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The Human Genome Project, gene therapyand patenting

Research Paper 97/128

1 December 1997

Alex Sleator

Science and Environment Section

This paper discusses the international research venture which is producing a map of the humangenome – the complete set of information for the human body. It considers the impact on medicalscience and outlines ethical and commercial concerns which arise.

House of Commons Library

Library Research Papers are compiled for the benefit of Members of Parliament and theirpersonal staff. Authors are available to discuss the contents of these papers with Membersand their staff but cannot advise members of the general public.

CONTENTS

I Introduction 9

A. DNA - chromosomes and genes 9

B. Genetic diseases 10

II The Human Genome Project 11

A. International co-ordination of research 11

B. Human Genome Project goals 11

1. Progress 12

C. Contributors to the Human Genome Project 13

1. United Kingdom 13

III The impact of the Human Genome Project on medical science 15

A. Basic understanding and development of new techniques 15

B. Genetic Testing 16

1. Diagnosis 16

2. Screening 17

C. Gene therapy 19

1. Cystic fibrosis 20

2. Cancer treatments 21

D. Pharmaceutical developments 22

1. Drug targeting 22

2. Genetically engineered therapeutic products 22

IV Social, ethical and commercial concerns and UK response 24

A. International debate 25

B. UK monitoring and regulation 26

1. Gene Therapy Advisory Committee 27

2. Nuffield Council on Bioethics 27

3. Science and Technology Committee 27

4. Advisory Committee on Genetic Testing (ACGT) 28

5. Human Genetics Advisory Commission (HGAC) 29

C. Specific issues 30

1. Germ-line modification 30

2. Insurance 31

V European Directive on the Legal Protection of BiotechnologicalInventions 33

A. Views on the Directive 35

1. The Government's view 38

2. Consultation 38

Summary

The genome is the term used to describe the complete set of genetic information for anindividual organism.

The Human Genome Project is an international research venture that seeks to provide agenetic map for humans; to pin-point the estimated 50,000-100,000 genes that comprise thehuman genome, and to determine their chemical composition and function.

When this information is available, we will have a greater understanding of the working ofthe human body, of ageing, and of how disorders such as cancer can arise. Many commonillnesses, such as asthma, hypertension, diabetes, cancers and mental disorders have a geneticcomponent and genetic mapping will improve our understanding of how genes interact withfactors in the environment to produce disease.

This paper looks at the scope of the project, at implications of our increase in knowledge formedical science, and at the concerns that arise in the fields of ethics and commerce.Particular attention is paid to the issue of genetic patenting.


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I Introduction

A. DNA - chromosomes and genes

Modern genetics is based on the recognition by Gregor Mendel (1822-1884) that physicalcharacteristics are passed down the generations. He suggested that there must be a physicalbasis to this inheritance. We now know that inherited characteristics are lodged in DNA(deoxyribonucleic acid).

The structure of DNA is that of two linear strands interwoven in the form of a double helix.Each strand consists of sequences of chemical units (bases) repeated along its length, andlinked in a ladder-like structure, thus forming base pairs (bp). There are four types of base inDNA, A, T, C and G1. There are thought to be some 3 billion base pairs in the humangenome.2

The DNA is held in the nucleus of the cells that comprise the organism and is packaged intolong strands of DNA called chromosomes. There are 23 pairs of chromosomes in humans,one pair of which determines our sex (called X and Y chromosomes). In normal cell divisionthe pairs of chromosomes divide, one from each pair going to the new daughter cells, andsubsequently replicating to reform a pair.

Particular characteristics of an organism are associated with only small regions of DNAwhich have specific places on identifiable chromosomes. These regions are called genes. Ifexpressed (“switched on”) in a particular cell, each gene gives to that cell a specific property.The order in which the bases occur along the DNA strand forms a complex code, whichdirects the combination of amino acids, the building blocks of proteins. Proteins are found inevery kind of cell where they determine everything that a cell is capable of doing. Forexample, the cells in the human pancreas are able to make insulin because there is a specificgene on one of the chromosomes that directs the production of insulin. If that gene were tobe faulty, or to be removed, the cell would cease to have that ability. Usually genes act inconcert, and in combination with factors in the environment, to produce their effect.

The genome also contains sequences which signal the beginning and end of a gene, or whichregulate and co-ordinate gene activities.

