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guishable one from the other. One chromosome carries one gene from each of the rarions pairs of genes associated with the chromosome pair, and its identical partner carries the other gene. The 45th and 46th chromosomes may or may not alike. These are the "sex chromosomes," so called because in male cells *ey are not identical, one being called an X and the other a Y chromosome. Female cells contain two X chromosomes. If an abnormal recessive gene occurs tan X chromosome it will be masked by the presence of a normal gene on anther X chromosome but may not be by the effects of the Y chromosome given a normal father to his son. The result is a sex-linked hereditary trait which will be much more common in men and for which only women can be carriers. A well-known example of this is color blindness, which occurs in about 8 percent men but in less than 1 percent of women. A woman carrier of a sex-linked order has a 50 percent chance of having an abnormal child for each of her zie offspring; even if her husband is normal.

Some inherited traits are controlled by more than one gene pair. Skin pigzentation is an example. All of the disorders listed below, however, appear to be the result of defects in a single gene type.

DISORDERS IN AMINO ACID CHEMISTRY

The following three disorders have similarities. In each the disease is associated with the inability of the body to handle normally one or more amino acids. Amino acids are the building blocks of proteins, and proteins in food are roken down to these before absorption from the digestive system. The body then uses as much as it needs of the dietary amino acids to build its own protein and normally degrades the excess into smaller pieces to be used for other purposes. If this disposal system is defective the amount of one or more of the amino acids in the blood will be increased and products from them appear which are not normally detectable in the body.

Phenylketonuria (PKU) is a disease caused by an inability to utilize normally the amino acid, phenylalanine. Abnormal products called phenylketones occur In urine. Children with this disease may grow to almost normal size but develop severe and irreversible mental retardation; the most severe cases die in early childhood. If detected in early infancy the disease can be helped and Rental retardation prevented by careful treatment with special diets low in phenylalanine.

Histidinemia is a recently discovered disease, in which the patient is unable to handle the amino acid histidine. Histidine is excreted in the urine along with abnormal products which can be detected by the common PKU tests. Before its discovery in 1961, this disease may, therefore, have been mistaken for PKU especially since over half of the patients have been mentally retarded. All of them have defective or retarded speech.

Maple sirup urine disease involves three amino acids-leucine, isoleucine, and Talice broken down by chemical steps which are similar. One step, which is common to all, is defective in this disease. The disease manifests itself in the first week after birth and the urine has a characteristic slight odor resembing maple sirup. Without treatment children rarely live for more than a year and again irreversible brain damage is a prominent feature of the disease. When the disease has been detected early and treated by a diet low in these amino acids, there has been some success in avoiding the brain damage and maintaining relatively normal growth.

DISORDERS IN CARBOHYDRATE CHEMISTRY

The carbohydrates in our diets are sugars and starches, which are broken down to sugars before absorption. The body burns sugars for energy or modifies them for use as parts of other substances.

Galactosemia occurs in babies who are unable to convert galactose into glucose. Galactose is a sugar which is one part of lactose, the major sugar in milk. Glucose is the normal blood sugar and is the main source of energy for most cells in the human body. In the normal conversion process by which galactose changes to glucose a galactose-phosphate compound is formed which then changes by several steps into glucose. In galactosemia the phosphate compound cannot be disposed of and it accumulates. Infants develop enlarged livers, cataracts, and ental retardation. Some die shortly after birth. Others with milder cases have been seen at older ages in mental institutions. If the disease is discovered shortly after birth and galactose is eliminated from the baby's diet all signs of The disease disappear.

Glycogen storage disease, type 1, gets its name from the accumulation glycogen in the liver, heart, kidneys, and other organs of children with the di order. Glycogen is a starchlike substance which occurs normally in sma amounts of many body tissues. It is built up as chains of glucose molecules ar serves as a reserve supply of this sugar. In this disorder glycogen can be forme but it cannot be broken down to sugar again. An essential biological catalys or enzyme, called glucose-6-phosphatase, is lacking. There is massive enlargemen of the liver since this is a major normal site of glycogen storage for controllin blood sugar levels. Some patients have fewer red blood cells than normal an poorly formed bones. There is no specific treatment for the disease and in th past most patients died in infancy or early childhood. Now, when given frequer small feedings and antibiotics for the infections to which they are prone, son children are surviving for longer periods.

