Jeffrey Agar, associate professor of chemistry and chemical biology at Northeastern, and colleagues from around the world are on a mission to deepen our knowledge of the human body. And their plan, which they’ve dubbed the Human Proteoform Project, could help humanity develop treatments for hundreds of currently untreatable diseases.
The initiative, Agar says, is the next logical step after the Human Genome Project: outlining the millions of forms of proteins that make up the human body.
“When they talk about the genome being a blueprint, guess what it’s a blueprint for,” Agar says. “Proteins.”
Much of the human body is made up of protein. But protein isn’t just one thing. There are thousands of different kinds of protein molecules that make up all kinds of things in our bodies.
Proteins are made up from a collection of building blocks, known as amino acids, which fold into particular shapes. One protein can form in several different shapes, Agar says, sometimes even millions. And it is that shape that influences the protein’s role in the human body.
Genes typically act as instructions to make proteins, so having sequenced the entire human genome in the Human Genome Project is helpful. But one gene can make several different forms of the same protein, called proteoforms.
“There’s this huge ballooning where you might have 25,000 genes, but we know that the proteoforms are in the many millions,” Agar says.
Extending the blueprint analogy for the human genome, he says, “The proteoforms are the way that when you take that blueprint, you know it’s a warehouse or factory, but that doesn’t tell you a lot about what goes on inside. It could be making—heaven forbid—weapons, or it could be making muffins.” The proteoforms make up the working parts of that factory, he says, so understanding what they look like adds crucial details.
The Human Proteoform Project aims to identify all of the proteoforms expressed in the human body to illuminate those details. Such a large-scale atlas of the human proteome (the set of proteins expressed by an organism) could help scientists identify the causes of some diseases—and develop treatments for them.
Some diseases, like mad cow disease, for example, Agar says, “are as simple as a protein changing shape. That’s it. The protein changes shape and then it runs into another protein and changes its shape.”
So, he says, if scientists can identify which protein is changing and which proteoform is toxic, they can work to develop a treatment to prevent that protein from changing to the dangerous form.
The Human Proteoform Project is proposed and outlined in a paper in Science Advances published last week. Agar is a co-author on the paper, as is the Consortium for Top-Down Proteomics. Like the Human Genome Project, the team expects it to take over a decade to assemble an atlas of all the human proteoforms and significant investment in the research and technology. That earlier project took over 13 years and billions of dollars of funding from the U.S. government alone.
If you accept that having the human genome fully sequenced has been a good thing, Agar says, you might ask, “well, why haven’t we cured everything? And the answer really comes down to, well, [what remains may not be] a problem with the genome. It’s a problem with the proteome.”
“We’re made of protein, not DNA,” he says. “This is what has to come next if you want to know more about people.”