A View of Congenital Heart Defect Research by a Basic Scientist
- Written by:
-
Raymond Runyan, Ph.D.
- University Heart Center, University of Arizona
- Tucson, AZ 85724-5044
- E-mail : rrunyan@u.arizona.edu
The heart is the first functional organ in the embryo. Due to its prominent location and its visible contractions it has been the object of study for centuries. However, as recently as the late 1970s and early 1980s, the field of heart development was still in its infancy. There was considerable debate on the origin of human heart defects but there were few ways to prove ideas. The primary method of analysis was largely observational and only a handful of laboratories were involved in studying heart development. In 1984, Dr. Constance Weinstein and colleagues at the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) organized a meeting to bring together both cardiologists and basic scientists to summarize what was known about the development of the heart. As a result of this meeting, the NIH initiated a series of research funding programs designed to foster new research programs and recruit scientists into this area. New research programs strengthened our biochemical and physiological knowledge in this area and brought molecular biology into the field of heart development.
Current Research in Heart Development
Click here for a summary of chromosomes, genes and proteins if you are not familiar with these terms.
Today, research in the basic biology of cardiac development is a diverse enterprise. There are approximately 100 laboratories around the world devoted full time to this area. Though the majority of this work is being performed in the United States, cardiac developmental biologists can also be found in Japan, England, France, Spain, Brazil and Mexico. Research relevant to human disease, has been significantly impacted by work using experimental animals such as fruitflies, fish, frogs, chickens, rats, mice and human tissues. Though one might wonder, for example, why studies on the primitive heart of a fruitfly would be useful, one of the more remarkable findings in the last few years was of a gene needed in fruitflies to produce a heart. Fly embryos with a defect in this gene failed to develop a heart. This gene, named "tinman" after the Oz character in need of a heart, proved to be related to a previously unknown class of genes critical to normal development of cardiac muscle in all animals. Heart development in vertebrates is much more complex than in flies. Higher animals appear to have several different genes related to "tinman" and scientists are now trying to sort out the functions of each one. More than 30 other proteins important to heart development have been found in different animal species and are being investigated. These proteins regulate such important processes as muscle development, valve formation, formation of the conduction system, and muscle contraction. One way to test the significance of specific proteins found in the heart during development is to genetically disturb their expression in mice and evaluate the defects that are produced in newborn and fetal animals. If both copies of a gene are removed from mouse DNA, the mouse will be unable to express the protein when it is needed. Recently, a group in Cincinnati produced a mouse without a gene for a protein known as Transforming Growth Factor beta 2. The mutant mice have a spectrum of heart defects similar to those of Tetralogy of Fallot.
An important element of our expanding knowledge of heart development is due to the contributions of genetics. Through studies from DNA collected from families with affected individuals the genetic contribution to cardiac anomalies is beginning to become clear. For example, recent efforts have identified a gene related to Long QT syndrome. Other studies have shown that familial hypertrophic cardiomyopathy is due to mutations in cardiac muscle proteins. A region of chromosome 22 appears to be particularly critical in development of the outflow tract of the heart. Both DeGeorge and Velo-cardial-facial Syndromes can be attributed to a deletion within the critical region of this chromosome. Similarly, several laboratories have focused upon the Down’s syndrome region of chromosome 21. Individuals with partial trisomies of chromosome 21 can be found to have some or all of the symptoms of Down’s syndrome while others, with a different extra piece of chromosome 21, are spared. Analysis of the relationship between specific extra regions and symptoms of Down’s syndrome has resulted in the identification of a Down’s region on chromosome 21. The current thought is that one of the genes in this region is directly responsible for the endocardial cushion defects seen in 60% of children affected by Down’s syndrome.
Studies in an extended family with AV canal defects recently allowed the identification of a critical region on chromosome 1. This same group of researchers examined 4 different families with a history of congenital heart defects and came up with 4 different chromosomal locations. Though none of the specific genes responsible have been identified, research is ongoing to identify them. There are several points to be made from these studies. First, that heart development is a complex process and that many separate events can lead to cardiac defects. Second, that genetics has progressed to the point where genes can first be identified from affected families and then subsequent studies can be undertaken to define what the products of these genes do during normal development. This is a much faster way to identify new molecules important in heart function. It has the advantage that we know that the gene we are studying is important. We expect that the identification of specific genes responsible for defects in heart development, combined with studies that examine how and when the proteins made from these genes are needed, will allow us to understand what went wrong during development. This type of knowledge is needed in order for physicians to intervene effectively to prevent defects.
