This publication gives you a thorough understanding of the key technologies underpinning modern biotechnology, as well as a comprehensive overview of medical biotechnology products.
Written for the non-specialist reader, this report clearly explains the science, lists the top players in all the key fields and provides wide-ranging insight into the hottest new topics in biotechnology.
This report will help you to:
Scrip's New Guide to Medical Biotechnology provides you with the facts you need to tackle these business challenges and succeed in the century of biotechnology.
PUBLISHED: July 2000
REF: BS1059E
PAGES: 600
PRICE: £495/$1,040/¥119,000
CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
ES.1 Introduction
ES.2 Industry growth forecasts
ES.3 Development overview
CHAPTER 1 REPORT STRUCTURE
1.1 Introduction
1.2 Background to biotechnology
1.3 Objectives of this report
1.4 Methodology
1.5 Report structure
1.6 Boundaries of the report
CHAPTER 2 INTRODUCTION TO MOLECULAR AND CELL
BIOLOGY
2.1 Cell structure
2.1.1 Organelles
2.1.2 Ribosomes
2.1.3 Nucleus
2.2 How DNA works
2.2.1 The structure of DNA
2.2.2 Transcription
2.2.3 Translation
2.2.4 The genetic code
2.2.5 Mutations
2.2.6 Replication
2.3 How RNA works
2.3.1 Transfer RNA
2.3.2 Messenger RNA
2.3.3 Ribosomal RNA
2.4 The structure of chromosomes
2.4.1 Extra-chromosomal DNA plasmids
2.5 Gene expression
2.5.1 Gene switches
2.5.2 Post-translation modification of proteins
2.6 Gene superfamilies
2.7 Cell signalling and signal transduction
2.8 Cell division
2.8.1 The cell cycle
2.8.2 Programmed cell death
2.9 Protein structure
2.9.1 Protein sequencing
2.9.2 Secondary, tertiary and quaternary structure
2.9.3 Active sites and binding domains
2.9.4 Protein separation
2.9.5 Synthetic proteins and peptides
CHAPTER 3 GENETICS AND GENOMICS
3.1 Genetics
3.1.1 The history of inheritance research
3.1.2 Introduction to genetic disorders
3.2 Structure of genes
3.2.1 Eukaryotic genes
3.2.2 Prokaryotic genes
3.3 Applying genetics to understand inheritance
3.3.1 Linkage and recombination
3.3.2 Classical recombination
3.3.3 Chromosome nomenclature and cytogenetics
3.3.4 Genetic markers
3.3.5 DNA fingerprinting
3.3.6 Polymorphisms
3.4 Genetic mapping
3.4.1 Low resolution physical maps
3.4.2 High-resolution physical maps
3.5 Sequencing DNA
3.5.1 Sanger's method
3.5.2 Sequencing by hybridisation
3.5.3 Mass spectrometry
3.5.4 Large-scale methods
3.6 Gene identification
3.6.1 Hybridisation
3.6.2 DNA probes
3.6.3 Blotting
3.6.4 DNA amplification
3.7 The Human Genome Project
3.7.1 Bioinformatics
3.7.2 Commercial development of genomics
CHAPTER 4 GENE THERAPY AND ANTISENSE TECHNOLOGY
4.1 Principles of gene therapy
4.1.1 Viral vectors
4.1.2 Bacterial vectors
4.1.3 Mammalian cells
4.1.4 Lipofection, liposomes and other chemical delivery methods
4.1.5 Naked DNA, gene guns and other mechanical methods
4.2 Commercial development of gene therapy
4.3 Somatic versus germ line gene therapy
4.4 Introduction to antisense technology
4.5 The principles of antisense
4.5.1 Antisense DNAs (oligodeoxynucleotides)
4.5.2 Antisense RNAs (oligoribonucleotides)
4.5.3 Ribozymes
4.6 Commercial development of antisense products
CHAPTER 5 RECOMBINANT DNA TECHNOLOGY
5.1 Introduction to recombinant DNA
5.2 Gene selection
5.2.1 Restriction endonucleases
