Genome Alterations and New Products of Biotechnology:- New Technologies Promise to Expedite the Discovery of New Pharmaceuticals

It is difficult to summarize all the ways in which genomics and proteomics might affect the development of pharmaceutical agents, but a few examples illustrate the potential. Hypertension, congestive heart failure, hypercholesterolemia, and obesity are treated by pharmaceutical drugs that alter human physiology. Therapies are arrived at by identifying an enzyme or receptor involved in the process and discovering an inhibitor that interferes with its action. Proteomics will play an increasing role in identifying such potential drug targets. For example, the most potent vasoconstrictor known is the peptide hormone urotensin II. First dis covered in fish spinal fluid, urotensin II is a small cyclic peptide, with 11 amino acid residues in humans and 12 or 13 in some other organisms. The vasoconstriction it induces can cause or exacerbate hypertension, congestive heart failure, and coronary artery disease. Some of the methods described in Section 9.3 for elucidating protein-protein interactions have been used to demonstrate that urotensin II is bound by a G-protein-coupled receptor called GPR14. As we shall see in Chapter 12, G proteins play an important role in many signaling pathways. However, GPR14 was an “orphan” receptor, in that human genome sequencing had identified it as a G-protein-coupled receptor, but with no known function. The association of urotensin II with GPR14 now makes the latter protein a key target for drug therapies aimed at interfering with the action of urotensin II.

Another objective of medical research is to identify new agents that can treat the diseases caused by hu man pathogens. This now means identifying enzymatic targets in microbial pathogens that can be inactivated with a new drug. The ideal microbial target enzyme should be (1) essential to the pathogen cell’s survival, (2) well-conserved among a wide range of pathogens, and (3) absent or significantly different in humans. The task of identifying metabolic processes that are critical to microorganisms but absent in humans is made much easier by comparative genomics, augmented by the functional information available from genomics and proteomics.

The Human Genome and Human Gene Therapy As biotechnology gained momentum in the 1980s, a rational approach to the treatment of genetic diseases became increasingly attractive. In principle, DNA can be introduced into human cells to correct inherited genetic deficiencies. Genetic correction may even be targeted to a specific tissue by inoculating an individual with a genetically engineered, tissue-specific virus carrying a payload of DNA to be incorporated into deficient cells. The goal is entrancing, but the research path is strewn with impediments. Altering chromosomal DNA entails substantial risk—a risk that cannot be quantified in the early stages of discovery. Consequently, early efforts at human gene therapy were directed at only a small subset of genetic diseases. Panels of scientists and ethicists developed a list of several conditions that should be satisfied to justify the risk involved, including the following. (1) The genetic defect must be a well-characterized, single-gene disorder. (2) Both the mutant and the normal gene must be cloned and sequenced. (3) In the absence of a technique for eliminating the existing mutant gene, the functional gene must function well in the presence of the mutant gene. (4) Finally, and most important, the risks inherent in a new technology must be outweighed by the seriousness of the disease. Protocols for human clinical trials were submitted by scientists in several nations and reviewed for scientific rigor and ethical compliance by carefully selected advisory panels in each country; then human trials commenced. Early targets of gene therapy included cancer and genetic diseases affecting the immune system. Immunity is mediated by leukocytes (white blood cells) of several different types, all arising from undifferentiated stem cells in the bone marrow. These cells divide quickly and have special metabolic requirements. Differentiation can become blocked in several ways, resulting in a condition called severe combined immune deficiency (SCID). One form of SCID results from genetically inherited defects in the gene encoding adenosine deaminase (ADA), an enzyme involved in nucleotide biosynthesis (discussed in Chapter 22). Another form of SCID arises from a defect in a cell surface receptor protein that binds chemical signals called cytokines, which trigger differentiation. In both cases, the progenitor stem cells cannot differentiate into the mature immune system cells, such as T and B lymphocytes (Chapter 5). Children with these rare hu man diseases are highly susceptible to bacterial and vi ral infections, and often suffer from a range of related physiological and neurological problems. In the absence of an effective therapy, the children must be confined in a sterile environment. About 20% of these children have a human leukocyte antigen (HLA)–identical sib ling who can serve as a bone marrow transplant donor, a procedure that can cure the disease. The remaining children need a different approach. The first human gene therapy trial was carried out at the National Institutes of Health in Bethesda, Mary land, in 1990. The patient was a four-year-old girl crip pled by ADA deficiency. Bone marrow cells from the child were transformed with an engineered retrovirus containing a functional ADA gene; when the alteration of cells is done in this way—in the laboratory rather than in the living patient—the procedure is said to be done ex vivo. The treated cells were reintroduced into the patient’s marrow. Four years later, the child was leading a normal life, going to school, and even testifying about her experiences before Congress. However, her recovery cannot be uniquely attributed to gene therapy. Before the gene therapy clinical trials began, researchers had developed a new treatment for ADA deficiency, in which synthetic ADA was administered in a complex with polyethylene glycol (PEG). For many ADA-SCID patients, injection of the ADA-PEG com plex allowed some immune system development, with weight gain and reduced infection, although not full immune reconstitution. The new gene therapy was risky, and withdrawing the inoculation treatment from patients in the gene therapy trial was judged unethi cal. So trial participants received both treatments at once, making it unclear which treatment was primarily responsible for the positive clinical outcome. Never the less, the clinical trial provided important information: it was feasible to transfer genes ex vivo to large numbers of leukocytes, and cells bearing the trans ferred gene were still detectable years after treatment, suggesting that long-term correction was possible. In addition, the risk associated with use of the retroviral vectors appeared to be low. Through the 1990s, hundreds of human gene therapy clinical trials were carried out, targeting a variety of genetic diseases, but the results in most cases were discouraging. One major impediment proved to be the inefficiency of introducing new genes into cells. Trans formation failed in many cells, and the number of transformed cells often proved insufficient to reverse the disorder. In the ADA trials, achieving a sufficient population of transformed cells was particularly difficult, because of the ongoing ADA-PEG therapy. Normally, stem cells with the correct ADA gene would have a growth advantage over the untreated cells, expanding their population and gradually predominating in the bone marrow. However, the injections of ADA PEG in the same patients allowed the untransformed (ADA-deficient) cells to live and develop, and the transformed cells did not have the needed growth advantage to expand their population at the expense of the others.

