UNLOCKING THE MYSTERIES OF HUMAN GENETICS
Dr. Wayne Grody
When the double helix, the structure of human DNA, was discovered in 1953, it marked the beginning of modern molecular biology, providing insights into our genetic code and unlocking the mystery of human genetic makeup. Since then, scientists have been able to develop an understanding of the structure and function of genetic material and use it to discover why some people are more prone to disease than others. As a child, Wayne Grody, .D, PhD, was fascinated by a Life magazine cover that featured the double helix, marking the beginnings of his life as a leader in diagnostic molecular pathology.
In the early 1990s, the Human Genome Project (HGP) started looking for ways to apply their findings about genetic coding to unlocking questions regarding some of the world's most troubling diseases. To begin to try and answer these questions, HGP launched the first nationwide molecular screening effort. In just a few short years, Dr. Grody helped develop what is now a widely used screening test for cystic fibrosis—a life-threatening genetic disease affecting approximately 30,000 people in the United States. Cystic fibrosis causes fluid to build up in the lungs and the ducts that run from the pancreas to the small intestine, which leads to frequent infections that contribute to an early death. Although there have been significant advances in the treatment of cystic fibrosis, there is still no cure, and most patients die around age 30. 1
DETECTING DISEASE
In 1992, Dr. Grody was an accomplished professor of medical genetics and molecular pathology at the University of California Los Angeles (UCLA) School of Medicine. He was approached by the HGP to try and determine the likelihood of a child being born with cystic fibrosis based on the parents' genetic makeup. According to Dr. Grody, the HGP decided to study cystic fibrosis because it is one of the most common, confusing and lethal diseases in the world. “The gene for cystic fibrosis was discovered in 1989, and turned out to be extremely large and complex,” explained Dr. Grody. He took on HGP's challenge and led one of five teams seeking to understand the genetic abnormalities that cause cystic fibrosis.
DNADr. Grody and his team from UCLA spent five years studying the genetic mutations that would indicate a patient had the cystic fibrosis gene. Although there are more than 1,300 mutations of cystic fibrosis, all the teams performing research for the HGP were asked to screen for the six most common forms.1 They then had to come up with a DNA-based test that would accurately assess the DNA with a high degree of sensitivity, since cystic fibrosis is a recessive disorder. They developed a test that captured a DNA sample through an oral swipe; no blood was required.
The team decided to pilot test the study among pregnant women, as they believed they would be the most receptive to a screening that could detect the likelihood that their child might have a serious illness. If the mother's test came back positive for being a carrier of cystic fibrosis, the father was then tested. If both tests came back positive, then it was found that the child had a significant risk of being born with cystic fibrosis. “Since one in 30 members of the population are carriers, and cystic fibrosis is a recessive disease, there's no way to know if you are a carrier without being screened,” said Dr. Grody.
CREATING A BETTER TOOL
When the team at UCLA received the DNA swipe tests from the clinics, they used a test strip designed to determine if the patient tested positive as a cystic fibrosis carrier. “Originally, the lab was creating its own test strips,” said Dr. Grody. “However, we were unsure of the tests' consistency.” To help solve this problem, Dr. Grody turned to a diagnostic test manufacturer who had reached out to him during an HGP committee meeting. Working with the diagnostic company, the team developed a test strip with DNA probes that scanned for each of the six cystic fibrosis mutations. The strip they originally designed was similar to the one Dr. Grody's team had started using for the project; however, since it was mass produced they could now be certain the same testing tools were being used for each sample.
Cystic Fibrosis Statistics
- Approximately 30,000 Americans have cystic fibrosis.
- Cystic fibrosis screenings alert up to 90 percent of carriers.
- Although there have been significant advances in the treatment of cystic fibrosis, there is no cure, and most patients die around the age of 30.
- Approximately 1 in 30 people are carriers of the cystic fibrosis recessive gene. The only way to determine who is a carrier is by being screened.
Over the research test period, Dr. Grody and the diagnostic company worked together to improve the test in hopes of garnering more accurate results. “We found that one of the probes for the six mutations was coming out lighter than the others and we suspected it was just because of the way the probe was constructed,” said Dr. Grody. Working together, they found a better design for the probe and the team was able to continue its research with an improved diagnostic tool.
A MYSTERY UNLOCKED
In 1997, the team presented their pilot test findings to a panel at the National Institutes of Health (NIH). The panel was impressed by the data the team was able to collect and decided to recommend that the cystic fibrosis test should be offered to all pregnant mothers. “Although we are far from offering the test 100 percent of the time,” Dr. Grody suspects that about 60 percent of obstetricians offer the test to their patients. He adds that advances in the testing materials can now determine with a much higher sensitivity if both parents are cystic fibrosis carriers, in which case the child has a 1-in-4 likelihood of being born with the disease.
The screening test has changed significantly since the research project ended in 1997. Dr. Grody has continued to work with the same diagnostic company to develop a more robust test that can scan for 23 different cystic fibrosis genetic mutations. Although this is far from testing for all 1,300 different mutations, these 23 mutations are the most common ones that can cause cystic fibrosis. “We could do a scan for all 1,300 mutations,” said Dr. Grody, “however, that would cost upwards of $3,000 per test.” The test is now typically performed with a blood sample, rather than an oral swipe test, because the teams found it to be more reliable. The sensitivity of the test has also improved dramatically. “We can now catch 90 percent of Caucasian carriers with the test,” said Dr. Grody, which is 10 percent better than during the pilot study nearly 10 years ago.
Today Dr. Grody is a Professor in the Departments of Pathology & Laboratory Medicine, Pediatrics and Human Genetics at the UCLA School of Medicine. In addition to working on fine tuning the cystic fibrosis screening test, he is also working with the Centers for Disease Control and Prevention (CDC) to artificially create “control” cells carrying mutations for a wide variety of diseases for use as quality control materials in molecular genetic testing. According to Dr. Grody, DNA testing could not be done without the innovation of biotechnology companies that give researchers the ability to develop and improve tests using the best tools available.
- March of Dimes. Birth Defects and Genetics Cystic Fibrosis. (25 September 2006).