5.3 Incorporation of the gene into a vector
5.3.1 Plasmids
5.3.2 Bacteriophages
5.3.3 Cosmids, phagemids and phasmids
5.3.4 Artificial chromosomes
5.3.5 Transposons and other mobile genetic elements
5.4 Insertion techniques
5.5 Transferring the vector into the host and detecting it
5.6 Gene expression
5.6.1 Gene expression in transgenic animals
5.6.2 Gene expression in transgenic plants
5.7 Extraction of proteins
5.8 Scale-up of recombinant DNA production
5.8.1 Biochemical engineering
5.8.2 Industrial organisms
5.8.3 Process development
5.8.4 Growth medium
5.8.5 Fermentation and cell-culture technology
5.8.6 Product recovery
5.9 Introduction to protein engineering
5.9.1 Oligonucleotide-directed mutagenesis
5.9.2 Hybrid proteins
5.9.3 Chemical modification of proteins
CHAPTER 6 THERAPEUTIC PROTEINS
6.1 Introduction to recombinant communicator proteins
6.2 Cytokines
6.2.1 Colony-stimulating factors
6.2.2 Interleukins
6.2.3 Interferons
6.2.4 Chemokines
6.2.5 Tissue-repairing agents
6.3 Other growth factors
6.3.1 Transforming growth factors
6.3.2 Osteogenic proteins
6.3.3 Tumour necrosis factor
6.3.4 Stem cell factor
6.4 Structural proteins
6.4.1 Surfactants (for lung cells)
6.4.2 Adhesion molecules and integrins
6.4.3 Collagens
6.5 Blood products
6.5.1 Alpha-1-antitrypsin
6.5.2 Blood clotting factors
6.5.3 Thrombolytics/fibrinolytics and anticlotting agents
6.5.4 Erythropoietin
6.5.5 Atrial natriuretic peptide
6.5.6 Blood substitutes
6.5.7 Sealants
6.6 Insulin-related proteins
6.6.1 Insulin
6.6.2 Insulin-like growth factors
6.6.3 Relaxin
6.7 Human growth hormone
6.8 Therapeutic enzymes
6.8.1 Superoxide dismutase
6.8.2 Enzymes deficient in lysosomal storage diseases
6.8.3 DNase
6.8.4 Collagenase
6.9 Leptin
6.10 Lactoferrin
CHAPTER 7 IMMUNOLOGY
7.1 Introduction
7.1.1 Natural immunity
7.1.2 Acquired immunity
7.1.3 Humoral immunity
7.1.4 T-cell maturation
7.1.5 B-cells
7.1.6 Natural killer cells
7.1.7 Lymphokine-activated killer cells
7.1.8 Intercellular co-operation
7.2 Immune disorders
7.2.1 Immunodeficiencies
7.2.2 Autoimmune diseases
7.3 The human leucocyte antigen system
7.4 The immunoglobulins
7.4.1 Immunoglobulin structure
7.4.2 Immunoglobulin diversity
7.4.3 Immunoglobulin superfamilies
7.5 Monoclonal antibodies
7.5.1 Monoclonal antibodies for product purification
7.5.2 Human monoclonal antibodies
7.5.3 Chemical modifications
7.5.4 Single-domain antibodies
7.5.5 Catalytic antibodies
7.6 Therapeutic monoclonals
7.6.1 Cancer therapies
7.7 Vaccines
7.7.1 Vaccination and immunisation
7.7.2 Recombinant vaccines
7.7.3 Anti-idiotype vaccines
7.7.4 Passive immunisation
7.7.5 DNA vaccines
7.8 Allergy and hypersensitivity
CHAPTER 8 CELL AND TISSUE-BASED THERAPIES
8.1 Stem cells
8.1.1 Embryonic stem and germ cells
8.1.2 Haematopoietic stem cells
8.1.3 Mesenchymal stem cells
8.1.4 Neuronal stem cells
8.1.5 Pancreatic stem cells
8.1.6 Other types of precursor cells
8.2 Cell transplants
8.2.1 Cell transplants for Parkinson's disease
8.2.2 Cell transplants for diabetes
8.2.3 Cell transplants for cancer therapy
8.2.4 Other applications of cell transplants and extracorporeal
cell therapy
8.3 Artificial organs
8.3.1 Artificial liver devices
8.3.2 Artificial pancreas devices
8.3.3 Artificial kidney devices
8.3.4 Other opportunities
8.4 Xenotransplantation
8.4.1 Infection risks
8.5 Replacement organs and tissue engineering