What Remains to be Done
The advent of molecular medicine and the promise of gene therapy are important for the area of CHD. It is expected that once we identify specific genetic basis for cardiac defects, it should be possible to identify individuals who might be at risk (or be predisposed) at an early stage for these defects and deliver a corrected gene copy in time. Alternatively, we might be able to choose drugs that would regulate gene expression in such a way as to overcome a problem. At the present time this is not possible. We cannot yet reliably deliver a corrected gene to a target tissue or regulate its expression. In order to do this, we need to understand how genes are normally regulated in the heart and how to deliver new genes that will work. One discovery in mice that affects this work is that a defective gene in one strain of mice can cause a specific defect while in another strain it may be harmless or produce a defect in another structure. This is due to "modifier genes" in different genetic backgrounds. We don’t know how this works yet, but it may be that some mice can make related proteins to replace the missing proteins. It will be important to understand these "modifiers" since they may explain the variability of defects in human populations.
In addition to identifying new molecules critical to normal heart development, studies need to be pursued concerning the process of normal gene regulation, the activities of modifier genes, and alterations resulting from environmental toxins such as dioxin and alcohol. Since the heart develops so early in the embryo, we need to extend the ability of physicians to find heart defects as early as possible so that they can be treated while the heart is still forming. Other scientists are trying to find the best way to deliver to specific parts of the body. Many favor the idea of producing a virus to deliver DNA with corrected genes but the details need to be worked out to make this useful. All of these studies will have to come together so that we can treat and correct specific defects. Then we will have to show that defects can be corrected in animals before they can be contemplated in humans. Though this list sounds daunting, we have the advantage that the community of scientists impacting this field is much larger than those working specifically on heart development and that advances in other areas can be incorporated by those working with the heart.
What You Can Do
There is a political element to research funding. Though we would like to believe that the best or most important science always gets funded, this is not the case. Though all grant applications that are funded were reviewed and selected on merit, there are other research grant applications of equal merit that fail to get funded because of the emphases of reviewers or administrators. Specific disease initiatives usually result in a shifting of dollars between areas since few, if any, new dollars are appropriated. While we don’t like to think that increased funding for another disease results in less for CHD research, the reality is that each new initiative alters the types of grant applications that get funded. Currently, about 20% of all research applications are \funded. Research in areas of political interest may be funded at a rate up to twice as high as average while other areas can be neglected. Though research related to CHD has grown considerably over the past decade, grant applications in this area do not reach the average 20% success level. Those of us working in the area feel that the lack of a political impact in regards to CHD has been a disadvantage relative to other areas of research. In general, diseases and defects in children get proportionally less emphasis than adult diseases.
The problem with low funding rates for a particular research area is not only that useful research opportunities are missed but that the low probability of success drives promising scientists into other research areas. Each federal grant review cycle takes approximately 9 months between resubmissions. Few investigators have sufficient job security to wait more than 2 or 3 cycles. An investigator who does not see much chance of success will switch research areas or leave science entirely. The loss of physician-investigators to a strictly clinical practice has been particularly high.
One simple mechanism to help keep health research in balance is to keep your congressional representatives aware of your interest in congenital heart defect research. A request to you local representative for information on what NIH is doing related to CHD would result in a conversation between a congressional staffer and the appropriate administrators at the NIH. A continuing series of requests from different congressional offices would be useful in keeping an emphasis on the types of research programs I’ve described here. As there is no national organization devoted to CHD research, individual efforts would provide considerable help in keeping this field of research going.
Some of you may also be able to provide some very direct assistance in the study of CHD. One resource that limits genetic studies of CHD is the lack of identified families where more than one member of the extended family has CHD. Potentially of equal importance, is the identification of families where one member has CHD and another has a different developmental defect. Basically, to map and identify the gene that might be responsible, blood samples would be collected from the affected individuals as well as siblings, parents and other relatives available. If there is more than one affected individual in your family and you would be interested in contributing to such a study, please contact (either directly or through your physician) me or
Dr. Ronald Lauer, Division of Pediatric Cardiology at the University of Iowa. We would make sure that your family is brought to the attention of the appropriate investigators.
- For additional information, please see:
- Consumer Issues in Genetics Services
-
Blazing a Genetic trail: Research on Mutant Genes and Heriditary Diseases
- This article was reviewed prior to publication by:
- Richard M. Donner, M.D.
- Co-Chief, Pediatric Cardiology, St. Christopher's Hospital for Children
- Philadelphia, PA
- Alan D. Tong, MD, FACC
- Pediatric Cardiologist
- Cedars-Sinai Medical Center
- Parent Reviewers:
- Barbara Will Bakel, M.Sc.
- Brenda Booth
Your feedback is very important! Please e-mail us with any questions or comments about this article.
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