1 Adenine, Thymine, Cytosine and Guanine2 “The global human genome programme” OECD – Organisation for Economic Co-operation and

Development - 1995


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B. Genetic diseases

Genetic variation giving rise to disease can be present in all body cells, including the germ(reproductive) cells, and can therefore be transferred from one generation to the next. Othervariation is present only in body (somatic) cells, and affects only the individual without beingpassed down the generations. Many types of cancer arise as a result of mutations3 ofsomatic4 cells.

Inherited genetic disorders fall into distinct categories5:

• Autosomal6 dominant disorders are those where inheritance of a gene defect from oneparent alone (or arising anew during egg or sperm formation) can be sufficient for theperson to be affected. Common dominant disorders in the UK include familialhypercholesterolaemia, Huntington’s Disease, adult polycystic kidney disease andneurofibromatosis.

• Autosomal recessive disorders are those where, for a person to be affected, the geneticcharacteristic has to be inherited from both parents. Such parents are usuallyunaffected carriers because they only have a single copy of the gene. Commonrecessive disorders in the UK are cystic fibrosis, sickle cell disease and thalassaemia.

• X-linked recessive disorders are those due to a defect on the X chromosome7. Theseusually only affect males, but the disorders can be transmitted through healthy femalecarriers. Examples are haemophilia, Duchenne muscular dystrophy, and the Fragile Xsyndrome which is associated with learning disability.

3 a change in the DNA not caused by normal genetic processes4 any cell in the body except reproductive cells5 "Code of Practice and Guidance on Human Genetic Testing Services supplied Direct to the Public" Advisory

Committee on Genetic Testing September 19976 the defect occurs on a chromosome that is not involved in sex determination7 the X and Y chromosomes in humans determine the sex of an individual. Females have two X chromosomes,

males have an X and a Y. The sex chromosomes comprise the 23rd pair


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II The Human Genome Project

A. International co-ordination of research

During the 1970s and 1980s rapid developments in technology took place, enabling isolationof increasing numbers of human genes. Discussions about the need to co-ordinate researchled to international adoption of the Human Genome Project (HGP) in 1988. The HGP is, ineffect, the sum of a number of individual countries’ programmes for mapping and sequencingthe genome. It is possibly the largest international scientific collaborative programme inexistence, and is created and led by scientists, not governments. The Human GenomeOrganisation (HUGO) is an organisation of scientists set up to co-ordinate the programme.

Work on the human genome has not been divided up in a formal way, but rather emphasis hasbeen placed on fostering collaboration and avoiding duplication. The HGP has beensuccessful as a basic science programme in creating a resource, the production of a set oftechniques, which can be used for the study of human genetic function.8

B. Human Genome Project goals

The overall goal of the project is to use the techniques of molecular genetics to analyse thestructure of the human genome (and also of a number of simpler organisms). This wasprojected to take 10-15 years. Several steps have been identified:

• Create a genetic map of the human genome: Genetic maps show the relative positions ofdifferent genes on each of the human chromosomes. The raw information for these mapscomes from studying how genes tend to be inherited in families. Genes which lie close toone another on a chromosome are said to be "linked". By identifying linked genes, it ispossible to build up a picture of the relative positions of genes on a chromosome.

• Create a physical map of the human genome: Physical maps consist of a collection oflarge DNA fragments lined up in the order they appear on chromosomes and show thedistances between landmarks in terms of the actual length of DNA. Once it is clear wherea gene is on the genetic map, it should, in theory, be possible to determine from thephysical map which DNA fragment contains the gene of interest.

8 "The human genome mapping project in the UK - priorities and opportunities in genome research" Office ofScience and Technology April 1994


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• DNA sequencing: Ultimately the goal is to determine the sequence of all 3 billion basepairs of the genome. At present priority is being given to the sequencing of gene-richregions of the genome9.

• Comparative studies: The relative simplicity of genomes of organisms such as bacteria,yeasts and nematode worms means that they are of use in preliminary studies, and indeveloping technology. There is great similarity in genes of different species. Muchuseful comparative information is being gained by sequencing the DNA of theseorganisms, and of the mouse genome.

• Create research databases and computerised analysis tools: Databases have had to bedesigned to store and analyse the different types of map information (linkage, physicallocation, disease loci) and link them to sequence formation.

Additional goals include development and technology training, and promotion of discussionof ethical, legal and social implications of the HGP. Both the US and EC programmes setaside funds for discussion of these issues.

