Monthly Archives: December 2018

Treating the Cancer Treatment: an Investigation into a Chemotherapy drug’s Toxic Product

One of the most difficult hurdles in cancer treatment development is designing a drug that can distinguish between a person’s healthy cells and cancer cells. Cancerous cells take advantage of the body’s already present machinery and biochemical processes, so when we target these processes to kill cancer cells, normal, healthy cells are also destroyed directly or through downstream effects of the drug. The trick to cancer treatment then is to design a drug that kills cancer cells faster than it harms healthy cells. To this end, efforts are being made to understand the finer details that differentiate the anti-cancer effects of a drug from its harmful effects on the individual. This is where the research of Dan Breysse comes in.

Dan a third-year master’s student working with Dr. Gary Merrill in the department of Biochemistry and Biophysics. Dan’s research focuses on a common chemotherapy drug, doxorubicin. Doxorubicin has been researched and prescribed for about 40 years and has been used as a template over the years for many other new drug derivatives. This ubiquitous drug can treat many types of cancer but the amount that can be administered is limited by its toxic effect on the individual. Nicknamed “the red death,” doxorubicin is digested and ultimately converted to doxorubicinol, which in high doses can cause severe and fatal heart problems. However, hope lies in the knowledge that doxorubicinol generation is not related to the drug’s ability to kill cancer cells. These mechanisms appear to be separate, meaning that there is potential to prevent the heart problems, while keeping the anti-cancer process active.

Cancer cells replicate and build more cellular machinery at a much faster rate than the majority of healthy cells. Doxorubicin is more toxic to fast-replicating cancer cells because its mechanism involves attacking the cells at the DNA level. Dividing cells need to copy DNA, so this aspect of doxorubicin harms dividing cells faster than non-dividing cells. It is common for chemotherapy drugs to target processes more detrimental to rapidly dividing cells which is why hair loss is often associated with cancer treatment.

Separately, doxorubicin’s heart toxicity appears to be regulated at the protein level rather than at the DNA level. Doxorubicin is converted into doxorubicinol by an unknown enzyme or group of enzymes. Enzymes are specialized proteins in the cell that help speed up reactions, and if this enzyme is blocked, the reaction won’t occur. For example, an enzyme called “lactase” is used to break down the sugar lactose, found in milk. Lactose intolerance originates from a deficiency in the lactase enzyme. During his time at OSU, Dan has been working to find the enzyme or enzymes turning doxorubicin into doxorubicinol and to understand this chemical reaction more clearly. Past research has identified several potential enzymes, one of which being Carbonyl reductase 1 (CBR1).

Doxorubicin is converted to doxorubicinol with the addition of a single hydrogen atom.

While at OSU, Dan has ruled out other potential enzymes but has shown that when CBR1 is removed, generation of doxorubicinol is decreased but not completely eliminated, suggesting that it is one of several enzymes involved. In the lab, Dan extracts CBR1 from mouse livers, and measures its ability to produce doxorubicinol by measuring the amount of energy source consumed to carry out the process. To extract and study CBR1, Dan uses a process called “immunoclearing,” which takes advantage of the mammal’s natural immune system. Rabbits are essentially vaccinated with the enzyme of interest, in this case, with CBR1. The rabbit’s immune system recognizes that something foreign has been injected and the system creates CBR1-specific antibodies which can recognize and bind to CBR1. These antibodies are collected from the rabbits and are then used by Dan and other researchers to bind to and purify CBR1 from several fragments of mouse livers.

Prior to his time at OSU, Dan obtained a B.S. in Physics with a concentration in Biophysics from James Madison University where he also played the French horn. Realizing he loved to learn about the biological sector of science but not wanting to completely abandon physics, Dan applied to master’s programs specific to biophysics. Ultimately, Dan hopes to go to medical school. During his time at OSU, he has balanced studying for the MCAT, teaching responsibilities, course loads, research, applying to medical schools, and still finds time to play music and occasionally sing a karaoke song or two.

To hear more about Dan’s research, tune in Sunday, December 16th at 7 PM on KBVR 88.7 FM, live stream the show at http://www.orangemedianetwork.com/kbvr_fm/, or download our podcast on iTunes!

Applying medical anthropology: a history of stress in Puerto Rico and its impacts on birth outcomes

Over the course of the last six years, Holly Horan, a doctoral candidate in the Applied Anthropology program at Oregon State University, has developed and carried out a course of research culminating in the largest-ever study measuring perceived and biological maternal stress during and after pregnancy in Puerto Rico. By combining in-depth interviews with Puerto Rican mothers with quantitative analysis of perceived stress and the stress hormone cortisol during each stage of pregnancy, Holly has gained insights into both the perceived and the physiological components of maternal stress that have potential to impact birth outcomes (in particular, timing of birth).

Holly describes herself as an applied medical anthropologist. She strives to take a holistic approach to health, considering not only the physiology of an individual, but external factors as well: the political situation, economics, the culture, and the historical context of the research site. She is passionate about “community-led research.” In community-led research, the community where the research is being conducted takes a role in the development, execution, analysis, and evaluation of the research.

