With the help of crowdsourced data, the scientists figured out how to choose the building blocks required to create a protein thatwill take on the shape they want. Photo Credit: John Hersey/NYT
Our bodies make roughly 20,000 different kinds of proteins, from the collagen in our skin to the haemoglobin in our blood. Some take the shape of molecular sheets. Others are sculpted into fibres, boxes, tunnels, even scissors. A protein's particular shape enables it to do a particular job, whether ferrying oxygen through the body or helping to digest food.
Scientists have studied proteins for nearly two centuries, and over that time they have worked out how cells create proteins from simple building blocks. They have long dreamed of assembling those elements into new proteins not found in nature. But they have been stumped by one great mystery: how the building blocks in a protein take their final shape.
David Baker, director of the Institute for Protein Design at the University of Washington, USA, has been investigating that enigma for a quarter-century. Now, it looks as if he and his colleagues have cracked it. Thanks in part to crowdsourced computers and smartphones belonging to over one million volunteers, the scientists have figured out how to choose the building blocks required to create a protein that will take on the shape they want.
In a series of papers published in 2017, David and his colleagues unveiled the results of this work. They have produced thousands of different kinds of proteins, which assume the shape the scientists had predicted. Often, those proteins are profoundly different from any found in nature. This expertise has led to a profound scientific advance: cellular proteins designed by humans, not by nature.
"We can now build proteins from scratch from first principles to do what we want," David said. Scientists soon will be able to construct precise molecular tools for a vast range of tasks, he predicts. Already, his team has built proteins for purposes ranging from fighting flu viruses to breaking down gluten in food to detecting trace amounts of opioid drugs. William DeGrado, a molecular biologist at the University of California, San Francisco, said the recent studies by Baker and his colleagues represent a milestone in this line of scientific inquiry. "In the 1980s, we dreamed about having such impressive outcomes," he said.
Every protein in nature is encoded by a gene. With that stretch of DNA as its guide, a cell assembles a corresponding protein from building blocks known as amino acids. Selecting from 20 or so different types, the cell builds a chain of amino acids. That chain may stretch dozens, hundreds or even thousands of units long. Once the cell finishes, the chain folds on itself, typically in just a few hundredths of a second. Proteins fold because each amino acid has an electric charge. Parts of the protein chain are attracted to one another while other parts are repelled. Some bonds between the amino acids will yield easily under these forces; rigid bonds will resist.
The combination of all these atomic forces makes each protein a staggering molecular puzzle. When David attended graduate school at the University of California, Berkeley, no one knew how to look at a chain of amino acids and predict the shape into which it would fold. Protein scientists referred to the enigma simply as 'the folding problem'. The folding problem left scientists in the Stone Age when it came to manipulating these important biological elements. They could only use proteins that they happened to find in nature, like early humans finding sharp rocks to cut meat from bones.
We have used proteins for thousands of years. Early cheese-makers, for example, made milk curdle by adding a piece of calf stomach to it. The protein chymosin, produced in the stomach, turned liquid milk into a semi-solid form. Today, scientists are still looking for ways to harness proteins. Some researchers are studying proteins in abalone shells in hopes of creating stronger body armour, for instance. Others are investigating spider silk for making parachute cords. Researchers also are experimenting with modest changes to natural proteins to see if the tweaks let them do new things.
To David and many other protein scientists, however, this sort of tinkering has been deeply unsatisfying. The proteins found in nature represent only a minuscule fraction of the 'protein universe' - all the proteins that could possibly be made with varying combinations of amino acids. "When people want a new protein, they look around in nature for things that already exist," David said.
Collective knowledge platform
In the late 1990s, the team at the University of Washington, USA turned to software for individual studies of complex proteins. The lab decided to create a common language for all this code so that researchers could access the collective knowledge about proteins. In 1998, they started a platform called Rosetta, which scientists use to build virtual chains of amino acids and then compute the most likely form they will fold into. A community of protein scientists, known as the Rosetta Commons, grew around the platform. For the past 20 years, they have been improving the software and using it to better understand the shape of proteins - and how those shapes enable them to work.
In 2005, David launched a programme called Rosetta@home, which recruited volunteers to donate processing time on their home computers and, eventually, Android phones. Step by step, Rosetta grew more powerful and more sophisticated, and the scientists were able to use the crowdsourced processing power to simulate folding proteins in greater detail. Their predictions grew startlingly more accurate.
The researchers went beyond proteins that already exist to proteins with unnatural sequences. To see what these unnatural proteins looked like in real life, the scientists synthesised genes for them and plugged them into yeast cells, which then manufactured the lab's creations. "There are subtleties going on in naturally occurring proteins that we still don't understand," David said. "But we've mostly solved the folding problem."
These advances gave David's team the confidence to take on an even bigger challenge: they began to design proteins from scratch for particular jobs. The researchers would start with a task they wanted a protein to do, and then figure out the string of amino acids that would fold the right way to get the job done. Recently, David's team presented one of its most ambitious projects: a protein shell that can carry genes. The researchers designed proteins that assemble themselves like Legos, snapping together into a hollow sphere.
Gary Nabel, chief scientific officer at Sanofi, said that the new research may lead to the invention of molecules we cannot yet imagine. "It's a new territory, because you're not modelling existing proteins," he said. For now, David and his colleagues can only make short-chained proteins. That is due in part to the cost involved in making pieces of DNA to encode proteins. But that technology is improving so quickly that the team is now testing longer, bigger proteins that might do more complex jobs.