[Congressional Record Volume 141, Number 139 (Friday, September 8, 1995)]
[Extensions of Remarks]
[Pages E1743-E1744]
From the Congressional Record Online through the Government Publishing Office [www.gpo.gov]


           MOLECULAR BIOLOGY MAY REDUCE RISK OF BIRTH DEFECTS

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                          HON. GEORGE W. GEKAS

                            of pennsylvania

                    in the house of representatives

                      Thursday, September 7, 1995

  Mr. GEKAS. Mr. Speaker, we have all been aware of the problems 
associated with birth--the possibility that an infant is born with 
certain defects--but up to now, we have not had a full understanding of 
why a child dies prematurely or fails to develop to its full human 
potential. Recently, at the 39th briefing before the Congressional 
Biomedical Research Caucus, Dr. James L. Mills, chief of the pediatric 
epidemiology section at the National Institute of Child Health and 
Human Development, described incredible advances in identifying causes 
of birth defects and their possible prevention.
  I believe that his remarks will indicate the remarkable advances made 
in molecular biology at the National Institutes of Health.
                             Birth Defects

                         (James L. Mills, M.D.)

       It is a great pleasure for me to have the opportunity to 
     come and share my enthusiasm for birth defects research with 
     you today. Had I been asked to give this talk in 1980, when I 
     first started doing birth defects research, I would have done 
     so with considerable trepidation. The fact is, most birth 
     defects research in those days was rather pedestrian. It was 
     good work but not exciting. It consisted of classifying and 
     describing various birth defects. We might have been fighting 
     a war on cancer then, but we were hardly fighting a skirmish 
     on birth defects.
       Today, the situation has changed dramatically. Dr. Holmes 
     has already pointed out that we have expanded our 
     understanding of how birth defects occur tremendously. We 
     have better strategies for identifying new causes of birth 
     defects, and we are able to identify families at risk more 
     accurately than we ever could before.
       I will discuss several areas of research that have 
     blossomed over the last decade. First, how biochemical 
     abnormalities cause birth defects; next, how factors in the 
     embryo's environment interact with intrinsic (genetic) 
     factors within us to produce birth defects; and finally, how 
     our understanding of these biochemical, environmental and 
     genetic factors can lead to preventing birth defects.
       First, I would like to speak about how biochemical 
     abnormalities in mothers cause birth defects in their 
     offspring. I have chosen as an example work done by us at NIH 
     with collaborators at five major universities in the Diabetes 
     in Early Pregnancy Study. Women who have diabetes at the time 
     that they become pregnant have a greatly increased risk of 
     having a child with a birth defect. Heart, brain and spinal 
     cord defects are just a few of the many birth defects that 
     infants of diabetic mothers are at increased risk of 
     experiencing. We have learned that this increased risk is 
     related to how well the mother is controlling her diabetes 
     early in pregnancy. The better her control, the lower the 
     risk. We also made a little bonus discovery. Diabetic women 
     are also at increased risk for miscarriage. We were pleased 
     to discover that a diabetic woman can also reduce 

