Biochemistry, Developmental Biology
University of Utah
Dr. Cairns is chair of the Department of Oncological Sciences at the University of Utah School of Medicine, and an investigator with the Huntsman Cancer Institute.
Chromatin-Remodeling Machines and Mechanisms
When Bradley Cairns was in fifth grade, he watched a movie about mitosis that would set the course of his life.
"I only knew a little bit about cells at that point," Cairns recalls. "We were learning that our inherited genetic material was this DNA in chromosomes, and during cell division, these chromosomes are transferred to daughter cells. But then they showed us a movie on mitosis and I saw the chromosomes lining up and then separating into two cells. My jaw just hit the ground.
I realized there had to be little machines in there that condensed the chromosomes and moved them around."
Some 15 years later, as a Stanford University graduate student, Cairns actually discovered molecular machines, called chromatin remodelers, that play an essential role in the structure and behavior of chromosomes. Chromatin contains DNA and proteins, known as histones, that form the structure of chromosomes. Remodelers do not act in mitosis, per se. Instead, they remodel the histone–DNA architecture to allow every cell in the body access to the DNA code, which is needed to eventually manufacture the protein drivers and components of all of life's functions.
Cairns always knew he was going to pursue science, but he deliberated between research and medicine. As a young man, he loved biology. "But at that time I considered most of the approaches to studying biology too descriptive and didn't provide explanations of mechanisms," Cairns says. He majored in chemistry in college to seek such scientific precision and found himself in a laboratory.
"I think it is very important that undergraduates are offered research opportunities. These are the years when they are first making their decisions about their future," Cairns says. "Reading scientific textbooks or hearing lectures about scientific facts doesn't really give kids an appreciation for how discoveries are made. It is critical for them to get into a lab and try the discovery process. For me, I was totally hooked."
Cairn's first laboratory work was technically challenging: "Everything had to be done under glass that was first flamed [with a Bunsen burner] to remove water, and then conducted with nitrogen running through the glassware because any oxygen or any water in the air would kill the reaction," Cairns says. His undergraduate thesis topic was biological but used chemistry. He studied how immune cells called neutrophils make a toxin, called superoxide, to kill bacteria.
After college, Cairns spent a year as a laboratory technician to learn the then new recombinant DNA technology. Then he applied to 10 graduate schools and was accepted at all of them. He chose Stanford and working in the laboratory of Roger Kornberg, who would later win the 2006 Nobel Prize in Chemistry for discoveries about how genes in higher organisms are expressed in the cell.
Not satisfied to master one topic for his dissertation, Cairns did ground-breaking research in two subjects, for essentially two Ph.D. degrees, although he received only one.
For his first project, Cairns was interested in how information from outside a cell is interpreted by signals inside to turn on gene expression. He used yeast as a model organism because its genetics allowed him to make mutations and see results. He found that the intermediary signal between a mating cue in the environment and genes is the MAP kinase pathway, a cascade of enzymes called kinases, each of which adds a phosphate group to proteins to activate them. Later, others showed that human cells use similar kinases to respond to external growth factors to ultimately spur gene expression.
In his second project, Cairns again used yeast to show how changes in chromatin structure allow gene expression. It was then that he identified the chromatin remodelers, two protein complexes, SWI/SNF and the more important RSC, that open up chromosomes and enable other proteins to come in and start gene expression. The same complexes work in humans. "Every time there is gene expression in a cell, which is happening all the time, RSC proteins help it occur," Cairns explains.
As an independent scientist, Cairns has dissected in great molecular detail the gears and energy the RSC complex uses to work on DNA and histones. He also analyzes how the remodelers find the right genes to act on so they are properly expressed at the correct time. He has made significant inroads in both areas and continues to probe the intricacies of the RSC "machine" and its specificity in activity.
Recently, he started exploring a new topic—how chromatin structure changes in the chromosomes of sperm and egg cells before and after fertilization and how these alterations influence whether genes are active or inactive during development. His model organism is the zebrafish.
What drives him today is the same inquisitiveness he had as a boy. "I am just a curious guy," he says. "I just want to know how things work. I am fascinated by nature. When things make sense, it is beautiful. The logic, the engineering, the regulation—I just love it all."