1. Progress

Significant progress has been made, particularly in identifying and mapping genes,developing DNA sequencing technology, and building the computational tools required foranalysis of sequence data. The expressed genes from hundreds of different human tissueshave been partially sequenced and stored on databases as "expressed tag sequences10" (ESTs)About 800,000 of these ESTs are available in public databases and at various web sites.Sequencing has as yet only been achieved for about 60 million base pairs, about 2 per cent ofthe human genome.11

Current state of genome sequence, as of September 199712

Organism Size (Mb) Sequenced Percent finishedMicrobial genomes (approx.11) 0.6-4.2 0.6-4.2 100E. coli 4.6 4.6 100Yeast 13 13 100Nematode 100 71 71Drosophila 130 8 6Mouse 3000 6 0.2Human 3000 60 2

(Mb - Million base pairs)

9 Most DNA has no known function – this is known as “junk” DNA10 DNA sequences that code for a particular product11 "Sequencing the Human Genome” Lee Rowan et al. Science vol 278 24 October 199712 ibid


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C. Contributors to the Human Genome Project

While many European countries, Canada, Japan, Australia and New Zealand (amongstothers) are funding work on the human genome, United States programmes account for atleast 50 per cent of the resources devoted world wide to the research.13 Alongside nationalprogrammes international agencies are involved. In addition to HUGO, there are14 theEuropean Molecular Biology Organisation, the EC and UNESCO15.

The Medical Research Council told the House of Commons Science and TechnologyCommittee in 199516:

"It is difficult to give an estimate of overall costs. The figures we have show that the USspend for 1993 was in order of £112 million; Japan spent £20 million. Genethon (France)has a budget of around £6.5 million. The Netherlands was allocated around £3.1 million;Germany some £1.8 million, Italy £1.2 million and the UK around £12 million; the EChuman genome programme had a budget of £11.5 million over 1990-92. The total cost ofsequencing the human genome is presently estimated to be around £300 million.Underpinning the work on model genomes and bioinformatics would be additional to thisfigure"

1. United Kingdom

The UK has been a centre of expertise in human genetics for many years. Human genomeresearch in the UK is funded through the Government and charities such as the WellcomeTrust and Imperial Cancer Research Fund. Funding exists in specific genome centres as wellas in research institutes and university departments. The direct government support has beenchannelled through the Medical Research Council (MRC). In 1989 the MRC was allocated17

£ll million of "new money" over three years, ring- fenced to set up the UK Human GenomeMapping Project18 (HGMP). In 1992, a sum of £4.5 million was consolidated into the MRC'sgrant-in-aid and allocated specifically for genome research for that financial year. Thisspecific funding has ceased, and applications for genome research now compete with otherbids for funds. £13 million per year was allocated by the Government to the HGMP in theyears 1994-95, 1995-96 and 1996-97.19

13 “The global human genome programme” OECD p 3314 The Human Genome Mapping Project in the UK- priorities and opportunities in genome research" Office of

Science and Technology April 199415 The United Nations Education Science and Culture organisation16 “Human Genetics: the science and its consequences” HC 41-1, 3rd report of the Science and Technology

Committee 1994/95 para 3117 “The global human genome programme” OECD p2618 The UK contribution to the HGP is known as the Human Genome Mapping Project (HGMP)19 HC Deb 26 March 1996 c 471W


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In addition to funding research grants and projects in MRC establishments, the Council hasset up the HGMP resource centre in Cambridge to provide centralised facilities and servicesto UK users. In collaboration with the Wellcome Trust it has also established the SangerCentre, also in Cambridge. The centre is carrying out programmes funded by the twopartners and serves as a “factory" to sequence the nematode20 and yeast genomes, as well asselected human chromosomes, and to develop robotics and informatics21 (both of which areessential for handling the huge quantities of information generated by the HGMP).

In 1993 the Office of Science and Technology established the Advisory Committee onHuman Genome Research with membership from the research councils, academia, industry,charities and Government, to advise them on the HGMP.

The importance of comparative mapping of animal and plant genomes is recognised in thefinancial support given in these areas by the Biotechnology and Biological Sciences ResearchCouncil (BBSRC) funded by the Department of Trade and Industry. Initiatives in plant andanimal genome analysis are being supported, and there is close liaison with the MRC'sresource centre.

20 roundworm21 the application of computer and statistical techniques to the management of information


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III The impact of the Human Genome Project on medicalscience

A. Basic understanding and development of new techniques

The rapid development of our ability to analyse genes will revolutionise our understanding offundamental biological processes. A gene holds the code which, when expressed (or"switched on"), directs the assembly of amino acids to form a protein. Each protein has aspecific function in the structure or working of the human body. It is becoming apparent thatsome genes control the expression of others.

