Life runs on proteins. The molecules, coded from genetic sequences, dictate how a body functions, either maintaining the status quo or, if something is awry, causing disease.
And while an understanding of how proteins operate — a field called proteomics — can be an immensely powerful tool in the fight against devastating conditions, researchers have been held back by the sheer complexity of the estimated 80,000 to 400,000 proteins in the human body.
But as scientists have made progress in understanding the human genome and technology improvements more precisely chart the inner workings of organs and cells, proteomics are a promising new frontier in drug research and development, said Bogdan Budnik, a principal scientist at Harvard University’s Wyss Institute.
Some pharma companies have begun to adopt proteomics as part of the Pharma Proteomics Project announced in 2020, including Johnson & Johnson, Pfizer, AstraZeneca and more. But so far, more of the work in the field has been done in laboratories like Budnik’s at Wyss.
“It’s important to know exactly what proteins do, how they behave, how they change, where the pockets are that small molecules can influence their capabilities. That’s why proteomics is essentially the bread and butter of the pharmacology industry."
Bogdan Budnik
Principal scientist, Wyss Institute at Harvard University
Budnik’s focus on proteomics has led him down several paths that could lead to better diagnostics and medicines, from discovering new biomarkers to using organs on a chip to analyze the role proteins play in certain diseases.
Here, Budnik discusses the intricate potential of single-cell research, where proteomics might have the greatest impact in the pharma industry and how personalized medicine could benefit from further understanding in the field.
This interview has been edited for brevity and style.
PHARMAVOICE: What is the importance of single-cell biology in the context of the biopharma industry, and how is it being used at this point?
BOGDAN BUDNIK: Stepping back about 10 years, the first single-cell RNA sequencing was happening at [the Broad Institute of MIT and Harvard] — it was the first analysis of the single cell, and that area grew quickly and brought a wide variety of new biology insights into our basic understanding of how cells’ heterogeneities play a role. Before that, analysis was done on a piece of tissue, like the brain or the liver or a lung, but for the pharmacology and pharma field, it’s very important to know what exact type of cells have been changed compared to other cells. That’s where single-cell proteomics play a key role, because by doing an analysis on a cellular level, you can learn the exact cells affected by a certain disease and how they might respond to a drug.
More than 90% of drug targets are proteins. So for the pharma industry, it’s important to know exactly what the proteins do, how they behave, how they change, where the pockets are that small molecules can influence their capabilities. That’s why proteomics is essentially the bread and butter of the pharmacology industry. But it’s difficult because you’re working with the material you have in a cell, and anything you want to manipulate is in a certain volume of liquid that is a problem for a human being to handle. That’s where automation and robotics are becoming crucial for handling.
Tell me a little more about how technology is helping drugmakers use proteomics more efficiently.
Here at the Wyss Institute, we are using something called the HP D100 from HP [now sold by the lab instrument company Tecan as the Uno single cell dispenser] that can separate single cells into individual well plates, which none of us can do physically by hand. From there, there’s a Tecan robot that operates in very small volumes, which is a very gentle and difficult procedure that needs to happen before we analyze peptides in our mass spectrometry instruments. This happens at the nanoliter level, which is nearly impossible for a human being to work with.
On the industry side, where do you see single-cell biology playing an important role in R&D?
We’ve seen very interesting publications where the Matthias Mann Group shows the specific capture of a single cell to provide a very drastic heterogeneity of the cancer environment. Cancer would be one of the main areas where this type of analysis is important because you need to understand the environment of the cancer cell versus the surrounding tissue, which is premalignant, and then a healthy tissue.
And then clearly for drug discovery purposes, you can see the heterogeneity of a cell and the response to a drug. That’s very important because when the first line of treatment comes into any cancer, some patients are cured to a certain point, but relapses occur, meaning the drug did not kill 100% of the cells, and a new generation returns that is resistant to that drug. By understanding the proteomics first, we can find effective cocktails of existing drugs or even something new that could benefit a particular patient in the first line of treatment.
How can proteomics help match diagnostic tests to drugs for more precise treatment?
There is a lot of room for the personalization process to work toward immunology, for instance, because immune responses can be quite different for different people. And looking into personalized medicine based on the knowledge of immune system responses would be something that could lead to many new treatments. There’s more happening in the area of diabetes, as well, because there are many different types of diabetes, and single-cell analysis and understanding of cell heterogeneity even in this one particular disease could help people return to a normal kind of lifestyle.
And then proteomics could be very important for neurodegenerative diseases where any tissue sample will contain five or six very general cells with different functions. That’s where the separation of particular cells will tell us which ones are being affected in a certain neurodegenerative disease, and provide targets that in the hands of biopharma could lead to cures.
