Science - USA (2021-12-17)

T

he first protein structures were determined by

x-ray crystallography in 1957 by John C. Kendrew

and Max F. Perutz. As a bioinorganic chemist, I

was delighted that the structures were myoglo-

bin and hemoglobin, both heme proteins with

big, beautiful iron atoms. It must have been an

extraordinary experience to stare at a physical

model of the structures and see something that had

previously only been imagined. Not long afterward,

Christian B. Anfinsen Jr. proposed that the structure of

a protein was thermodynamically stable. It seemed pos-

sible that the three-dimensional structure of a protein

could be predicted based on the sequence of its amino

acids. This “protein-folding problem,” as it came to be

known, baffled scientists until this year, when the pa-

pers we’ve deemed the 2021 Break-

through of the Year were published.

I came of age as a biochemist in

an era when scientists could de-

scribe but not solve protein folding.

Chemical force field and molecular

dynamics modeling just couldn’t

quite get there. The early days of de

novo protein synthesis were heady

because complicated structures could

be designed and synthesized, but

elaborate structures and multiprotein

assemblies remained out of reach.

When I left the lab in 2006 to go fight

administrative windmills, I thought

the protein-folding problem would never be solved.

A lot has happened in the 15 years since. Structures

started coming much faster after the development of

cryo–electron microscopy (cryo-EM), a method requir-

ing very expensive instrumentation that can determine

protein structures without crystallized samples. Then

the Critical Assessment of Protein Structure Prediction

(CASP) competition, in which scientists were chal-

lenged to match algorithms to known protein struc-

tures, really took off. As these annual competitions

proceeded, DeepMind—a UK subsidiary of Alphabet,

Google’s parent company—began showing results from

an artificial intelligence algorithm that mined known

protein structures to predict unknown structures.

Their program, AlphaFold, made a big impression at

the fall 2020 CASP conference on Minkyung Baek, a

researcher at the University of Washington. Baek de-

vised RoseTTAFold, an algorithm that uses less com-

puting power and can predict structures of protein

complexes. The methods of DeepMind and Baek et al.

were published simultaneously in Nature and Science,

respectively, this year. Both AlphaFold and RoseTTA-

Fold are available free for researchers (as is a data-

base of protein structure predictions), and scientists

immediately began obtaining protein structures from

these algorithms without having to crystallize their

proteins or access cryo-EM tools. Now structures can

be obtained for samples that defy experimental meth-

ods, and moreover, in labs that can’t afford the experi-

mental approaches. It is truly protein structure for all.

This is a breakthrough on two fronts. It solves a scien-

tific problem that has been on the to-do list for 50 years.

And just like Fermat’s Last Theorem or gravitational

waves, scientists kept at it until it was done. Also, it’s a

game-changing technique that, like CRISPR or cryo-EM,

will greatly accelerate scientific dis-

covery. It would have been the Break-

through of the Year for either reason,

but it’s a twofer for sure.

The breakdowns of the year are

all topics that were covered heavily

in Science. The disastrous US Food

and Drug Administration (FDA) ap-

proval for Alzheimer’s disease of

aducanumab—a costly treatment

with little if any clinical efficacy—

was discussed in an Editorial by Joel

Perlmutter. Perlmutter resigned in

protest from the committee that ad-

vised the FDA on the drug. Continued

inaction on climate has rendered unlikely the 1.5°C tar-

get as a limit on the increase in global temperature. And

scientists have been attacked in new ways and with new

methods by politicians who are exploiting social media

and long-tested methods of indoctrination to undermine

scientific authority on issues ranging from vaccines in

the midst of a pandemic to the impending devastation

of climate change.

The contrasts of the breakthrough and breakdowns

are stunning. The breakthrough in protein folding is

one of the greatest ever in terms of both the scientific

achievement and the enabling of future research. Mean-

while, the tragic loss of respect for scientific authority

around the world is demoralizing, and it’s hard to see the

trend reversing any time soon.

It is truly the best of times and the worst of times in

2021—an age of wisdom and an age of foolishness. The

scientific tale of two cities will be with us for a while

to come.

–H. Holden Thorp

Proteins, proteins everywhere

H. Holden Thorp

Editor-in-Chief,

Science journals.

[email protected];

@hholdenthorp

10.1126/science.abn
PHOTO: CAMERON DAVIDSON

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1415

EDITORIAL

“The

breakthrough

in protein folding

is one of the

greatest ever...”