8.5.1 Corneas
8.5.2 Skin
8.5.3 Bladder
8.5.4 Blood vessels
8.5.5 Other soft tissue
8.5.6 Nerves
8.5.7 Bones and teeth
8.5.8 Cartilage repair
8.5.9 Tendon and ligament repair
CHAPTER 9 DIAGNOSTIC APPLICATIONS OF
BIOTECHNOLOGY
9.1 Monoclonal antibody-based diagnostics
9.1.1 Radioimmunoassays
9.1.2 Enzyme immunoassays
9.1.3 Other types of immunoassays
9.1.4 In vivo diagnostic imaging
9.2 DNA diagnostics
9.2.1 Genetic diseases and disease-associated genes
9.2.2 Cancer
9.2.3 Neurological diseases
9.2.4 Cardiovascular disease
9.2.5 Infectious diseases
9.2.6 Drug metabolism
CHAPTER 10 PATENTS AND INTELLECTUAL PROPERTY IN
BIOMEDICAL TECHNOLOGY
10.1 Introduction to patents
10.2 Types of patentable subject matter
10.3 Legal tests of patentability
10.4 Describing the invention
10.5 Chemical and pharmaceutical inventions
10.6 Patenting natural products
10.7 Patenting living organisms
10.8 New European legislation
10.9 The importance of patents to commercial development
10.10 Prospects in patenting
CHAPTER 11 SAFETY AND ETHICAL ISSUES
11.1 Introduction
11.2 Legal and ethical concerns over medical treatment
11.2.1 Medical experimentation
11.2.2 Xenotransplantation
11.2.3 Genetic screening/testing
11.2.4 Gene therapy
11.3 Reproductive technologies and embryo research
11.3.1 Assisted reproductive methods
11.3.2 Human cloning
11.4 The genetic modification of animals
11.5 Safety issues in biotechnology
11.5.1 Containment and release of genetically modified organisms
11.5.2 Transgenics and genetically engineered foods
11.5.3 Product and process safety
11.6 Summary
CHAPTER 12 FUTURE TRENDS IN MEDICAL
BIOTECHNOLOGY
12.1 Industry demographics
12.2 Predictions
12.2.1 Industry infrastructure
12.2.2 Pharmacogenetics and proteomics
12.2.3 Gene therapy
12.2.4 Reproductive technologies
12.2.5 Regenerative medicine
12.2.6 Infectious diseases
12.2.7 Cancer and other major medical problems
12.2.8 Diagnostics
12.3 Disasters
12.4 Technological convergence
APPENDIX
ABBREVIATIONS FOR SUBSTANCES AND PROCESSES
GLOSSARY
SUGGESTIONS FOR FURTHER READING
INDEX
LIST OF TABLES
Table 3.1 Key landmarks in genetics research
Table 3.2 Linkage analysis of genes
Table 3.3 Bioinformatics software
Table 3.4 Important databases for genomics and proteomics
Table 3.5 Important biotechnology companies involved in genomics
and proteomics
Table 4.1 Important biotechnology companies involved in gene
therapy
Table 4.2 Important biotechnology companies involved in antisense
Table 5.1 Restriction endonucleases
Table 5.2 Some therapeutic proteins produced in the milk of
animals
Table 6.1 Top selling biotechnology products (1997)
Table 6.2 Current approved clinical uses for G-CSF
Table 6.3 Current approved uses for GM-CSF
Table 6.4 Currently approved uses of IL-2
Table 6.5 Currently approved uses of IFN-(
Table 6.6 Currently approved uses for IFN-(
Table 6.7 Currently approved uses for IFN-(
Table 6.8 Currently approved uses for urokinase products
Table 6.9 Currently approved uses for streptokinase products
Table 6.10 Currently approved uses for tPA
Table 6.11 Currently approved uses for EPO
Table 7.1 Human immunoglobulins
Table 7.2 Source nomenclature for monoclonal antibodies
Table 7.3 Target nomenclature for monoclonal antibodies
Table 7.4 Therapeutic monoclonal antibodies on the market
