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SUNDAY SCIENCE: SHINING A LIGHT ON THE WORLD OF TINY PROTEINS  
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Carl Zimmer
June 12, 2025
The New York Times
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_ From viruses to humans, life makes microproteins that have evaded
discovery until now. _

Ribosomes, shown in blue in this scanning electron micrograph, are
molecular factories inside a cell that use genetic information to
build proteins., Science Source

 

You could be forgiven for assuming that scientists know how many kinds
of proteins exist. After all, researchers have been studying proteins
for more than two centuries. They have powerful tools in their labs to
search for the molecules. They can scan entire genomes, spotting the
genes that encode proteins. They can use artificial intelligence to
help decipher the complex shapes that allow proteins to do their jobs,
whether that job entails catching odors in our noses or delivering
oxygen in our blood.

But the world of proteins remains remarkably mysterious. It turns out
that a vast number of them have been hiding in plain sight. In a study
published on Thursday, scientists revealed
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unknown proteins that are made by viruses such as influenza and H.I.V.
Researchers elsewhere have been uncovering thousands of other new
proteins in bacteria
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even humans
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Many of these newly discovered proteins probably play a vital role in
life, according to Thomas Martínez, a biochemist at the University of
California, Irvine. “There is no way to get around this,” he said.
“If we ever want to understand fully how our biology works, we have
to have a complete accounting of all the parts.”

For a long time, scientists depended on luck to find new proteins. In
1840, for example, Friedrich Ludwig Hünefeld
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German chemist, became curious about earthworm blood. He collected
blood from a worm and put it on a glass slide. When he looked through
a microscope, Hünefeld noticed platelike crystals: He had discovered
hemoglobin.

A century later, scientists accelerated the search for proteins by
working out how our bodies make them. Each protein is encoded by a
gene in our DNA. To make a protein, our cells make a copy of this gene
in the form of a molecule called messenger RNA, or mRNA. Then a
cellular factory called a ribosome grabs the messenger RNA and uses it
to assemble the protein from building blocks.

The search sped up even faster when scientists began sequencing entire
genomes in the 1990s. Researchers could scan a genome for
protein-coding genes, even if they had never seen the protein before.
Scanning the human genome led to the discovery of 20,000 genes
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But scientists later discovered that they were actually missing a lot
of proteins by searching this way.

Once more, the discovery
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Researchers at the University of California, San Francisco, wanted to
monitor the proteins that cells made. They figured out how to fish
ribosomes from cells and inspect the messenger RNA that was attached
to them.

The method, called ribosome profiling
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closer inspection, many of the messenger RNA molecules did not
correspond to any known gene. Previously unknown genes were making
previously unknown proteins.

In the years that followed, scientists learned how genome scanning had
led them to miss so many proteins. For one thing, they thought they
could recognize protein-coding genes by a distinctive sequence of DNA
that told a cell to start copying a gene. It turns out that a lot of
genes don’t share that start sequence.

Scientists also assumed that most proteins were big, made of hundreds
or even thousands of building blocks known as amino acids. The
thinking was that proteins needed to be big in order to carry out
complex chemistry. But in fact a lot of the new proteins turning up
were smaller than 100 amino acids long. Some of these microproteins
contain just a couple dozen amino acids.

One open question is how many microproteins humans make. Each time
scientists come across evidence of a new microprotein, they must look
closely to be sure that evidence is solid. But Dr. Martínez suspects
that the total figure will be enormous. “I would say a fair number
that’s in the ballpark is at least 10,000,” he said.

Other scientists have been uncovering a similar abundance of
microproteins in other species. “All these studies in all these
organisms have discovered a new universe of proteins that previous
methods failed to detect,” said Shira Weingarten-Gabbay, a systems
biologist at Harvard Medical School.

As a graduate student, Dr. Weingarten-Gabbay became interested in
looking for hidden proteins in viruses. But it’s a challenge:
Scientists must infect human cells with viruses, then wait for the
cell’s ribosomes to start grabbing viral messenger RNA and make
proteins.

Unfortunately, scientists don’t know how to grow a lot of human
viruses quickly in the lab. And even when scientists can coax them to
grow, the experiments still take a long time to carry out because of
the safeguards required to make sure nobody gets sick. When the
Covid-19 pandemic started in 2020, Dr. Weingarten-Gabbay and her
colleagues carried out a ribosome study on the new coronavirus. It
took four months
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“The truth is that for the great majority of the viruses, we don’t
have information on these hidden microproteins,” Dr.
Weingarten-Gabbay said.

Now Dr. Weingarten-Gabbay and her colleagues have invented a new
method to test viruses for proteins quickly and safely. They copy
parts of the virus genome and then insert these fragments of DNA into
cells.

To test the new method, the scientists ran an ambitious experiment.
They gathered every genome that has been sequenced from a human virus
— 679 in total. They copied pieces of the viral genomes and put them
into human cells. The cells quickly started using those pieces to make
proteins, including thousands of microproteins new to science.

“I was amazed that it worked,” Dr. Weingarten-Gabbay said.

On their own, these ribosome experiments don’t reveal what
microproteins actually do. It’s possible that some don’t do
anything and are simply destroyed as soon as they’re made.

But at least some microproteins appear to do important jobs. Viruses
need microproteins to infect cells, for instance. In humans, some
microproteins are crucial for cell growth. Others appear to be
released by cells, perhaps as signals to other cells.

These studies raise the possibility that scientists could target
microproteins to treat diseases. Some companies are developing cancer
vaccines [[link removed]] that will teach
immune cells to recognize certain microproteins in tumors, for
instance.

And if another virus causes a new pandemic, Dr. Weingarten-Gabbay
said, researchers could safely discover many of its microproteins in
just two weeks. “We want to have this information in hand when we
think about developing vaccines,” she said.

CARL ZIMMER [[link removed]] covers news
about science for The Times and writes the Origins column
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