Problems Underlying Proteomics Research

Our current understanding of human, animal and plant biology is largely based on insights gained from studying the DNA code. However, this code is only one integral part of the central dogma of biology. DNA must be read and converted into proteins, the cell’s “workers” responsible for coordinating and performing specific functions.

With the introduction of high-throughput techniques, bioinformatics tools, and artificial intelligence (AI)-based methods, proteomics The past few years. Although not yet in the ‘clinical’ stage, so to speak, the study of proteins expressed in health or disease states has led to the development of diagnostic biomarkers, identification of drug targets, and the manufacture of new biopharmaceuticals. The applications of proteomics are numerous and diverse across the broader life sciences.

Human Proteome Project (HPP), With the aim of creating a map of the protein-based molecular structure of the human body, we discovered 93.2% of the human proteomeidentified 18,407 proteins.

“Proteomics has transformed from an isolated field into a comprehensive tool for biological research that can be used to describe biological function.” write Yahui Liu et al.

The future of proteomics is definitely bright.However, the explanation Published article of nature’s way by Kustatscher et al. Some proteins receive more research attention than others.

The publication states that an estimated 500 proteins (approximately 25% of the human proteome) account for 95% of all life science publications. Most of these proteins were already known to the scientific community in the pre-Human Genome Project era. Tumor protein 53 (p53), sometimes referred to as the ‘guardian of the genome’ for its role in DNA repair and cell division, is one of the most frequently studied proteins. “One of the many chilling stats that has come to light is the fact that p53 is the subject of two publications per day,” he said. Professor Kathryn LillyProfessor of Cell Mechanics at the University of Cambridge, and co-author of the publication.

Why does this annotation bias exist?

Lilley explains that this inequality in protein annotation is caused by a variety of factors. This may be due to the fact that it is expressed at such low levels that it is rarely ‘measured’ experimentally. ”

Very small proteins, or proteins with specific properties (such as hydrophobicity), can prove difficult even with the most sophisticated analytical techniques. Some proteins can adopt unstable states. A “fleeting protein” likely not captured in most studies.

“It is possible that its corresponding gene or transcript may not be considered ‘interesting/important’ in genomics studies or associated with a disease state. It may not resemble any other protein in terms of its documented motifs, or distinct evolutionary trajectory,” Lilly says.

She describes the unrealistic reason as “not very acceptable” to her mind. If a protein is well studied, there may be more available resources that can be shared among different groups. Through the mechanism, research results are more likely to be published, leading to higher citations and subsequent continued funding. ”

This cycle is perhaps not unique to the field of proteomics, but rather speaks to broader issues in scientific research. We’re taking risks and promoting what we call it.

“Historically, when research has uncovered a series of proteins that warrant further investigation, they have been neglected, many of them lack significant interest to pursue, and are not trendy enough to attract funding. , or it’s frustrating to rummage through the literature just to discover something that isn’t commonly thought of.

Why are understudied proteins a problem?

A prejudice against well-studied proteins undermines our knowledge of cellular function and dysfunction, ultimately stunting progress in life science research as a whole. It contains many examples of proteins that are essential for growth, an important cellular process, whose abnormal function underpins many diseases, and cancer is the most relevant area of ​​research for many. It spans most cellular processes, and without the functional annotation of this protein subset, we are unlikely to fully understand how cells function.”

Many of the drugs used to treat human diseases target proteins.data from DrugBank database The entire collection of drugs approved by the US Food and Drug Administration (FDA) suggests that they target a total of 620 proteins, including transporters, enzymes, ion channels and receptors. “The understudied proteome contains quite a few. [of proteins] It’s expected to be draggable,” says Lilley.

New drug development requires various stages of preclinical and clinical development.Bench studies and preclinical studies rely on models that allow scientists to investigate drug functions in vitro When In vivo. But if our basic knowledge of cellular mechanisms is flawed, so are our models. “Knowledge of the function and role of this substantial subset of the proteome in disease could be game-changing for future drug discovery,” she said.

Understudied Protein Initiative

Kustatscher and colleagues have made clear the scale of this problem, but how do we tackle it? It is clear that proteomics approaches require changes to halt perpetual cycles. Understudied Protein Initiativenovel welcome trust– A funded initiative developed by Kustatscher et al. outlines the solution. This initiative suggests collecting sufficient data on understudied proteins (perhaps their interactions, localization, or expression) so that hypotheses about their function can be formulated. “In an ideal world, researchers could perform systems-level functional assays where all proteins are tested for a particular function. A good example of this is testing whether a protein binds to RNA. There are many routine methods to perform such functional screens, and they can be applied to many conditions, and some proteins may only bind to RNA under a specific set of circumstances,” Lilley says. explains.

With this functional data, it becomes easier to define the best areas or laboratories for further in-depth study of that protein. Essentially, the task is divided into two parts. Large-scale pre-characterization by omics scientists followed by intensive molecular biology studies. “More whole-systems research requires agreement on biological systems, sets of conditions tested, resource sharing, and comprehensive sets of methods to ‘poke’ the understudied proteome.” We need it,” she says Lilley. “Of particular importance are data sharing, curation, database integration, and the creation of dynamic cell models. Building on resources such as: MuSIC 1.0, Hierarchical Map of Cells from Ideker Lab, is a very good starting point. ”

She continues: The size of the proteome has not yet been fully calculated. Considering the number of proteoforms that may exist, i.e. the number of different chemicals due to post-transcriptional and post-translational processing, and the possible combinatorial nature of this processing, the size of the proteome expands by several orders of magnitude. . ”

Regardless of the size of the anticipated challenge, it has to start somewhere.Understudied Protein Initiative Public invitation has been issued Provide researchers with an overview of the project’s “roadmap”.Ann Openly accessible research was started as a first step. This presents a randomly selected human protein and asks the user to assign it to an annotation level. The survey then asks users to describe the tools, resources, and considerations they suggest for their evaluation.

“Based on the responses to the survey, we aim to define challenges for community efforts to address protein annotation bias. We will present and discuss the results at the workshop,” said the initiative leader. state. The main questions to be addressed in the workshop are:

• What new information about uncharacterized proteins might trigger detailed mechanistic studies?
• What tools provide that information?
• How will the consortium be structured?
• How does information efficiently reach molecular biologists and drive change?

take action

Some of the greatest successes in science are based on taking potential risks. Regardless of the expected analytical challenges and perceptions of proteins as ‘dull’, it is perhaps now possible for researchers to confidently and comfortably pursue the study of lesser-known or poorly understood proteins. Seems more essential than ever. Who knows what we’ll find?

It is spearheaded by the Understudied Protein Initiative, which encourages the community to participate by taking surveys and spreading the word.

“By providing the fundamental molecular properties of all proteins, the Understudied Proteins Initiative will facilitate the investigation of understudied protein mechanisms, advance new biomedical research, and contribute to its success in the human proteome and disease. We will deepen our understanding of the role.” – The Understudied Protein Initiative.