We depend on fat. Within every cell of our bodies, greasy molecules, called lipids, carry out vital functions. Cells use lipids to build membrane barriers between the inside and outside of the cell and between different compartments within the cell. In addition, lipids facilitate a variety of functions that are crucial to the body’s overall health, including promoting cellular signaling pathways. “Cells receive signals from outside that cause them to respond with a behavior, such as migration or division,” explains Jeremy M. Baskin, Chemistry and Chemical Biology. “Lipids can act as intermediaries in the transfer of this information from an outside signal to the ultimate behavior the cell will carry out.” When signaling pathways become scrambled, disease often results.
Baskin wants to understand the roles lipids play in a variety of diseases, including cancer and multiple sclerosis. The innovative, novel research approaches he uses have led to collaborations with colleagues across Cornell, including Barbara A. Baird and David A. Holowka, Chemistry and Chemical Biology; Chun Han and Marcus B. Smolka, Weill Institute for Cell and Molecular Biology; and Michael L. Goldberg, Molecular Biology and Genetics.
Cell Behavior Precipitated by a Signaling Lipid
In one study with ramifications for the understanding and treatment of cancer, the researchers are exploring phosphatidic acid, a lipid that acts as a signaling molecule within cells. This lipid is one of the simplest of the phospholipids that make up the membrane of the cell and is normally present in small amounts. “When phosphatidic acid accumulates in large amounts, it is very potent and can cause all kinds of very rapid signaling leading to changes in the cell’s behavior,” Baskin says. “When too much accumulates in the cell, you get outcomes reminiscent of cancer. The cells divide rapidly and changes take place within the cell that encourage cell migration similar to what happens when cancer metastasizes.”
Exploring the possible connection between high amounts of phosphatidic acid and cancer can be difficult because the researchers need to pin down exactly where in the cell the lipid is being produced, a tall order given that several different enzymes located in membranes throughout the cell can synthesize it. “We think that the location of phosphatidic acid signal-production within the cell can have an important effect on which of the many different outcomes actually happen,” Baskin says.
Innovative Chemical Imaging
To help pinpoint the lipid’s location within cells, the Baskin Lab developed an ingenious chemical imaging technology. Known as IMPACT (Imaging Phospholipase D Activity Using Clickable Alcohols via Transphosphatidylation), the technique centers on a special reaction, called click chemistry, that Baskin helped pioneer as a graduate student at the University of California, Berkeley. “Two chemical components preferentially recognize each other and form a bond; they click together only with each other,” he explains. Baskin and his colleagues use a two-step approach: First they create special molecules that carry tiny chemical tags, which are converted inside the cell by the enzyme phospholipase D into the lipid phosphatidic acid. Then they append a fluorescent molecule to the lipid using click chemistry to form the bond. When the treated cells are imaged, the fluorescing lipids glow brightly, showing the quantity and the location of phosphatidic acid within the live cell.
“There’s a big potential application for this in cancer research. We want to explore the connection between the enzymes that make phosphatidic acid and the aggressiveness of cancer.”
Baskin envisions using IMPACT to understand the cause-and-effect relationship between phosphatidic acid and the cellular behaviors that lead to cancer. “There’s a big potential application for this in cancer research,” he says. “We want to explore the connection between the enzymes that make phosphatidic acid and the aggressiveness of cancer. If we can understand the connection, we can use that to inform cancer treatments. There are inhibitors of the enzymes, for instance, that would prevent the formation of phosphatidic acid, and these might be useful in the treatment of some forms of cancer.”
Lipids and Leukodystrophies, Multiple Sclerosis
The Baskin Lab is carrying out another series of projects seeking to understand the role played by a group of lipids called phosphoinositides in the formation of the myelin sheath, a greasy coating that insulates nerves inside the body much like plastic insulates electrical wires. As a postdoctorate at Yale University, Baskin helped discover the connection between inadequate production of phosphoinositides and a genetic disease known as a hypomyelinating leukodystrophy, where the myelin sheath is not formed adequately leading to symptoms such as muscle atrophy and cognitive impairment. “Scientists already knew that the disease was connected to a gene mutation,” Baskin says. “They knew both the gene and the disease, but no one knew the connection, the mechanism for how the disease came about. This discovery has motivated a lot of the work we’re doing in my lab now. We study other components that produce, destroy, or interact with phosphoinositides and how they coordinate the growth and maintenance of the myelin sheath.”
Along with shedding light on a family of genetic diseases known as leukodystrophies, Baskin’s research also has potential to impact the understanding and treatment of non-genetic myelin diseases such as multiple sclerosis (MS). In MS, the immune system erroneously attacks the myelin sheath, destroying it. The disease affects more than a million people in the United States. Its cause is unknown and current treatments are unable to fully reverse its effects.
“We’ve identified phosphoinositides as key lipids in the process of myelin production, and we’re continuing to study the fundamental mechanisms this lipid uses to promote the myelin sheath,” says Baskin. “One possible way to go about treating MS is to enhance the natural ability of the body to regenerate myelin tissue. There’s a lot of push in research labs to develop drugs that can stimulate myelin regeneration, but to develop a drug that promotes remyelination, you have to be able to evaluate whether the drug is working. This is a challenge because it’s difficult to distinguish newly made myelin from pre-existing myelin in the body.”
The researchers are addressing this problem by creating another fluorescent tagging tool that can help them visualize the activity of lipids inside the cells of zebrafish embryos as the cells go about making myelin. “We’re taking what we know about the biosynthesis of the different lipids that make up the myelin sheath and developing this tool so we can see exactly the amount and location of myelin regeneration,” Baskin says. “We hope we can eventually use this information to evaluate current therapies for MS and to discover new treatments.”