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SUNDAY SCIENCE: SPERM CAN’T UNLOCK AN EGG WITHOUT THIS ANCIENT
MOLECULAR KEY  
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Elizabeth Preston
October 17, 2024
New York Times
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_ Using Google’s AlphaFold, researchers identified the bundle of
three sperm proteins that seem to make sexual reproduction possible. _


Still from video of the egg of a zebrafish, marked in blue, being
fertilized by a sperm, marked in orange. , Credit...Institute of
Molecular Pathology

 

They’re the original odd couple: One is massive, spherical and
unmoving. The other is tiny, has a tail and never stops swimming. Yet
the union of egg and sperm is critical for every sexually reproducing
animal on Earth.

Exactly how that union occurs has long been a mystery to scientists.
A study [[link removed]] published
Thursday in the journal Cell that relied on Nobel Prize-honored
artificial intelligence technology shows that an interlocked bundle of
three proteins is the key that lets sperm and egg bind together. That
crucial bundle is shared by animals as distantly related as fish and
mammals, and most likely including humans.

For nearly all animals
[[link removed]] on
Earth, life begins with a sperm cell making its way to an egg’s cell
membrane. Somehow, the two cells recognize each other and bind
together. Then, in a flash, the sperm head passes into the egg, as if
stepping through a door. Now the fused cell is a zygote and ready to
grow into a new animal.

The egg of a zebrafish, marked in blue, being fertilized by a sperm,
marked in orange. Credit...Institute of Molecular Pathology

In earlier research, scientists had found four proteins on mammal
sperm that are also present on fish sperm and are needed for
fertilization. But no one knew whether they might work as a team to
enter an egg, or how.

In the new study, Andrea Pauli, a molecular and developmental
biologist at the Research Institute of Molecular Pathology in Vienna,
and collaborators across several institutions asked how sperm proteins
might team up during fertilization.

The researchers relied on AlphaFold, a technology that shared the
Nobel Prize in Chemistry last week. It uses A.I. to predict the shape
of a protein. With AlphaFold, the team could compare the four sperm
proteins shared across mammals and fish against a library of about
1,400 other proteins found on cell surfaces in zebrafish testes,
looking for potential partners.

In the new study, Andrea Pauli, a molecular and developmental
biologist at the Research Institute of Molecular Pathology in Vienna,
and collaborators across several institutions asked how sperm proteins
might team up during fertilization.

The researchers relied on AlphaFold, a technology that shared the
Nobel Prize in Chemistry last week. It uses A.I. to predict the shape
of a protein. With AlphaFold, the team could compare the four sperm
proteins shared across mammals and fish against a library of about
1,400 other proteins found on cell surfaces in zebrafish testes,
looking for potential partners.

With AlphaFold, researchers compared four sperm proteins shared across
mammals and fish against a library of proteins found in zebrafish
testes, looking for potential partners. Institute of Molecular
Pathology

A fluorescence microscopy image of mouse eggs, in red and green, and
sperm, in blue. Earlier research had identified proteins on mammal
sperm that are also present on the sperm cells of fish. Yonggang
Lu/Osaka University

“We wanted to find something that we knew would be at the right
place and at the right time,” said Victoria Deneke, a postdoctoral
researcher in Dr. Pauli’s lab.

Even for AlphaFold, this was a challenge. “It was running for two or
three weeks,” Dr. Deneke said, monopolizing the campus’s computing
resources.

“Other people at the institute were not so happy,” Dr. Pauli
added.

Finally, AlphaFold predicted that two of the original shared sperm
proteins would bind to each other, along with a third protein that was
previously unknown, creating a team of three.

Lab experiments confirmed the program’s guess: Male zebrafish
missing the newly discovered third protein were infertile, as were
male mice. Their sperm swam normally but couldn’t fuse with an egg.
The scientists also found biochemical evidence that the three sperm
proteins were working as a unit, both in zebrafish and humans.

It’s likely that the same crucial bundle exists in many — or all
— animals with a backbone, Dr. Pauli said.

She described the sperm protein bundle as a kind of key, which fits
with a lock on an egg cell. In fish, that lock is a protein named
Bouncer — appropriately, as the sperm head can’t enter the egg
without it.

A comparison of the three proteins in zebrafish, mice and humans.
Institute of Molecular Pathology

Earlier research also identified a lock molecule in mammal eggs, which
binds to one of the proteins in the three-protein bundle. Oddly,
though, the mammalian lock isn’t Bouncer. It’s an unrelated
protein called Juno.

That means somewhere in history, animals must have evolved different
egg proteins to bind the sperm protein bundle. That presents a
mystery, Dr. Pauli said: The lock has changed, yet somehow, “the key
on the sperm stayed the same.”

“We would love to know the answer,” she added.

Amber Krauchunas, a reproductive biologist at the University of
Delaware who was not involved in the new research, called the new
paper “really exciting.”

Earlier this year, a different research group independently used
AlphaFold and predicted
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three-protein bundle in mammals. “The fact that two independent
groups came to the same conclusions certainly increases our confidence
in the results,” Dr. Krauchunas said.

Even so, she said, “more work certainly remains to uncover the
mysteries of fertilization.” For example, some sperm proteins are
known to be shared across mammals and fish but aren’t part of this
bundle; what are they doing?

“This is such a fundamental question with so few molecular
answers,” Dr. Pauli said. “It’s amazing.”

_About ELIZABETH PRESTON: I’m a freelance science journalist and
editor. My writing has appeared in publications including the New
York Times [[link removed]], Science,
the Boston Globe, the Atlantic, and Orion. Right now I’m working on
a book [[link removed]] about
the evolution of parenting, which will be published by Viking. I won
the 2017 Kavli Gold Award
[[link removed]] in
Children’s Science News. In less serious moods, I’m also a humor
writer for outlets such as McSweeney’s, Parents, and Real Simple._

_Between 2008 and 2014 I was the editor of Muse
[[link removed]],
a magazine about science and ideas for kids. I also wrote almost 400
news stories there in the voice of a highly knowledgeable cow. Other
past projects include Child Proof
[[link removed]], a parenting science
column published by Medium, and Inkfish, a science blog hosted by
Discover. “Inkfish” is another name for cephalopods such as
octopuses and squid._

_Besides cephalopods, I write most often about evolution, animal
behavior, health, parenting, and intersections between science and
society. I studied biology and English at Williams College. In order
from least to most tedious, I’ve used the following lab skills:
sucking up fruit flies from tree fungi; sequencing human DNA;
liquefying leaves; and sorting grass roots with tweezers. I live in
the Boston area with my husband and two daughters._

_For updates on my writing, subscribe to my biweekly newsletter here.
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_Subscribe to the NEW YORK TIMES
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__

MicroRNA − a new Nobel laureate describes the scientific process of
discovering these tiny molecules that turn genes on and off
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Victor Ambros
The Conversation 

The 2024 Nobel Prize in physiology or medicine goes to Victor Ambros
and Gary Ruvkun for their discovery of microRNA, tiny biological
molecules that tell the cells in your body what kind of cell to be by
turning on and off certain genes.

The Conversation Weekly podcast caught up with Victor Ambros from his
lab at the UMass Chan Medical School to learn more about the
Nobel-winning research and what comes next. Below are edited excerpts
from the podcast.

October 17, 2024

* Science
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* biology
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* sperm
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* egg
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* sexual reproduction
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* protein folding
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