[[Page E 1744]]
     her risk for having a miscarriage by improving her control. In fact, a 
     diabetic mother in excellent control has no greater risk for 
     having a miscarriage than a woman with no medical problems.
       More work remains to be done on diabetes. Although we know 
     that some aspect of maternal diabetic control causes 
     malformations, diabetes is not just high blood glucose. It is 
     more complicated than that. In addition to raising blood 
     glucose, diabetes can cause numerous other metabolic changes. 
     Scientists are now trying to determine which of the many 
     biochemical abnormalities caused by diabetes is responsible 
     for birth defects--as a way of identifying more precisely 
     those at highest risk, and to improve our understanding of 
     the mechanisms by which these defects occur.
       Diabetes illustrates another fascinating riddle about birth 
     defects. We know that those diabetic women in very poor 
     control are at highest risk for having a malformed infant, 20 
     percent or more of their offspring will have major birth 
     defects (that's about ten times the rate in the general 
     population). Why is it that the other 80 percent are not 
     affected? We know that women who take medications that are 
     known to cause birth defects during the critical period when 
     the embryo's organs are developing still do not have a 100 
     percent chance of having affected offspring. What we do not 
     know is why some embryos escape unscathed.
       We do have some ideas, however. One of the reasons we think 
     not every exposed embryo gets malformations brings me to the 
     next topic; that is, how factors from outside the developing 
     embryo--in the embryo's environment--and genetic factors 
     interact to cause birth defects. Now let me explain just what 
     I mean by factors outside the developing embryo. The embryo's 
     environment means whatever is in the mother's blood--drugs 
     she takes for acne, high blood glucose, or low vitamin 
     levels. By genetic factors, I mean anything hereditary that 
     make the embryo directly susceptible to birth defects.
       In order to illustrate how the embryo's environment and 
     genetic factors together produce birth defects, I want to 
     tell you a story about neural tube defects and folic acid. 
     Neural tube defects are a malformation of the nervous system. 
     They are among the most devastating defects. Anencephaly is a 
     uniformly fatal defect in which most of the brain is missing. 
     Spina bifida is a disruption of the spinal cord that is often 
     fatal. In survivors, it causes paralysis, bladder and bowel 
     problems and severe disability.
       Many years ago scientists observed that neural tube defects 
     were much more common in poor families. Some suspected that 
     dietary deficiency was an important factor. When women who 
     had delivered an affected child were tested, they were found 
     to have significantly lower levels of several vitamins--
     notably folate--in their blood. This prompted scientists to 
     give women vitamins before they became pregnant to try to 
     prevent neural tube defects. When investigators gave women 
     vitamin tablets containing folic acid before they became 
     pregnant, they were able to decrease the risk for neural tube 
     defects, thus proving that folic acid was an important factor 
     in the causation of NTDs. In fact, the United States Public 
     Health Service now recommends that all women who could 
     possibly get pregnant take folic acid to prevent these 
     defects. So, investigators had found the environmental piece 
     of the puzzle--folate. But remember, I said this was a story 
     about an environmental-genetic interaction. What about the 
     genetic piece that completed the puzzle?
       We know something else about the causes of neural tube 
     defects; certain ethnic groups are known to be at high risk. 
     In the Celtic population, in particular in Scotland and 
     Ireland, the risk is up to five times higher than the risk in 
     the U.S. They call neural tube defects the curse of the 
     Celts. So there is clearly a high risk genetic group.
       We saw this as a golden opportunity to look for an 
     environmental, that is vitamin-related, genetic, that is 
     Celtic, interaction. We at NIH and our collaborators at the 
     Health Research Board of Ireland and Trinity College, Dublin 
     explored what it was about these high risk Irish mothers that 
     put them at risk for having a child with a neural tube 
     defect.
       We had several clues. First, we knew that folate was 
     important. This made it very likely that these women or their 
     embryos had a problem absorbing folate from their diet, or 
     using folate normally in their metabolic reactions. 
     Unfortunately, humans use folate in over a dozen different 
     reactions, making it very difficult to determine where the 
     problem was. But we were lucky.
       We had a second clue--low vitam B12 levels also seemed to 
     increase the risk for neural tube defects, and of all the 
     dozen plus reactions that involved folate, only one involved 
     B12 as well. In this reaction, B12 and folate are used to 
     eliminate a chemical known as homocysteine. Homocysteine is 
     converted into methionine, an essential ingredient in the 
     production of proteins, DNA and other critical items for the 
     embryo.
       We hypothesized that women whose fetuses had neural tube 
     defects could not covert homocysteine to methionine normally. 
     We were able to measure homocysteine levels in the blood of 
     women who were pregnant, carrying fetuses with neural tube 
     defects. The homocysteine levels were higher than normal, 
     indicating that these women were not able to convert 
     homocysteine normally.
       We believe that this inability to convert homocysteine is 
     the reason that these women have babies with neural tube 
     defects--either because homocysteine is toxic to the embryo, 
     or because the embryo does not receive a sufficient amount of 
     the products of the reaction. Genetically, these women seem 
     to have an abnormal enzyme (a chemical that moves the 
     reaction forward). Adding more of the vitamin, folic acid, in 
     essence pushes this chemical reaction forward and converts 
     the homocysteine normally.
       Here then was the missing piece of the puzzle. A 
     combination of an environmental factor--insufficient folate--
     and a genetic factor--impaired ability to clear 
     homocysteine--causes neural tube defects.
       This leads me to the last major topic--how our 
     understanding of these biochemical and genetic factors can 
     lead to the prevention of birth defects. After all, it may be 
     very satisfying to know how birth defects occur, but we are 
     really in this business to save children from death and 
     disability. In order to do this, we are constantly on the 
     lookout for markers to identify women at risk, and for 
     interventions to prevent birth defects.
       We now know of several biochemical risk factors. The 
     diabetes specialist can use clinical markers like blood 
     glucose to identify women in poor metabolic control, women 
     who should avoid getting pregnant until their medical 
     problems can be corrected. We hope that we will soon have a 
     practical test to identify women who do not convert 
     homocysteine well and, thus, are at increased risk for having 
     children with neural tube defects. These women could then be 
     targeted to receive extra folic acid to prevent neural tube 
     defects. In the meantime, we can still prevent many neural 
     tube defects by ensuring that all women who might become 
     pregnant take folic acid supplements.
       What will the future bring? To use the illustration of 
     neural tube defects again, we expect to find the specific 
     biochemical reaction that is working too slowly in converting 
     homocysteine. Once this is done, we will look at the enzyme 
     that is supposed to move that reaction ahead. Because each 
     enzyme is manufactured by a specific gene, it will be 
     possible to see if the women with the homocysteine 
     abnormality have a defective gene for that enzyme. This is as 
     simple as finding out whether the genetic code contains an 
     error for that gene. When that is accomplished, women can be 
     screened by gene testing as another method of identifying 
     women at higher risk for having babies with neural tube 
     defects--those who especially need additional folate before 
     they become pregnant.
       Looking even farther into the future, we may be preventing 
     birth defects by gene therapy. When a couple has a gene 
     abnormality that prevents them from having normal children, 
     it may be possible to perform in vitro fertilization and 
     insert the proper gene into the fertilized egg to correct the 
     defect--and to do it even before the fertilized egg is put 
     into the mother's uterus.
       Of course, we face new challenges with these new scientific 
     advances. Moral issues, such as when to perform genetic 
     testing and gene therapy, will require very careful 
     consideration. Fortunately, when the goal is to save the life 
     of the child by preventing birth defects, the moral questions 
     often have clear answers.
       In conclusion, Mark Twain once said that everybody always 
     talks about the weather but nobody ever does anything about 
     it. Until recently it could have been said that we scientists 
     always talked about birth defects but never did anything 
     about them. Now we are in an exciting new era where we are 
     not just talking about birth defects; now we are doing 
     something about them. We are preventing them.
     

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