Dr. Liu discussed his research for "Humans of HUPO"

What is your current position and location?

I am an Associate Professor in the Department of Pharmacology at Yale University School of Medicine, located in New Haven, Connecticut. My lab (https://www.yslproteomics.org/), however, is situated at the Yale Cancer Biology Institute on the Yale West Campus in West Haven, which is about a 15-minute drive from New Haven.

How did you get started in the field of proteomics?

I began my journey in proteomics in 2005 as a Ph.D. student at the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. My Ph.D. lab, led by Dr. Rong Zeng, was one of the earliest proteomics laboratories in China. I was fortunate to work with one of the first Orbitrap mass spectrometers. My dissertation was entitled 'Cancer biomarker discovery based on multiplexed quantitative proteomic strategies.' After earning my Ph.D., I joined Dr. Ruedi Aebersold’s lab at ETH Zurich as a postdoc, where I further specialized in DIA-MS and continued my research in the field. So next year will mark my 20th anniversary in proteomics!!

What does being a member of HUPO mean to you?

Being a member of HUPO holds deep significance for me. My first major international conference was HUPO Sydney 2010, not only my first journey outside of China but also the pivotal event where I met Ruedi Aebersold and was accepted as a postdoc in his lab. Over the past 14 years, I have attended most HUPO congresses and now serve on both the HUPO Award Committee and the HUPO Education and Training Committee. I was deeply honored to win the HUPO ECR Manuscript Competition award at HUPO Reconnect 2021. Being part of the HUPO community, where I can share my research, gain insights from others, and collaborate with fellow scientists who share a passion for proteomics, truly makes me feel fortunate and valued. Reflecting on the Chinese proverb, 'The joy of meeting an old friend in a foreign land is one of life’s greatest pleasures,' I resonate with this sentiment each time I attend a HUPO conference.

What makes your research program exciting and unique?

In my lab, we are dedicated to addressing a fundamental question: Can we measure not only the abundance of any given protein or its modifications but also determine and comprehend their persistence within a cell system? This research focus has catalyzed several exciting directions. First, we have integrated pulse-chase SILAC labeling (pSILAC) with DIA-MS, or plex-DIA, to measure protein turnover rates on a large scale. We've optimized the mass spectrometry methods on our Lumos Orbitrap MS and developed a bioinformatics pipeline to accurately determine protein lifetimes. Second, we ventured into uncharted territory by “marrying” protein turnover measurements with post-translational modification (PTM) profiling, such as phosphoproteomics. This approach allows us to explore how site-specific phosphorylation impacts protein turnover. Interestingly, we've observed that phosphorylation often reduces protein turnover, a phenomenon that was underappreciated in previous studies. Third, we have applied protein turnover measurements across various biological and disease contexts, including cancer aneuploidy, cell starvation, and cell fate decisions. One of our recent discoveries revealed that protein turnover control varies significantly among different 'gain-type' and 'loss-type' lung cancer aneuploidies. Together, our goal is to augment the traditional 'abundance-centric' perspective with a 'lifetime-centric' view on proteins and PTMs, thereby establishing a new paradigm in protein research that spans basic and translational sciences.

In addition to our primary research focus, we are also deeply engaged in understanding biodiversity between human individuals and other species on Earth through proteomics and PTM profiling. Furthermore, we actively collaborate with many local Yale scientists and other global collaborators, supporting their research endeavors, as I firmly believe in the transformative power of proteomics in modern biology.

What are your interests outside the lab?

Outside of the lab, I treasure every moment spent with my wife and our energetic 3.5-year-old son. Besides family time, I dive into the worlds of science fiction novels, classics like 'Dream of the Red Chamber,' and those endlessly fascinating Chinese cultivation and immortal novels—not to mention a good movie binge. These are my favorite ways to blissfully ignore the passage of time. As for exercise, I once wielded a badminton racket, but I've recently traded it in for a home treadmill. I must admit, it’s definitely less smashing!

Where do you envision the field of proteomics in the next 10 years?

Over the next ten years, I envision the field of proteomics expanding to broadly encompass a wider array of non-MS technologies. The detection and quantification of proteins, particularly at the total protein level and in clinical applications, will likely see the emergence of many non-MS technologies. These new methods may compete with, and in some areas surpass, mass spectrometry. Technologies such as multiplex antibody techniques, SomaScan, Olink-like technologies, super-resolution imaging for direct observation of peptide sequences or PTM structures, and nanopore approaches for single-molecule analysis are poised to make significant strides and challenge MS experts.

Additionally, I believe that mass spectrometry will not become obsolete but will continue to develop rapidly. For example, the MS-based analysis of post-translational modifications (PTMs) and protein dynamics, including protein turnover as we are exploring in our lab, will remain essential. Mass spectrometry will continue to generate vast and complex datasets, such as those involving giant patient cohorts, in the future. The development of innovative data analysis and bioinformatics tools will remain a hot topic. Over the next ten years, we might see AI tools like transformers become mainstream in mass spectrometry data analysis and even in routine protein identification and quantification. However, we will also continue to face challenges with data noise, practical issues with sample preparation, and the stability of mass spectrometry system (especially the LC ;-) ).

Moreover, an especially exciting area I foresee is spatial proteomics. My lab recently began incorporating ion mobility separation and MALDI MS imaging into our toolkit. Although these are new territories for us, these emerging spatial 'omics' and spatial proteomics analyses will uncover the cell-type heterogeneity in the disease process, uncovering new disease dependencies and vulnerabilities.