“Genetic engineering”, the isolation and transfer of identified genes (including human genes),can now be carried out with great precision. Recombinant DNA techniques allow a piece ofDNA to be taken from one organism and joined artificially to that of another. First, the DNAfrom the donor organism is broken down into fragments by enzymes. These enzymes are veryspecific and can be targeted at the segment of DNA with the required gene. A carrier, orvector, (such as a virus) is then used to ferry the fragments into the host cells. Here thegenetic material divides as the cell divides producing clones (exact copies) of the requiredgenes. The host used for the cloning procedure is usually a micro-organism such as bacteriaor yeast.

A further advance, a laboratory process called "polymerase chain reaction (PCR)", can nowbe employed allowing a specific DNA sequence to be amplified many millions of times inonly a few hours, a much speedier process than duplication in bacteria.

Genetic engineers are now creating genetically modified micro-organisms for use in industry,medicine and agriculture. Human insulin produced by bacteria after insertion of a humangene, was one of the first pharmaceutical products to be produced in this way.

Genes are now routinely cultured in cell lines by using viral DNA vectors (carriers). Solubleforms of the resulting protein can be produced and rapidly purified in large amounts. Thismechanism can be used to produce antibodies, grow crystals for structural studies, or probeprotein function in vitro, or in vivo in animal models.22

22 "Prospecting for gold in the human genome" British Medical Journal vol 314 4 January 1997


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The increased understanding of the basis of disease, which results from these techniques willfacilitate23:

• better tests to detect carriers of gene variants which render either them or theiroffspring liable to certain diseases;

• the definition of the genetic components of common disorders;

• a clearer understanding of disorders at a biochemical level;

• preventative medicine through screening for genes which predispose an individual tocertain diseases;

• new therapies, developed because our improved understanding of disease enables amore rational approach to drug development and treatment (we will know the exacttarget of the drug), and because gene transfer is becoming possible.

B. Genetic Testing

Genetic testing can be performed for two reasons: diagnosis and screening. Diagnosis isaimed at individuals; genetic screening routinely covers populations, or identifiable groupswithin populations (for example men or women only, or ethnic groups at increased risk forparticular diseases).

1. Diagnosis

Currently most genetic tests are done for people known by family history to have acomparatively high risk of carrying certain abnormal genes. Genetic diagnosis of late onsetdiseases, perhaps years before symptoms develop, is problematic, particularly if there is nocurative treatment available. This may merely render the individual liable to years of anxiety.Others will value the ability to decide their life-style, make provisions for the future, andmake decisions about parenthood (since the disease may be passed on to offspring).

Counselling is critical if individuals are to make an informed choice whether to proceed withtesting. Genetic diagnosis can also have implications for family members who are unaware(and may wish to remain unaware) of their genetic status. Discussion of these ramifications

23 Report of the Genetics Research Advisory Group - a First Report to the NHS Central Research and DevelopmentCommittee on the new genetics Department of Health May 1995


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is an integral part of counselling, which will need also to cover implications in the field ofobtaining insurance, and possible employment discrimination.

An example here is Huntington's disease, a dominant single gene disorder. All those whopossess the gene will eventually develop the condition, though not until the fourth or fifthdecade. Progressive neurological disability ensues, with dementia and personality changes,and at present there is no curative treatment.

The Science and Technology Committee found that24:

One unexpected consequence of the availability of a test for Huntington's and the intensivecounselling given before the test has been a fall in the perceived demand for such a test.Before such a test existed 80 per cent of those with a family history of the disease thoughtthey would like to know their status; when the test became available and those comingforward had been counselled, only 10 per cent did so.

2. Screening

For population screening to be appropriate for public health reasons, it should address animportant condition, offer a clear diagnosis and treatment, inform choice and possibly offeropportunities for prevention. Screening tests should be sufficiently sensitive to avoid falsenegative results and yet specific enough to avoid false positive results. Tests to be employedon a large scale need also to be safe, simple and reasonably inexpensive.

Screening can be offered for many purposes: pre-natal screening will give a choice aboutwhether to terminate a pregnancy affected by a genetic disorder; carrier screening will givechoices about childbearing and partners; adult screening for predisposition to disease canallow alterations in lifestyle or preventive treatment to avoid the disease.