Holly has found a way to combine her personal and professional interests in maternal and infant health with her desire to engage in research with Puerto Rican communities. Holly’s mother is Puerto Rican, and she had long wanted to engage in research that could benefit the island. While completing a master’s degree in anthropology at the University of Montana, Holly did preliminary research on the early onset of puberty among Puerto Rican girls. Here at OSU, Holly has been able to use both qualitative and quantitative methods to research maternal and infant health within a community-led framework.

At the beginning of her dissertation research, Holly learned that the cesarean birth rate in Puerto Rico was close to 50% — far higher than the rate in the continental U.S., which hovers around 30%. Both rates are much higher than the rate recommended by the World Health Organization, which indicates that the cesarean birth rate should be no higher than 15%. She also learned that the island struggled with high incidence of preterm birth and low birth weight, both of which are important population-level health indicators. Holly’s advisor, Dr. Melissa Cheyney, is a home-birth midwife and an associate professor within the Applied Anthropology program in the School of Language, Culture, and Society. Dr. Cheyney helped connect Holly to Puerto Rican midwives, who, in turn, connected them to other medical providers in Puerto Rico.

In the summer of 2014, Holly conducted a pilot study, spending six weeks in Puerto Rico interviewing maternal and infant health-care professionals. These interviews allowed her to develop goals for her dissertation research that aligned with the needs of the community. Participant narratives frequently displayed concerns associated with unexplainable high rates of preterm birth.

Holly’s National Science Foundation (NSF)-funded dissertation research examined the relationship between perceived maternal stress, biological maternal stress, and prematurity. After the 2014 pilot study, she moved to Puerto Rico for 16 months, where she used semi-structured interviews and perceived stress questionnaires to develop an understanding of this relationship. In addition to this qualitative component, she also measured the stress hormone cortisol from maternal hair samples. Cortisol is one of the most well-understood biological stress indicators. Up until recently, the primary available way to measure cortisol levels was through blood or saliva samples, which provided only an indication of short-term stress. As it turns out, however, cortisol is also incorporated into hair. Hair cortisol provides a measure of long-term stress — the type of stress that is speculated to impact maternal and infant health outcomes, including preterm birth.

In the summer of 2016, Holly initiated her dissertation research with an extensive series of in-depth interviews with pregnant and recently-postpartum women. At this time, the ZIKA virus was declared a public health emergency, and there was a variety of public health messaging concerning delayed reproduction and the risk of microcephaly. Through these interviews, Holly learned that the U.S. Government’s public health messaging led to an internal conflict for many pregnant Puerto Rican women. Families felt stress and fear about the prospect of infants developing microcephaly. However, the warnings and official recommendations to delay reproduction provided uncomfortable reminders of the island’s colonial past, which includes targeted experimental clinical trials of oral contraceptives and sterilization offered primarily to low-income women. This led many interviewees to be skeptical about the threat of the Zika virus, but did not deter them from being concerned for their fetus’ well-being.

These participants identified sources of stress that varied widely, ranging from socioeconomic concerns, political changes, and gender-based inequalities. For example, in May 2016, Puerto Rico’s government defaulted on over 70 billion dollars of debt. Under the regulations passed by La Junta, the appointed fiscal board, many employees were fired and then rehired for lower pay. Also affected was the secondary public-school system: nearly 150 schools were closed. While these events are structural, the interviews revealed that within the Puerto Rican people, the impact of the events was personal, and the magnitude of impacts depended on individuals social support networks and life circumstances.

After comparing maternal cortisol levels with the perceived maternal stress from the structured surveys, which were collected in each trimester across pregnancy, Holly found a counter-intuitive result: some of the mothers who had most problems with their pregnancies (such as premature birth) had unusually low levels of cortisol. One current theory is the concepts of allostasis or allostatic load and “weathering,” a term which has been in the media in recently describing the cumulative effects of chronic stress on health (discussed in an NPR interview here in the context of race-based discrimination). Normally, the body responds to stress by heightening the amount of hormones such as cortisol. After the stressor is removed, hormone levels shift back to a low-stress state. However, if stress is prolonged over months or years–such as when living under a system of oppression–the body starts to experience “wear-and-tear,” causing the body’s stress response system to become ineffective. This ultimately impacts health outcomes, such as premature birth.

There have been road bumps along the way. In late summer 2017, Holly was nearly three quarters completed with data collection and the project was moving along smoothly. However, Mother Nature had different plans: In September 2017, Puerto Rico was hit first by Hurricane Irma and then by Category 4 Hurricane Maria two weeks later. The hurricanes destroyed the power grid and most of the island’s infrastructure. Holly was evacuated by OSU a week after the storm. Although she was worried about the well-being of her participants, and the impact this storm would have on the research project, NSF and her other funders graciously supported her to return and complete the study, which she did in February and March of 2018. As a separate side-project, Holly plans to return to Puerto Rico this summer to share study results with the community and with community partners.

To hear more about Holly’s research, tune in Sunday, December 9th at 7 PM on KBVR 88.7 FM, live stream the show at http://www.orangemedianetwork.com/kbvr_fm/,  download our podcast on iTunes, or listen to this episode directly!