A gene therapy trial initiated in 1999 was successful in correcting a form of SCID caused by defective cytokine receptors (in particular a subunit called c), as reported in 2000 by physician researchers in France, Italy, and Britain. These researchers introduced the corrected gene for the c cytokine–receptor subunit into CD³⁴⁺ cells. (The stem cells that give rise to immune system cells have a protein called CD³⁴⁺ on their surface; these cells can be separated from other bone marrow cells by antibodies to CD34.) The transformed cells were placed back into the patients’ bone marrow. In this trial, introduction of the corrected gene clearly conferred a growth advantage over the untreated cells. A functioning immune system was detected in four of the first five patients within 6 to 12 weeks, and levels of mature immune system T lymphocytes reached the levels found in age-matched control subjects (who did not have SCID) within 6 to 8 months. Immune system function was restored, and nearly 4 years later (mid 2003) most of the children are leading normal lives. Similar results have been obtained with four additional patients. This provided dramatic confirmation that human gene therapy could cure a serious genetic disease. In early 2003 came a setback. One of the original four patients who had received cells with the correct cytokine receptor gene developed a severe form of leukemia. During the gene therapy treatment, one of the introduced retroviruses had by chance inserted it self into a chromosome of one CD³⁴⁺ cell, resulting in abnormally high expression of a gene called LMO 2. The affected cell differentiated into an immune system T cell, and the elevated expression of LMO-2 led to uncontrolled growth of the cell, giving rise to the leukemia. As of mid-2003 the patient had responded well to chemotherapy, but there may be more chapters to write. The incident shows that early worries about the risk associated with retroviral vectors were well founded. After a review of the gene therapy trial protocols, including consultations with ethicists and parents of children affected by these diseases, further gene therapy trials are still planned for children who are not candidates for bone marrow transplants. The reason is simple enough. The potential benefit to the children with these debilitating conditions has been judged to outweigh the demonstrated risk. Human gene therapy is not limited to genetic dis eases. Cancer cells are being targeted by delivering genes for proteins that might destroy the cell or restore the normal control of cell division. Immune system cells associated with tumors, called tumor infiltrating lymphocytes, can be genetically modified to produce tumor necrosis factor (TNF; see Fig. 12–50). When these lymphocytes are taken from a cancer patient, modified, and reintroduced, the engineered cells target the tumor, and the TNF they produce causes tu mor shrinkage. AIDS may also be treatable with gene therapy; DNA that encodes an RNA molecule complementary to a vital HIV mRNA could be introduced into immune system cells (the targets of HIV). The RNA transcribed from the introduced DNA would pair with the HIV mRNA, preventing its translation and interfering with the virus’s life cycle. Alternatively, a gene could be introduced that encodes an inactive form of one subunit of a multisubunit HIV enzyme; with one nonfunctional subunit, the entire enzyme might be in activated. Our growing understanding of the human genome and the genetic basis for some diseases brings the promise of early diagnosis and constructive intervention. As the early results demonstrate, however, the road to effective therapies will be a long one, with many detours. We need to learn more about cellular metabolism, more about how genes interact, and more about how to manage the dangers. The prospect of vanquishing life-destroying genetic defects and other debilitating diseases provides the motivation to press on

