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Scoliosis Gene Discovery Project

Interview with Ken Ward, M.D.

Ken Ward, M.D., is the Chief Scientist for EmerGen Labs, a gene discovery company in Salt Lake City, Utah. EmerGen is an important part of the scoliosis gene discovery project.

How do you go about finding a gene for a disease that affects humans?

Dr. Ward: The way we go about finding genes is to let the families who have a disease tell us where the gene is physically located. We do this by examining their genetic material to find areas where the DNA may have been damaged. When I started my career we knew that there must be a gene accident somewhere to cause a family's condition, but there were no gene maps to help us to find where this accident occurred. As the result of a worldwide scientific effort and the human genome project, there are now great gene maps that help us to quickly localize where a genetic mistake has occurred. Pinpointing the physical location of a gene is the first step in deciphering what a gene does and how it may cause a certain disease.

Finding a gene without knowing anything about it is somewhat similar to trying to find the place where I live without having any directions. You could start with the assumption that I lived in Salt Lake City (since we are having this conversation in Utah), but it would still be a very difficult project to find my home, especially if I am not listed in the phone book. But, if I told you I lived on Main Street in Salt Lake City, it would be much easier to find my home. And, if I told you I lived between 3rd and 4th on Main Street it would take less than an afternoon to find out where I lived. You could find my house by knocking on all the doors, and asking all the neighbors, until you find where Dr. Ward lives.

This process is very similar to what we do genetically. In the clinic and in the hospital we have found families that are struggling with a condition that is occurring over and over again, in generation after generation, and in multiple siblings and cousins. Because a disease is clustered in this family, we know there has to be some pattern of genetic inheritance. In family members who are willing, we collect a sample of DNA from their blood or from a brushing of the cells on the inside of their cheek. We analyze the DNA in these samples in order to tell us where the gene is located. By looking at DNA from enough families, we can usually tell what street the gene is located on, what block on that street is likely to contain the gene, and finally where the actual genetic accident has occurred.

What are the ideal families or situations to look for a given gene?

Dr. Ward: We look for very large extended families where there are five or ten, or even better, dozens of family members who all have the same condition. In the case of scoliosis, we would look for dozens of adolescents who have scoliosis in a single family. We would then ask them to participate in this research by donating a sample of their DNA.

Another strategy to find the gene for a condition as common as scoliosis would be to look at the DNA of sisters who both had scoliosis of equal severity. The fact that they both had scoliosis would raise a high suspicion that it is due to genetics, and their DNA might be very revealing.

The other situation that is very helpful in gene mapping projects is to find a rare person who has the condition we are interested in and who also has a change in their chromosomes. These changes are actually visible under the microscope, such as a broken chromosome, a chipped chromosome, or a rearranged chromosome that a doctor has seen in the past when they have had their karyotype analyzed. In this situation, there is a good chance that the damaged chromosome could lead us to the gene that causes the condition.

So, these are the three kinds of resources that are most helpful for finding genes; affected siblings, large families with multiple family members who are affected, and the rare individual who has a chromosome problem and the condition we are interested in.

What genes have you mapped so far?

Dr. Ward: In my work at the University of Utah, we have mapped genes for other orthopedic conditions such as multiple hereditary exostoses. We have also mapped genes for pregnancy complications like pre-ecclampsia, toxemia, and placental infarctions where there are large areas of the placenta that have a stroke like illness that cause a number of pregnancy complications. We have mapped genes for one of the most common congenital heart defects where the left side of the heart doesn't form correctly or it doesn't form at all. We have also mapped genes for neural tube defects (Spina Bifida) where the spine doesn't close completely.

What is the evidence that there is there a gene for scoliosis?

Dr. Ward: There probably is a gene for scoliosis, but there may be more than one gene. The best information that has been collected from all of the different orthopedic practices around the country is that there probably is what is called a major gene responsible for developing scoliosis. We don't know what that gene does yet, but by discovering that gene, we can move quickly toward understanding its effects. Once you know what a gene does, then the wheels can start spinning to find out whether or not there is going to be a new type of treatment for that condition.

Do you envision that there will be gene therapy for scoliosis?

Dr. Ward: I think it would be very tough to prevent or treat a condition like scoliosis using gene therapy. However, in the past we have seen very severe conditions that can be prevented by providing an additional nutrient or vitamin to the diet. For instance, there is a Greek family that we have studied that had neural tube defects over and over again. We found that this family has a unique, severe problem processing a folic acid vitamin and by giving them huge amounts of folic acid at hundred times of the normal dose, they were able to get their folic acid level up to normal and they were able to successfully complete their pregnancies and have had 6 healthy children.

Sometimes the answers prove to be pretty simple. If there is a gene for scoliosis, that means there is also a pretty simple chemical or protein pathway for the predisposition. A gene simply equals a protein. The protein is somehow changing the way the spine grows or functions. How this is happening, we don't understand yet. One of the things that is most exciting about genetic research is that it leads you to pathways that you never imagined were possible as part of the cause.

Will there be a drug for treating scoliosis?

Dr. Ward: If you took all of the best scoliosis researchers in the world right now and asked them to come up with a drug that cures scoliosis, they could spend decades and billions and billions of dollars and not necessarily get anywhere because we don't have enough fundamental understanding of the chemistry of scoliosis. However, if we ask the families who have this condition to participate in this genetic research and find a gene, it would be the breakthrough that really allowed that larger discovery effort to finally become efficient because you would understand scoliosis at the chemical and molecular level. A chemical or molecular cause has not yet been found for scoliosis, but has been seen for hundreds of other conditions. Sometimes the treatments come rather immediately after discovery of the gene. More often it is still decades away, but hopefully we would have some answers before the current generation with scoliosis has to face this condition in their children.

What is the best example of a form of a gene therapy that is being used at the present time?

Dr. Ward: In a sense, almost all drugs used in medical therapies represent a form of gene therapy. For example, giving diabetic insulin is a form of gene therapy. It would be a better form of gene therapy if we were able to give diabetic people the insulin gene instead of insulin shot. When you are talking about gene therapy actually going in and splicing out the abnormal gene or putting back in the normal gene, there are actually very few experiments where that has been done successfully. It usually only tried in absolutely fatal diseases. For instance, many people are familiar with the "boy in the bubble" disease, where the child was born without an immune system. Other children born with that condition started to have the abnormal gene replaced and are living very healthy lives today without immune deficiencies. So, we have only started to scratch the surface on actually gene therapy. I think the progress in gene therapy has been faster than anybody has ever imagined. It is especially fast in plants and animals where the safety issues are not as large as they are in human patients.

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  • Published: December 19, 2001
  • Updated: July 22, 2008