Uncovering bacterial evolution in our microbiome
How studying microbial mutations in the human body can lead to new advancements in medical therapies
The microbiome encompasses the genetic material of all the microbes living in and on us. Ask most biologists, and they’d share Dr. Tami Lieberman’s earnest enthusiasm for the field’s innumerable possibilities. Dr. Lieberman recently completed a post doctorate with professor Eric Alm and was appointed as MIT faculty a little over a year ago. She is currently an Assistant Professor at both the Institute for Medical Engineering and Science (IMES) and the Department of Civil and Environmental Engineering. As she put it:
There is enormous potential to engineer the microbiome to improve our human health, either by introducing natural bacteria that we are missing or synthesizing new bacteria. For example, creating a bacteria that secretes sunscreen whenever you’re under the sun.
To do so, however, scientists must be able to understand and predict how the microbiome will behave. This is Dr. Lieberman’s guiding question. Her group focuses on the evolution of bacteria in the human ecosystem by observing how various microbial strains colonize, adapt, and mutate in the human microbiome. Dr. Lieberman views her work as complementary to recent applied work in the field, such as fecal transplants. Fecal transplants have gained widespread attention for their near 90 percent efficacy in treating the gastrointestinal infection C. difficile colitis. In analogous terms, the therapy “plants a tree in a wiped out forest.” However, little is understood about what would happen if a tree were introduced to an “already-thriving forest.” This is where Lieberman’s research fits in.
While the microbiome has been a consistent theme in Lieberman’s research, her recent endeavors pave their own path. Her group aims to be able to reconstruct what has recently occurred in the human body by identifying which microbial mutations have accumulated. If successful, they would be able to (1) infer past transmissions from person to person and (2) infer the genes in the occurring mutations. Their wider-reaching, more theoretical objective is to characterize the capacity of evolution in our microbiome.
It is estimated that a billion new bacterial mutations are created every day in the human body. There are 10 trillion bacteria in the body, each of which have a million nucleotides of DNA, and each time each of these nucleotides replicate they have a one in a billion chance of mutation. While Dr. Lieberman asserts that most of these mutations don’t do anything, “a few may [actually] hurt the bacteria,” and most importantly, “some of these mutations enable bacteria to do even better at living in you.”
Dr. Lieberman finds that research on how microbial strains adapt has been limited due to the shortcomings of current methods for accurately analyzing all possible evolutions (e.g. single-cell sequencing). Her group addresses this by isolating microbial cells into petri dishes. In this environment, the cells make fewer mutations and are easier to sequence. Then, a parsimonious model is used to infer past evolutionary history.
“Acne doesn’t kill as many people as cancer, but it sets up how people think about evidence.” Dr. Lieberamn thinks of acne as most people’s first experience with evidence-based medicine, and it is most often negative. This is because acne patients, in general, get prescribed medicine that does not work. “It’s crazy how something so ubiquitous, we really don’t understand. We need to fix this to have trust in medicine”
As universal a frustration as acne is, there remains limited medical consensus on the precise cause. Everyone has the underlying bacteria, Cutibacterium acnes, in their facial pores, so the question of “who will get acne?” remains open to study. Dr. Lieberman is currently conducting a study wherein children are monitored as they age, curious if any microbiome indicators predict whether or not the children will get acne. Lieberman is primarily interested in the number and type of strains that develop.
Most recent is the group’s work on colorectal cancer. A consistent finding with colorectal cancer is the high abundance of the oral bacteria Fusobacterium nucleatum on almost every tumor. Evidence suggests that the tumor forms first, and then bacteria attaches to the tumor’s sugars. By several mechanisms, the bacterial colonization accelerates the tumor genesis. Dr. Lieberman appropriately describes this as “an exciting opportunity to watch coevolution” — mutations in the bacteria result in mutations in the tumor. As a follow up, Dr. Lieberman asks the following questions: How did the bacteria get there? Was it a single transmission or multiple transmissions from the mouth to the gut? And do the bacteria acquire new mutations to allow them to live on the tumor?
If the answer to the last question turns out to be yes, the group hypothesizes that therapies can be developed to weaken the adaptations necessary to survive on these nascent tumors and prevent the bacteria from colonizing altogether.
The final project discussed is atopic dermatitis, better known as eczema. The disease is most common among children and is characterized by red, weepy, broken skin. A particular bacteria, Staphylococcus aureus (staph) thrives in the skin lesions, and its relative abundance has been found to correlate with the amount of eczema. Leiberman’s group evaluates how staph adapts in these areas and how quickly it spreads from one location to another. Their preliminary results suggest that a specific gene mutation, found across different patients, causes the rapid spread of the disease. Once these genes are identified and understood, her group aims to develop therapies that target some of those pathways and reduces the growth of Staphylococcus aureus.
The methods she’s refined are very clearly applicable across various medical interests and will prove to be career-changing. Best of all, her tenacity and raw enthusiasm is endlessly infectious. If all goes well, Lieberman hopes to apply her analysis to the development of more targeted and successful medical therapies.