High on a hilltop above the city, the researchers at Lawrence Berkeley National Lab are working every day to contribute to both the scientific and world communities.
In the Donner Lab under Dr. Kenneth Downing, graduate student Alison Killilea works on a microscopic level to understand the medications used to treat breast, lung and ovarian cancer. She works with a chemotherapeutic drug, commercially sold as Taxol and generically known as paclitaxel, which inhibits the replication, or mitosis, of cells. Rapid mitosis is the basis for tumors.
Since the discovery of paclitaxel in 1960, researchers have produced a multitude of drugs that work on the same principle. They target microtubules, a structure used in the division of cells, and stabilizes them to the extent that mitosis is disrupted. Microtubules are “very dynamic- they are like the railroad system of the cell. They transport proteins around the cell and are essential for mitosis,” Killilea said.
“But cells are very smart,” she said. “If you inhi bit the dynamic nature of microtubules with a stabilizing drug, this blocks mitosis and the cell realizes that something is wrong. Since the cell can no longer proceed through mitosis, the cell essentially commits suicide. This keeps the cancer from growi ng.”
Despite its effectiveness, paclitaxel has some drawbacks. Paclitaxel targets the fastest-growing cells, but it isn’t specific to cancer cells. It also kills hair cells and cells in the stomach lining, leading to the hair loss and nausea that are associated with chemotherapy. It is possible for patients to be resistant to it, and also to develop a tolerance, limiting the drug’s ability to fight future occurrences of cancer. The drug itself is mildly toxic, and it isn’t water soluble, necessitating a carrier to deliver it to cells. The carrier is toxic as well.
Killilea is exploring how new drugs, similar to paclitaxel, bind to microtubules because the new drugs have the potential to be less toxic and more effective against drug resistance. According to Killilea, her goal “is to map the drug binding site, leading to a better understanding of how chemotherapeutic agents work on their biological targets.” This better understanding should contribute to the discovery and application of more effective can cer treatments.
“The hope is that in a decade people will have more and better options,” Killilea said.
Working alongside Killilea is Nicholas Leiby, an MIT undergraduate who is at the lab for the summer. His project involves microtubules as well, but g oes in a different direction. He is working on developing a model of how Parkin, a protein implicated in the onset of Parkinson's disease, binds to microtubules. To achieve this he looks at the complex in an electron microscope. The model may take between six months and a year to complete.
Though their research has a known application, Killilea feels the exploration of how proteins bind to tubulin has its own merit.
“Pure or raw science is terribly important, because you never know what will come of it. Sometimes it’s an atomic bomb; sometimes it’s a vaccination. You just never know when you start how much can be affected later on,” she said.
Numbers and data are the inevitable result of research, and in the William Jagust Lab, Drs. Beth Kuczynski and J amie Eberling and research assistant Amy Gitcho spend their days analyzing observations of brain functions. They are looking at information gathered from a longitudinal study of Alzheimer’s Disease and Cerebrovascular Disease (CVD).
Both diseases are pre valent in the elderly population and are often co-concurrent, Kuczynski said. It is her hope to separate the symptoms and disassociate the diseases to determine the cause of dementia in each.
From a cohort of subjects from a multi-institutional study (UC Berkeley and LBL, UC Davis, UCSF and USC) on memory, Kuczynski and her team found that certain brain activities (or lack thereof) indicate a change in metabolic activities in subsequent years. All activities in the brain are fueled by glucose, so a reduc tion in glucose use indicates reduced brain function. By tracing the delivery of a substance that acts like glucose, scientists can determine with parts of the brain aren’t working as hard as they should.
The next step for the team is to examine the whit e matter tracts, or axons. Axons are a part of the brain’s communication system. A new technique called diffusion tensor imaging allows one to see the white matter tracts, and more importantly, to see if there are any disruptions in pathways to areas of the brain that show a metabolic decrease. It is Kuczynski’s hope that this will reveal more about the ways memories are lost in a brain afflicted with Alzheimer’s.