A remarkable new study from scientists at Stanford University has revealed thousands of previously undiscovered small proteins produced by bacteria in the human microbiome. Almost all of these newly described proteins serve unknown functions in the human body and the researchers suggest their discovery opens up a new frontier for future therapeutic drug development.

"It's critically important to understand the interface between human cells and the microbiome," explains Ami Bhatt, senior author on the recently published study. "How do they communicate? How do strains of bacteria protect themselves from other strains? These functions are likely to be found in very small proteins, which may be more likely than larger proteins to be secreted outside the cell."

These tiny proteins have traditionally been ignored by researchers due to fundamental difficulties in detecting them. They are generally smaller than 50 amino acids in length and most likely serve critical communication functions between bacterial strains and the hosts they inhabit. To track down these small signaling proteins, the researchers zoomed in on the bacterial genomes.

"The bacterial genome is like a book with long strings of letters, only some of which encode the information necessary to make proteins," says Bhatt. "Traditionally, we identify the presence of protein-coding genes within this book by searching for combinations of letters that indicate the 'start' and 'stop' signals that sandwich genes. This works well for larger proteins. But the smaller the protein, the more likely that this technique yields large numbers of false positives that muddy the results."

Using a novel computational approach the researchers carried out a comparative genomics study revealing over 4,000 protein families, the majority of which have never previously been identified. The sheer volume of the discovery surprised the research team, which expected to maybe find a few hundred novel strings of small-protein-coding genes, but instead discovered thousands.

The study offers hypotheses as to the function of some of these small protein families, based on their genomic neighborhood, prevalence across certain human body sites, and other factors. Some of the newly discovered small protein families, for example, share genetic traits with previously discovered proteins known to enhance antibiotic resistance.

The paper, published in the journal Cell, offers a comprehensive summary of all 4,539 newly discovered small protein families, essentially serving as a large new catalog for future research. The next step is to begin understanding what mechanical functions these novel small proteins serve, opening the door to potential new antibiotics or other drugs for therapeutic human uses.

"Small proteins can be synthesized rapidly and could be used by the bacteria as biological switches to toggle between functional states or to trigger specific reactions in other cells," says Bhatt. "They are also easier to study and manipulate than larger proteins, which could facilitate drug development. We anticipate this to be a valuable new area of biology for study."

The new research was published in the journal Cell.