Nav: Home

Human microbiome churns out thousands of tiny novel proteins, Stanford researchers find

August 08, 2019

Your body is a wonderland. A wonderland teeming with trillions of bacteria, that is. But it's not as horrifying as it might sound. In fact, there's mounting evidence that many aspects of our health are closely intertwined with the composition and hardiness of our microscopic compatriots, though exactly how is still mostly unclear.

Now, researchers at the Stanford University School of Medicine have discovered that these microbial hitchhikers -- collectively known as the human microbiome -- are churning out tens of thousands of proteins so small that they've gone unnoticed in previous studies. The proteins belong to more than 4,000 new biological families predicted to be involved in, among other processes, the warfare waged among different bacterial strains as they vie for primacy in coveted biological niches, the cell-to-cell communication between microbes and their unwitting hosts, and the critical day-to-day housekeeping duties that keep the bacteria happy and healthy.

Because they are so small -- fewer than 50 amino acids in length -- it's likely the proteins fold into unique shapes that represent previously unidentified biological building blocks. If the shapes and functions of these proteins can be recreated in the lab, they could help researchers advance scientific understanding of how the microbiome affects human health and pave the way for new drug discovery.

A paper describing the research findings will be published Aug. 8 in Cell. Ami Bhatt, MD, PhD, assistant professor of medicine and of genetics, is the senior author. Postdoctoral scholar Hila Sberro, PhD, is the lead author.

'A clear blind spot'

"It's critically important to understand the interface between human cells and the microbiome," Bhatt said. "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."

But the proteins' miniscule size had made it difficult to identify and study them using traditional methods.

"We've been more likely to make an error than to guess correctly when trying to predict which bacterial DNA sequences contain these very small genes," Bhatt said. "So until now, we've systematically ignored their existence. It's been a clear blind spot."

It might be intimidating for the uninitiated to think too deeply about the vast numbers of bacteria that live on and in each of us. They account for far more cells in and on the human body than actual human cells do. Yet these tiny passengers are rarely malicious. Instead, they help with our digestion, supplement our diet and generally keep us running at our peak. But in many cases, it's been difficult to pick apart the molecular minutiae behind this partnership.

Bhatt and her colleagues wondered if answers might be found in the small proteins they knew were likely to wiggle through the nets cast by other studies focusing on the microbiome. Small proteins, they reasoned, are more likely than their larger cousins to slip through the cell membrane to ferry messages -- or threats -- to neighboring host or bacterial cells. But how to identify and study these tiny Houdinis?

"The bacterial genome is like a book with long strings of letters, only some of which encode the information necessary to make proteins," Bhatt said. "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."

A big surprise

To tackle the problem, Sberro decided to compare potential small-protein-coding genes among many different microbes and samples. Those that were identified repeatedly in several species and samples were more likely to be true positives, she thought. When she applied the analysis to large data sets, Sberro found not the hundreds of genes she and Bhatt had expected, but tens of thousands. The proteins predicted to be encoded by the genes could be sorted into more than 4,000 related groups, or families, likely to be involved in key biological processes such as intercellular communication and warfare, as well as maintenance tasks necessary to keep the bacteria healthy.

"Honestly, we didn't know what to expect," Bhatt said. "We didn't have any intuition about this. The fact that she found thousands of new protein families definitely surprised us all."

The researchers confirmed the genes encoded true proteins by showing they are transcribed into RNA and shuttled to the ribosome for translation -- key steps in the protein-making pathway in all organisms. They are now working with collaborators to learn more about the proteins' functions and to identify those that might be important to the bacteria fighting for space in our teeming intestinal carpet. Such proteins might serve as new antibiotics or drugs for human use, they believe.

"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," Bhatt said. "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."
-end-
Other Stanford co-authors are graduate student Brayon Fremin; postdoctoral scholars Soumaya Zlitni, PhD, and Fredrik Edfors, PhD; and Michael Snyder, PhD, professor and chair of genetics.

Researchers from One Codex, the Joint Genome Institute of the Department of Energy, the Alexander Fleming Biomedical Sciences Research Center in Greece, and Lawrence Berkeley National Laboratory also contributed to the study.

The study was supported by the National Institutes of Health (grants HG000044, K08CA184420, P30CA124435, and 1Ro1AT010123201), the PhRMA Foundation, the U.S. Department of Energy and a Damon Runyon Clinical Investigator Award.

Stanford's departments of Medicine and of Genetics also supported the work.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu.

Stanford Medicine

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#542 Climate Doomsday
Have you heard? Climate change. We did it. And it's bad. It's going to be worse. We are already suffering the effects of it in many ways. How should we TALK about the dangers we are facing, though? Should we get people good and scared? Or give them hope? Or both? Host Bethany Brookshire talks with David Wallace-Wells and Sheril Kirschenbaum to find out. This episode is hosted by Bethany Brookshire, science writer from Science News. Related links: Why Climate Disasters Might Not Boost Public Engagement on Climate Change on The New York Times by Andrew Revkin The other kind...
Now Playing: Radiolab

An Announcement from Radiolab