The Magazine of the University of Minnesota Duluth
(Left): Lester Drewes, Professor, UMD School of Medicine
Over a dozen mice are working for Joe Z. Tsien in his stainless-steel and white-tiled laboratory. Their furry gray bodies glisten as they swim in their "Mouse Motel 6" pool, diving to find platforms that they are coached to discover. Tsien's research team also has these mice choosing Lego blocks by color and then pushing them around tables.
Does it sound like a child's game? Tsien's research with mice may be an important breakthrough in the treatment of memory-related diseases such as Alzheimer's.
UMD alumnus Tsien uses his "Mouse Motel 6" laboratory to study mice that he has genetically altered to be smarter in memory tests. Tsien returned to UMD to present his latest research in a seminar entitled "Genetic Enhancement of Learning and Memory in Mice," in October 1999.
Tsien grew up in Wuxi, China, and attended the East China Normal University in Shanghai. He wanted to earn his doctorate in the United States. Choosing Minnesota was easy. The Chinese characters for Minnesota translated into "clean air, blue sky." He then narrowed it to UMD because the school offered to waive the application fee which Tsien could not afford. Beginning in 1986, Tsien began working on his doctoral thesis with the help of Dr. Lester R. Drewes, professor and head of the UMD Department of Biochemistry and Molecular Biology. Together they studied the mechanisms of chemical communication between cells of the brain.
In Tsien's final year at UMD, he worked with Drewes under a research grant to study cell signaling mechanisms. Tsien's work examined how a chemical outside of a cell is able to trigger a biological event inside the cell and start a chain of events that ultimately ends in some physiological response such as muscle contraction or hormone secretion.
Tsien used his UMD research as a foundation for work that expanded into the area of the cellular and molecular basis for memory and learning.
Tsien received his Ph.D. in biochemistry and he was awarded the prestigious Bacaner Research Award sponsored by the Minnesota Medical Foundation, both in 1990. This award is given annually to a doctoral student in recognition of outstanding creative achievement.
After obtaining his Ph.D. at UMD, Tsien moved on to Columbia University, the Massachusetts Institute of Technology and finally to his present location at Princeton University where he is an assistant professor of molecular biology. This is where his decade of research into the genetic link between brain proteins and memory has taken place. Tsien made national and international news when he announced that he had created a smarter strain of mice by genetically altering a gene for memory and intelligence. These findings appeared in the September, 1999 issue of Nature. These mice, nicknamed "Doogie Mice," were named for the young main character from television's "Doogie Howser, M.D."
Here is how the process works. Tsien inserts a gene called NR2B into the hippocampal neurons of mice while in the embryonic stage. When grown, the new mice produce a much higher quantity of the NR2B brain protein. NR2B is a key switch that controls the brain's ability to associate items or events. The extra amount of this protein produces a change in a brain-cell component known as the NMDA receptor, believed to be a key component of memory. The NR2B protein keeps the NMDA receptors open longer, giving the mice more time to make the associations needed to process the information.
The "Doogie Mice" retain into adulthood certain brain features of younger mice, which are believed to aid in absorbing new information. Altering their protein levels helps the mice retain past experiences of getting through a maze and they are able to duplicate the path more often than untreated mice. In short, they learn better and out perform other mice at maze running and other parallel tests of mouse aptitude.
There is no evidence that the NR2B protein makes the new mice smarter or boosts their rodentine IQ. However, it clearly does improve their memory of successful strategies employed in dealing with certain challenging and complex tasks, like detecting a platform in a pool of opaque water.
What does this mean for humans? Tsien's research can be used to find treatments for Alzheimer's disease and other memory-related problems. With the information the mice have given Tsien, it can be used to create drugs to treat the diseases through gene therapy. Before this research with humans is underway, however, more testing needs to be performed with animals. Since news of his research with mice, hundreds of people have called him to ask for his help with their relatives. "They really cry for help. That's something I had never experienced before," Tsien said.
Tsien's research raises ethical questions that need to be examined. "The NMDA receptor in humans is nearly identical to the receptor in mice, rats, cats and other animals," Tsien said. "We believe it's highly likely that it plays a similar role in humans." Tsien acknowledges that the possibility exists to genetically engineer smart babies in the not-so distant future. Ethical guidelines currently prohibit such an experiment with humans. Besides, the research Tsien conducted is to find treatments for diseases, not to make "Einstein babies."
Tsien's October seminar was a momentous occasion for UMD. Alumni are greatly appreciated at UMD and it was especially thrilling for students and faculty to hear from Tsien about the knowledge he has acquired since leaving the institution.
Drewes said that when Tsien was at UMD he was fairly shy, but he was also tenacious. "He was not easily swayed to change his opinion unless the data was conclusive," Drewes said.
Tsien brought his fiancee from China and the UMD staff and students held a celebration in the Rose Garden on Lake Superior after their wedding ceremony. Tsien gained confidence at UMD. Drewes said he was proud to know Tsien. "It was great to see him develop in the field of neuroscience and excel in the ways he has done," he said.
Tsien said, "This is truly a terrific place. My education started here and it built a strong foundation for me." Tsien considers UMD his second home.
-- Teresa Thompson