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Three years ago, Google’s AlphaFold pulled off the biggest artificial intelligence breakthrough in science to date [see here]. Yasemin Saplakoglu explains how this has accelerated molecular research and kindled deep questions about why we do science….

In December 2020, when pandemic lockdowns made in-person meetings impossible, hundreds of computational scientists gathered in front of their screens to watch a new era of science unfold.

They were assembled for a conference, a friendly competition some of them had attended in person for almost three decades where they could all get together and obsess over the same question. Known as the protein folding problem, it was simple to state: Could they accurately predict the three-dimensional shape of a protein molecule from the barest of information — its one-dimensional molecular code? Proteins keep our cells and bodies alive and running. Because the shape of a protein determines its behavior, successfully solving this problem would have profound implications for our understanding of diseases, production of new medicines and insight into how life works.

At the conference, held every other year, the scientists put their latest protein-folding tools to the test. But a solution always loomed beyond reach. Some of them had spent their entire careers trying to get just incrementally better at such predictions. These competitions were marked by baby steps, and the researchers had little reason to think that 2020 would be any different.

They were wrong about that.

That week, a relative newcomer to the protein science community named John Jumper had presented a new artificial intelligence tool, AlphaFold2, which had emerged from the offices of Google DeepMind, the tech company’s artificial intelligence arm in London. Over Zoom, he presented data showing that AlphaFold2’s predictive models of 3D protein structures were over 90% accurate — five times better than those of its closest competitor.

In an instant, the protein folding problem had gone from impossible to painless. The success of artificial intelligence where the human mind had floundered rocked the community of biologists. “I was in shock,” said Mohammed AlQuraishi, a systems biologist at Columbia University’s Program for Mathematical Genomics, who attended the meeting. “A lot of people were in denial.”

But in the conference’s concluding remarks, its organizer John Moult left little room for doubt: AlphaFold2 had “largely solved” the protein folding problem — and shifted protein science forever. Sitting in front of a bookshelf in his home office in a black turtleneck, clicking through his slides on Zoom, Moult spoke in tones that were excited but also ominous. “This is not an end but a beginning,” he said…

[Saplakoglu tells the story of AlphaFold and of subsequent developments…]

… Seventy years ago, proteins were thought to be a gelatinous substance, Porter said. “Now look at what we can see”: structure after structure of a vast world of proteins, whether they exist in nature or were designed.

The field of protein biology is “more exciting right now than it was before AlphaFold,” Perrakis said. The excitement comes from the promise of reviving structure-based drug discovery, the acceleration in creating hypotheses and the hope of understanding complex interactions happening within cells.

“It [feels] like the genomics revolution,” AlQuraishi said. There is so much data, and biologists, whether in their wet labs or in front of their computers, are just starting to figure out what to do with it all.

But like other artificial intelligence breakthroughs sparking across the world, this one might have a ceiling.

AlphaFold2’s success was founded on the availability of training data — hundreds of thousands of protein structures meticulously determined by the hands of patient experimentalists. While AlphaFold3 and related algorithms have shown some success in determining the structures of molecular compounds, their accuracy lags behind that of their single-protein predecessors. That’s in part because there is significantly less training data available.

The protein folding problem was “almost a perfect example for an AI solution,” Thornton said, because the algorithm could train on hundreds of thousands of protein structures collected in a uniform way. However, the Protein Data Bank may be an unusual example of organized data sharing in biology. Without high-quality data to train algorithms, they won’t make accurate predictions.

“We got lucky,” Jumper said. “We met the problem at the time it was ready to be solved.”

No one knows if deep learning’s success at addressing the protein folding problem will carry over to other fields of science, or even other areas of biology. But some, like AlQuraishi, are optimistic. “Protein folding is really just the tip of the iceberg,” he said. Chemists, for example, need to perform computationally expensive calculations. With deep learning, these calculations are already being computed up to a million times faster than before, AlQuraishi said.

Artificial intelligence can clearly advance specific kinds of scientific questions. But it may get scientists only so far in advancing knowledge. “Historically, science has been about understanding nature,” AlQuraishi said — the processes that underlie life and the universe. If science moves forward with deep learning tools that reveal solutions and no process, is it really science?

“If you can cure cancer, do you care about how it really works?” AlQuraishi said. “It is a question that we’re going to wrestle with for years to come.”

If many researchers decide to give up on understanding nature’s processes, then artificial intelligence will not just have changed science — it will have changed the scientists too.

Meanwhile, the CASP organizers are wrestling with a different question: how to continue their competition and conference. AlphaFold2 is a product of CASP, and it solved the main problem the conference was organized to address. “It was a big shock for us in terms of: Just what is CASP anymore?” Moult said.

In 2022, the CASP meeting was held in Antalya, Turkey. Google DeepMind didn’t enter, but the team’s presence was felt. “It was more or less just people using AlphaFold,” Jones said. In that sense, he said, Google won anyway.

Some researchers are now less keen on attending. “Once I saw that result, I switched my research,” Xu said. Others continue to hone their algorithms. Jones still dabbles in structure prediction, but it’s more of a hobby for him now. Others, like AlQuraishi and Baker, continue on by developing new algorithms for structure prediction and design, undaunted by the prospect of competing against a multibillion-dollar company.

Moult and the conference organizers are trying to evolve. The next round of CASP opened for entries in May. He is hoping that deep learning will conquer more areas of structural biology, like RNA or biomolecular complexes. “This method worked on this one problem,” Moult said. “There are lots of other related problems in structural biology.”

The next meeting will be held in December 2024 by the aqua waters of the Caribbean Sea. The winds are cordial, as the conversation will probably be. The stamping has long since died down — at least out loud. What this year’s competition will look like is anyone’s guess. But if the past few CASPs are any indication, Moult knows to expect only one thing: “surprises.”…

When one door closes, another opens: “How AI Revolutionized Protein Science, but Didn’t End It,” from @yasemin_sap in @QuantaMagazine.

See also: “How Colorful Ribbon Diagrams Became the Face of Proteins” from the same author.

* Bernard Haisch

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As we ponder progress, we might spare a thought for Edmond H. Fischer; he died on this date in 2021. A biochemist, he and his collaborator, Edwin G. Krebs were awarded the Nobel Prize in Physiology or Medicine in 1992 for describing how reversible phosphorylation works as a switch to activate proteins and regulate a number of cellular processes. Their discovery was a key to unlocking how glycogen in the body breaks down into glucose. It fostered techniques that prevent the body from rejecting transplanted organs and opened new doors for research into cancer, blood pressure, inflammatory reactions, and brain signals.

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