In high school, your science education most likely consisted of sharply segmented classes such as biology and physics with no overlap. But what if the real world doesn’t work this way?

Within Princeton’s Lewis Sigler Institute for Integrative Genomics (LSI), scientists traditionally identified as “molecular biologists,” “chemists,” and more, adopt an interdisciplinary approach to solve problems intractable through one field alone. Dr. Quan Wang is one of those scientists. Originally trained as a physicist, Wang is a “Lewis-Sigler Fellow” — the recipient of a unique grant designed to allow recent PhD graduates to attain independence earlier by giving them their own lab with which to pursue research. He is applying his training in classical physics to biological research, discovering new methods to study individual biomolecules.

As microscopes have become increasingly powerful, now able to pierce through the shroud of mystery that once surrounded individual cells and expose their functions in clear detail, researchers have hit a wall. This wall is the diffraction barrier, which prevents the effective visualization of objects smaller than the wavelength of light. This has stopped scientists from being able to view the structure and function of individual molecules, leaving a great deal to be understood. Wang is attempting to overcome this limit by directly studying the dynamics of biomolecules at the nanometer scale. To do this, he has developed several methods. First, he tags single molecules with fluorescent markers in order to confirm their presence. Fluorescence is highly useful, as it is allows for the detection of single molecules. By tagging target molecules and detecting the resulting fluorescence, Wang is able to isolate and study single molecules.

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Figure 1: In order to visualize and track individual molecules, Wang utilizes highly sensitive fluorescent markers.

However, just being able to detect and track these molecules isn’t enough. To glean information on the size and charge properties of individual biomolecules, Wang studies how these molecules move in solution. He does this by measuring diffusion, which refers to how molecules introduced to a solution spread out and move throughout the system. Diffusion is a useful property to measure, in this case, because its magnitude is related to size and charge. Larger molecules will move through solution slower, leading to decreased diffusion. Meanwhile, applying an electric field to a solution will make charged particles move faster and exhibit patterns of movement that correspond to their charge. Therefore, by comparing the diffusion rates of different particles and seeing how these rates are affected by the application of an electric field, it is possible to learn more about a specific molecule’s size and charge. This research is augmented by the use of a single-molecule trap, which actively contains a single molecule within a confined area so that it is easier to study for extended periods of time.

Wang’s research, although highly physical in nature, is in fact closely intertwined with some of the most important concepts of molecular and cellular biology. The interaction between proteins and DNA, along with other proteins, underlie biological processes as fundamental as DNA synthesis, transcription, and translation. These interactions will affect the size and charge of individual protein and DNA molecules, and, as such, Wang’s technique may one day allow biologists to learn more about these processes. Indeed, this single-molecule technique represents a “bottom-up approach” that may be indispensable for future research. While biologists are focused on function at the systems level — the genome and proteome are clear examples of this — Wang believes that his technique will help “find general principles of how things work at the single-molecule level, which helps understanding at the systems-level.” The holy grail of any biological research, in many people’s eyes, is the ability of the research to be applied clinically. Wang believes that a “better understanding of single molecules leads to better medicine.” As an archetypal example, a single-molecule understanding of DNA synthesis may one day enable researchers to develop better inhibitors to treat cancer.

While biologists are focused on function at the systems level — the genome and proteome are clear examples of this — Wang believes that his technique will help “find general principles of how things work at the single-molecule level, which helps understanding at the systems-level.”

It may seem odd that a classically trained physicist would jump into research of such a biological nature. But Wang believes that his training allows him, and other physicists, to bring new techniques and a “method-oriented” mindset that can be harnessed to find and solve problems that do not respond well to approaches traditionally utilized in molecular biology. For him, “biology is fascinating due to the lack of understanding at the single-molecule level” and he can bring a “physical point of view and different perspectives” that may lead to new research insights. This spirit of fascination and a desire to contribute one’s unique skills to new fields is clearly evident in the Lewis Sigler institute, where there is a “good mixture of traditional physicists and biologists… a great interchange of ideas.”

Ultimately, Wang is a firm believer in the interdisciplinary nature of scientific research. For two years, he has been teaching the Integrated Science Curriculum, a unique Princeton course that seeks to bridge the gap between fields of science traditionally thought to be separate. The dissolution of the barriers that have divided science for so long is picking up momentum, and represents a revolution in the way that we approach research. Considering the vastly complex, interwoven nature of the modern world, this revolution couldn’t come fast enough.

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Jasper Lee