Billions of microbes live on our skin and inside our bodies. For the past century science has taken the position that these microbes are our enemies. Antibiotics were the wonder drugs of the early twentieth century, designed to combat the bacterial infections that commonly killed millions of people. While antibiotics were busy destroying killer bacteria, they were wiping out hosts of beneficial ones as well.
“In the past, we primarily thought of microbes in a pathogenic way, as something bad,” says Chih-chun Lin, Cornell Presidential Postdoctoral Fellow. “The more we learn now, the more we realize there are different types of microbes. Some have been living with humanity a very long time, and they are actually very beneficial to our health.”
As one of the inaugural group of Presidential Postdoctoral Fellows, Lin works in the lab of Andrew G. Clark, Molecular Biology and Genetics, where she explores interspecies interactions as a follow-up to her groundbreaking PhD research on the environmental factors that shape bacteria-host communication. She will be building on discoveries she made with the worm Caenorhabditis elegans, in the lab of Meng Wang at Baylor College of Medicine in Houston, Texas. In her study, Lin raised Escherichia coli bacteria in either a nutrient-rich environment or in one that was nutrient-poor. Then she and Wang fed the bacteria to the C. elegans worms, which normally live and interact with bacteria in their guts, similar to humans. What the researchers found was unprecedented.
“Worms feed on bacteria and scientists have always thought of the bacteria as their food, but we didn’t think about what the bacteria might mean to the worms beyond that,” says Lin. “So I developed the experiment looking at a three-layer system: environment, bacteria, and host. We discovered that bacteria are more than just food. In fact, bacteria also act as a major environmental sensory input for worms. In response to environmental changes, bacteria pass on different chemical signals to worms to regulate worm metabolism and fat levels.” The researchers found that when C. elegans ingested bacteria raised in a nutrient-poor environment, the worms ended up with twice as much fat in their bodies as compared to worms that ate bacteria from nutrient-rich environments.
In another collaborative study, Lin joined with colleagues to take a complete set of 4,000 E. coli bacterium, each of which lacked one of the 4,000 genes that make up the bacterium’s genome. They fed each mutant bacteria strain to C. elegans worms in an attempt to pinpoint which genes in the bacteria affect the worms’ lifespans. They discovered that 29 of the genes increased the worms’ lifespans, and 12 of the genes protected the worms against tumor growth and the accumulation of amyloid beta, which is associated with Alzheimer’s Disease. “Both of these studies opened a new door to how we view the microbiome,” Lin says.
Communication between Bacteria and Host
The researchers also discovered that the communication between the bacteria and the host is facilitated by mitochondria. Mitochondria are crucial organelles within most cells that produce the majority of the energy the cell needs to survive. “Before it was incorporated into cells, mitochondria used to be a prokaryote, just like bacteria,” says Lin. “Then it was engulfed by eukaryotic cells and formed an endosymbiotic relationship. It is exciting to find that this mitochondria that used to be a bacterium still plays a role in helping us communicate with the bacteria that live inside us.”
That microbe-host communication may be the key to good health and disease resistance. “If we can discover the key component for interspecies communication, we might be able to bypass the microbes and regulate the host directly to promote health or prevent disease,” Lin says.
From Worm to Fruit Fly, Studying Microbe-Host Interactions
“My multidisciplinary project wouldn’t happen without the chance for all these collaborations. The friendly, collaborative atmosphere is something unique to Cornell. It’s a game changer.”
Over the next three years, Lin will use the Cornell Presidential Postdoctoral Fellowship to further pursue her interspecies interaction study by applying genetic and genomic approaches to characterize the interactions of microbes in the gut of drosophila, the common fruit fly. In Clark’s lab, she will be using bioinformatic tools such as high-throughput sequencing methods to look at changes in gene expression in the fruit fly host as it responds to different bacteria.
“Bioinformatics is a tool that lets you come at interspecies interaction from different angles,” Lin explains. “We can learn how host health and physiology can be affected by these interspecies interactions. Andy’s lab uses drosophila, and that’s exciting to me because this insect has a more complex physiology than C. elegans. Besides, a lot of genetic tools have been developed in the drosophila field. These genetic tools will enable us to directly characterize the functions of gene targets that are identified from bioinformatic predictions. By harnessing the power of system biology and molecular genetics, I aim to construct a network that defines the functional factors involved in the interplay between microbes and host.”
The Presidential Postdoc, an Opportunity for Extensive Collaborative Research
Winning the fellowship has given Lin a special chance to follow her interests. “This is a very valuable opportunity for me because it allows me to do the multidisciplinary research I really want to do,” she says. “I’m excited that I will be initiating collaborations to open up new questions and new fields. I will interact closely with faculty and students at the Cornell Institute for Host-Microbe Interactions and Disease. I am currently seeking collaborations with drosophila labs, bacteria labs, and other microbial labs. To do bioinformatics and sequencing analysis, I’ll be working with statisticians as well. Once we identify an interesting microbe-host interaction, I want to determine the chemical language used between microbes and host by working with chemists. If we can synthesize and modify the compounds, it will open the door to even more research. My multidisciplinary project wouldn’t happen without the chance for all these collaborations. The friendly, collaborative atmosphere is something unique to Cornell. It’s a game changer.”