• Neo-natal screening

Early diagnosis in children is considered to give a better chance for effective management ofa metabolic condition. Newborn infants are routinely screened for phenylketonuria (PKU),haemoglobin disorders (in some health authorities), and hypothyroidism. There have beensuggestions that these programmes should be expanded. A new technique (tandem mass

24 “Human Genetics: the science and its consequences” HC 41-1, 3rd report of the Science and TechnologyCommittee 1994/95 para 78


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spectrometry), that screens for 17 metabolic diseases is being considered by the NationalScreening Committee.25 There is also some pressure for neonatal screening for cystic fibrosis.

• Carrier screening and adult screening

The issues of informed consent and adequate counselling are again important. While mostgenetic testing is done through NHS services, there is an increasing market of genetic testingbeing carried out through postal services. At least two companies in the UK are offering"postal" testing for cystic fibrosis through analysis of a sample of saliva.

Increasing numbers of genes are becoming recognised where genetic variations, inconjunction with environmental factors, lead to common conditions. There are already testsavailable for several of these mutations - for example the ApoE4 gene that predisposes toAlzheimer's, and the BRCA1 and BRCA2 breast cancer genes. The complicated nature ofgene interaction means that although testing may be simple, interpretation of the result maybe difficult.

The new Advisory Committee on Genetic Testing have issued guidance to ensure that genetictesting offered through the post will meet uniform standards of safety and efficacy, and areonly carried out in appropriate circumstances.

The "Code of Practice on Human Genetic Testing Services Supplied Direct to thePublic” 26 recommends that opportunities should be given for appropriate pre and post-testgenetic counselling, and states:

"ACGT considers that the main role for genetic tests supplied direct to the public should belimited to determination of carrier status for inherited recessive disorders in which anabnormal result carries no significant direct health implications for the customer. ACGTconsiders that the provision of such tests poses fewer difficulties than the provision of testsfor inherited dominant and X-linked disorders, chromosomal disorders, for adult onsetgenetic disorders regardless of inheritance, or for the genetic components of multifactorialdiseases including tests for somatic mutations."

Thus testing for presence of the cystic fibrosis gene (that would indicate carrier status in anasymptomatic adult) would be allowed, but identification of genes which indicate apredisposition to, for example, cancer, when taken in conjunction with environmental factors(such as smoking) would contravene the guidelines.

25 British Medical Journal 11 October 1997 p 90126 Department of Health September 1997


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The Guidance will be reviewed periodically in the light of genetic discoveries and theavailability of preventive and therapeutic measures. However, it should be remembered thatthis is guidance only, not backed by legislation. Moves in the pharmaceutical industryindicate that this is a field poised for expansion. Abbott, the largest US diagnostics companyhas joined with Genset, the French gene-hunting company; and SmithKline Beecham of theUK has linked up with Incyte, a US gene-hunting company. Roche, the Swisspharmaceutical group, is also very active in this field, and Zeneka of the UK will soon also bea participant.27

C. Gene therapy

Gene therapy is a term that can be applied to any clinical therapeutic procedure in whichgenes are intentionally introduced into human somatic28 cells. Two approaches are used:

• gene augmentation - introducing a gene into cells in a way that will allow it toproduce sufficient of its product to compensate for the lack of expression of itsdefective counterpart.

• gene correction - specific alteration of the aberrant gene sequence by recombination

The technical difficulties are challenging. There must be an efficient mechanism for insertingthe gene into target cells. The relative advantages of a variety of different delivery systemsincluding viruses, liposomes29, and receptor-mediated uptake30, are being researched. Safetyis obviously important. Viral vectors, for example, must have their own genes inactivated sothat there is no danger of the virus causing disease.

Such are the difficulties and precautions undertaken, that although more than 200 genetherapy protocols have been approved and over 2000 patients treated, as yet only a handful ofpatients with rare conditions have benefited.31 There is, however, considerable optimism forthe future, particularly in the field of cancer treatments.

Disorders caused by a single gene (monogenic disorders) are obvious targets for genetherapy. There is also a wide range of human diseases which are polygenic, produced by aninterplay between several genes, and often influenced by environmental factors. These

27 "FT guide to genetic engineering" Financial Times 29 September 199728 any cell in the body except reproductive cells29 fatty envelopes which encapsulate DNA30 in this method of gene transfer a carrier molecule is used which binds specifically to a desired target31 “Gene therapy” Stephen J Russell, British Medical Journal 15 November 1997 p. 1289


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include the most common and serious chronic diseases, such as heart disease, asthma anddiabetes.

