Macrophages and microglia are the waste collectors of the body. They clean up dead cells, foreign particles, and microbes—whatever needs tidying up or clearing out. This function, known as endocytosis, has been the career focus of Frederick Maxfield, Biochemistry, Weill Cornell Medicine, for over three decades. The biochemistry professor at Weill Cornell Medical School has used his background in chemistry and imaging to unveil how endocytosis functions and why it sometimes fails—revealing potential therapeutic applications to serious diseases along the way.
Maxfield was well into his graduate studies as a chemist when he first attended lectures on the interface between the physical sciences and biology. “I had not paid attention to the biology side of things, and during those lectures I realized people were applying physics and chemistry tools to biomedical studies,” he says. “That was eye-opening for me.” His interest piqued. He went on to work as a postdoc at the National Cancer Institute with molecular biologist Ira Pastan, who was doing some of the first research on endocytosis using new, sensitive imaging detectors on microscopes. By tagging molecules with fluorescent dyes, Maxfield and his colleagues were able to observe cells engulfing these molecules in real time. “This was a field day,” says Maxfield. “Everything we saw was new. It opened up whole new areas of biology.”
Cell Cleanup, Alzheimer’s, and other Neurological Diseases
This “fun and fascinating” field of study has been Maxfield’s main area of research ever since, and he’s enjoyed seeing it change along with the technology. “The tech keeps improving on you. Things that were impossible to do in the 70s and 80s are now routine,” he says. With cutting-edge technology such as quantitative fluorescence microscopy and kinetic modeling, Maxfield’s lab is able to examine how the endocytosis contributes to certain diseases, including Alzheimer’s. The illness causes misfolded proteins to build up in the extracellular space in the brain, and is thought to lead to the death of neurons. “We wondered why microglial cells were not cleaning up these misfolded proteins,” says Maxfield.
By tagging molecules with fluorescent dyes, Maxfield and his colleagues were able to observe cells engulfing these molecules in real time… “Everything we saw was new,” says Maxfield.
His group synthesized these misfolded proteins and observed how they were engulfed by microglial cells and delivered to the cells’ lysosomes, the ‘stomach’ of the cell. “They just sat there and didn’t get digested,” Maxfield says. “With our background in chemistry, we wondered what the pH was of these cells’ lysosomes—typically, as the digestive organelle, they’re acidic.” After closer examination, Maxfield’s team found these lysosomes were much less acidic than what was typical for the organelle.
Maxfield and his team tried stimulating microglia into acidifying their lysosomes by using activators of inflammation. Their hope was that the organelles would digest offending amyloid proteins. The trick worked. Through simple chemistry, these formerly dysfunctional cells were degrading the amyloid peptides without issue.
While this finding was exciting, Maxfield explains it can’t yet be leveraged into a safe therapy for human patients. “If we increased the lysosome acidity of the brain’s microglia this way, it would cause other serious problems, including a widespread inflammatory response,” he says. “But we’re looking to see if there are benign ways we can do this and trying to better understand this lack of acidity in the microglia.”
Maxfield’s research has uncovered much more immediately applicable solutions in another serious neurological disease, known as Niemann-Pick disease (Type C). Victims of this rare, inherited disease have cells that are unable to export cholesterol from their lysosomes. A family foundation funded research labs, including Maxfield’s, to study causes and potential cures for the condition. Using their expertise in quantitative fluorescence microscopy, Maxfield and his team set up a screen for drugs that might remove cholesterol from the cells of Niemann-Pick C patients. “In this screen, we actually found many compounds that would remove the cholesterol from the cells,” says Maxfield. In a stroke of good fortune, one drug happened to be an FDA-approved cancer drug. “That saves about a billion dollars in the process of getting it to patients,” he says. The drug, called Vorinostat, is now being used for a clinical trial to treat Niemann-Pick Type C, thanks to Maxfield’s efforts and his collaborators. “Now, we’re trying to go back and fill in why this particular class of drugs works on this disease,” he says.
Exploring New Truths in Cellular Biology
Beyond his work discovering potential therapies, Maxfield also wants to uncover new truths in basic cellular biology. He and his research group are examining how macrophages digest dead fat cells that are 100 to 1,000 times larger than them. “These macrophages are simply too small to be able to engulf a fat cell,” he says. Currently, how the relatively tiny macrophages break down larger cells is somewhat of a mystery.
Maxfield has a theory that is considered slightly unorthodox in the scientific community. He suspects that macrophages are binding tightly to the fat cell and secreting acid and enzymes to dissolve it, bit by bit. The idea is unusual, but his group has already published papers on the idea and continues to make headway with the theory.
“People may think I’m a little crazy for the idea, but it’s what I like to do,” Maxfield says. “It comes back to being trained first and foremost as a chemist. We don’t think about the details. We look at very basic cellular biological processes, notice there’s something that doesn’t quite make sense, and then try to see what makes sense instead.”