اخر الاخبار

اخبار العتبة العباسية المقدسة

وفد العتبة العباسية المقدسة يزور شعبة الإعداد البدني للاطّلاع على برنامج تأهيل المنتسبين الجدد

قسم بين الحرمين يقدم جهودًا مضاعفة لإعادة المفقودات إلى الزائرين

بعد برامج تدريبية متخصصة.. متحف الكفيل يبيّن منجزات ملاكاته في فن الخاتم (الأرابيسك)

شعبة مدارس الكفيل الدينية تعقد الاجتماع التحضيري الأول لمهرجان روح النبوّة الثقافي

المزيد

الآخبار الصحية

ماذا يحدث إذا تناولنا الطعام مرة واحدة فقط في اليوم

اكتشاف عوامل خطر غير متوقعة لمرض الكبد الدهني

فيروس هانتا والسفينة الموبوءة.. تحديث من الصحة العالمية

طبيب يحسم الجدل السجائر الإلكترونية وعلاقتها بالسرطان

المزيد

الآخبار التكنلوجية

لأول مرة في الولايات المتحدة.. تشغيل مفاعل مصغر نووي يغذي الذكاء الاصطناعي بالطاقة

الكشف عن تفاصيل أول عملية ناجحة لاستعادة انتاج الحيوانات المنوية

أطلس يكشف خفايا الجسم البشري بدقة أرفع بـ50 مرة من شعر الإنسان

المتحف المصري الكبير يتحول إلى "أيقونة خضراء" بدعم ياباني

المزيد

مواضيع ذات صلة

Storage Lipids: - Triacylglycerols Are Fatty Acid Esters of Glycerol

Storage Lipids:- Fatty Acids Are Hydrocarbon Derivatives

Genome Alterations and New Products of Biotechnology: -Recombinant DNA Technology Yields New Products and Challenges

Genome Alterations and New Products of Biotechnology: -Manipulation of Animal Cell Genomes Provides Information on Chromosome Structure and Gene Expression

Genome Alterations and New Products of Biotechnology:- A Bacterial Plant Parasite Aids Cloning in Plants

From Genomes to Proteomes:- Detection of Protein-Protein Interactions Helps to Define Cellular and Molecular Function

From Genomes to Proteomes:- Cellular Expression Patterns Can Reveal the Cellular Function of a Gene

From Genomes to Proteomes:- Sequence or Structural Relationships Provide Information on Protein Function

From Genes to Genomes:- Genome Sequences Provide the Ultimate Genetic Libraries

From Genes to Genomes:- The Polymerase Chain Reaction Amplifies Specific DNA Sequences

From Genes to Genomes:- DNA Libraries Provide Specialized Catalogs of Genetic Information

DNA Cloning: The Basics:- Alterations in Cloned Genes Produce Modified Proteins