pp. 289-291 in Intractable Neurological Disorders, Human Genome Research and Society. Proceedings of the Third International Bioethics Seminar in Fukui, 19-21 November, 1993.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1994, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

New trends in the U.S. genome project and gene therapy

Kyohei Igarashi
Producer, NHK Fukuoka Station, Fukuoka 810, JAPAN

1. Introduction

This year, from June to July, I went to the USA in order to plan a NHK special program "The Impact Of Genetic Screening" . Although I feel it is slightly inappropriate for me to talk about what I have seen of the American genome project at such an authoritative meeting as this, Professor Fujiki, the chairman, strongly requested that I talk about my impressions of the situation at this meeting today. The television program that I just referred to was broadcasted on the 27th August, therefore some of you may have seen it.

2. Gene Therapy

In mid July, I interviewed Dr. James Wilson, Director of the Institute for Human Gene Therapy, University of Pennsylvania School of Medicine in Philadelphia. He has treated three patients with familial hypercholesterolemia with gene therapy and has come up with good results, where the amount of cholesterol (LDL) has dropped by 22%.

Furthermore, researchers are trying to start gene therapy for cystic fibrosis, an autosome recessive ailment that afflicts the lungs and pancreas. Human beings need to balance the plasma and cellular levels of chlorine and sodium ions, but patients of cystic fibrosis are unable to do this as there is a mutation in the gene that produces the protein which controls the concentration of the chlorine and sodium ion inside and outside the cells. Therefore, by using adenovirus, the cold virus, as a vector for the normal gene, and administering these through the patients nose and mouth and into the lungs, they are aiming to produce normal proteins there. In fact, the research group of Dr. Ronald Crystal of the NIH has already started clinical trials of this since July, 1993.

The permission to conduct gene therapy was first given formally in 1990 by the FDA, and the RAC (Recombinant DNA Advisory Committee of the NIH) conducts a strict examination before allowing gene therapy trials. Gene therapy trials are showing good results with patients of ADA deficiency, and a girl living in Texas who was treated is already attending her school. However, there are still some questions about the long term safety of transporting viruses and whether there are side effects, and whether other genes may get damaged is not yet clear.

3. Cystic Fibrosis

"Genetic diagnosis" has started to be widely performed in the USA and Britain. This is because one in twenty five Caucasians in the USA and Europe are carriers of the gene mutation for cystic fibrosis (CF), a high frequency rate compared to most other countries. Genetic diagnosis also seems to be carried out frequently in Australia and Northern Europe.

This gene was discovered in August, 1989 by the research teams of Dr. Lap-Chee Tsui of Hospital for Sick Children in Toronto, and Dr. Francis Collins of Michigan University. The gene is situated on Chromosome 7p and it is known that 67% of the mutations worldwide are the same single base change, called ÆF508. So far, only about 85% to 90% of the total mutations have been discovered. However, since the discovery of the gene the detection rate has increased. At first, only the gene mutation of ÆF508 was discovered, which meant that the detection rate was less than 70%.

The fact that practical genetic diagnosis, or genetic screening, is not 100% accurate, has an extremely important meaning. For example, when a person is genetically diagnosed as a "gene carrier", they are considered as being possible "patients". Indeed there was a case of one carrier whom I happened to interview, who was considered as very likely to be a "patient" and was denied insurance coverage. This person is a forty year old woman living in California. She has two sons, both of whom are healthy. The results of genetic diagnosis shows that neither are carriers. Her sister had died of CF ten years ago. This woman had bronchitis and a slight asthma, an ailment of the respiratory organs. Her family doctor asserts that from the results of various symptoms and X-ray check ups, she cannot be a patient of CF. However the insurers treat her as a high risk individual. Because of this, she is unable to buy insurance and can only see her doctor twice a year. In addition, it costs her US$50 for a little consultation, ten times the amount necessary had she been able to buy insurance.

Dr. Paul Billings of Pal Alto Veterans Hospital, takes such cases up seriously and is doing a detailed research on them. He has also testified at the public hearing of the Senate. Nevertheless, in the state of Colorado, new born screening already started in 1983, for eight diseases, including phenylketonuria, galactosemia, homocystinuria. At first, new born screening for CF were performed by enzyme and sweat tests, but after the gene was discovered in 1990, confirmation is made using genetic tests. At the moment, four states (Wyoming, Indiana, Wisconsin [with control studies], and Colorado) are doing this screening. There are many doubts as to whether screening for CF are of significance, when a cure for the disease is still not yet established (gene therapy is still at an early stage of testing). In the case of CF, some develop the disease when they are newly born, but in a large number of cases they develop around the age of two or three years.