ABNORMALITIES OF HEMOGLOBIN

Hemoglobin is the substance in red blood cells which gives them their red colo More important, it binds oxygen inside these cells and thereby allows blood transport more oxygen from the lungs to the rest of the body than would be po sible if the oxygen were only dissolved in blood fluids. Hemoglobin has tw parts: Heme, an iron-containing pigment, and globin, a complex protein. TH globin protein is composed of four pieces or minute "chains." These are reall two pairs of chains. One pair, called alpha chains, is the same for all norma blood. The other differs normally in newborn babies ("gamma") and even ha two different forms ("beta" and "delta") in normal adults.

Sickle cell disease occurs in adults in whom the beta chain is abnormal becaus one of its 146 "links" has been changed. In combination with normal alph chains these form hemoglobin "S," which will cause the normal disk-shaped re blood cells to become elongated and sickle shaped under certain circumstance These odd-shaped cells plug up small blood vessels and stop the flow of blood t the tissues supplied by those vessels. The result is damage to the bones, kidney lungs, heart, nervous system, and other organs. Sickle cells are also more easil destroyed in the body than normal red blood cells. Most patients are severel deficient in red cells and are also prone to infection. The disease is seen in chi dren and is often fatal in young adults. There is no known specific treatment. Thalassemia is a term for a variety of disorders in which either one of th chains, alpha or beta, is not produced in normal amounts. The result is a de ficiency in the total amount of body hemoglobin. This shows up in a reduce

number of red blood cells which contain within them less than the usual amoun of hemoglobin. There is marked anemia for which there is no known treatmen

OTHER DISORDERS OF BLOOD

Hereditary methemoglobinemia: Although hemoglobin functions to bind an carry oxygen within the red blood cells, it can be slightly altered by certai chemicals or in some circumstances, by oxygen itself, to a dark-brown form calle methemoglobin, which will not carry oxygen. There are very slight amounts o methemoglobin in normal human blood cells, but these contain chemical system for continuously changing the altered form back to normal hemoglobin. One o these systems accounts for more than half of the ability to regenerate hemo globin. It is lacking in this hereditary disorder, which is characterized by re blood cells containing up to half methemoglobin. The effect is to reduce th oxygen-carrying capacity of blood in those children just as though up to half o the red cells were not present. Many of these children are mentally deficient, bu it is not clear whether this is due to a lack of oxygen for the brain at some stag of development or to some other aspect of the disease.

Pyruvate kinase deficiency, hemolytic anemia): There are 20 steps in the major chemical pathway of the human body for obtaining energy from the sugar glucose. One of these steps requires an enzyme called pyruvate kinase. Th enzyme is absent in red blood cells in patients with this disorder. The cells ar unable to obtain sufficient energy from blood glucose to maintain their structura integrity and they break up long before their usual lifespan of 4 months. I spite of compensatory efforts of the body to make more red cells there are neve enough of these at one time and the patient is anemic. There is no treatment except blood transfusions.

Glucose-6-phosphate dehydrogenase deficiency: Normal red blood cells contain a substance, reduced glutathione (GSH). Cells lacking adequate GSH are sensi

tive to and may be destroyed by the effects of a number of common medicines, including some analgesics, some sulfa drugs, and many of the drugs used for treating malaria. In the absence of these or some other chemicals the cells behave normally. The preservation of adequate GSH levels is dependent upon everal chemical steps which use energy from blood glucose to regenerate GSH from another form to which it is easily changed in the body. One of those steps requires a biochemical catalyst (or enzyme) called glucose-6-phasphate dehydrorenase, absence of which occurs as an inheritable disorder, characterized by a breakdown of red cells when one of these medicines gets into the body; producing bemolytic anemia.

