“As a scientific discipline, proteomics isn’t really that old – it’s like protein biochemistry gone crazy,” Dr. Jennifer Van Eyk, professor of cardiology, director of the Advanced Clinical Biosystems Institute and the Erika Glazer Endowed Chair in Women’s Heart at Cedars-Sinai Medical Center, said.
Prof. Van Eyk’s journey in clinical proteomics began when she was a peptide chemist: “I was a minimalist, taking big proteins and breaking them down to their fundamental amino acids.”
In peptide chemistry, proteins are typically studied in isolation using techniques such as sodium dodecyl-sulfate polyacrylamide gel electrophoresis or Edman degradation. In the latter portion of the 20th century, proteomics – the study of the proteome – emerged as its own field. Over recent decades, it has evolved to new heights thanks to projects such as the Human Genome Project, the launch of organizations such as the Human Proteome Organization (HUPO) and increasingly higher-throughput techniques for protein analysis.
Now an international leader in clinical proteomics, Prof. Van Eyk is no longer a minimalist and strives to achieve a completely different goal in her work: characterizing as many proteins as possible at once.
What is clinical proteomics?
Clinical proteomics, as the name suggests,describes the study of the proteome and the application of subsequent insights in a clinical context. Such insights might be used to interrogate the biological underpinnings of a disease, identify and validate disease biomarkers, identify novel drug targets, predict disease outcomes or understand drug resistance mechanisms.
The proteome is dynamic and incredibly complex. Studying it with the aspiration to translate basic research into clinical insights is far from easy, but it’s a field that Prof. Van Eyk has always been passionate about:
“It’s my personal belief that if I am lucky enough to work as a scientist, I want to be able to pay back to society – I want to help change lives. You can do that in a lot of different ways, and I’m choosing to do it through medicine,” she said.
Having worked in clinical proteomics for over 25 years, Prof. Van Eyk’s research has helped to shape the field as we know it today. The laboratories at Cedar-Sinai are set up to explore and quantify proteins in all their forms, on small and large scales. Prof. Van Eyk is renowned for her research developing technical pipelines for de novo discovery and larger-scale quantitative mass spectrometry (MS) methods.
Primary research in the Van Eyk laboratory has two core goals:
Understand the molecular mechanism underlying acute and chronic disease and treatment therapies, and
Develop clinically robust circulating biomarkers.
At HUPO’s 2024 World Congress, Technology Networks had the pleasure of interviewing Prof. Van Eyk – who is also the organization’s President – to learn more about the exciting work going on in her laboratory, how she hopes to address bottlenecks in clinical proteomics and what she hopes her legacy will be in this field.
Innovations in clinical proteomics
Remote sampling devices
Prof. Van Eyk highlighted microsampling as a particularly exciting area of research within clinical proteomics. “Not everybody has the money and access [to healthcare] that we have in the Western World, but we all have the right to know the status of our health,” she said.
“Microsampling can help science and medicine become more inclusive, reduce costs for healthcare systems and help people access important insights about their health.”
Human blood is a rich source of protein biomarkers that can be used to determine our health status at a given time point. Repeated blood samples taken from the same individual can also provide insights into their health over time. The insights from such data cannot be understated – it could facilitate the discovery of novel biomarkers associated with disease progression, provide insights into the effectiveness of lifestyle interventions or monitor an individual’s response to a drug treatment.
However, current health assessments require in-clinic venipuncture by a trained phlebotomist. The blood sample is then safely packaged and transported to a laboratory for processing and analysis. There are several issues with this system: first, it’s not always convenient for individuals to access even one clinic appointment, let alone make repeated visits to have blood drawn over time. Second, venipuncture can be uncomfortable, which may discourage individuals from undergoing blood tests.
Collectively, these factors limit accessibility to important health insights and make it challenging to conduct large-scale population health studies.
Imagine being able to collect a smaller sample of blood at home, using a safe, minimally invasive device, before packaging your sample and posting it for analysis at a location that’s convenient for you. This vision for the future of telehealth is driving the development of remote sampling devices, capable of collecting important protein biomarker data using increasingly smaller samples of blood (microsampling).
Prof. Van Eyk has been contributing to this emerging area of research for many years, developing robust MS-based workflows for remote sampling devices and exploring their viability compared to existing approaches for health analysis. Though remote sampling devices remain in development, Prof. Van Eyk is enthusiastic that they can one day democratize health care: “It’s going to be a long road, but I think we have a responsibility to help people access their data and have some level of control over their health.”
