Bilirubin, a waste product spawned from the body trashing old red blood cells, has long been viewed as harmful refuse and a sign of illness by medical and biology students. High blood levels resulting from bilirubin cause jaundice, which turns the eyes and skin yellow and can signal liver trouble. However, this previously negative view of bilirubin may be changing as researchers uncover its potential benefits. Lab, animal, and epidemiological data suggests that bilirubin plays a vital role in the body as a fierce antioxidant and anti-inflammatory.
The molecule naturally arises when the spleen and other parts of the body dispose of heme, the core of the hemoglobin molecule in red blood cells. Heme is highly toxic; bilirubin, the breakdown product in mammals, is less so. Each week, the average person generates about 2 grams of the yellowish substance, most of which the liver dumps into the intestines for elimination from the body.
Research has found that bilirubin neutralizes reactive oxygen species (ROS), destructive byproducts of metabolism that can injure DNA and other important cellular molecules. When mixed with lab-grown cells, bilirubin shields them from ROS, and mice lacking the molecule are more vulnerable to oxidative damage. Bilirubin is also the most potent antioxidant substance in the body and tamps down damaging inflammation. Scientists have found that bilirubin may steer immune cells called macrophages to curtail their secretion of inflammatory molecules.
In several studies, people who have moderately elevated bilirubin levels are less likely to develop various illnesses, including heart disease, inflammatory bowel disease, diabetes, and many types of cancer. On the flip side, people with relatively low bilirubin levels are more vulnerable to these diseases. Multiple studies show that bilirubin is protective, and this evidence has encouraged researchers to try to boost its levels in the past.
Bilix, a South Korean company, has discovered a way to overcome the challenges faced with turning bilirubin into a therapy, such as its insolubility and how rapidly injected doses are broken down or excreted. Bilix’s co-founder, chemist Sangyong Jon, and colleagues affixed the water-soluble molecule polyethylene glycol to one end of bilirubin, which in water creates nanoparticles that make the bilirubin soluble, protect it from light, and extend its life span in the blood from less than 20 minutes to several hours. These nanoparticles can enter immune cells, allowing their bilirubin cargo to combat reactive oxygen species inside these cells and thereby fight inflammation.
Animal studies suggest that bilirubin-toting nanoparticles are effective against a range of conditions. One is graft-versus-host disease (GVHD), a serious complication of organ and bone marrow transplants in which immune cells in the transferred tissue attack the recipient. Bilix has chosen Australia for its phase 1 safety trial due to the country’s ethnic composition and the similarity to that of the United States, which would make it easier to gain permission for future U.S. trials from the Food and Drug Administration. If the nanoparticles prove safe in the trial, the company plans to test whether they can prevent tissue damage in transplanted kidneys, which are inundated by reactive oxygen species after their blood circulation resumes. Other potential targets include the skin condition atopic dermatitis, asthma, multiple sclerosis, and stroke.
Bilix’s nanoparticles aren’t the only way to boost bilirubin levels. Exercise, certain foods, and a number of drugs, including statins, can all have that effect. However, the old view of bilirubin as molecular trash is still holding back research on how to take advantage of its salutary effects. Bilirubin has the potential to be a treatment in organ transplant recipients and patients with conditions such as multiple sclerosis and stroke, and researchers are hoping to uncover further potential therapeutic uses for the molecule.
