The George Lab aims to model tumor microenvironments and physiological networks for cancer patients three dimensionally.

Though two-dimensional animal modeling has provided valuable information for human cellular interactions and disease mechanisms, it faces limitations. Human cells adopt different behaviors across two-dimensional and three-dimensional models.

In the human body, cells are surrounded by other cells from all sides in a dynamic environment. These interactions are difficult to capture in a two-dimensional cell model, such as cell culture, which produces flat layers of human cells in media. In animal modeling, promising cancer and cardiovascular therapy treatments identified in mouse models have led to toxic effects in humans. Consequently, the George Lab, part of the UC Davis biomedical engineering department, uses “organ-on-a-chip” technology to model complex cellular interactions and behaviors across human tissue and organ systems with cancer.

Organ-on-a-chip technology models intricate human organs inside a palm-sized, clear and flexible chip, complete with a vascular network and cell culture media to nourish cells three-dimensionally.

“It’s the same process of design that you would see on a circuit in a computer chip, except in this case, it’s microfluidics,” said Steven George, a professor in the UC Davis Department of Biomedical Engineering. “You’re actually passing fluids, cells and other components into these chips.”

The George Lab seeks to model breast cancer among physiological networks inside these chips.

Breast cancer is the second most frequent cancer diagnosis for women in the United States. Additionally, it is the second leading cause of cancer death.

“20 percent of women diagnosed with early stage breast cancer will develop the recurrent disease,” George said. “Breast cancer recurrence drops the five-year survival rates among patients from over 80 to 20 percent.”

The George Lab aims to understand breast cancer dormancy and recurrence, along with the early steps in cancer metastasis that allows these processes to occur. In turn, organ-on-a-chip technology can be used as a clinical tool to develop personalized medicine. For breast cancer patients, chips could be generated to grow samples of tumors, administer chemotherapy trials and determine optimal chemotherapy strategies for each patient.

“Breast cancer tumors manipulate the bone marrow environment,” said Drew Glaser, a postdoctoral scholar in the George Lab. “The bone marrow is a space for white blood cells that work to remove cancers.”

Breast cancer recruits normal immunosuppressive cells and redefines the bone marrow environments.

“If you think about bone marrow, most of the time you think about the soft, squishy tissue,” Glaser said. “There is also hard pieces of bone interspersed among the soft, squishy tissue.”

Breast cancer can metastasize in either of these bone marrow microenvironments. Bones constantly and gradually remodel their environments, maintaining a balance between bone growth and clearance. Breast cancer tumors disrupt this balance, preferring active osteoclast cells, bone-clearing cells, over osteoblasts, bone-forming cells. By preferring bone clearance, the remodeled bone environment leads to bone destruction and creates a challenge for cancer treatment.

“The remodeled bone environment becomes difficult to treat,” Glaser said. “These cancers become chemorefractive, meaning they do not respond to chemotherapy. Patients can be exposed to radiation to remove the tumor, but this is when patients are at risk for developing fractures and pain, which can lead to morbid secondary outcomes.”

Glaser investigated the morphology and vessel network interactions between the two bone marrow environments through cancer migration assays, which involves physically separating the two environments inside of the chip while maintaining a small connection that links them. Glaser hopes to determine how each bone marrow environment shapes breast cancer metastasis and tumor aggression.

“Our current goal is to fabricate a representative bone marrow model of healthy patients, then we can see how cancer cells navigate in this environment,” said Aravind Anand, a fourth-year biomedical engineering major.

Organ-on-a-chip technology shows promise for mapping complex relationships between human organ environments and breast cancer cells, which could eventually lead to more ideal medical treatment for patients.

“While bone metastasis is the intended application of this project, this device may ultimately be able to model many other diseases or provide a platform to study hematopoiesis,” Anand said.

Written by: Foxy Robinson – science@theaggie.org

The team’s process in preparing for the competition

After months of reading through articles, touring various farms and listening to experts, the UC Davis Animal Welfare Judging team’s efforts paid off as they placed well at the Animal Welfare Judging Contest held by the American Veterinary Medical Association at Colorado State University. The undergraduate team placed fourth for the overall team category, while the graduate team placed second and fifth in individual categories and third in the overall team category.

Prior to this success, UC Davis didn’t even have a team to compete. Allison Pullin, a Ph.D. student in the animal behavior graduate group, was asked by her advisor, Maja Makaton, to coach UC Davis’ first team due to her prior experience in these competitions. Pullin decided to compete in this contest while working toward her Bachelor’s degree at Ohio State University in her senior year and served as a coach while working on her Master’s at OSU.