The Molecular Twin
In oncology, Prof. Van Eyk shared a novel precision medicine platform known as the “Molecular Twin”. Precision oncology is an innovative approach that considers a patient’s unique molecular makeup when designing and implementing their treatment plan. Genetic insights provide one layer of detail, but even with the same genetic mutations, some cancer patients respond differently to identical treatment plans.
At Cedars-Sinai, Prof. Van Eyk and Prof. Dan Theodorescu and many other colleagues helped to build Molecular Twin by integrating clinical and multiomic features from patients with resected pancreatic ductal adenocarcinoma. Multiomic features were gathered using techniques including next-generation sequencing, full-transcriptome RNA sequencing, paired tumor tissue proteomics, unpaired plasma proteomics, lipidomics and computational pathology. This data was integrated and, with a helping hand from machine-learning models, accurately predicted disease survival rates. “It turned out that plasma proteomics was a very good indicator of disease survival,” Prof. Van Eyk said.
By continuing to build Molecular Twins across multiple cancer types, she hopes that clinicians can compare incoming cancer patients with their “twin” data from the platform and better tailor their treatments: “We will know who [from the database] the patient looked like at the beginning of their treatment, and then either follow the same course because it was successful or move to another course.”
Understanding drug responsiveness using single-cell analysis
“We also have some remarkable work looking at how patients respond to treatment in inflammatory bowel disease (IBD),” Prof. Van Eyk said. IBD is a group of inflammatory conditions that represent a major public health burden. A cure does not exist, but symptoms can be managed using medication. If medications fail to calm inflammation, surgery may be required. IBD patients who require surgery to remove part of the colon will typically be prescribed anti-TNF therapy as a standard of care.
“Unfortunately, many of these patients will become unresponsive to that therapy within a few weeks. Then at some point, whether it’s one year, two years or five years after surgery, it will no longer work in all patients and they will have to move onto another therapy,” Prof. Van Eyk explained. Her laboratory is looking to the proteome to identify biomarkers of unresponsiveness and to investigate whether it’s possible to predict which patients might benefit from changing therapies earlier.
The lab is also adopting single-cell proteomics techniques to understand how populations of cells respond differently to drugs. “If we think about the heart as an example, and the cells that cause the heart muscle to contract, we now know that there are multiple populations of cells that almost ‘group’. When you give these cells a drug, they might not respond equally. If a drug fails, it might be because the individual does not have enough of that specific population of cells for the drug to be effective,” Prof. Van Eyk said. “Which, of course, has important implications for drug development. We’ll see how this research progresses in the long run, but I think these types of technology advancements are letting us answer questions that we never even thought to ask before, which is very cool.”
Moving biomarkers to the clinic – overcoming obstacles and carving a legacy
Despite incredible advances over recent decades, translating proteomics insights to the clinic is a work in progress. Prof. Van Eyk discussed some of the key challenges in discovering biomarkers, validating them and their route to clinical implementation:
“I think the idea that we can identify analytes that closely define pathophysiology within a group of individuals is becoming a closer reality. The challenge of getting this research into clinical implementation is that, often, the middle technologies or expertise in that domain are not as well established in academia. There are funding issues, and there isn’t always a clear route to success. Lots of factors can influence that success, which ultimately has nothing to do with whether you have a good biomarker.”
Prof. Van Eyk emphasized that, even if researchers create an assay and gather sufficient data to prove its usefulness, there is still a long way to go for that assay to become a part of standard care. It’s a process that requires input from a group of different communities, and oftentimes, the original researchers working on the discovery aspect are not involved in it. Clinicians also need to be able to inform researchers completing the discovery work – and those responsible for its funding – about the key questions that need to be answered through discovery research.
“It has to be a two-way conversation,” Prof. Van Eyk said. While knitting these communities together isn’t easy, it’s going to be critical for the future of the field, she emphasized: “I think a lot of clinical proteomics over recent decades has been about developing tools that ensure our data is reproducible. Now, we’re at the point where we need to engage in conversations about how this data is actually used. Those conversations need to happen globally within the field.”
Looking to the future, Prof. Van Eyk is determined to continue her work addressing these bottlenecks. “I think the legacy that I’d like to leave in this field is that I made it easier for researchers to get their biomarkers to the clinic efficiently. That way, they don’t have to go through all the learning processes that I did,” she said.
A highly respected mentor in proteomics, Prof. Van Eyk is passionate about using her expertise and experience to support early-career researchers.
“When I first started in proteomics, it wasn’t even a word,” she laughed. “What we now know, and what we can achieve, is just remarkable. Every year, I see a new level of sophistication, innovation and thinking in my trainees, who are so adept at speaking the language of this evolving field. I want to continue watching their capabilities grow and support them for a little while longer because it’s such a joy.”