Molecular Medicine

Genomics to Personalized Healthcare

R.J. Trent

• Publisher: Academic Press
• Year: 2005
• ISBN:
  9780080454382
• Edition: 3
• Topic: Biowissenschaften
• Subtopic: Genetik & Genomik

Molecular medicine is the application of gene or DNA based knowledge to the modern practice of medicine. This book provides contemporary insights into how the genetic revolution is influencing medical thinking and practice on a broad front including clinical medicine, innovative therapies and forensic medicine.

• Extensively revised just after the completion of the Human Genome Project, it provides the latest in molecular medicine developments
• The only book in Molecular Medicine that has undergone three editions
• Current practice as well as future developments identified
• Extensive tables, well presented figures - resources for further understanding

1

HISTORY OF MOLECULAR MEDICINE

Publisher Summary

This chapter focuses on the history of molecular medicine. The term molecular medicine is used to describe the role that the knowledge of DNA has in medical practices. The ability to take DNA in vitro and to produce a protein from it became an important step in the commercialization of molecular medicine. The latter half of the 1970s saw the development of the biotechnology industry based on this type of DNA manipulation. During the 1980s, transgenic mice were produced by microinjecting foreign DNA into the pronucleus of fertilized oocytes. In the late 1980s, an alternative approach to the study of genetic disease became available through positional cloning. This method bypassed the protein and enabled direct isolation of genes on the basis of their chromosomal location and certain characteristics that identified a segment of DNA as “gene-like.” During the 1980s–1990s, the application of molecular biology techniques to medicine or molecular medicine proved to be critical for the proper understanding of cancer. More recently, the identification of cellular sequences that normally repress or control cellular growth led to the discovery of tumor suppressor genes. The old concept of molecular medicine as the study of DNA → DNA → RNA → protein in a single gene or genetic abnormality has evolved into the study of many genes, RNA species and proteins in a particular cell. A new term has also crept into the molecular medicine vocabulary called phenome. The phenome follows on the “all” theme as the total phenotypic characteristics of an organism reflecting the interaction of the complete genome with the environment.

THE FOUNDATIONS: 1869–1980s

Introduction

DNA

Technological Developments

Gene Structure and Function

Commercialisation

MODERN ERA: 1980s–2000s

Gene Discovery

Polymerase Chain Reaction (PCR)

Genes and Cancer

Mutation Analysis

Genetic Therapies

DNA Polymorphisms

World Wide Web

RNAi

HUMAN GENOME PROJECT: 1990–2000

The Start

Two Five-Year Plans

The Completion

FUTURE

FURTHER READING

THE FOUNDATIONS: 1869–1980s

Introduction

The term molecular medicine is used to describe the role that knowledge of DNA is having on medical practice. Because of the broad implications of DNA in medicine, molecular medicine cannot be considered a traditional discipline since DNA crosses natural boundaries such as the species, as well as artificial ones exemplified by the medical disciplines.

Other terms that overlap with molecular medicine include molecular biology (the use of DNA-based knowledge in research), genetic engineering or recombinant DNA (rDNA) technology (the use of DNA-based knowledge for new products in industry or research). The common thread in these names is how an understanding of DNA and the ability to manipulate it in vivo and in vitro have greatly advanced the options that are available in clinical practice, research and industry. The impact made by molecular medicine is seen from the choices made by the prestigious journal Science for molecules or achievements of the year—an annual event since 1989 that identifies what development that year has led to a major contribution in advancing science and providing a benefit to society (Table 1.1).

Table 1.1

Scientific breakthroughs involving molecular medicine

Year	Considered by the journal Science to be the outstanding achievement during the year
1989	Polymerase chain reaction (PCR)
1993	TP53 (p53) gene
1994	DNA repair enzyme
1996	AIDS research: New hope in HIV disease (chemokines)
1997	Cloning: The lamb that roared
1999	Stem cells—capturing the promise of youth
2000	Genomics comes of age
2002	Small RNAs make a big splash
2003	SARS: A pandemic prevented

