From Raman Labels to the Clinic

In a SciX 2026 interview with Spectroscopy, University of Utah Distinguished Professor Emeritus Marc Porter reacted to receiving the American Chemical Society (ACS) Division of Analytical Chemistry Award in Spectrochemical Analysis and explains how surface-enhanced Raman spectroscopy (SERS)-based immunoassays and extrinsic Raman labels turned a spectroscopic signal into a practical diagnostic readout.^1–5 Below is a transcript of our conversation with Porter at SciX.

Congratulations on being named the recipient of the ACS Division of Analytical Chemistry Award in Spectrochemical Analysis. What does winning this award mean to you and your research?

It really is difficult to express how it feels. There's a large mix of emotions. Concern sometimes: Did you really earn it? There was a whole bunch of these things, at least for me, that ran through my head while I was thinking it through. The first response was, "Wow." The second was, "Wow." And then the third response was, "Oh, my goodness.” So, it was really great news, and to be fair about it, me receiving the award reflects the contributions all the folks I've worked with over the years and their willingness to work hard. As a team, we came up with our own ideas. Some of the ideas in the group were from me; some of the ideas in the group were from my students, post-docs and other colleagues. That's how things have been done throughout my career with the folks I work with. So, it is really wonderful to win this, but I want to make sure that I shout out clearly and strongly to all the folks I worked with because this is really theirs as much as it is mine.

Your work on SERS-based immunoassays and Extrinsic Raman Labels turned a spectroscopic signal into a practical diagnostic readout. What was the key engineering or chemistry insight that made Raman labels viable as an alternative to fluorescent or enzymatic labels?

That’s a great question but let me first give you a little backstory. In the mid-'90s, we were spending a lot of time studying organic monolayer assemblies formed on gold, and that came in part from my work as a post-doc at Bell Laboratories with Dave Valera, where I got to know Ralph Nuzzo. Those are really the two folks that really drove that development; I was really there along for the ride.

But we were doing a lot of work with that. We'd been doing some scanning tunneling microscopy, atomic force microscopy (AFM), and a lot of infrared (IR) spectroscopy as part of our group from the beginning. I'm actually formally trained as an electrochemist. Electrochemists want to know when they modify a surface what it looks like, and that's what really drove our interest in terms of surface characterization. And we'd been doing a lot of this work, acoustic wave devices for sensors and different things, and two of my students came in one day for a meeting. We would have meetings to brainstorm and talk about what we want to do next, and they'd taken this a little bit more to heart than usual, and they said, "We need to do something that we're not doing now." What they really meant, what I read, is they said, "We really think we need to do something important." And, you know, we were doing things that I thought were important, but nonetheless, they said, "We need to do something in bioanalytical chemistry. We know how to characterize surfaces. We should figure out how to use those kinds of tools and figure out what we can do." And they said, "We want to do immunoassays."

To be fair, I didn't know a whole lot about what immunoassays were at the time. They explained it all to me, and we came up with a short-term plan to test out a few ideas. One idea was to use gold nanoparticles and do plasmonics. The other part of the work we were going to do was to study polymeric nanoparticles, and there, the infrared spectrum of a densely packed particle could give us a lot of signal as well.

Being an infrared spectroscopist at the time, I favored the polymer particle strategy, and it was similar to what we're doing with gold particles. You then stick an antibody on it. It sticks to the surface as part of the labeling step, and you do the infrared spectrum. I learned to build these things when I was at Bell Labs with Dave. So that's how we got started.

Over a period of time, we got some preliminary results in that six-month test drive, and the momentum just continued to build. To be fair, more of the folks that joined the group wanted to do that more than some of the other stuff. And so, there was an evolution and we really began to chase these things and make some headway, and we learned a lot along the way. What we decided to do is, because of the stability of the materials and the concerns people had about reproducibility, we settled on 60-nm, spherical particles in a gold-on-mirror type strategy that folks had talked about sometime in their earlier work. We settled on that. Then, we basically spent time learning how to modify the particles and spent a lot of time understanding how to do the assay. We decided to keep the Raman enhancement component (the plasmonic enhancement component) fixed at the time because there was clearly a lot to learn about how to do the bioanalytical side of things.