There has been success in preliminary trials of gene therapy for the Severe CombinedImmunodeficiency Syndrome (SCID)32. It is expected that safe and effective gene therapymay become available over the next five to ten years for a number of diseases, includingsome of the immunodeficiencies, cystic fibrosis, some cancers, haemophilia, and a rare formof atherosclerosis caused by hypercholesterolaemia. 33

Benefits will also arise in unexpected areas. A gene which stimulates growth of bloodvessels has been injected into patients with blocked arteries in their legs, successfullystimulating collateral blood vessel growth and effective circulation around the blockage. Sofar, only patients with peripheral artery disease have been treated, but this could be used totreat coronary artery disease in the future.34

1. Cystic fibrosis

Because of the frequency and severity of this condition it is regarded as a yardstick forsuccess in gene therapy. About 1 in 25 people is an asymptomatic carrier of a cystic fibrosismutation. The child of two carriers has a one in four chance of inheriting a mutation fromeach parent and thus being affected by cystic fibrosis.

Cystic fibrosis leads to a build up of sticky mucous in the lungs, predisposing to life-threatening respiratory infections. The defective CFTR35 gene was located in 1989, andmany different variations have been described.

Initial work on ferrying the normal gene into human cells (in vitro) concentrated on viruses asvectors. American studies have been testing the safety of using genetically engineeredadenoviruses to transfer genes into the airways of CF patients.

In the UK two clinical trials have shown that copies of healthy genes can be delivered to cellsin the lining of the nose using liposomes36. These vectors are considered intrinsically saferthan viruses, as there is concern that a viral protein might be inadvertently activated and

32 "Results from the first human gene therapy clinical trial" the National Human Genome Research lnstitute[US] 19October 1997

33 "A first Report to the NHS Central Research and Development Committee on the new genetics" Report of theGenetics Research Advisory Group Department of Health 1995

34 “Vascular gene therapy shows promise” The Lancet vol 350 November 15 1997 p145135 cystic fibrosis transmembrane conductance regulator gene36 fatty envelopes which encapsulate DNA


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cause disease. They are however, generally less effective. Dr Martin Scott, of the CysticFibrosis Trust, has said37:

"We were looking for safety and the actual transfer of genes. Both studies have shown thatthis system is safe, and have produced weak signals that the gene instructions are beingswitched on."

A further clinical trial using liposomes has begun in London to try and introduce the genesinto the lungs.38

2. Cancer treatments

It is becoming increasingly apparent that it is the interplay between many genes, (as well asfactors in the environment such as tobacco) which can result in the chaotic cell division ofcancerous growth. The locations of these genes provide targets for intervention.

A gene labelled p53 has been found to be faulty or absent in over 60 per cent of cancer types.This gene is responsible for the elimination of abnormal cells and has become know as thetumour suppressor or “suicide” gene. This gene has been successfully inserted into tumourcells to bring about tumour regression. One strategy is to introduce a drug susceptibilitysuicide gene to target cells which are selectively killed when the appropriate drug issubsequently given. 39

Similarly, tumour-infiltrating lymphocytes (white blood cells) have been modified to increasetheir capacity to destroy tumours. Although such therapeutic approaches are stillexperimental they have shown promising results in volunteer cancer patients.40

DNA vaccines are being explored which involve incorporation of an element of the cancerprotein into the vaccine, which will then direct an attack on the cancer cells.41

37 "Gene therapy offers hope for cystic fibrosis patients" Independent 4 March 199738 ibid39 “In situ use of suicide genes for cancer therapy” Freeman et al. Semin. Oncol. 1996 23:31-4540 "Our genetic future – the science and ethics of genetic technology” British Medical Association Oxford

University Press 199241 “Genetic modification of tumour cells isolated from marrow” Gene Therapy, British Medical Bulletin vol 51,

London 1995 p177


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D. Pharmaceutical developments

1. Drug targeting

Genetic engineering techniques open up the prospect of targeting drugs more effectively.Computers are beginning to be used to design drugs precisely for chemical synthesis. As itbecomes apparent that several genes are involved in a disease process, it is hoped that, in thefuture, instead of a generalised treatment for a condition such as breast cancer, the patientwill receive drugs targeted to fight a particular genetic variant. This pharmacogenetics isexpected to develop rapidly in the next few years. Similarly, preliminary findings byresearchers have implicated a second gene (on chromosome 3) which interacts with thepreviously discovered ApoE4 gene on chromosome 19 to give an increased risk ofdeveloping late onset Alzheimer's Disease42. This detailed knowledge may provide targets forinterrupting the disease process with drugs.

