Cancer Biology, Genetics
Dr. Xu is also professor and vice chairman of genetics at Yale School of Medicine, director of the Mouse Functional Genome Project, and adjunct professor and director of the Fudan-Yale Biomedical Research Center at Fudan University.
Deciphering Mechanisms of Development and Cancer by Model Organism Genetics
Tian Xu decided to study genetics because he didn’t know what it was. He just figured he’d earn a college placement if he chose something obscure, because Fudan University in Shanghai allocated slots by subject. Thirty years later, he’s still studying genetics. “Because I had a lot of sufferings early on, I would like to help people,” says Xu, who invents genetic methods for probing the causes of disease. “It’s quite shocking,” he says. “Other than for some major diseases, such as cancer, almost no major [disease] genes are known.”
Xu’s hardships began during China’s Cultural Revolution, when he was denied medical care and humiliated publicly at school because of his intellectual parents. Years later, after the revolution ended and he was about to graduate from Fudan, he won a World Bank fellowship to study in the United States. But that same year, tennis player Hu Na defected to this country, and Xu wasn’t allowed to accept the fellowship. When he finally arrived in the United States the next year, with $50 in his pocket, he found that his host university was woefully unequipped for graduate-level genetic studies. Moreover, the stipend it offered was no match for New York rents, so Xu slept in an abandoned building, where he was mugged. After knocking on the door of nearly every genetics professor in the city and finding no alternative to his plight, he scraped up enough money to buy a train ticket to New Haven—and Yale University.
Xu thought he had reached “New Heaven” when he encountered Spyridon Artavanis-Tsakonas, a food-loving, fruit fly geneticist at Yale. Although Xu’s English was almost nonexistent, the two were able to discuss Chinese food, since the names needed no translation. “My funny clothes made me look as if I had just come from rural China,” he recalls. “But Spyros understood that I was someone who really wanted to study science.”
Artavanis-Tsakonas figured that if Xu could cook he could do molecular biology, and he offered him a place in his lab. By 1990, Xu had finished a Ph.D. and was starting postdoctoral work at the University of California, Berkeley. “I am forever grateful to Spyros and to my postdoc advisor, Gerry Rubin, who is a vice president of HHMI now,” Xu says.
When Xu joined the faculty at Yale (after rejecting nine other offers), he continued to study fruit flies. He made a splash when he used the method he developed for mutating genes in somatic cells to screen for genes that stop tumors in flies. He showed that the tumor suppressor genes in flies also have counterparts in mammals, including humans, and that a human gene that blocks tumors has a counterpart in the fly that halts cell growth and division. These studies convinced skeptical scientists that Drosophila is a good model for studying cancer biology. Using this model, Xu’s group has identified more than 500 mutations that promote tumor growth and nearly 2,000 that suppress it. Two of the mutations resemble those in humans that cause tuberous sclerosis complex (TSC), which produces abnormal growths throughout the body. As a result of studies on how those genes malfunction, potential drugs to treat TSC are being tested in clinical trials.
Xu was not content to look only for genes that cause tumors, however. “I said, ‘Why don’t we study the spread of cancer, because if we can stop that, cancer will become a chronic, instead of a fatal, disease,’” he recalls.
Because no one has yet discovered a family with both inherited alterations that trigger cancer and that cause cancer to spread, Xu’s group developed a genetic method that mutates normal cells into tumor cells and then alters genes in the tumor cells to see which ones caused metastasis. This approach has identified more than 200 such mutations. Some of those, when functional, determine which end of a cell is which (cell polarity). Xu’s group showed that loss of cell polarity in tumor cells reduces the production of intercellular “glue” and leads to the breakdown of basement membrane, which supports layers of cells, and triggers cell migration. “The degradation of basement membrane is absolutely essential for tumor cells to come out and also for them to invade a new organ or tissue,” Xu says.
While this work was in progress, Xu was looking for a better way to mutate mouse genes, because 99 percent of human genes have counterparts in mice. After the sequences of the human and mouse genomes had been determined, scientists wanted to figure out what each gene does. One of the most direct approaches to this problem has been to disrupt a gene in the mouse and examine the physiological defect associated with the mutant animal. The advent of “knockout” mice, in which specific genes are mutated, was such an important advance that it earned three scientists a Nobel Prize in 2007. “But this method is very laborious, technically challenging, time-consuming, and expensive,” Xu says, adding that only 15 percent to 20 percent of mouse genes have been altered in mice to date and that it would cost billions of dollars to produce mouse mutants for the rest of the genes.
When Xu asked HHMI to fund his mouse gene project 10 years ago, he had never touched a mouse. “They probably thought, ‘Here is this crazy Chinese, but we will give him a chance,’” Xu says. Despite little progress over the next 5 years, HHMI continued the funding. And in 2005, Xu made a breakthrough by using a jumping gene from a moth to disrupt genes in mice. Jumping genes, or transposons, are pieces of DNA that hop from one part of the genome to another. In doing so, they often disrupt genes.
The unlikely partnership between moths and mice was possible because the transposon of the cabbage looper moth, called piggyBac, is very strange. Therefore, it is not recognized by the mouse genome, which has grown wise to most transposons and is able to suppress them before they create havoc. After Xu modified piggyBac, it worked so well in mice that his group has launched the Mouse Functional Genome Project, a combined effort at Yale and Fudan. The project aims to produce the first functional map for a mammalian genome by mutating most mouse genes and examining the defects associated with each mutant strain. “Right now, when a patient comes into the hospital for a complete physical checkup, we can tell them what is wrong but not what are the underlying causes,” Xu says. “By systematically mutating genes and then giving each mouse a complete physical checkup, we should be able to correlate each clinical outcome with a genetic basis.”
The group already has made more than 700 mutant mice. They envision a mutant bank from which scientists and physicians around the world will check out mice for their own studies. Xu hopes this work will uncover the genetic basis of most common and uncommon diseases.
Xu’s team has quickly looked at the first 100 mutants. They include a mouse that fails to thrive, as some human infants do, and mice that have autoimmune defects or neurological problems. “Perhaps the most exciting mutant to many is a sterile mutant,” Xu says. Late-night sessions with an infrared video camera revealed that these “not tonight, honey” males are always rejected when they try to mount females. “It will be interesting to see whether overexpressing this gene in males will make them superpopular,” says Xu, whose work has not escaped the attention of perfume makers.
Xu hopes to enlarge the scope of these functional studies. For example, he would like to feed the mutant mice junk food to see which ones fail to develop obesity and diabetes. This approach would identify genes that normally promote those conditions. He also would like to study aging and longevity by observing a complete set of mutant mice (in which a different gene is mutated in each mouse) for a long time to see which ones live longest or die prematurely. But perhaps his most fervent wish is to place each mutant mouse in an MRI machine and image it from head to toe. “Because if you have, say, a group of neurons that made the wrong connection in the brain, that is very difficult to determine [with a physical exam],” Xu says. After all the images were placed in a database, researchers could mine the data to determine how each mutation changes anatomy. “I think that will be as important as sequencing the genome,” says Xu.