Diseases of Genetic Origin

Most of us do not suffer any harmful effects from our defective genes because we carry two copies of nearly all genes, one derived from our mother and the other from our father. The only exceptions to this rule are the genes found on the male sex chromosomes. Males have one X and one Y chromosome, the former from the mother and the latter from the father, so each cell has only one copy of the genes on these chromosomes. In the majority of cases, one normal gene is sufficient to avoid all the symptoms of disease. If the potentially harmful gene is recessive, then its normal counterpart will carry out all the tasks assigned to both. Only if we inherit from our parents two copies of the same recessive gene will a disease develop.

On the other hand, if the gene is dominant, it alone can produce the disease, even if its counterpart is normal. Clearly only the children of a parent with the disease can be affected, and then on average only half the children will be affected. Huntington’s chorea, a severe disease of the nervous system, which becomes apparent only in adulthood, is an example of a dominant genetic disease.

Finally, there are the X chromosome-linked genetic diseases. As males have only one copy of the genes from this chromosome, there are no others available to fulfill the defective gene’s function. Examples of such diseases are Duchenne muscular dystrophy and, perhaps most well known of all, hemophilia.

Queen Victoria was a carrier of the defective gene responsible for hemophilia, and through her it was transmitted to the royal families of Russia, Spain, and Prussia. Minor cuts and bruises, which would do little harm to most people, can prove fatal to hemophiliacs, who lack the proteins involved in the clotting of blood, which are coded for by the defective genes. Sadly, before these proteins were made available through genetic engineering, hemophiliacs were treated with proteins isolated from human blood. Some of this blood was contaminated with the AIDS virus, and has resulted in tragic consequences for many hemophiliacs. Use of genetically engineered proteins in therapeutic applications, rather than blood products, will avoid these problems in the future.

Not all defective genes necessarily produce detrimental effects, since the environment in which the gene operates is also of importance. A classic example of a genetic disease having a beneficial effect on survival is illustrated by the relationship between sickle-cell anemia and malaria. Only individuals having two copies of the sickle-cell gene, which produces a defective blood protein, suffer from the disease. Those with one sickle-cell gene and one normal gene are unaffected» and, more importantly, are able to resist infection by malarial parasites. The clear advantage, in this case, of having one defective gene explains why this gene is common in populations in those areas of the world where malaria is endemic.

What is Gene Therapy?

Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result.

Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes:

• A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.

• An abnormal gene could be swapped for a normal gene through homolo­gous recombination.

• The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.

• The regulation (the degree to which a gene is turned on or off) of a particular gene could lie altered.

Gene Therapy

Much attention has been focused on the so-called genetic metabolic diseases in which a defective gene causes an enzyme to be either absent or ineffective in catalyzing a particular metabolic react ion effectively. A potential approach to the treatment of genetic disorders in man is gene therapy. This is a technique whereby the absent or faulty gene is replaced by a working gene, so that the body can make the correct enzyme or protein and consequently eliminate the root cause of the disease.

The most likely candidates for future gene therapy trials will be rare dis­eases such as Lesch-Nyhan syndrome, a distressing disease in which the pa­tients are unable to manufacture a particular enzyme. This leads to a bizarre impulse for self-mutilation, including very severe biting of the lips and fingers. The normal version of the defective gene in this disease has now been cloned.

If gene therapy does become practicable, the biggest impact would be on the treatment of diseases where the normal gene needs to be introduced into only one organ. One such disease is phenylketonuria (PKU). PKU affects about one in 12,000 white children, and if not treated early can result in severe mental retardation. The disease is caused by a defect in a gene producing a liver enzyme. If detected early enough, the child can be placed on a special diet for their first few years, but this is very unpleasant and can lead to many problems within the family.

The types of gene therapy described thus far all have one factor in common: that is, that the tissues being treated arc somatic (somatic cells include all the cells of the body, excluding sperm cells and egg cells). In contrast to this is the replacement of defective genes in the germline cells (which contribute to the genetic heritage of the offspring). Gene therapy in germline cells has the potential to affect not only the individual being treated, but also his or her children as well. Germline therapy would change the genetic pool of the entire human species, and future generations would have to live with that change. In addition to these ethical problems, a number of technical difficulties would make it unlikely that germline therapy would be tried on humans in the near future.

Before treatment for a genetic disease can begin, an accurate diagnosis of the genetic defect needs to be made. It is here that biotechnology is also likely to have a great impact in the near future. Genetic engineering research has produced a powerful tool for pinpointing specific diseases rapidly and accurately. Short pieces of DNA called DNA probes can be designed to stick very specifically to certain other pieces of DNA. The technique relies upon the fact that complementary pieces of DNA stick together. DNA probes are more specific and have the potential to be more sensitive than conventional diagnostic methods, and it should be possible in the near future to distinguish between defective genes and their normal counterparts, an important development.