“I think that this contest is really cool because I think it really challenges students to apply a really holistic view of animal welfare and animal management,” Pullin said. “Because animal welfare isn’t just about health. It’s not just about behavior. It’s not just about nutrition. It’s really all of these factors coming together and taking this really holistic view of what actually promotes good animal welfare and gives the animal a good life.”

Pullin also added that while it may be easy to anthropomorphize animals when thinking about animal welfare, the contest reminds students that objective and scientific perspectives on animal welfare may be more beneficial to the animal than what our human points of view may assume.

Karli Chudeau, a second year Ph.D. student in the animal behavior graduate group, stated that the preparation process for the competition was more than the majority of the team had expected since none of them had prior experience in such a competition. Starting in June, the team began to review scientific articles concerning the four species that the competition would focus on: dairy goats, egg-laying ducks, green iguanas and polo ponies. Dividing up the readings, the students and coaches scourged the articles for topics important to the animals’ welfare, such as health promotion, normal and abnormal behaviors and housing and disease prevention, before coming together every week to discuss their findings. The students also listened to various experts on each of the species talk about animal welfare and toured facilities such as the UC Davis dairy goat facility.

Transitioning into the quarter, the team compiled the information they had retrieved into resource packets that would be used during the competition, as the students are required to give oral reasonings on the prompts given using scientific evidence. Once all of the information was organized, coaches Pullin and Kaleiah Schiller tested the students with mock scenarios that they would have to assess, such as being given information on two barns and having to determine which one is better for animal welfare. These mock scenarios were similar to how the contest itself is structured.

Chudeau described the atmosphere at the contest as crazy and intense, especially during the individual scenarios when the room was silent and the tension palpable as students flipped through their resource packets. The students were required to sit at large ballroom tables and assess different scenarios presented through a slideshow. As a competitive swimmer during her undergraduate years, Chudeau found the difference between athletic competitions and intellectual competitions to be very interesting. While the atmosphere was competitive, Chudeau enjoyed how everyone was working as a team.

“I get the feeling that welfare tends to be on the outskirts of animal sciences, and so it was just really nice to have the comradery of everyone who feels the same way as you do about how we should be caring for and managing animals,” Chudeau said.

According to Sabrina Mederos, who competed on the undergraduate team, the competition was nerve-wracking at times since they were surrounded by experts and competitors from other schools, but the consistency of their training during the summer led to their success. Through the training process, she believes that she not only broadened her knowledge but also improved her presentation and collaboration skills.

“To do well, we really had to hone our public speaking skills, our ability to work under pressure and really expand our knowledge of animal welfare assessment and concepts,” Mederos said.

In addition to the immense commitment and passion of the students leading up to the competition, Pullin believes that the resources the team had to their disposal contributed greatly to the team’s success. With four animal experts within the Animal Welfare Center guiding the team, the students were given access to farms and experts on the species. Furthermore, the undergraduate and graduate team also collaborated with the veterinary team coached by UC Davis’ veterinary school. This allowed the undergraduate and graduate teams to view animal welfare from a more health-centered focus, as they came from a background that was more focused on behavior. Pullin believes that all of these resources allowed the students to grasp a more holistic view on animal welfare in both the academic world and in the real world.

Mederos found it to refreshing to learn about unique species that aren’t commonly studied in general animal science courses and interact with people who are passionate in the field. She believes that the competition brings awareness to all different components of animal welfare.

“I think one thing that I learned from this whole experience is that because animal welfare is so multi-facilitated, people from different areas of specialization can contribute in their own way,” Mederos said. “Animal welfare encompasses so many different factors such as physical health, affective state and natural conditions. Depending on a person’s background, they can identify things others may not have noticed.”

Pullin hopes that people interested in improving the lives of animals can become educated on the scientific field of objectively and scientifically judging animal welfare, as it is often difficult to know where to start when trying to do what is best for animals. In addition, Chudeau believes that animal welfare applies to all animals and that everyone has a responsibility to care for the animals in our surrounding environment.

“I think welfare is something that once you start thinking about it, I think it’s very hard to not think about it,” Chudeau said. “If everyone can get in that mindset of how we can provide the best lives possible for animals that are around us, I think the better off our whole world would be.”  

Written by: Michelle Wong – science@theaggie.org