That was, in fact, one of the bigger challenges of the two key components of the project. However, it required a lot of work, a lot of trial and error, a lot of results that didn't make sense, and a lot of experiments to try to figure out what they were, and things just got better. However, the one thing we did learn was to spend a lot of time talking to the clinicians and ask them what they need. We wanted this to be a technology pull by them and not a technology push by us in the laboratory. Those are all important questions and things we've been asking ourselves more and more in recent times.

Your work applies surface-enhanced Raman scattering as a readout for heterogeneous immunoassays in infectious disease and cancer detection. How does SERS compare to more conventional readout methods (like fluorescence or colorimetric assays) in terms of sensitivity and practicality for real diagnostic use, and how close is this to clinical deployment?

The first answer is in terms of comparison to other types of assays, we've been able to show, not in every case, but in a lot of cases, that SERS actually gives us a better level of performance with respect to limits of detection as well as analytical sensitivity. What I mean is that's the slope of the dose-response curve. We get a higher signal discrimination capability from that, meaning if you're infected or you've got markers that have a given circulating level and they're up-regulated or down-regulated, we can follow those changes more quantitatively than we've been able to with both the ISO and the fluorescence techniques.

I believe a lot of that has to do with sample preparation. The take-home message for us is that the SERS technique has a lot of challenges. It's an extremely sensitive technique, so the demands on sensitivity and all the variables that affect sensitivity and reproducibility are amplified because we can measure things at levels that people haven't been able to do before. Therefore, a lot of things we didn't pay attention to became important. In terms of translation to clinical analysis, we've been working in particular on a SERS test for tuberculosis. That's been with colleagues at the University of Utah and Colorado State University. Our early work there suggested we could measure things quite well in buffer, but as soon as we put it in human serum, we lost three or four orders of magnitude in detection capabilities, which is a classic symptom of interference.

Long story short, we went back to the library and then went back to the laboratory and learned that some of these complications with some of the markers we were looking at with tuberculosis had been mentioned in the literature, but nobody had really dug into them. We spent some time on that and then developed first an acidic approach to denature the proteins, which would release our marker, which is immunocomplexed with proteins in serum that inhibited either the capture step in the immunoassay or the labeling step in the immunoassay. By breaking up the complex and denaturing the protein, it freed the marker for us to detect in our immunoassay. That has played a big role in what we're able to do now, and we're now presently working with a company in England about commercializing that test.

With over 430 invited lectures, you've had an unusual amount of exposure to how different scientific communities—chemists, engineers, clinicians—react to the same Raman-based technology. What's the most common misconception you've had to correct across audiences?

It’s reproducibility. Everybody asks what's your reproducibility, and to be fair, when we're talking about doing measurements at picomolar and femtomolar levels and sometimes potentially lower than that, everything matters. We spend a lot of time, as I had already alluded to, in sample preparation. In fact, a few years ago, we gathered a community at the HPLC conference, and the title of the symposium was "Garbage In, Garbage Out." It's all about sample preparation. That's really what it was. And we've learned to really make these tools that we have in hand to work well. We've got to pay attention to every piece of it. The pre-analytics, as our clinical colleagues talk about it, mean everything.

The other thing we need to pay attention to is what our clinical colleagues are actually willing to put in a clinical laboratory. In some of our early work on tuberculosis, we were denaturing using acid, and that was basically a non-starter. We then worked quite carefully on understanding how to use a different series of different enzymes to denature the proteins and hit on proteinase K.

In fact, what we're able to do now is that if we spike proteinase K in a human serum sample after our pretreatment, we get a dose-response plot that's statistically indistinguishable from what you get in buffer. That's what's gotten interest by the folks in England about seeing how things might move forward, so reproducibility means everything, but it's not just the SERS part. We're doing measurements at levels that are new to us. And as I've already said, everything matters.

The title of your talk connects the physical basis of Raman scattering to the mechanics of hitting a 95+ mph major league fastball. Where did that comparison come from, and what do you think it captures about Raman scattering that a more conventional physics analogy wouldn't?