Hemophilia is due to a deficiency in one of the several blood fluid components which are essential for the clotting of the blood. As a result patients with the sorder bleed easily and for prolonged periods after a cut or bruise and they may bleed spontaneously. They therefore, run the risk of severe blood loss. In addition they may bleed repeatedly in muscles or joints and end with deformed and wasted limbs. The common type of the disease and several related types ceur almost exclusively in males. Women are carriers, and they show a decrease but not an absence of the essential blood component. The treatment is transfusion with fresh blood or blood plasma or a concentrate from blood plasma which contains the missing factor in order to stop bleeding episodes. It is virtually impossible to treat with sufficient frequency to maintain adequate amounts of this material in the blood at all times. Some patients may build up a resistance to the injected material because of repeated transfusions.

OTHER HEREDITARY DISORDERS

Familial goiter is caused by a number of different inborn defects all of which prevent the thyroid gland from producing thyroid hormone. The lack of the bormone leads to the enlargement of the thyroid as part of a normal, but in this instance fruitless, effort to increase the output of thyroid hormone. The grossly enlarged gland appears in the neck as a goiter. Deficiency in thyroid hormone manifests itself shortly after birth and in some cases is present even before birth. The children become cretins unless thyroid hormone can be given before the irreversible mental retardation and physical changes of that condition set in. Some familial goiters are accompanied by a kind of deafness which does not respond to treatment.

Vitamin D-resistant rickets: Rickets is a disease of children who do not incorporate enough calcium and phosphorus into their growing bones. Lacking these minerals, parts of the bones are soft and misshapen. The common cause of rickets has been an inadequate supply of vitamin D. There is frequently a low level of calcium in the blood. This disease in this case is not inherited and it responds quickly to modest amounts of vitamin D. Another form of the disease is inherited. It occurs even when the body contains normal amounts of vitamin D. There is a normal amount of calcium but a low level of phosphorus in the blood. It responds to massive doses of the vitamin D but this treatment must be done very carefully to avoid kidney damage from prolonged treatment.

Hypophosphatasia is another disease in which severe bone defects occur because of a failure of minerals to deposit in bone even though there is a normal amount of phosphorus and even a greater than normal amount of calcium in the blood. What appears to be missing is a substance called alkaline phosphatase which is involved in getting phosphorus and perhaps also calcium into the bone tissue. There is no satisfactory treatment.

Childhood muscular dystrophy is degenerative disease of muscles which appears primarily in boys, most of whom are invalids by adolescence and do not survive to adult life. The disease appears to occur as familial trait in two thirds of the cases and one of the inheritable forms of the disorder can be transmitted by healthy mothers. There is no single specific chemical disorder upon which to base treatment and no accepted therapy has been found.

Pseudocholinesterase deficiency was discovered in 1952 shortly after a new drug was introduced to produce muscle relaxation during surgery, electric shock therapy, and treatment of tetanus. The drug inhibits a normal body substance called cholinesterase, which is necessary for nerves to produce proper muscular Contraction. The normal transient therapeutic effect of the drug depends upon a somewhat similar subtsance, pseudocholinesterase, which quickly destroys the drug. Some patients proved to have a deficiency in pseudocholinesterase, which at that time was unsuspected. Instead of relaxing briefly, they were unable to breath without mechanical assistance for periods up to 2 or 3 hours.

Vasopressin-resistent diabetes insipidus resembles the more familiar "sugi diabetes (diabetes mellitus) in only one respect; namely, the production excessively large quantities of urine, which is called diabetes, the Greek w for a siphon. This flood in diabetes insipidus arises from the inability of 11| kidneys to salvage water from the wastes it excretes. In some cases this occ because the kidneys are not responsive to vasopressin, a substance secreted i the blood by the pituitary gland to signal the kidneys that they should pref entially retain water. The familial form of the disease appears character tically in males. Women are healthy carriers of the trait. The disease can be cured. Several forms of treatment decrease the flow somewhat by deplet the amount of salt in the body.

Ocular albinism is an eye disease of men denoted by a lack of pigment various parts of the eye. This is accompanied by poor vision and uncontrolla twitching movements of the eyeball. There is no treatment for the disorder.

