In 1954, James Badhouin, a Ph.D. student at the Karolinska Institute in Sweden, discovered a tiny spherical compartment of the cell that displayed unique biochemical properties. Badhouin appropriately termed this the “microbody” but despite the fact that it housed enzymes, it was perceived in the literature as merely “junk” within the cell. This piqued the interest of future Nobel Laureate Christian de Duve, who identified that a key detoxification enzyme, catalase, resides within microbodies. The job of catalase is to decompose the toxic hydrogen peroxide to non-toxic water and oxygen; the term “peroxisome” was appropriately used to replace microbody.

Fast forward 20 years, and the research community still believed peroxisomes were junk components in the cell. However, a series of biochemical and pathological experiments in the 1980s found that mutations in DNA encoding for peroxisomes actually resulted in severe childhood disorders known as Zellweger spectrum disorders (ZSD). Thus, peroxisomes were not junk but served an important biological function. Specifically, ZSDs were characterized by an accumulation of distinct types of fats called very-long chain fatty acids (VLCFAs). It was later discovered that peroxisomes were responsible for converting VLCFAs into shorter fats which could be used for key cellular signaling and metabolic processes.

As a cancer researcher, when I explain what peroxisomes are to people, they often still refer to them as junk, or ask me what does that even have to do with cancer? I thrive under such scrutiny. Cancer is a disease characterized by disordered metabolic wiring and cellular signaling, and the peroxisome is a bona fide metabolic and signaling hub within the cell.

My research has recently found that peroxisomes were elevated in chemotherapy resistant cancer cells cultured in a petri dish, and even in patients who don’t respond to chemotherapy. This is an association however, but the best way to figure out if something is contributing to a process is to mess with it.

For instance, let’s say there was this disc on two wheels of a car and you didn’t know what it did. You could remove it, and discover that the car would no longer be able to stop. Or maybe you could add discs to the other wheels, or better discs, and find that the car stops more efficiently. Well that’s the same principle behind what I did to peroxisomes in cancer cells. I literally removed them and found that the cells lost their resistance to chemotherapy. Even in cells that do respond to chemotherapy, when I remove peroxisomes and add chemo, the cells die, but way more than they do with chemo alone.

Currently there are no drugs that target peroxisomes in cancer, but hopefully my research will lead to this one day. It is also important to note that there are many efforts being made to use drugs to promote peroxisome function in childhood disorders. Such investigations are equally important. What we do know about drug screens though is that if we have a panel of say 1000 drug candidates, some will improve function, and some will do the opposite of what we intend (and vice versa).

So, perhaps in drug screens that are aimed to improve peroxisome function in young adults, we may stumble across some that do the opposite. Conversely, if we screened for drugs that break peroxisome function in cancer maybe we would come across some that improve it. One field’s junk could be another field’s treasure. So, what have I learned from all this so far? Go against the grain, listen to those who doubt you, and if it aint’ broken….break it.

Michael Dahabieh, Ph.D. candidate

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