OTC News Archive

Engineer receives $400,000 CAREER award to develop disease-fighting cells

UT College of Engineering
February 21, 2006

Developing the technology to stimulate mouse stem cells to become disease sentinels of the immune system is the focus of a $400,000 National Science Foundation Early Career Development (CAREER) award received by Krishnendu Roy, a biomedical engineer at The University of Texas at Austin.

CAREER awards, given to future academic leaders, are the foundation’s most prestigious grants for young teacher-scholars.

Roy received the funding to find an effective way to ultimately generate large numbers of immune cells called CD8 T cells primed to kill cancerous or invader cells such as a bacterium. Because mice and humans are similar, the laboratory approach could help researchers seeking to generate the human version of these protective immune cells to rapidly treat diseases.

“It would be very beneficial if we could have a readily available source of these (CD8 T) cells that can be used in patients on demand,” Dr. Roy said, noting that this faster approach to adoptive immunotherapy could take decades to achieve.

Embryonic stem cells can develop into all cell types in the body. Because these starter cells can be manipulated into becoming specific cell types, they hold the potential to treat diabetes, heart disease and other conditions by providing normal cells to replace disease-damaged ones.

Roy’s efforts could one day affect the treatment of diseases such as cancer and AIDS that involve damaged T cells or require specialized T cells to fight the disease. Laboratory grown CD8 T cells could fight specific infectious diseases or cancers such as leukemias if researchers can teach the cells to recognize a unique feature, called an antigen, on the surface of diseased cells.

To begin, Roy will take mouse stem cells and grow them inside three-dimensional plastic scaffolds with a nutrient-rich broth. The plastic in the scaffold helps stem cells to develop into more specialized cells called hematopoietic stem cells, precursors to all blood cells.

The human counterpart of these cells has been used for decades in bone marrow transplants to treat blood-borne cancers and certain other life-threatening conditions. But rather than having the mouse hematopoietic stem cells recreate all blood-cell types as in these transplants, Roy will use a two-step process to favor their development into CD8 T cells.

In the first step, he will add the mouse hematopoietic stem cells to a container holding miniature beads that are 4 micrometers wide (about 18 times thinner than a human hair). Roy and graduate student Sabia Taqvi will have already coated the commercially available beads with a protein that stimulates the stem cells’ development into immature forms of T cells. In preliminary experiments, the bioengineers converted up to 40 percent of stem cells to these early T cells with this approach.

In step two, the researchers will combine the young T cells with microbeads coated with a different stimulant. The goal is to prime their development into disease-specific fighter cells (CD8 T cells).

That process usually occurs in two steps in humans and other animals. The cells’ destiny as CD8 T cells is determined by their interaction in the thymus gland with specialized cells coated with a display protein.

These CD8 T cells then learn to react to a specific antigen, which is a small bit of unique protein from an invasive organism, when the antigen is presented by specialized cells using the same display proteins.

The specialized presenting cells can do this because they previously internalized an intact microbe and shredded its proteins into bits for display purposes. Roy’s laboratory will recreate both parts of this training process by coating microbeads with the mouse version of the display proteins, carrying a particular antigen.

“We will present a certain antigen to these developing T cells, and then see if we can actually mimic what normally happens inside the mouse’s body by training these lab-generated T cells to become disease-specific,” Roy said.

Roy’s laboratory will optimize the microbead incubation steps by adjusting the ratio of cells to microbeads, how much stimulant is coated on the beads’ surfaces, and how long cells and beads need to interact to promote the developmental steps. After each incubation step, the researchers will verify cell conversion by analyzing their surface for the presence of new markers that are a hallmark of the altered cell type.

Scaling up the process to produce large numbers of early T cells and primed T cells will also be a major goal.

“This is essentially a platform technology, where you could develop the cells to fight one antigen involved in one disease, but then substitute the antigen with another antigen to tackle another disease,” Roy said.

As part of the educational outreach for the CAREER grant, two students from local high schools will be selected to participate in research in Roy’s laboratory over the summer. Graduate students of Roy will then serve as informal advisers for the high schoolers regarding future engineering and science opportunities.

[ Cockrell ]