Many of you will know that I mostly write about physics. My knowledge of human biology is limited to being reasonably certain that I have a body. At one point, some of my research could have had a medical application, but it involved diseases, which was knowledge I didn’t have. A recent paper on using quantum effects to improve medical diagnosis has given me flashbacks to those halcyon days, even though I still don't understand diseases.

One thing I am aware of is that it is usually preferable to be diagnosed for a disease early. It might be the difference between taking a pill and having your liver decorate a surgeon’s instruments. That means your doctor needs a cheap and effective way to see whether you have the disease. This is where, hopefully, physicists—and maybe even some physics—can come into play.

Most diseases release proteins or other molecules that signal the problem. If you have sensitive enough detectors, then you can pick up these signals and identify potential problems early. The challenge is that almost all tests of this sort are concentration sensitive: that is, if there aren’t many molecules, the signal will be weak and the test will return a false negative.

This is where a group of researchers decided that quantum mechanics held the answers. In fact, the researchers go one further, combining plasmonics with quantum mechanics to build a fantastic detector that can theoretically pick up the signal of a single molecule.

Shiny plasmons

To overcome the problems of sensitivity, we often use techniques to amplify weak signals. Surface plasmon resonances have long been thought to be really good at this. In fact, they are even used in pregnancy tests to predict pending parenthood.

A plasmon is, essentially, a light wave and electrons feeding off of each other. A light wave consists of an electric field that oscillates in time and space. When that field encounters a metal, the electrons are driven to oscillate with the electric field. That generates a new light wave that counters the original one.

However, if the metal is just a very tiny sphere, less than about 100nm (a nanometer is one-billionth of a meter), then the electrons cannot travel very far. The light wave pushes the electrons in one direction, where they pile up at the edge of the metal, leaving the positive nuclei on the other edge exposed. This generates a large counter field that pulls the electrons back.

This process is exactly like pushing a swing. If the light wave pushes the electrons at exactly the right rate, then the piling up and pulling back of electrons inside the metal builds up, sucking energy out of the incoming light field. The electrons give up that energy by emitting light, glowing brightly against a dark background. A tiny ball of the metal that supports a plasmon resonance for red light will be invisible when illuminated by green light but will shine brightly under red light: the plasmon resonance makes the invisible visible.

To turn plasmons into detectors, the basic idea is to get them to change the color of light that they resonate at. This is usually done by bringing metal spheres close together. The electrons in each sphere still slosh back and forth, but the neighboring sphere is doing the same, and they have to choose a frequency that works for both. The result is that the color of light required to excite the resonance shifts dramatically compared to when there's just one sphere. And, more importantly, the color shift depends on the material that lies between the two spheres.

Hence, putting water between the spheres will result in a shift to one color; if there's some of the protein that we want to detect dissolved in the water, then the shift will be to a different color. These types of detectors work pretty well, but, as the amount of protein goes down, the color shift gets smaller.

Flashy-light molecules

To overcome the sensitivity problem, the researchers propose using a combination of plasmonic enhancement and light-emitting molecules. In this procedure, the protein that you want to detect is bound to a molecule that will emit light the same color as that of the plasmon.

The plasmon and the glow of the emitter influence each other. Essentially, if one is excited, it will happily transfer that energy to the other, and then take it back again at regular intervals. This continuous exchange, called Rabi oscillation, is so rapid and induces such strong electric fields that it alters the emission color of the molecule. In doing so, neither the molecule nor the plasmon can emit at their natural color—instead, they emit redder and bluer light.

The color shift does not depend on how many molecules are present—a single molecule generates the same shift as 10 or 1,000 molecules. Hence, a kind of binary detector is achieved.

Plasmon medical misadventure

As cool as this is, it also misses the point, I think. We already have microscopes that can detect single proteins if you attach a glowing molecule to them. Not only that, but proteins do not bind as specifically as we would like. The end result is that random other proteins attach to your glowing molecule, and these will dominate when the target protein is at low concentration.

Finally, we get to the hidden technical problem. The detector works if the emitter and the plasmon are strongly coupled. That means that the emitter would much rather give its energy to the plasmon than anything else. And, likewise, the plasmon would much rather transfer energy to the emitter than anything else. Typically, this requires a very careful setup, with highly reflecting mirrors and great molecule characteristics. These requirements are the opposite of cheap and easy.

I still like the work, though. Apart from being a nice calculation that shows some interesting possibilities, there are plenty of applications. It might even end up in a hospital as a high-end diagnosis system. It won’t end up in your doctor’s office, though.

ACS Nanoletters, 2019, DOI: 10.1021/acs.nanolett.9b01137 (About DOIs)