Life activities are driven by proteins. These molecules, encoded by gene sequences, determine how the human body operates—maintaining homeostasis when normal, or triggering disease when aberrant.

Proteomics—the study of how proteins function—could have been a powerful tool against major diseases, but researchers have long been constrained by the estimated80,000 to 400,000 proteinsin the human body and their extreme complexity.

However, as scientists make progress in understanding the human genome and as technological improvements enable more precise mapping of organ and cellular internal workings, proteomics is becoming a new frontier in drug discovery, says Bogdan Budnik, lead scientist at the Wyss Institute at Harvard University.

Some pharmaceutical companies have begun integrating proteomics into their R&D systems, participating in thelaunchedin 2020 "Pharmaceutical Proteomics Project," including Johnson & Johnson, Pfizer, AstraZeneca, and others. But so far, more work in this field remains concentrated in laboratories like the Wyss Institute where Budnik works.

"Precisely understanding how proteins function, behave, change, and where the binding pockets are that small molecules can influence their activity is crucial. This is why proteomics is the cornerstone of the pharmacology industry."

—Bogdan Budnik, Lead Scientist, Wyss Institute at Harvard University

Budnik's focus on proteomics has led him down multiple paths that could yield better diagnostics and drugs, from discovering new biomarkers to using organ-on-a-chip technology to analyze protein roles in specific diseases.

Here, Budnik discusses the fine-grained potential of single-cell research, where proteomics might have the greatest impact in the pharmaceutical industry, and how personalized medicine could benefit from deeper understanding in this field.

This interview has been edited for length and style.

What is the importance of single-cell biology in the biopharmaceutical industry, and how is it currently applied?

Looking back about a decade ago, the first single-cell RNA sequencing occurred at the Broad Institute of MIT and Harvard—this was thefirst analysisof single cells, and the field grew rapidly, bringing broad new biological insights into how cellular heterogeneity functions. Previously, analyses typically targeted tissue sections, such as brain, liver, or lung. But for pharmacology and pharmaceuticals, precisely understanding which cell types are altered relative to others is crucial. This is where single-cell proteomics plays a key role—by analyzing at the cellular level, you can determine the exact cells affected by a specific disease and their potential response to drugs.

Over 90% of drug targets are proteins. Therefore, for the pharmaceutical industry, precisely understanding how proteins function, behave, change, and where the binding pockets are that small molecules can influence their activity is crucial. This is why proteomics is the cornerstone of the pharmacology industry. But the challenge is that you are dealing with material inside cells, and any component requiring manipulation is in a certain volume of liquid, which poses difficulties for manual handling. Automation and robotics thus become indispensable.

How can technology help pharmaceutical companies use proteomics more efficiently?

At the Wyss Institute, we use the HP D100 (now sold by laboratory instrument company Tecan as the Uno single-cell sorter) to isolate single cells into separate well plates, which cannot be done by hand. Then, Tecan robots operate at extremely small volumes—a very delicate and difficult process that must be completed before mass spectrometry analysis of peptides. This operation occurs at the nanoliter scale, making it nearly impossible for humans to perform.

From an industry perspective, what are the key application areas of single-cell biology in R&D?

We have already seen some interesting studies, such asthe Matthias Mann research groupdemonstrating how specific capture of single cells reveals significant heterogeneity in the cancer environment. Cancer is one of the important areas for such analysis because you need to understand the environmental differences between cancer cells and surrounding precancerous and healthy tissue.

Clearly, in drug discovery, you can observe cellular heterogeneity and response to drugs. This is very important because when first-line treatment is used for any cancer, some patients may achieve a degree of cure, but relapse still occurs—meaning the drug did not kill 100% of cells, and a new generation of resistant cells emerges. By first understanding proteomics, we can find effective combinations of existing drugs, or even develop new drugs, so that specific patients benefit from first-line treatment.

How can proteomics help match diagnostic tests with drugs for more precise treatment?

The personalization process has great potential in immunology because immune responses vary significantly among individuals. Personalized medicine based on knowledge of immune system responses could lead to many new therapies. There is also more progress in the diabetes field, because diabetes has multiple types, and single-cell analysis and understanding of cellular heterogeneity—even for just this one disease—can help patients return to a normal lifestyle.

Additionally, proteomics could be extremely important for neurodegenerative diseases, because any tissue sample contains five to six common cell types with different functions. Isolating specific cells will tell us which cells are affected in a particular neurodegenerative disease and provide targets that, in the hands of biopharmaceutical companies, could lead to cures.