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Retired Biochemist Eugene DeSombre studied how different kinds of breast cancer responded to estrogen so that doctors would know how their patients would respond to different medicine or surgery.
If you could research any sickness, what sickness would you research and why?
Thanks to Eugene DeSombre, choosing how to treat breast cancer is often as easy as seeing whether it lights up. DeSombre is a biochemist, which means he’s spent his career solving mysteries about how our bodies work on a tiny scale. He figured out how estrogen, a hormone that usually affects the reproductive system, binds to its target cells, and for half a century now his discovery has been saving the lives of people with breast cancer.
Not all children are really sure what they want to be when they grow up, but Eugene was always interested in science. He spent his childhood catching “butterflies and various insects” and identifying them. Sometimes he’d be lucky enough to find the butterflies’ caterpillars. He’d collect them, keep them safe and fed, and watch as they wove themselves into cocoons and then emerged as full-grown swallowtail butterflies. The hobby “reflected a basic desire” for biology, DeSombre says, and he followed his passion right through college and graduate school and into cancer research.
For many years, DeSombre devoted himself to figuring out why some breast cancers seem to need estrogen to survive while others do fine without it. Our bodies normally produce estrogen, so either kind of cancer can be dangerous, but it’s a lot easier to treat the estrogen-dependent cancers because we know how to keep them from getting enough estrogen. We can do that either by physically removing the organs that make estrogen (the ovaries and the adrenal glands) or by using drugs that block the parts of cells that normally interact with estrogen: the estrogen receptors.
DeSombre and his colleagues started searching for the estrogen receptor in the 1950s.The world had already discovered that removing the ovaries and reducing the amount of estrogen in the body could help some people with breast cancer, but nobody knew why it helped. DeSombre wanted to figure out how estrogen works. What protein, out of all the proteins building the different parts of the human body and helping keep it healthy, does it bind to?
To solve the mystery of the estrogen receptor, DeSombre first had to get enough of it in one place to study. Each cell that responds to estrogen only has a few receptors for it (maybe a thousand or two), but a biochemist can only detect a molecule if it exists in huge numbers, billions in one place. To get hold of enough estrogen receptors, DeSombre knew he had to extract it from animal tissues, but what kind of tissue would be best? To answer this question, he had to go a little radioactive.
At the time DeSombre was doing his research, radioactivity was the best way to find a molecule within the body of an animal. He gave lab rats a tiny bit of estrogen that had had some of its hydrogen atoms replaced with tritium, a form of hydrogen that has one proton, like normal hydrogen, but also has two neutrons where normal hydrogen has none. This makes it unstable—radioactive. By monitoring the low level of radioactivity within the body of the rats, DeSombre was able to figure out that estrogen is mostly found in the female sexual organs, the uterus and—aha!—the ovaries. He knew he was on to something. And he made good use of the fact that he lived and worked in Chicago, home to stockyards, slaughterhouses, and meat-packing companies.
If you needed to get your hands on as many estrogen receptors as possible, which organ would you pick—the ovaries or the uterus? To Eugene, it was obvious: the uterus has more receptors per pound. Even so, it took “a tremendous amount of calf uteri” to get enough of them. Once he’d collected enough organs, Eugene took the uterus tissue, broke up its cells, and removed most of the larger components of the cells by spinning the tissue in a centrifuge. He then took the leftover liquid, the supernatant, and added just a little bit of radioactive estrogen. Then he spun his samples in another centrifuge, one much more powerful than the other, making the heavier molecules in it, like the receptor, sink toward the bottom.
Once DeSombre had separated the heavier molecules in his sample from the lighter ones, he was able to see whether the sample actually had any estrogen receptor in it or not. The receptor is heavy, but estrogen itself is relatively light. If he found radioactivity in the bottom of the sample, he knew that the radioactive estrogen must have been attached to some larger molecule—the receptor. This test was pretty difficult to perform, but it was successful, helping DeSombre and his colleagues identify the protein.
DeSombre also had to demonstrate that the estrogen receptor was actually relevant to cancer patients. So far he had clues but no proof. The proof he needed came when he got access to samples of breast cancer from patients being treated with antiestrogen drugs (at this point, nobody knew whether the drugs would work for any individual patient or not, so they just gave them to everyone). DeSombre tested the samples and found a strong correlation between the results of his estrogen receptor test and the patient’s response to antiestrogen drugs: 60-80% of the patients with the receptor responded to the drugs, a much better response rate than for average breast cancer patients.
DeSombre and the other researchers in his lab next set to work on making the test for the receptor quicker and easier. He didn’t just want to make the test possible for a few patients: he wanted every breast cancer patient to be able to find out whether their cancer was vulnerable to a lack of estrogen. As you can probably guess, he succeeded. It turned out that the best way to test for a protein in the body was with the body’s own system for recognizing proteins: antibodies.
The body creates antibodies to identify specific proteins and latch onto them. They’re usually used to identify invaders like viruses, but DeSombre and his team created an antibody that bound to the estrogen receptor. And they attached a tiny molecule to the antibody that fluoresces—glows—under ultraviolet (UV) light. Today, a doctor in the pathology laboratory of any hospital, not just in a specialized research facility, can take a sample of breast cancer tissue, treat it with Eugene DeSombre’s antibody, shine some UV light on it and see whether it lights up. If it does, they know that their patient is likely to get better if doctors can reduce her (or sometimes his) estrogen level.
DeSombre retired from running his research lab ten years ago, but he keeps up with the new advances in cancer treatment that have been developed since then. He’s still fascinated by all the tiny little pieces that work together to make up living things.
