Dr. Lizhuo “Liz” Ai, a postdoctoral fellow in Dr. Jennifer Van Eyk‘s lab at Cedars-Sinai in Los Angeles, is unravelling the hidden diversity of heart cells through cutting-edge single-cell proteomics. This approach, which centres on investigating cardiomyocyte heterogeneity in response to drug treatments, could transform how we develop and prescribe heart medications. Between the major breakthroughs, however, it’s the journey that Liz has learned to embrace – the unexpected results, the failed experiments, and the challenges and small wins that ultimately lead to discovery.

From Transcripts to Proteins

“My interest in proteomics started during my master’s program,” Liz explains, recalling her early research on adolescent binge drinking and its effects on the developing heart. “We performed bulk RNA-Seq analysis and identified several interesting pathways related to cardiac development and stress responses. However, when we tried to validate some of these findings using western blots, the results didn’t always match what we expected based on the transcriptomic data.”

This disconnect between RNA levels and actual protein expression became a pivotal moment in her scientific journey. “That experience really sparked my curiosity and made me realise how critical it is to study proteins directly if we want to truly understand biological function and disease mechanisms,” she reflects.

This realisation led her to join Dr. Van Eyk’s lab, where she completed her PhD in 2024, focusing on understanding the global proteomic effects of drug candidates on heart muscle tissue after heart attacks. Her dissertation aimed to explore potential strategies for preventing heart failure—a condition that affects millions worldwide.

Unexpected discoveries change perspective

Scientific breakthroughs often come from unexpected places, as Liz discovered during her PhD research. “One moment that really changed my perspective came from a paper we published last November in the European Heart Journal,” she shares. “We were investigating the global proteomic changes in heart tissue after treatment with a drug candidate, following a heart attack.”

Going into the study, Liz expected to see activation of known protective mechanisms. Instead, she found something surprising: “The protein expression profile of the treated hearts actually clustered much closer to the healthy hearts, rather than following the trajectory toward pathological remodelling. In other words, the drug seemed to halt or even reverse the shift toward a pathological proteome.”

This finding fundamentally shifted her approach to drug development research. “Instead of focusing only on specific molecular mechanisms, I started thinking more about the overall global changes, and how a successful therapy might work not by just ‘fixing’ or ‘targeting’ a few key proteins, but by nudging the entire proteomic landscape back toward health.”

The village behind single-cell proteomics

Now, as a postdoctoral researcher, Liz has turned her attention to investigating cardiomyocyte heterogeneity in response to drug treatments using cutting-edge single-cell proteomics. This work allows her to study patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes, exploring whether the variability in drug responses can be explained by inherent cellular differences.

Building the single-cell proteomics platform was no small feat. “Being part of the single-cell proteomics team in the Van Eyk lab has been one of the most memorable and rewarding experiences of my career,” Liz says. “It took a village to establish a reliable SCP workflow for cardiomyocytes.”

The journey began in 2020 when Liz was a rotating PhD student. “One of my first tasks was manually pipetting 1 ng of lysate into the wells of a 384-well plate,” she recalls. “Every step of the workflow required careful optimisation, from optimising the lysis buffer to fine-tuning digestion times.”

The collaborative nature of this work extended far beyond their lab, involving multiple research groups. “Along the way, there were many failures, such as when sample prep didn’t work or MS acquisition didn’t go as expected, but every failure taught us something valuable and moved us closer to success.”

After four years of collective work, the team published their most recent single-cell proteomics study, which focused on human cardiomyocyte proteome heterogeneity. “That moment was incredibly gratifying,” Liz says. “This experience taught me the value of persistence, creativity, and collaboration in science.”

Breakthrough discoveries at the single-cell level

The lab’s recently published paper in Molecular & Cellular Proteomics represents a significant achievement in the field; presenting one of the largest and most diverse single-cell proteomics datasets to date, spanning five differentiation stages from iPSCs to iPSC-derived cardiomyocytes (iCMs) and adult cardiomyocytes (aCMs).

“Single-cell proteomics reveals rare hybrid cells expressing both cardiac-specific and neuronal-enriched proteins, found in both iCMs and aCMs,” Liz explains. This discovery of hybrid cells with mixed protein expression profiles could have significant implications for cardiac biology and disease understanding.

The analysis also highlighted important differences among iCMs, particularly in myofilament proteins critical for muscle contraction and metabolic pathways.

The success of Liz’s pioneering work relies heavily on having the right tools. “For my project on iPSC-derived cardiomyocytes, they are smaller than isolated adult cardiomyocytes, which presented a challenge for single-cell proteomics detection,” she explains. This is where reliable chromatography columns played a key role.

Since upgrading their instrument, Liz’s team has observed notable improvements in sensitivity and data quality, particularly when coupled with industry-leading columns. “Using IonOpticks’ Aurora Series columns, we have obtained reproducible results with consistent quality, which has been important for this project,” she notes.

As Liz’s team continues their research on cardiomyocyte heterogeneity, they’re working to further improve their single-cell proteomics capabilities through ongoing refinements in chromatography and mass spectrometry.

Read the full paper here.

Lessons from the journey: patience and celebration

Reflecting on her career thus far, Liz shares: “If I could go back, I would tell my younger self that science takes time and patience, and that’s okay.”

She initially approached her work with rigorously planned schedules and extensive to-do lists. “If I wasn’t able to complete everything on that list, I would feel like I was slacking,” she admits. “Over time, I’ve learned that the best science often comes from the unexpected results, the failed experiments, and the lessons that come from collaboration.”

This perspective has helped her develop a more balanced approach to scientific progress. “It’s not about checking off every task on the list; it’s about embracing the process, learning from challenges, and appreciating the journey of discovery.”

Just as importantly, Liz has learned to celebrate achievements along the way. “I’d also tell my younger self to celebrate the small wins. It’s so easy to get caught up in chasing the next paper, but looking back, some of my favourite moments in science have been when I learn a new technique or establish a new collaboration.”

These celebrations don’t need to be elaborate – Liz has developed her own ritual: “Now, I make a point to celebrate those moments, usually with a slice of my favourite Chantilly cake from Whole Foods on my way home or a Starbucks drink with extra pump of syrup. It’s a small ritual, but it reminds me how important it is to recognise progress, even when it feels incremental.”

Looking ahead: the promise of precision medicine

As Liz continues her work in cardiac proteomics, her goal remains steadfast: advancing precision medicine. “I am curious whether the variability we observe in drug responses can be partially explained by inherent cardiomyocyte heterogeneity,” she explains.

By uncovering the molecular differences between heart cells and how these differences affect drug responses, Liz hopes to contribute to a future where treatments can be tailored to individual patients. “Ultimately, I hope this work will contribute to advancing precision medicine, helping tailor therapies to individual patients, and ultimately saving lives.”

Through her work with single-cell proteomics, Liz’s path toward advancing precision medicine continues to unfold – not as a series of checkboxes, but as a rich and evolving scientific journey. After all, for Liz, it’s the process itself – with all its challenges and revelations – that ultimately brings us closer to a future where heart treatments can be as unique as the patients they serve.

Would you like to be featured in an upcoming Community Newsletter? Email us at [email protected] and tell us a bit about yourself and your research.