Table 7.5 Some therapeutic monoclonal antibodies in development
Table 7.6 Recombinant vaccines on the market
Table 7.7 Recombinant vaccines in development
Table 7.8 DNA vaccines in development
Table 9.1 Top 10 diagnostics companies, 1999
Table 9.2 Approved monoclonal antibody-based diagnostic imaging
products
Table 9.3 DNA-based diagnostic tests for clinical use
Table 11.1 Principal national medical biotechnology regulations
Table G.1 Common amino acids
LIST OF FIGURES
Figure 2.1 Diagrammatic representation of cell signalling
Figure 2.2 Diagram of an untwisted length of DNA indicating how
the base pairs attach alongside the sugar and phosphates
Figure 2.3 The three-dimensional structure of double-stranded DNA
Figure 2.4 Making the polypeptide chain
Figure 2.5 DNA replication
Figure 2.6 Semi-conservative replication of DNA
Figure 2.7 The clover-leaf structure of tRNA
Figure 2.8 The three-dimensional structure of tRNA
Figure 2.9 Structure of chromatin. A nucleosome 'bead' showing
the duplex DNA wrapped around an octomer of histone proteins
Figure 2.10 Cyclical molecular clock gene switch
Figure 3.1 Cistrons and the cis-trans test
Figure 3.2 The structure of a gene
Figure 3.3 The structure of a bacterial operon
Figure 3.4 Crossing-over
Figure 3.5 Types of cross-over event that occur in genetic
recombination
Figure 3.6 Structure of a chromosome showing division sites
Figure 3.7 Nick translation
Figure 3.8 The PCR reaction
Figure 5.1 Summary of the steps typically involved in forming
a recombinant DNA molecule
Figure 5.2 Synthesis of cDNA
Figure 5.3 How disease genes are isolated in chromosome walking
Figure 5.4 cDNA cloning
Figure 5.5 Types of DNA cleavage produced by different
restriction enzymes
Figure 7.1 The structure of IgG
Figure 7.2 Production of a conventional polyclonal antiserum in
the mouse
Figure 7.3 Steps in the production of monoclonal antibodies
Figure 7.4 The purification of antigens using monoclonal
antibodies
Figure G.1 A hairpin or Gierer loop
EXECUTIVE SUMMARY
ES.1 Introduction
The term 'biotechnology' is a broad one, encompassing many ways
of using biological processes to improve and create new methods
of food production, industrial procedures and, particularly,
medical treatment. In medicine, biotechnological research is
expected to provide new treatments for many chronic and/or fatal
diseases, and for those with high morbidity factors. Innovation,
not only in diagnosis and treatment, but in linking understanding
of the molecular basis of disease to appropriate preventative
therapies, will provide the medicine of the next millennium.
Biotechnology is more than just a research tool for drug
development. In medicine, biotechnology is used at all stages:
Medical biotechnology products are readily accepted when they can offer a novel and cost-effective approach to treatment or disease management. If they can also offer earlier, more accurate, cheaper or simpler diagnosis for conditions, this too will lead to commercial success. In the long-term, however, biotechnology offers not only new methods of producing existing drugs, new drugs and new diagnostic methods, but also the ability to understand disease processes at the molecular level and on an individual basis, which is expected to revolutionise medicine over this century by tailoring treatment and prophylaxis to each patient.