The Human Genome Program in the U.S. will provide about $200 million each year to scientists in multidisciplinary research centers who are attempting to determine the makeup of all human genes. Together with similar programs in Europe, it is hoped that in 15 years time we shall be able to identify and treat all diseases to which humans are susceptible. This will revolutionize modern medicine, and hopefully improve the quality of life of all men, women, and children. Already, the genes for Duchenne muscular dystrophy, cystic fibrosis, and retinoblastoma have been identified, and more such information is emerging all the time.

Exercises

A.Comprehension

I. Answer these questions.

1. Is an inherited genetic disorder always apparent?

2. What are the cases when it is possible to avoid all the symptoms of disease? Give an example.

3. What is a gene?

4. How can you characterize gene therapy? What approaches are applied?

5. What is t he factor common for all the types of gene therapy?

6. What should be done before the beginning of treatment for a genetic disease?

II. Are these statements true or false?

1. About one in ten people has, or will develop at some later stage, an inherited genetic disorder.

2. Males have one X and two Y chromosomes, the former from the mother and the latter from the father.

3. One normal gene is not sufficient to avoid all the symptoms of disease.

4. If the gene is dominant, it alone can produce the disease, even if its counterpart is normal.

5. Not all defective genes necessarily produce detrimental effects.

6. Gene therapy is a technique whereby the absent or faulty gene is ex­pressed.

7. Gene therapy in germline cells has the potential to affect not only the individual being treated, but also his or her children as well.

8. The abnormal gene may be inserted into a nonspecific location within the genome.

9. Genetic metabolic diseases are those, in which a defective gene causes an enzyme to be either absent or ineffective in catalyzing a particular meta­bolic reaction effectively.

10. Genes are specific sequences of bases that encode instructions on how to make proteins.

11. Queen Victoria was a carrier of malaria.

12. The Human Genome Program is hoped to enable usto identify and treat all diseases to which humans are susceptible in 15 yea in time.

III. Summarize the text, using vocabulary from Exercise 4.

B.Vocabulary

IV. Match the words in the left column with their Russian equivalents in the right column

1) remain unaware	1) оставаться в неведении
2) inherited	2) нарушение, расстройство
3)admission	3) госпитализация
4) disorder	4) давать возможность
5) enable	5) склонный (к чему-либо), подверженный
6) prone	6) страдать
7) (the) former	7) мужские хромосомы
8) male sex chromosomes	8) (из двух вариантов) первый
9) transmit	9) последний ( из двух названных)
10) (the) latter	10) достаточный
11) detrimental	11) пораженный болезнью
12) become apparent	12) точное определение положения
13) pinpointing	13) дефектный
14) affected	14) хорея
15) sickle-cell	15) проявляться
16) avoid	16) выполнять (функцию)
17) sufficient	17) передавать
18) suffer	18) испытывать недостаток, нуждаться
19) fulfill	19) избегать
20) chorea	20) губительный, вредный (to)
21) lack	21) серповидноклеточный
22) contaminate	22) заражать, инфицировать
23) heredity	23) зародышевый
24) germline	24) наследственность

V. Find synonyms of these expressions among the words and word combinations of the previous exercise (left column):

1) allow; facilitate; permit; make possible;

2) previous; earlier;

3) inheritance; genetics;

4) be ill with; have a medical condition; be diagnosed with;

5) be short of; be deficient in; need; require;

6) perform; do; accomplish; carry out; implement; realize;

7) become known; become obvious; come to light; be revealed; come out;

8) illness; sickness; complaint; disarray; chaos; mess;

9) keep away from; stay away from; evade; elude;

10) enough; satisfactory; adequate; plenty;

11) harmful; damaging; disadvantageous; unfavorable; injurious; negative;

12) pollute; infect; foul;

13) pass on; spread; diffuse;

14) last; later; final; concluding; second;

15) hospitalization.

VI. Complete the sentences with words/expressions from Exercise 4.

1. About one in ten people has, or will develop at some later stage, an inherited genetic ……. .

2. We ……. of the disease unless we, or one of our close relatives, are amongst the many millions who suffer from a genetic disease.

3. Most of us do not ……. any harmful effects from our defective genes because we carry two copies of nearly all genes.

4. The work will ……. scientists and doctors to understand the genes that control all diseases to which the human race is ……. and hopefully develop new therapies to treat and predict diseases.