I was back in Ohio with my family at Thanksgiving a few years ago. My brother's a baseball coach, played baseball in college, and he was a pretty gifted athlete, and he was teaching his grandchildren how to hit. He was talking about all the video recording and things that they were doing now because you can begin to talk about where the ball hit the bat, the size and the smoothness of the bat, and the trajectories of the baseballs when hit. We were talking about that, and it occurred to me that this is just Stokes and anti-Stokes scattering, depending upon if you're a right-handed or left-handed hitter. Left-handers pull the ball, and the exit velocity to right field is often more than it is to left field, so there's anti-Stokes and Stokes.

I've been working through this idea, and the first simple approach is where the ball hits the bat, which changes its trajectory. It’s not too much different than a photon encountering the pi electron cloud or the polarizable cloud on a molecule. So, we're working through that.

The other analogy that I've learned in this is that there are a lot of other things in terms of spectroscopy that baseball has in common. Absorption is a catch. Fluorescence is a catch and then a throw. Raman scattering is a line drive to the catcher. So that's where the analogy comes from.

As an emeritus professor still actively publishing and lecturing, what unfinished question from earlier in your career are you still actively trying to answer?

I've been thinking about this, and the idea that it was time to move on and do some other things came up. Specifically, I began to think about what questions haven't we answered yet. One of these questions is where does the hydrogen go when alkanethiol adsorbs on gold? We know there's a gold–sulfur bond formed, but we don't know what happens to the hydrogen. Is it hydrogen atoms? Is it a proton? The answer could be a mix, so I'm spending time and starting to craft a proposal together to see if we can get some support to try to chase that down.

The other is thinking about experiments where you could set things up any way you want and see how low you can go. How hard can we push limits of detection? A lot of measurements you might do in that case may not be relevant today. But sometimes, you got to do these things because the things you discover along the way will potentially become important.

In the nanoscience class I used to teach, one of the things I tell the students is we're doing plasmonics. We did a lot of work in spintronics over the years. Can we detect one in a liter? Students didn't know what that was, and it turns out it's jotamolar. Ten to the minus twenty-four, so like nothing in a liter. Well, how close can we get to that? Now we get to design the experiment, we can tilt everything in our direction. The greater the molar absorptivity, the highest-power laser we can use.

I'd also like to say we're doing some other things. We've got a startup company, Litmus Analytical, that's looking to develop a test for field-deployment measurements of per- and polyfluoroalkyl substances (PFAS) in the field. I'd also like to say to conclude that all of this has been a good deal. It's been a rush. On days I've had a lot of committee meetings, maybe I didn't look forward to going to work that day, but the rest of the time it was fun. And if you work with the right people, you can't go wrong.

References

1. Porter, M.; Workman, J., Jr.; Wetzel, W. Marc Porter on SERS Immunoassays, Raman Labels, and a 95-mph Fastball. Spectroscopy Online, 2026. https://www.spectroscopyonline.com/view/marc-porter-on-sers-immunoassays-raman-labels-and-a-95-mph-fastball (accessed October 28, 2026).
2. Porter, M.; Workman, J., Jr.; Wetzel, W. Taming Serum Interference: Marc Porter on Moving SERS Immunoassays Toward the Clinic. Spectroscopy Online, 2026. https://www.spectroscopyonline.com/view/taming-serum-interference-marc-porter-on-moving-sers-immunoassays-toward-the-clinic (accessed October 28, 2026).
3. Porter, M.; Workman, J., Jr.; Wetzel, W. Why Reproducibility Starts with Sample Preparation. Spectroscopy Online, 2026. https://www.spectroscopyonline.com/view/why-reproducibility-starts-with-sample-preparation (accessed October 28, 2026).
4. Porter, M.; Workman, J., Jr.; Wetzel, W. Stepping Up to the Plate: A Baseball Analogy for Raman Scattering. Spectroscopy Online, 2026. https://www.spectroscopyonline.com/view/stepping-up-to-the-plate-a-baseball-analogy-for-raman-scattering (accessed October 28, 2026).
5. Porter, M.; Workman, J., Jr.; Wetzel, W. Marc Porter on Open Questions, Detection Limits, and What Comes Next. Spectroscopy Online, 2026. https://www.spectroscopyonline.com/view/marc-porter-on-open-questions-detection-limits-and-what-comes-next (accessed October 28, 2026).