2. Genetically engineered therapeutic products

Using genetic engineering techniques, genes can now be successfully incorporated intobacterial or yeast cells. The host is then capable of producing the required “recombinant”protein, which can be harvested and purified in large quantities. Human insulin was one ofthe first therapeutic recombinant proteins to be produced. Recombinant factor 8 (fortreatment of haemophilia) is another example of a drug produced in this way. It is much indemand as it removes the concern about transmission of infection from donated bloodproducts. It is, however, expensive. Similarly, recombinant human growth hormone avoidsthe pitfalls of potential infection posed by growth hormone extracted from the humanpituitary (CJD has been transmitted in this way, and extracted human growth hormone is nolonger used). Recombinant Interferon ß is now on the market for the treatment of multiplesclerosis. This molecule is produced naturally in the body in only tiny amounts.

Techniques are being developed to program bacteria to produce antibodies43 in this way.This may be useful not only in the treatment of infectious diseases, but in the treatment ofsome forms of cancer. There have also been reports44 of human antibody production bygenetically engineered plants. The human gene for a specific antibody product has beentransferred to corn reproductive cells, and soybeans are also being cultivated that containantibodies against herpes simplex 2 virus (a cause of venereal disease). If technicaldifficulties can be overcome, it is thought that antibodies produced by plants could becheaper than those produced by animals.

42 Work by Prof. David Smith et al., Oxford University, published in Human Molecular Genetics, as reported by TheIndependent 14 October 1997

43 a protein manufactured by an organism to neutralise a foreign protein in the body; usually a response to infection.44 Scientific American November 1997 p 23


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Pharmaceutical development is being rapidly developed in the production of proteinsproduced by transgenic animals. These animals contain copies of genes from another species,and copies of genes from man are used for this purpose. Techniques involve micro-injectinga gene into a single celled embryo under the microscope. The embryo is then reimplantedinto a surrogate mother and the injected gene gets incorporated into every cell of the resultingoffspring. The modification is permanent and is passed down the generations. The successrate is only about 1 per cent45.

Work at the Roslin Institute in Scotland has produced a sheep "Tracey", geneticallyengineered to produce in her milk large quantities of a human protein (alpha-1-antitrypsin)which can be used to treat cystic fibrosis. The Institute’s recent cloning of “Dolly” waspartly a response to the need to make this process more efficient, as the technology involvedin the gene transfer has only a small success rate. The cloning technique could be used toduplicate those cells that have successfully incorporated the human alpha-1-antitrypsin gene.Human proteins for the treatment of burns could also potentially be produced in this way.

It was recently announced that pigs have been genetically modified to produce factor 8 intheir milk.46 Researchers expect that this will be less expensive than that now made infermenters containing genetically engineered animal cells. It is reported that milk from pigscontains much higher concentrations of factor 8, making it cheaper and easier to purify.

Transgenic pig organs have been suggested as a possible additional source of organs fortransplantation. A human gene is incorporated into the DNA of the donor animal, which thenproduces a human protein. The transplanted organ is then more likely to be recognised as"self " by the recipient immune system. This process of transplantation of viable tissue fromanimals to humans is called xenotransplantation. However, there are many technical andsafety issues to be overcome, and The UK Xenotransplantation Interim Regulatory Authorityhas been established to review ethical implications and regulate developments in this field47.There is at present a moratorium on xenotransplantation.

45 "Biotechnology and farm animals" Graham Bulfield, Bulletin of Medical Ethics No. 131 September 199746 "Clotted milk" New Scientist 27 September 199747 Department of Health Press Notice 97/010 "Report on animal to human transplants published - consultation

exercise launched" 16 January 1997


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IV Social, ethical and commercial concerns and UK response

This paper concentrates on the implications of our increase in knowledge of human genetics.Cloning has already been discussed in Research Paper 97/43 "Cloning". Geneticmodification of food is discussed in Research Paper 97/8.

Some fear the results of our being able to manipulate genes - the very basis of "who we are".If we are able to diagnose disablement before birth, will those born disabled be valued less, asa drain on health resources that was "avoidable"? Will mothers feel pressured to abort"imperfect" foetuses? Will genetic screening put us into a category that will be unable to getinsurance? If genetic screening demonstrates carriage of an inherited disease, who has theright to know - just the individual tested? Do relations have a right to this information toenable them to make informed choices in life?

