Exploring Cells’ Chemical Secrets—Why Basic Science Matters
.jpg "Dr. Crooke in his laboratory")
As we celebrate the Darwin bicentenary year, it is fitting to reflect upon the enduring significance of his observation that the mechanisms regulating human biology derive from simpler life forms. Elliott Crooke, PhD, professor and chair of the Department of Biochemistry and Molecular & Cellular Biology, will tell you that one good way to understand human beings is to get to know e. coli a little better.
One reason for that is a principle of evolution called molecular economy, which holds that nature prefers to retain and repurpose successful developmental processes at all levels of biological development, as opposed to reinventing the wheel. To understand how a human cell loses the ability to faithfully replicate its genome—one feature of cancer—Crooke’s lab studies the control of chromosomal replication in unicellular organisms.
Cells grow and divide, a process called the cell cycle. Their genome has to be replicated and segregated into daughter cells. Science is trying to understand the linkages—the precise timing of cyclin-dependent kinase progressions—that makes this such an exquisitely regulated process. Crooke’s lab is currently interested in how this cascade of progressions leads to the onset of DNA synthesis. “There is a trigger, an initiator protein, that says, ‘O.K., now we’re going to initiate the DNA synthesis of chromosomal replication.’ The regulated control of initiator protein activity is what we’re looking at right now.”
“In some ways we’re really the oddballs at the medical center,” says Crooke, “because what we are doing is really basic scientific research using a unicellular model organism, looking at really fundamental biological processes, not necessarily those tied to a single human disease.”
“The protein we are most focused on, DnaA, is an initiator protein that, structurally, is analogous to what is known to be a cell cycle protein in humans.” By understanding the normal function of these mechanisms, scientists can better comprehend how they malfunction in disease and how they can be mediated to preempt disease. “You can’t understand how to repair a broken car engine unless you know how it works when it’s running,” says Crooke.
Crooke’s lab is also studying polyphosphates, long, linear polymers linked together by high-energy bonds. Similar high-energy bonds are found in all known cell types.
Cells that have lost their ability to make polyphosphates are highly susceptible to death when they are exposed to various environmental stresses. Says Crooke, “Our recent work with E. coli indicates that poor survival is because cells lacking polyphosphates are compromised in how they carry out error-prone DNA repair.”
Crooke says he prefers dissecting molecular mechanisms in vitro where he can control all the variables, but he is aware that this provides barely a glimpse into the “black box” of the living cell. “There’s so much that you don’t know going on in there,” he says. “But what we can do is take our in vitro findings back to the living cell to test them. It’s the going back and forth that lets you know what’s really happening.”
Still, there is an evolutionary ocean separating man and microbe, and Crooke is comfortable at his end of the divide. “We like to understand cell physiology at the biochemical and molecular level, and we go where the science takes us,” he says, “but we have many collaborations here at GUMC working to translate our findings, hopefully at some point all the way to the clinic.”
One translational possibility—by studying the differences between human and microbial cell physiology, potentially you can exploit those differences to develop new antimicrobial agents. “We need entirely new strategies for how antibiotics can disable microorganisms without doing damage to the host,” says Crooke. “This will enable the development of whole new classes of antibiotics.”
By Frank Reider, GUMC Communications
