Did you always want to be a scientist?
Not so much a scientist, no – my father was an engineer, so I had inclinations in that direction. As a child, my favorite pastime was to disassemble clocks, often much to the irritance of my father. I remember one day he told me, “You’re really good at taking clocks apart, but if you really want to feel like you’ve accomplished something, try putting one back together so it works again.” It took me three months, but eventually I reassembled one successfully – and he was right about the feeling of accomplishment.
After finishing high school, I was uncertain about what I wanted to do. This was the Vietnam War era, and so I faced a choice: join the Air Force, Navy, or be drafted. I joined the Air Force, served four years – including a tour in Vietnam – and then started university, initially thinking I might become a pharmacist. After taking a few courses, I realized I really liked chemistry and physics. I ended up majoring in math and physics and did some research with a physics professor on protonated helium – my first exposure to mass spectrometry. It was only later I learned we were actually doing ion mobility.
In my junior year, I attended a seminar on mass spectrometry, while also taking a physical organic course and advanced physics. I was intrigued by the speaker’s work on ion-molecule reactions, and so I began reading about ion cyclotron resonance and molecular chemistry. This inspired me to go to graduate school at the University of Nebraska to work with Mike Gross, whose papers I had read with keen interest. After earning my PhD, I spent two years at Oak Ridge National Laboratory before moving to Texas A&M University, where I began my research program in mass spectrometry.
You’re known for pushing the limits of mass spectrometer performance, as well as for your work applying mass spectrometry in biological systems. Do you think of these as separate endeavors?
Mass spectrometry has many dimensions in terms of experimental capabilities and opportunities for learning. My engineering background meant I was always drawn to complex instrumentation and the challenges it presents. Early in graduate school, I realized that mass spectrometry could contribute to understanding organic chemistry, inorganic chemistry, basic physics – and more.
Initially, my research interest was driven by the instrument itself and what it could do. Over time, however, I began to see mass spectrometry not just as a way to study problems, but as a tool to solve them. This epiphany shaped my focus to develop technology and instrumentation with a specific problem in mind, with biology and biochemistry providing ideal problems to justify the creation of advanced instrumentation.
Since the mid-to-late 1980s, that’s been my approach – starting with peptides, then moving to proteins, then protein complexes. Today, we’re studying how metal ions, cofactors, and water influence the structure, stability, and dynamics of these complexes, using fundamental thermochemical measurements on the mass spectrometer. By integrating multiple analytical and instrumental approaches with collaborators, we’re tackling problems directly related to drug discovery, disease research, and beyond. It’s an incredibly exciting time to be doing science!
Are you driven more by curiosity or a desire to make an impact?
I’d say I’m more interested in discovery-based science. We can identify problems in biology, medicine, and so forth, but the creativity from the mass spec perspective comes in designing the tools you need to gain new insights into those problems – though not necessarily to solve them. Creating solutions to some of these challenges is about as difficult as getting someone to Mars. But I think we’re at a point where technology is really driving new innovations, new insights, and new ideas. I love to play golf, especially discovering better ways to hit the ball so it lands where I want it to. It’s the same with research: if you can develop a new technology that gives fresh insights, you create the opportunity to discover something novel – or sometimes solve an age-old problem.
Occasionally, people come to me after reading one of our papers and ask if we could help with a specific problem. In those cases, we’re not inventing new technology, rather applying existing tools to real problem-solving – and more often than not, we’re successful. In my group, students often spark new directions. They’ll come in and say, “I read this paper, and I think we could help solve this problem.” That’s one of the most exciting parts of academic research – bright minds learning something and then wanting to learn more. They often become the drivers of new research paths.
Would you say that there are any key “innovation lessons learned” – especially advice to continue innovating throughout a career – that you could share?
Early in my career at Texas A&M, I had accumulated a collection of very sophisticated mass spectrometers, and so designed my experiments around said instruments. One day, I told my group we were going to change our mindset: instead of building experiments to suit the instruments we already had, we’d identify problems first, then design new instruments or technologies to solve them.
I sold the instruments in my lab to the department to set up a mass spectrometry facility, and we began building our own time-of-flight instruments – simple in design but capable of complex experiments. Not long after, Mike Bowers published a paper on ion mobility that caught my attention, and I soon realized time-of-flight was a perfect match for ion mobility, so we started building instruments that combined the two. This shift in direction drew us deeper into biological studies. We went through a five- or six-year period focused more on technological development than direct problem-solving, but this work created new capabilities that we could then apply to real challenges.
Ion mobility now plays a leading role in many biological mass spectrometry studies. It’s not a perfect tool, but it complements techniques like cryo-electron microscopy, NMR, and fluorescence resonance energy transfer. Together, these methods provide a richer understanding of aspects such as protein folding, protein–ligand binding thermodynamics, and other processes relevant to drug discovery.
