Scientists find new genes for cancer, other diseases in plants, yeast and worms

AUSTIN, Texas—From deep within the genomes of organisms as diverse as plants, worms and yeast, scientists have uncovered new genes responsible for causing human diseases such as cancer and deafness.

The University of Texas at Austin scientists exploited the fact that all life on Earth shares common ancestry, and therefore shares sets of genes.

They found genes in yeast, for example, that humans use to make veins and arteries, even though yeasts have no blood vessels at all. Yeasts use those same genes to fix their cell walls in response to stress.

"Basically, we figured out a way to discover the genetic basis for disease by looking at organisms other than humans and finding disease equivalents," says Edward Marcotte, professor of chemistry and biochemistry.

To find the new genes, Marcotte and his graduate students developed a computer algorithm that first sifts through vast sets of existing genomic data for worms, mice, yeast, plants and humans. The algorithm pairs up sets of genes that overlap between these organisms and humans.

In doing so, it highlights genes that are known to work together to do one thing in the non-human organism, but the function of which are not yet known in humans. The scientists can then test those new genes in the lab to determine their function.

"The basic essence of the method is that there are ancient modules of genes that have been reused in different contexts over time," says Marcotte. "So the yeast uses a particular module with a particular set of inputs and outputs to do one task. Humans use this same module with different inputs and outputs to do another."

In the case of blood vessel formation, or angiogenesis, the scientists found 62 genes that yeast use to fix their cell walls that matched with a few genes known to be responsible for vein and artery formation in humans.

Developmental biologist John Wallingford and his graduate students then tested the human equivalents of the 62 yeast genes in developing frog embryos in the lab. This confirmed that eight of those 62 genes help build blood vessels in animals. Several of these genes were also confirmed in humans.

The newly found human angiogenesis genes are great candidates for drugs, says Marcotte.

"Tumors fool your body into feeding them by initiating blood vessel growth, and that's the reason we're interested in angiogenesis," says Marcotte. "So, genes for angiogenesis are common targets for chemotherapy. Some of the most effective chemotherapies block angiogenesis."

The scientists also found a set of genes in nematode worms involved in human breast cancer. Surprisingly, it is the same set of genes in the worms responsible for determining how many male offspring a parent worm births.

In plants, they found a gene that is involved with a genetic disorder called Waardenburg syndrome, which causes a significant fraction of cases of human deafness. (Strangely, plants use the gene as part of their system for sensing gravity, called gravitropism.)

The researchers are teasing out genes for a variety of human disorders, from mental retardation and birth defects to cataracts. Their goal is to find new genetic targets for therapy.

"By exploiting evolution and looking at lower organisms that don't even have the organs we're looking for—blood vessels or even heads—but share some of the underlying molecular processes, we're able to discover genes relevant to human diseases," says Marcotte.

Marcotte admits it may seem odd to look for human disease genes in something like a plant or yeast, but that the information is proving to be extremely useful, if not surprising.

"When we found the genes in plants responsible for Waardenberg syndrome in humans," he says, "we were screaming in the halls."

Marcotte, Wallingford and colleagues published their research in PNAS (Proceedings of the National Academy of Sciences).

Marcotte and Wallingford are members of the Center for Systems and Synthetic Biology and the Institute for Cellular and Molecular Biology. Wallingford, associate professor of molecular cell and developmental biology, is a Howard Hughes Medical Institute Early Career Scientist. Co-authors Kriston McGary, Tae Joo Park, John Woods and Hye Ji Cha are graduate students at The University of Texas at Austin.

For more information contact: Edward Marcotte, professor of chemistry and biochemistry, 512-471-5435; John Wallingford, associate professor of molecular cell and developmental biology, 512-232-2784.

Current wisdom on the role of genes in malignancy may not explain some features of cancer, but stepping back to look at the bigger picture inside cells reveals a view that just might. When I first began to study cancer as a young postdoctoral fellow in the early 1960s, it looked to leading scientists as though viruses could be the cause of most, if not all, malignancies. That idea was based on the discovery of several tumor- and leukemia-producing viruses that could infect a host cell and insert their own genetic material into its genome, sparking a cancerous transformation and proliferation of the cell. I was optimistic and naive enough to hope that if researchers could understand the exact molecular mechanisms by which such viruses caused cancer, we could develop vaccines to eliminate one of humanity’s most dreaded diseases. My own contribution to that pursuit came in 1970, when my colleagues, Michael Lai and Peter Vogt, and I managed to isolate a specific gene, src, which was suspected to be the tumor-initiating culprit in avian Rous sarcoma virus. Within a few years, more creative scientific minds than mine had followed this lead to a realization that a closely related gene was already present in the normal DNA of animals, including humans. And a new cancer model was born: it proposed that some triggering event, such as a mutation in a human cell’s own version of src, could ignite tumorigenic powers like those possessed by its viral counterpart. The cancer-promoting potential of such a time bomb buried in our personal genomes earned it the title of “proto-oncogene.” Once the mutation occurred, it would become a full-fledged oncogene. The theory that mutations in certain key human genes are at the root of all cancers has dominated research for the past 30 years. Yet despite all the attempts of investigators, including myself, during that time to demonstrate that a handful of such oncogenes alone can transform normal cells into malignant ones, none abnormality as a root cause for cancer, in contrast, are controversial but are being ac- tively investigated by mainstream science. ■ Prevailing cancer theory blames mutations in important regulatory genes for upsetting normal controls on cells. But it does not give a primary role in carcinogenesis to the gross changes to whole chromosomes that are seen in all cancer cells. ■ The author argues that these chromosomal mutations, which unbalance thousands of genes en masse, are sufficient to trigger cellular instability that leads to further chromosome disruption and to account for properties of malignant cells that cannot be explained by the activity of specific genes. Our research group arrived at a chromosomal theory of cancer in part by thinking about the basic biological features that make a normal human cell “normal,” or even “human.” By looking at exceptions to the current rule, evidence suggests that this chaos on the chromosomal level is not just a side effect of malignancy, as the prevailing model holds, but the direct cause and driving force of cancer. With several colleagues in the U.S. and Europe, I have been investigating this possibility for more than a decade, and the recent work of many other researchers is also pointing to the conclusion that changes to the number and structure of entire chromosomes, rather than single genes, are sufficient to initiate and sustain malignancy. This view has important implications for cancer treatment and prevention, as well as for diagnosis of precancerous lesions when there may still be time to intervene. It also finally explains some characteristics of cancer cells and whole tumors that the gene mutation hypothesis leaves unresolved. Peter Duesberg

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