In control studies in Wisconsin, Dr. Norman Jean, a pediatrician at the University of Wisconsin, and his research group, are studying the benefits of screening for CF considering it is still incurable. In the case of Wisconsin, they have decided to group those newborns that are screened and those that are not, in order of birth. Although the results are still incomplete, the two groups were compared for growth rate over a five year period. One group received therapy (dosage of antibiotics, vitamin pills, and enzymes) after they showed signs of developing the disease and the second group received therapy as soon as they were diagnosed positive in newborn screening. There was no significant difference between their growth rate. Moreover, newborn screening had a big psychological effect on the parent, causing them to be overprotective towards their children in many cases. Also, there are suggestions that the cost of newborn screening for the administrative organisations is high.

Genetic diagnosis companies have directed their attention to this screening. One company developed an easy kit in November 1992, where you only have to brush the inside of your cheeks to get the cheek cells for screening. More than a 100 physicians all over the USA are using this kit at the moment and the numbers are growing at great speed. This market is trying to spread outside the U.S and to other genetic ailments besides CF. Biotechnology companies look upon genetic screening as multi-million dollar markets and are desperately trying to enlarge it.

4. Huntington's Disease

Huntington's disease starts to show its symptoms in the thirties and forties. This autosomal dominant hereditary neurotic disorder causes the arms, legs and the body to move as though the person is dancing, and causes mental disorder and character disorder leading to eventual death. The gene for this disease was discovered on chromosome 4p by Dr. James Gusella of Massachusetts General Hospital in March this year after 13 years of an International collaborative effort. The name of the gene is IT15. It was shown that this ailment was caused when the GC base arrangement repeated itself over 37 times at a certain part. The DNA chain becomes long and unstable. Within a normal gene, the repeat was about 25 times. Even before this gene was discovered, genetic diagnosis was possible with a linkage marker probe, but the discovery of the gene increases the accuracy from 95% to almost 100%.

In addition, prenatal diagnosis and pre-symptomatic diagnosis have become possible, this however, caused unfortunate results with some cases. I interviewed a 35 year old woman living in Texas. Her father died 15 years ago from Huntington's disease. The probability of her having the disease as his child is 50%. When she applied for health insurance, the insurance company requested her to take genetic testing, saying "We will consider your application if you take the test." She expressed her anger to us. "Why must I know my future? Right now I'm healthy. What right do the insurance companies have to demand such a thing? I don't want to know my future." Genetic testing may decide the fate of humans lives. For those people who claim their "right not to know", this can be a cruel test. The woman whom we interviewed is getting on to her late thirties and the fear towards the disease is increasing. She gave up bearing a second child. "What happens to my work? What will happen to my only daughter?" She turns for support by meditating alone at the church.

5. The Future of Genetic Analysis

The NIH (National Institute of Health) has given research grants for the development of screening technology for the genes over the next 15 years to researchers at the MIT, and private research institutes. The development of a machine that will be able to screen the genes 10 to 100 times faster than before is expected. The vice manager of San Diego Genome Center of General Atomic, Harold Garner, confidently declares that, "We should be able to screen all the genes in another 15 years." Genetic testing will not only cause insurance problems, but it could also lead to employment problems. According to an old report from the OTA in 1982, 5 or 6 companies had already done genetic testing to check the genetic aptitude when employing or transferring an individual to a certain post. More than 50 companies are showing an interest in putting similar genetic screening tests into effect in the future.

Under such circumstances, the state of Wisconsin, proclaimed a law forbidding the introduction of "genetic testing" where "insurance" and "employment" are concerned. For example, Wisconsin Act 117 which was proclaimed on March 19,1992, is a law which forbids employers, labour unions, employment organisations and license supplying organisations to do genetic tests, and provides a penal code. Also, Wisconsin Act 269 was proclaimed on April 30, 1992. This law forbids insurers and school concerned people to do "genetic tests " without reason and take discriminatory actions. "If you ignore the rise of genetic testing, the days of the Nazis may very well return", answered Marine Schnider who was involved in making the law. This law was received with surprise all over America and is showing signs of spreading to other states.

The answer to the question, "What is man ?" will be given when all the genes are known. Lastly, I would like to quote the words of Dr. Thomas Murray who studies at Case Western Reserve University Bioethics Center in Cleveland, Ohio. "If the present genetic screening situation goes ahead blindly, it will bring about a fearful state of affairs in the society. Unless we take measures to prevent the abuse of genetics, the future world will be a disaster. Genetic discrimination and eugenics may well thrive. However, the future is not definite. To prevent the government and other organisations from conducting genetic discriminations, the public must be educated. We must answer the question, "what is man?", to say man is not just an accumulation of DNA. DNA is just a plan, something like a music score. Even masterpieces of music are just black dots on music sheets. The crucial point is on how you perform the music. A splendid symphony exceeds the black dots on the music sheets without question. The same can be said with the enumeration of DNA. Man is just like a performance of genetic codes, a wonderful symphony. It is necessary to keep in mind that man is a symphony that abounds in variety and exceeds far more than genetics."

Human society will progress greatly owing to the genome project. However, the bioethical problems must be resolved at the same time if we do not wish to bring about frightening social conditions. It is necessary to develop social conditions where genetic screening will not put a ranking on every human being.

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