The Colgate Scene
September 2004

The optimist
Finding solutions to genetic birth defects

Last fall, Charles Schwartz '70 delivered Colgate's inaugural Oswald T. Avery Lecture to a packed audience in Lathrop Hall. One of the first molecular biologists in history, Avery, Class of 1900, is best known for his co-discovery that DNA (deoxyribonucleic acid) is the material of which genes and chromosomes are made. [Photo by Timothy D. Sofranko]

Geneticist Charles Schwartz '70 wants to give families an answer to why their sons were born with mental retardation, and to help determine ways to prevent or alleviate the condition.

"We have been studying some families for 10 to 12 years," said Schwartz, director of the J.C. Self Research Institute at the Greenwood Genetic Center in Greenwood, S.C. "You get to know people, and some of these families are extremely helpful. They call up periodically. `Is there anything more we can do? Have you gotten blood from Uncle Joe?' We may not have been able to identify yet what the genetic defect is in their family; however, they want to know, because they want to be able to help their child or grandchild."

In fact, Schwartz has been able to provide an answer for many families. Working on the leading edge of molecular genetics, Schwartz's research team has found several of the genes responsible for X-linked mental retardation (XLMR), including Fragile X syndrome, the leading cause of mental retardation in males worldwide, and they are hot on the trail of a number of other answers.

Associated XLMR conditions involve anomalies in the genes on the X chromosome. Males are affected because they have only one copy of the X chromosome, while females, who have two X chromosomes, are often carriers. In addition to mental retardation, males with XLMR may have other distinguishing features of the face, head, and genitals, as well as behavior problems that are often associated with autism. According to Schwartz, approximately one in 1,000 males is affected with XLMR worldwide. Often, those with mental retardation in their family histories are advised to seek genetic counseling to assess the potential for having children with XLMR, and how severely their descendants might be impaired.

While there is no cure for XLMR, Schwartz is working to identify ways to screen for, lessen the severity of, or even prevent mental retardation by delving into potential biochemical causes -- and solutions -- to the development of these conditions.

The biochemistry behind the genetics
A tantalizing example of the potential for finding biochemical solutions to genetic problems is the Greenwood Genetic Center's contributions to the prevention of another condition. In the mid-1990s, they conducted experiments to identify genes that confer a high risk for couples of giving birth to a child with neural tube defect (NTD), which can cause a range of crippling or even fatal conditions. Schwartz's team was able to show that a certain genotype (a specific sequence of DNA; inheritable information) increases the risk of NTD. Further, they determined that that genotype may account for a substantial proportion of NTDs that are preventable if the mother were to take folic acid supplements.

At that point, the center came to the forefront of a public relations campaign to promote folic acid usage in women of childbearing age that resulted in a 50 percent reduction in the incidence of neural tube defect in South Carolina.

"This is important because the northern and western parts of South Carolina had a high incidence of neural tubes, about 8 per 1,000, in part related to genetic background," said Schwartz. "Those areas were settled by people from the British Isles, who have a very high incidence of NTD."

In terms of XLMR research, in just the past year, Schwartz's team (in collaboration with others) has identified four new genes, and, likely most importantly, have documented that mutations in a specific gene -- the creatine transporter -- have an incidence of about one percent in males with mental retardation.

"This is significant, since only the Fragile X syndrome appears to have a higher incidence," Schwartz said. Further, the group has determined that a simple urine test can find the defect in this gene, a much less expensive option than genetic testing.

Creatine is known as a supplement that helps weight-lifters build muscle mass. But, in certain mentally retarded patients who also tend to suffer from seizures or autistic-like behavior, he said, "the level of creatine in the body is very elevated because it is not being transported into the brain or into the cells as it should. That points to a critical function for creatine in brain development that was not known before."

Schwartz is actively promoting his team's discovery, including making a presentation at the European Society on Human Genetics conference this past June. "What we're saying is that any boy with MR who has severe speech and language delay or has had seizures should be tested for elevated creatine in their urine."

Award-winning detective work
Schwartz entered the field of genetic disease mapping in its earliest days. It was a case of being in the right place at the right time, said Schwartz, who earned graduate degrees from Oklahoma State and Vanderbilt universities and completed postdoctoral studies in molecular research at the University of Vermont.

Until the early 1980s, Schwartz had been doing cancer and cellular research at the La Jolla Cancer Research Foundation. During a six-month sabbatical, he took a job as a sous chef at his brother's restaurant in Salt Lake City that, through connections, led to a fellowship at Utah School of Medicine. He then did work investigating infectious disease at Latter-Day Saints Hospital.

"I was getting interested in that form of detective work called epidemiology [the study of disease in human populations]," said Schwartz. Then, he received a rare opportunity. He was hired by the University of Utah's department of hematology.

"I was interested in the epi-geneology aspect, and [they were] looking for a molecular biologist," said Schwartz. "The tracking of diseases in families was a natural extension of that interest." The job put Schwartz in the lab with the pioneers who uncovered the genetic basis for cancer.

"Essentially, I am in genetics because I got in on the ground floor for gene mapping and disease mapping," he said. "I trained with the people who actually came up with the idea of how you identify the location of genes causing disease."

After that experience, in 1985, Schwartz was hired by the Greenwood Genetics Center to create and direct its DNA Laboratory. This lab later became the Center for Molecular Studies, a division of their research arm, the J.C. Self Research Institute.

"They were looking for someone to start, in particular, trying to do the genetics of the Fragile X syndrome and clone the gene. I was coming in to study their families and try to narrow the region where the gene would be."

In recognition of his accomplishments since then, Schwartz received the 2003 Robert Guthrie Award from the American Association on Mental Retardation's Health Promotion and Disability Prevention Committee. The award honors scientists who make significant contributions to the prevention of genetic disorders through the use of biochemical or molecular genetic technologies, or a combination of both.

The pathway to potential cures
It was in January that Schwartz, who also teaches graduate-level genetics courses at Clemson University and whose group is also studying the causes of a condition called ectrodactyly (split hand/split foot), was promoted to director of the J.C. Self Research Institute. Next on his plate, he said, is to set up a new division in cell biology within the institute that will help in researching new therapies, including for the creatine transport problem.

"I think the molecular -- that is, gene identification and mutation identification -- will become the easy part," he said. "The rate-limiting step is going to be the cell biology, the functional work to understand why the alterations in these genes lead to impairment. The more we understand about the pathway, the better able we will be to get to a point in the pathway that will be easier to deal with for treatment than with gene therapy."

He cited as an example the condition phenylketonuria (PKU), in which the lack of a particular enzyme causes an accumulation of phenylalanine in the body, leading to brain malfunction. A measurable biological test done in newborn screening allows for prevention of PKU through a phenylalanine-free diet. "We don't fully understand why excess of phenylalanine leads to a problem in the brain. We just know it does. But you can go right to the treatment because you understood the pathway. For some of these genes [such as the creatine transporter], we have the gene defect, but we don't fully understand the pathway. Once we do, it may give us a point of entry that will be easier to deal with for treatment than actually having to replace the gene with a new gene."

Schwartz is optimistic about the future of his field: "We have recognized now that there is no reason why we cannot look at curing disabilities."

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