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, Ph.D., assistant professor of medicine and of genetics,
is the senior author. Postdoctoral scholar Hila Sberro, Ph.D., 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."
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