This shift away from 'evidence-based medicine', in which diseases are defined by symptoms, towards 'individualised medicine', in which each patient's situation and treatment regime is individually characterised, represents the greatest challenge and opportunity for the pharmaceutical industry of this new century, and may eventually completely change not only diagnostic and prescribing practice, but our current views of therapeutic classes as well.
The field of medical biotechnology is a very broad and complicated one. The primary aim of this report is to offer an introduction to the field, covering most of the major products now on sale or in development and explaining some of the underlying biochemistry, genetics and molecular biology in sufficient detail that their application to technology and product development may be understood. It is not the purpose of this report to give an overview of the target markets, the financial climate or individual company profiles, since these are available from other sources. However, in the process of discussing the types of products in development, company involvement will be noted, since the focus is on the commercial development of biotechnology for medical applications.
The last few years have seen a number of new concepts that will help direct the development and utility of biotechnological advances. These include the generation of new technologies and improvements on existing ones, ranging from genomics and microarray technology, proteomics, and effective gene therapy to regenerative medicine and the possibility of therapeutic cloning. Bioinformatics remains a growing and important area underlying basic technology, with substantial improvements in data analysis and sequencing technology regularly bringing nearer the time horizons for completing sequencing of human and other genomes (on 26 June 2000 first mapping of human genome announced complete).
While the hope and expectation is that genomics will offer newer and better ways of approaching the treatment of disease, especially the ability to treat the underlying aetiology rather than the symptoms, current biotechnology products are still mostly based on recombinant technology.
Therapeutic monoclonal antibodies have finally 'come of age'
with the approval of several products, most notably Genentech's
Herceptin to treat some cases of breast cancer, which also
represents the first individualised biotechnology product
requiring prior 'theranostic' intervention, ie the use of a
diagnostic test to determine whether the therapy is effective for
a specific patient. More than 700 therapeutic monoclonal antibody
products are in development.
In recent years, gene therapy has also really begun to progress
and is still believed to have great potential, albeit accompanied
by many technical difficulties.
The most commercially attractive applications of gene therapy are now not in genetic diseases, but in other more complex conditions, such as cancer, and over 400 gene therapy clinical trials are in progress. Diagnostic uses of monoclonal antibodies and genetic tests continue to be developed, with an increasingly important issue being the ability to detect conditions that cannot yet be treated effectively, and a growing drive to produce more tests that can effectively predict drug suitability based on genotype. The use of DNA-based tests in clinical trials is expected to become widespread over the next few years, with routine genetic testing for many genes affecting drug response likely within a decade.
Biotechnology continues to be a roller coaster ride for investors and company founders with a number of high-profile product failures, but now also a steady stream of successes. Although many of the biotechnology products in companies' pipelines have now been in research and development for several years, and some will inevitably fall by the wayside, it is certain that some of them are likely to be very successful, and a few have already made their producing companies profitable pharmaceutical companies.
However, the emergence of new technological advances such as patient-based therapy will demand increasing legislation and controls, and the sociological impact of using such methods will be considerable in some cases. The recent European public backlash against genetically modified foods seems not to be affecting acceptance of medical biotechnology products significantly (with the notable exception of edible vaccines), but it remains a concern for companies operating in this sector that adverse public opinion might lead to unwieldy and costly legislation and dampen investor confidence and interest. Operating in opposition to this seems to be enthusiasm for genomics progress, which despite some public concerns over the effects of patenting some genes on the cost and availability of diagnostic tests and the freedom of researchers to study disease genetics, seems to be fuelling a resurgence in investor interest in the genomics sector in early 2000. This is, until political leaders expressed concerns over the extent of commercial involvement and secrecy in genomics research.
