Anyone who has suffered from jet lag knows the side effects of adjusting to a new time zone. Fatigue, insomnia, nausea, and more—it’s all part of a disturbed circadian rhythm.
The circadian clock is a biochemical mechanism that exists in organisms from plants to insects to humans. Its basic function is to oscillate in periods of approximately 24 hours, managing various behaviors on a day-night cycle. The mechanism itself, however, is incredibly complex and difficult to understand. That’s where Brian R. Crane, Chemistry and Chemical Biology, comes in.
Crane and his lab are studying photoreceptor proteins involved in circadian clocks. Photoreceptors sense and respond to light and are essentially responsible for setting the clocks. When the lab embarked on the research several years ago, researchers understood little about how these photoreceptors actually work.
Since then, Crane’s lab has identified the structure of cryptochrome—a photoreceptor in both flies and humans—and a light-activated light, oxygen, or voltage (LOV) protein in the fungus Neurospora crassa. Through this and other research, they have a much better grasp on how these proteins function: for example, the compounds required for their activity; how the proteins bind small light-responsive molecules; the chemistry they undergo when absorbing light; and how that photochemistry allows them to engage other targets in the cell and send signals.
Although most of the work has been done using fungal and fly model organisms, Crane says that his lab has begun looking at mammalian molecules as well. Model organisms are useful for studying the core processes of the circadian clock and share similarities to humans. Cryptochrome is also found in mammalian cells. Recently, researchers have discovered that it’s possible to target cryptochrome with drug-like molecules in order to affect the circadian rhythm.
Circadian clocks are not only a key component of annoyances such as jet lag. Disturbances in circadian rhythms are also coupled with illnesses, such as bipolar disorder, schizophrenia, narcolepsy, and more. “The hope is if you can understand circadian clock mechanisms, you might be able to come up with ways to intervene using pharmaceutical agents or other types of treatment that might be able to help these maladies,” Crane says.
The next steps of the research include asking bigger questions about how changes in photoreceptor molecules affect downstream processes. Crane’s lab is looking at the core oscillators themselves and how their components interact with the photoreceptors. Much like the state of photoreceptor understanding years ago, there’s very little understanding of the mechanisms at a molecular level. As Crane says, “There’s really a lot to do in these areas. There a lot of opportunities, a lot of things to chase down.”
How Electrons Move in Proteins
In most of the Crane lab’s work, the researchers want to understand how electrons move around in proteins, whether photoreceptor proteins in circadian clocks or ones involved in nitric oxide signaling, or at the basic level in general.
The lab designs synthetic model systems that allow them to photochemically induce electron transfer reactions using light. They then follow these reactions to see how far the electrons travel and the paths they take. So far, they’ve found what appear to be stations where electrons jump as they move across a relatively long distance.
Circadian clocks are not only a key component of annoyances, such as jet lag. Disturbances in circadian rhythms are also coupled with illnesses, such as bipolar disorder, schizophrenia, and narcolepsy.
“It’s almost like the frog jumping along the lily pads to get to where it needs to go,” Crane says, in reference to the game Frog Jump. “Where these sites are positioned might be really critical for controlling the charge flow. We think in the circadian photoreceptors this might be a really important component of what they are able to do.”
Encouraging Students to Participate in the Joys of Scientific Research
Crane says that he’s always been interested in science, specifically chemistry. Although he entertained several career paths after graduating from college, ultimately he enrolled in the PhD program at Scripps Research Institute as part of its inaugural class. Through support from a Howard Hughes Medical Institute (HHMI) grant, Crane helps undergraduates succeed in chemistry and hopes to encourage them to do research.
Crane is one of 15 faculty members, nationally, named an HHMI professor. The grant provides funding to create programs that excite undergraduates about scientific endeavors and research. Crane and faculty colleague Stephen Lee, Chemistry and Chemical Biology, are developing pre-freshman chemistry courses that better prepare students to succeed at Cornell.
“Very large segments of the population are underrepresented in the scientific endeavor, and that’s only going to get worse as time goes on,” Crane says. “Unless we engage these groups, we will not be drawing from the total pool of talent that’s present in the country. We want to encourage students to go into science, and we’ve been working to give them a better footing to get going.”
He adds that the teaching methods are available to any students interested in science but may feel that they do not have the talent for it or are not prepared. The goal is to encourage these students who may not have been on a scientific track, for whatever reason, to succeed in science and engage in scientific research.
Crane is a well-suited advocate of chemistry for the younger generation. When he talks about the future of his own work, he takes both an open-minded and intellectually curious approach. “I hope I’ll be doing something that I couldn’t predict I’d be doing now,” he says. “I think that’s one of the joys of scientific research—the unpredictability of what you find and where it might take you.”
“To me, one of the most interesting questions is, why do organisms do what they do? How can you understand the free will of a fruit fly?” he says. “Is it completely biochemical? Extrapolating this to something as complex as people is not going to be easy, but there has to be commonality. How far can we push that relationship? Once we understand these areas really well, can we engineer living systems? Can we intervene?”