5. In the majority of cases, one normal gene is ……. to ……. all the symptoms of disease.

6. Clearly only the children of a parent with the disease can be ……., and then on average only half the children will be ……. .

7. Queen Victoria was a carrier of the defective gene responsible for hemophilia, and through her it was ……. to the royal families of Russia, Spain, and Prussia.

8. Not all defective genes necessarily produce ……. effects, since the environment in which the gene operates is also of importance.

C.Reading, Writing and Discussion

VII. Read the text carefully, without a dictionary. While reading, pay special attention to the words that you don't know: look carefully at the context and see if you can get the idea of what they mean. After reading answer the questions: 1) How is a carrier molecule called and what is its function? 2) What are different types of viruses used as gene therapy vectors? 3) What is the current status of gene therapy research?

In most gene therapy studies, a «normal» gene is inserted into the genome to replace an «abnormal,» disease-causing gene. A carrier molecule, called a vector, must be used to deliver the therapeutic gene to the patient’s target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsu­lating and delivering their genes to human cells in a pathogenic manner. Scien­tists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causing genes and insert therapeutic genes.

Target cells such as the put lent’s liver or lung cells are infected with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state.

Some of the different types of viruses used as gene therapy vectors:

Retroviruses—A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus.

Adenoviruses— A class of virtues wit h double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus.

Adeno-associated viruses - A class of small, single-stranded DNA viruses that can insert their genet ii material at a specific site on chromosome 19.

Herpes simplex viruses - A class of double stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores.

Besides virus-mediated gene-delivery systems, there are several nonviral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA.

Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core. This liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell’s membrane.

Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule that will bind to special cell receptors. Once bound to these receptors, the therapeutic DNA constructs are engulfed by the cell membrane and passed into the interior of the target cell. This delivery system tends to be less effective than other options.

Researchers also are experimenting with introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autono­mously alongside the standard 46 — not affecting their workings or causing any mutations. It would be a large vector capable of carrying sub­stantial amounts of genetic code, and scientists anticipate that, because of its construction and autonomy, the body’s immune systems would not attack it. A problem with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell.

The Food and Drug Administration (FDA) has not yet approved any human gene therapy product for sale. Current gene therapy is experimental and has not proven very successful in clinical trials. Little progress has been made since the first gene therapy clinical trial began in 1990. In 1999, gene therapy suffered a major setback with the death of 18-yeaf-old Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures 4 days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier.

Another major blow came in January 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as «bubble baby syndrome.»

FDA’s Biological Response Modifiers Advisory Committee (BRMAC) met at the end of February 2003 to discuss possible measures that could allow a number of retroviral gene therapy trials for treatment of life-threatening diseases to proceed with appropriate safeguards. FDA has yet to make a deci­sion based on the discussions and advice of the BRMAC meeting.

VIII. Read the text. Express your own attitude to the problem raised in the text, giving your own arguments. Write a summary of the text.

What factors have kept gene therapy from becoming an effective treatment for genetic disease?

· Short-lived nature of gene therapy. Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.

· Immune response. Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk Furthermore, the immune system’s enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients.

· Problems with viral vectors. Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient — toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always t he fear that the viral vector, once inside the patient, may recover its ability to cause disease.

· Multigene disorders. Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer’s disease, arthritis, and diabetes, are caused by the com­bined effects of variations in many genes. Multigene or multifactorial disor­ders such as these would be especially difficult to treat effectively using gene therapy.

IX. Read and translate the text without a dictionary.

Background

In the 1980s, advances in molecular biology had already enabled human genes to be sequenced and cloned. Scientists looking for a method of easily producing proteins — such as insulin, the protein deficient in diabetes mellitus type 1 — investigated introducing human genet to bacterial DNA. The modified bacteria then produce t he corresponding protein, which can be harvested and injected in people who cannot produce it naturally.

On September 14, 1990 researchers at the U.S. National Institutes of Health performed the first approved gene therapy procedure on four-year old Ashanti De Silva. Born with a rare genetic disease called severe combined immunodeficiency (SCID), she lacked a healthy immune system, and was vulnerable to every pass­ing germ. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness like chickenpox is life- threatening. Ashanti led a cloistered existence — avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.

In Ashanti’s gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient’s bloods! ream. Laboratory tests have shown that the therapy strengthened Ashanti’s immune system; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, and I he process must be repeated every few months.

Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; tin- road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. The public policy debate surrounding the possible use of genetically engineered material in human subjects has been equally complex. Major participants in the debate have come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion.

Scientists took the logical step of trying to introduce genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia. However, this has been much harder than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering it to the right site on the genome.

X. Retell the text in English.