The lines between medical biotechnology and pharmaceuticals are becoming increasingly blurred. Many so-called biotechnology companies (British Biotech being a good example) are actually developing small molecule drugs which will be produced by conventional chemical synthesis, not by biotechnological means, although biotechnology may have played a key role in the identification of the targets for these drugs. Conversely, biotechnology is used to produce some drugs that are too expensive to synthesise cost-effectively (eg taxol) and there is renewed interest in biomaterials, some of which combine cells or proteins with mechanical devices. The heady enthusiasm for 'platform technologies' notable in the first half of the 1990s is declining, as the technologies involved become more complex and interdependent, more data becomes available in the public domain and such data-based companies fail to generate profits as quickly as expected. Meanwhile, however, there is renewed interest in vaccines and a long-term need to consolidate therapeutic and diagnostic activities. The latter is perhaps the most important new trend to emerge from genomics, and is expected to drive many new alliances and some consolidations of pharmaceutical and diagnostics business interests.
As the developments from biotechnology become accepted and commonplace, it is not so far-fetched to imagine a society where everyone carries a 'smartcard' of their genetic characteristics for routine medical use, where illnesses can be eliminated for life by gene manipulation, where healthy societies become the norm because of prenatal interference, and where even the characteristics of babies can be chosen in advance. Many ethical issues require resolution before such a future could or should come to pass, and may be one of the biggest challenges facing the use of biotechnology today. These are constantly under review and a summary of developments in legislation, bioethics and public opinion is given towards the end of this report.
ES.2 Industry growth forecasts
Despite a steady stream of mergers and acquisitions (over 40 in
1999), the biotechnology industry also still spawns a steady flow
of start-ups (particularly in continental Europe), although
predictions of serious consolidation in the near future have
become more frequent. There are in total about 1,300
biotechnology companies in the US and about 1,200 in Europe, not
all of which are involved in human healthcare. It is widely
believed that there is insufficient finance available to develop
all the drugs in the pipelines of the healthcare biotechnology
companies and so more consolidation is expected in 2000. To what
extent that will be balanced by new start-ups remains to be seen.
The continuing trend for major pharmaceutical company mergers
also has an impact on the biotechnology sector, creating fewer
potential partners and conflicting alliance portfolios, which
require rationalisation post-merger, as well as distracting
management attention from product and technology development
issues.
In the US, revenues from product sales by public biotechnology companies increased by 15% in the year 1997 to 1998. Biotechnology products are already worth billions of dollars per annum. Twenty-two new biotechnology products were approved by the US Food and Drug Administration in 1999, 92 are now on sale in the US (from a total of 143 approvals for various uses) and more than 350 drugs and vaccines are said to be in late stage clinical trials, according to the BioIndustry Organization.
The number of US approvals in the last five years is more than double that of the previous 13 years, according to the BioIndustry Organization, and the number of products currently in the pipeline means that there should be an increasing number of biotechnology products marketed each year. However, the failure rate is still high with 19 high profile therapeutic biotech products withdrawn from development in 1998 and a further nine in the first half of 1999 (Burrill & Co).
ES.3 Development overview
In this report, the underlying science that drives biotechnology
is reviewed and the ways in which it is being applied to the
direct development of biotechnological products (proteins such as
antibodies, cytokines and enzymes, as well as cells, antisense
molecules and gene therapy treatments). The report also covers
the ways in which biotechnology now underpins the entire research
process for pharmaceuticals, providing the engine driving both
target and lead identification.
The increasing availability of genome data for drug target identification is also raising the importance of diagnosis in medical treatment, not just to confirm symptoms and eligibility for treatment, but also to determine individual suitability for receiving specific medications and disease predisposition. The impact that biotechnology has had on disease diagnosis and prospects for the future are described.
The regulatory climate for pharmaceuticals generally affects medical biotechnology, but legislation on related topics such as patenting is also important. This report summaries relevant recent developments such as the failure of anti-biotechnology legislation in Switzerland, the final approval of European Directives on patenting biotechnological inventions and in vitro diagnostics, and new European orphan drug legislation.
Finally, the ethics of medical technology are inextricably linked to biotechnology and will increasingly be regulated. Some of the key issues involving medical research, genetic testing, embryo research, xenotransplantation, the use of transgenic animals to manufacture drugs and human cloning are examined in this report.
© PJB Publications Ltd. 2000 All rights reserved. |