To fight disease, science must look beyond Kardashian proteins

The writer is a scientific commentator

If there was a hierarchy of celebrity proteins, p53 would be its Kim Kardashian. The protein inhibits tumor growth: a lack of p53 – for example through a mutation in the gene that produces it – predisposes a person to cancer.

Therefore, it is the most studied protein in the human body, with two scientific papers published on it per day. While p53 is undeniably important for health, it is also a beneficiary of the “street light effect,” in which a phenomenon that is already illuminated attracts further attention (this bias is sometimes compared to a drunk looking for his keys lost under a street lamp ).

Now a consortium of researchers is assembling the Understudied Proteins Initiative to find the Cinderella proteins lurking beyond the spotlight. “Our main aim is to provide a basic molecular characterization of all human proteins and remove barriers to their study,” explains cell biologist Georg Kustatscher from the University of Edinburgh, who is helping to lead the initiative funded by the Wellcome Trust and co-author of a paper. on it for the Methods of Nature. Hundreds of scientists from laboratories around the world have responded to the open call, and a conference is planned for the spring.

Proteins are the basic building blocks of life. They make up our tissues and organs; they act, among other things, as enzymes, antibodies and hormones; they transport chemicals around the body. But scientists are still unsure exactly how many proteins make up the human proteome, the name given to the complete complement of human proteins.

It is possible to make a lower guess: there are 20,000 genes in the human body, and each one is associated with at least one protein. However, there are thought to be hundreds or even thousands of undiscovered genes hiding in the human genome, each associated with undiscovered proteins. Furthermore, each protein can appear in multiple modified forms, pushing some numbers (depending on definitions) into the millions. Whatever the final number, scientists have come across very few of them. In a scoping exercise, Kustatscher and colleagues found that just 5,000 proteins accounted for 95 percent of all published papers in the life sciences.

The identification and characterization of lesser known proteins should not be dismissed as science for its own sake, but welcomed as a potential game changer in biology and healthcare. Microproteins, often overlooked for study because of their small size, are involved in brain development; others attract little interest because they are linked to rare diseases, even though the more than 7,000 diseases under that umbrella collectively affect one in 10 Americans. Discovering these could transform medicine by revolutionizing pharmaceutical pipelines: scientists estimate that, of around 3,000 “druggable” proteins – those open to manipulation by drugs for therapeutic effect – only up to a tenth are currently targeted of approved medicines.

This is partly due to practicality: small proteins can be difficult to detect, purify and handle. Researchers can also have difficulty knowing where to start when investigating a new protein of unknown function. The second reason is more damaging: the benchmark of scientific success is the publication of highly cited papers in prestigious journals. It means following the crowd pays dividends. “If you work on a protein that 10,000 other people are working on, then there are 10,000 other people who can cite your paper,” says Kustatscher. “But if you work on something that no one else is working on, you won’t get any citations and the big journals won’t be interested. Doing dangerous science can be career suicide.”

This disincentive may even narrow our horizons when it comes to finding pandemic treatments. Of the several thousand human genes known to be involved in the human response to the Covid virus, most subsequent research has involved genes and proteins that were already known before 2019.

Sometimes science must gamble on paths not yet taken in order to progress, especially when well-trodden paths are not leading to promising new pastures. Alzheimer’s disease is one example: decades of research have focused almost exclusively on the role of the amyloid protein as the likely culprit. However, many drug candidates targeting amyloid plaques in the brain have failed to provide clinical improvement. It wouldn’t be surprising, says Kustatscher, if an unknown, smaller protein turns out to play an important role in the disease.

Unless we take a chance and look, we may never know.

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