Dr. SHANNON. The important thing is not that these diseases ha been identified but rather that tests are now available to apply to t apparently normal carrier of this genetic defect. These tests will ha predicted value as to what will happen to the offspring. I think t] i is the major thrust of this development.

FRENCH ACCOLADES ON AMERICAN CONTRIBUTION TO RESEARCH

The 1965 Nobel Prize in Medicine and Physiology was awarded French scientists at the Pasteur Institute for their studies of ge regulation. Two of these three scientists have been NIH grantees 1 the past 4 years. One of these grantees, Dr. Jacques Monod, used t occasion to severely criticize the lack of support available in Fra for fundamental research, especially in relatively new fields whi have not yet been recognized as separate disciplines by the highly co servative French universities. In a widely quoted press interview said:

If we have a debt, it is above all to the United States ***. French resea has benefited enormously from the American contribution.

I would only add, Mr. Chairman, that medical science has also b efited enormously and that, in the long run, the health of the Americ people will benefit enormously from the trail-blazing work done these French grantees.

SUPPORT OF RESEARCH GRANTS OVERSEAS

Mr. FOGARTY. Dr. Taussig, President of the American Heart As ciation, wrote me a letter a month ago and mentioned this to me couple of weeks ago. She was very much concerned. I thought t program was being cut back. She gave me examples of grantees w whom she had worked, exchange doctors. It was in both Germa and here.

Dr. SHANNON. I think our highest level of expenditure for supp of research grants overseas was in 1963. It was at a level of ab $15 million.

As the result of implementation of policies proposed by the Bure of the Budget this has been progressively reduced over the past f years so that now it is at a level of about $9 million.

Mr. FOGARTY. I thought Dr. Taussig made a lot of sense. S didn't agree with the Bureau of the Budget and the administrati at all in cutting back on this program. She thought it was a ve important program.

Do you think it is important?

Dr. SHANNON. I think it is very important. We have examined this program in great detail. There are several interesting characteristics. The quality of science we support overseas is superb. Our idelines provide that no grant can be made unless it is well in the upper half of the priorities. Actually, it is usually in the upper 25 percent of the conventional priorities.

We find, furthermore, that the bulk of the American scientists who have traveling fellowships to obtain specialized training outside the United States will go to places where some of our funds are supporting some of the research, so that in a very real way we are providing training spots for our own U.S. nationals.

We find no evidence that these funds in any way substitute for domestically available funds abroad; their effect is to expand research opportunity.

For example, in the field of germ-free life there are two laboratories that have contributed most to it-that of Reyniers in this country and Gustafsson in Sweden.

Many of the practical advances which now make germ-free life generally available to scientists actually came from Gustafsson's laboratory.

Mr. FOGARTY. Didn't he go out of business for a while and didn't Reyniers pick it up?

Dr. SHANNON. I think Reyniers did the pioneering work in the field. Mr. FOGARTY. Where is Reyniers now?

Dr. SHANNON. Tampa, Fla., sir.

Mr. FOGARTY. I met the fellow who took his place and he seems quite able.

Dr. SHANNON. He is.

Mr. FOGARTY. What is his name?

Dr. SHANNON. Dr. Pollard.

Mr. FOGARTY. What is Walter Reed doing?

Dr. SHANNON. That activity is small. It really has not developed much beyond the initial stages.

Mr. FOGARTY. Are they raising chickens out there?

Dr. SHANNON. I don't know what they are doing right now.

The reason Walter Reed got into it initially was that in the handling of shock in trauma it was apparent that infection was one of the important factors. They had in mind the possibility of developing a research tool which would permit much more careful study of the role infection played in the development of shock. I think they have long since moved away from that. I don't know what they are doing at the present time.

COOPERATION WITH ATOMIC ENERGY COMMISSION

Mr. FOGARTY. Before you complete your statement and before I forget it. I serve on another committee which appropriates funds for the Atomic Energy Commission. Would you make a short statement as to how you work with them and how you avoid duplication, if you do? I generally ask them the same thing.

Dr. SHANNON. Do you want it now?
Mr. FOGARTY. Submit it for the record.
Dr. SHANNON. All right, sir.

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