Are there any emerging technologies or trends that excite you?
We’ve recently been using mass spectrometry and ion mobility as a way to study the thermodynamics of protein–ligand binding, made possible by developing what we call a “variable temperature electrospray ionization” source. This setup lets us heat a solution of interest anywhere from freezing to boiling, so we can examine reactions as a function of temperature, enabling us to observe the thermodynamics of the process.
One of the most interesting aspects of this is how it’s allowing us to explore enthalpy–entropy compensation from the Gibbs equation; as entropy increases, enthalpy decreases (and vice versa). These measurements tell us not only about the chemistry involved in ligand binding, but also how cofactors, metals, buffers, or hydration affect that chemistry.
This approach opens new avenues for understanding fundamental aspects of protein–ligand interactions. For example, we’ve shown that we can follow the sequential binding of up to 14 ligands to a molecule – tracking each binding event individually and obtaining a thermodynamic signature for each one. This level of detail simply isn’t possible with ensemble measurements.
It’s providing new insights into allostery, thermodynamics, and the influence of cofactors and hydration – and for me, developing the technology to make these experiments possible is probably the most exciting thing I’ve done in my career.
What’s the biggest challenge facing mass spectrometry today?
One of the biggest challenges is convincing researchers in drug discovery – who traditionally rely on established methods and technologies – that mass spectrometry should be a key tool in their arsenal. It’s not about replacing existing approaches, but rather integrating MS alongside techniques like cryo-electron microscopy, FRET, and NMR. Each method brings a unique perspective, and together they can offer a more complete picture of complex biological problems.
The future lies in this kind of integration, where multiple technologies are applied in a concerted fashion to tackle a specific problem from different angles. That’s the philosophy behind a center I’m involved in with Vicki Wysocki at Georgia Tech and Brandon Ruotolo at Michigan, funded by the NIH. Its explicit goal is to combine these tools to address challenging questions in structural biology and drug discovery.
Has there been a mentor or role model who has significantly influenced your career?
Yes – several! My PhD mentor, Michael Gross, was an early and important influence. At the time, he was at the University of Nebraska (he’s now at Washington University in St. Louis) – he set the foundation for much of my thinking.
I also had formative encounters with Dudley Williams, a professor at Cambridge in the UK. He would read my papers and then write or speak to me with probing questions – “What made you think of this?” or “What’s driving your thoughts here?” – which pushed me to think more deeply about my work. The same was true of Jack Beauchamp at Caltech and Graham Cooks at Purdue, both of whom challenged me to examine my assumptions and be clear on why I was pursuing a given line of research.
Another memorable influence was Al Cotton here at Texas A&M. He often provoked me by saying mass spectrometry was only about gas-phase ions, and that he was interested in solution chemistry – so when mass spec could do solution chemistry, he’d then care. That challenge stuck with me, and now, ironically, we are doing solution chemistry with mass spec. Sadly, he passed before seeing that progress, but I like to think he would appreciate that his skepticism ultimately helped drive us towards it.
What advice would you give to the next generation of analytical scientists?
Particularly in proteomics, I would tell young scientists that although the technology is mature and capable of solving many problems, it’s important to be adventurous. Look for the next big development, ask what comes after the “omics” era, and think about what mass spectrometry might be able to do that we haven’t yet discovered.
Focus on discovery, rather than routine analysis or simply repeating what others are doing. Set yourself apart: establish your own identity, work on important problems in a deliberate and well-defined way, and aim to do something genuinely new.
What’s your overall outlook on the future of analytical science?
I think analytical science has often been seen as sitting on the sidelines in many disciplines within chemistry, but now it’s becoming central. So many challenges in catalysis, energy, the environment, and developing new chemistry hinge on understanding exactly what’s being made and why it matters. Often, when chemists run into a problem, there’s already an analytical method that could provide the answer – they just need to be aware of it and open to using it. By the same token, as mass spectrometrists, if we better understood the chemistry, we could design better solutions to the problems others are facing.
For me, the future lies in open communication: talking with people in other disciplines, learning about their challenges, and sharing our own. The trend toward ever-larger, hyper-focused conferences can sometimes make this harder, so I think smaller, discussion-driven meetings – like the Gordon Research Conferences – are invaluable for sparking new ideas and collaborations.
Overall, the outlook is bright. Although political or logistical barriers can slow progress in the short term, these are just temporary obstacles – what I’d call “entropic barriers” – which I have no doubt science will eventually overcome.
David H. Russell is Professor of Chemistry and AB/MDS Sciex Instruments Professor of Mass Spectrometry, Texas A&M University, USA
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