DNA

In 1869, a Swiss physician named F Miescher isolated an acidic material from cell nuclei which he called nuclein. From this was derived the term nucleic acid. The next discovery came some time later in 1944, when O Avery and colleagues showed that the genetic information in the bacterium Pneumococcus was found within its DNA. Six years later, E Chargaff demonstrated that there were equal numbers of the nucleotide bases adenine and thymine as well as the bases guanine and cytosine in DNA. This finding, as well as the X-ray crystallographic studies by R Franklin and M Wilkins, enabled J Watson and F Crick to propose the double-stranded structure of DNA in 1953, an event described as the beginning of molecular biology. Subsequently, it was shown that the complementary strands that made up the DNA helix separated during replication. In 1956, a new enzyme was discovered by A Kornberg. This enzyme, called DNA polymerase, enabled small segments of double-stranded DNA to be synthesised (see Chapter 2).

Other discoveries during the 1960s included the finding of mRNA (messenger RNA), which provided the link between the nucleus and the site of protein synthesis in the cytoplasm, and the identification of autonomously replicating, extrachromosomal DNA elements called plasmids. These elements were shown to carry genes such as those coding for antibiotic resistance in bacteria. Plasmids would later be used extensively by the genetic engineers (or molecular biologists)— terms used to describe individuals who manipulated DNA. A landmark in this decade was the definition of the full genetic code, which showed that each amino acid was encoded in DNA by a nucleotide triplet (see Table 2.1). In 1961, M Lyon proposed that one of the two X chromosomes in female mammals was normally inactivated. The process of X-inactivation enabled males and females to have equivalent DNA content despite differing numbers of X chromosomes. In 1966, V McKusick published Mendelian Inheritance in Man, a catalogue of genetic disorders in humans. This became a forerunner to the many databases that would subsequently be created to store and transfer information on DNA from humans and many other species (see Bioinformatics in Chapter 5 and the Human Genome Project later in this chapter).

Technological Developments

The dogma that DNA → RNA → protein moved in only one direction was proven to be incorrect when H Temin and D Baltimore showed, in 1970, that reverse transcriptase, an enzyme found in the RNA retroviruses, allowed RNA to be copied back into DNA; i.e., RNA → DNA. This enzyme would later provide the genetic engineer with a means to produce DNA copies (known as complementary DNA or cDNA) from RNA templates. Reverse transcriptase also explained how some viruses could integrate their own genetic information into the host’s genome (see Chapters 2, 6, 8 and Appendix).

Enzymes called restriction endonucleases were isolated from bacteria by H Smith, D Nathans, W Arber and colleagues during the late 1960s and early 1970s. Restriction endonucleases were shown to digest DNA at specific sites determined by the underlying nucleotide base sequences. A method now existed to produce DNA fragments of known sizes (see Appendix). At about this time an enzyme called DNA ligase was described. It allowed DNA fragments to be joined. The first recombinant DNA molecules comprising segments that had been stitched together were produced in 1972. P Berg was later awarded a Nobel Prize for his contribution to the construction of recombinant DNA molecules. This was one of many Nobel Prizes that resulted from work that had or would have a direct impact on the development of molecular medicine (Table 1.2). In the same year, S Cohen and colleagues showed that DNA could be inserted into plasmids, which were then able to be reintroduced back into bacteria. Repli...

Table of contents

• Cover image
• Title page
• Table of Contents
• PREFACE
• Chapter 1: HISTORY OF MOLECULAR MEDICINE
• Chapter 2: DNA, RNA, GENES AND CHROMOSOMES
• Chapter 3: MENDELIAN GENETIC TRAITS
• Chapter 4: COMPLEX GENETIC TRAITS
• Chapter 5: GENOMICS, PROTEOMICS AND BIOINFORMATICS
• Chapter 6: GENETIC AND CELLULAR THERAPIES
• Chapter 7: REPRODUCTION AND DEVELOPMENT
• Chapter 8: INFECTIOUS DISEASES
• Chapter 9: FORENSIC MEDICINE AND SCIENCE
• Chapter 10: ETHICAL, LEGAL AND SOCIAL IMPLICATIONS
• APPENDIX: MOLECULAR TECHNOLOGY
• GLOSSARY
• ABBREVIATIONS
• INDEX