target in order to shift the composition of microbial populations like the ones we see in different diseases?

Aside from the conference you just mentioned, what resources do you take advantage of most as part of the ChEM-H program?

There are a lot of different ways that you can utilize CBI and ChEM-H. Something that's been really valuable is going to happy hours, talks, and retreats, and being able to see the different research that other trainees are doing. It’s been so inspiring and powerful to see what everyone is doing, being in awe of how they have been able to combine chemistry and biology in their research to come out with these really cool stories.

Another thing that has been useful is that in ChEM-H's process of finding new faculty members, we've been able to go to different job talks and have lunches with candidates, getting a little bit of insight into how ChEM-H has thought about where they want to take the institute. We’re able to have candid conversations with up-and-coming people at the intersections of different fields.

What do you like most about ChEM-H?

As someone who cares about the success of academic research, I have seen through my own narrow lens how, as academics, we need to re-evaluate and tear down and rebuild what academia should look like. It’s seeing how we can make concrete strides towards improving diversity and the inclusion of people from systemically marginalized backgrounds, and how we can continue to support further diversity and equity in STEM.  I have noticed a lot of work from ChEM-H, both from the top and from the CBI trainees for these kinds of policies. The actions that they've made seem very impactful, and while all progress is slow, it seems like they are doing a great job of making strides in the right direction.

What are you most proud of accomplishing to date?

I am very proud of how I have developed as a scientist in graduate school. I think I have become a lot more independent, and a lot more curious. Being in an environment where I've been able to do chemistry, and proteomics, and microbiology, I think I've learned a lot, both technique-wise and also how to think about science and how to think about it on my own.