The possibility of development of genetic "poisons" as opposed to genetic therapy has beenraised. The British Medical Association is to launch a study on the feasibility of designinggenetic weapons which could be used for high technology ethnic cleansing - could aparticular genetic marker be identified and targeted in one ethnic group? The study willconsider what regulatory steps would be needed to prevent this kind of research.48

A gene that influences human intelligence has recently been located on chromosome six.49

Location of this gene, called IGF2R, by a team at the Institute of Psychiatry in London, willimprove our knowledge of how genetics contributes to human intellect. This forms a naturaltarget for media speculation. Will manipulation of this gene be attempted for the purposes ofproducing highly intelligent offspring? In 1992 the Committee on the Ethics of GeneTherapy50 recommended that51:

“Gene therapy should be directed to the alleviation of genetic disease in individual patients. Itshould not be used to change or enhance normal human traits”

New developments tend to emerge in the press in a sensational form (as in the cloning of"Dolly") and the necessity for informed public debate has been increasingly apparent.

48 "Ban urged on genetic weapons" The Guardian 2 July 199749 "Scientists discover gene that creates human intelligence" Daily Telegraph 31 October 1997 The work is yet

unpublished50 a non-statutory body set up in 1989 under the Chairmanship of Sir Cecil Clothier KCB QC51 Report of the Committee on the Ethics of gene Therapy Cm 1788, January 1992


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A. International debate

The two international programmes set up specifically to research and discuss ethical socialand legal implications of the Human Genome Project have not achieved a high profile.

ELSI - The Ethical, Legal, and Social Implication (ELSI) program was set up as a integralpart of the Human Genome Project in the United States. Amongst major issues identified forresearch are: clinical introduction of new genetic services; access to and use of geneticinformation and public and professional education.

ELSA - A corresponding programme operates in the EU, known as ELSA (Ethical Legal andSocial Aspects). This was allocated a budget of ECU 1 million by the European Parliament.A variety of studies has been carried out, including one on life insurance.

Attempts to reach Europe-wide consensus in the Convention of Human Rights andBiomedicine52, recently adopted by the Council of Europe, have been hampered by the needto serve a wide diversity of ethical and social positions. The Convention maintains theposition of forbidding genetic alteration of the germ-line. An opinion on the DraftConvention53 by Rapporteur Mr Plattner makes some important comments:

16. What ought to be more generally understood is the distinction between negative geneticengineering (for example to cure blindness) and positive engineering (the purpose of which isimprovement). Attempts at the latter come close to eugenics, an early twentieth centuryscience which was exploited for the purpose of racial supremacy. But 'genetic determinism'of 'social Darwinism’ are the last things we wish to revive at a time when social and ethnictensions have already reached an explosive level. It is the duty of democracies to protect theindividual and society from the establishment of biogenic heirarchies.

17. In this context, the most sensitive aspects of this chapter of the draft convention are:

a. prohibition of any discrimination against a person on the grounds of his or hergenetic heritage. This general rule constitutes a solid base for future protocols aimed atfurther developing the protection of human rights against any abuse of the rapidly increasingknowledge about genetic predispositions.

b. protection of the species through prohibition of intervention affecting the geneticheritage, in which respect Article 13 is an important safeguard. The Assembly's amendment,adding a prohibition of any intervention" in the human germ cell line", that is, in humanreproductive cells, has been taken up by postulating that the aim of an intervention seeking tomodify the human genome may not be "to introduce any modification in the genome of anydescendants.”

52 formerly known as the European Convention on Bioethics53 COE DOC7622. 19 July 1996


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c. protection of the individual and of society through a judicious regulation of tests topredict genetic diseases and the use of the results of these tests. Notwithstanding the non-discrimination clause in Article 11, the convention must give a clear signal on this subject,since the question will assume dramatic proportions in the years to come, and will be a farmore important social phenomenon than Aids tests.

18. There are already some countries where employers, financial institutions and, moreparticularly, insurance companies, are sorely tempted to use the results of these tests beforeoffering contracts. The moratoria in force at the moment will soon come to an end. If noremedy is found for this situation, a new social category will emerge, a 'genetically inferior'group of people who, for reasons over which they have no control, will find that they arerefused jobs, loans and life insurance. This is why the Assembly should fully support Article12, which restricts tests to health purposes.

19. Everybody should be in a position to have unhindered access to genetic testing whichmay serve their health purposes. Therefore, it is important to prevent third parties frommaking use of genetic information. Otherwise, the individual could refuse to undergo a testand obtain essential information about his or her health because of the fear of consequences.This holds in particular when the attainment of social goods is involved (eg. employment,life, health and disability insurance). Therefore, the use of results of genetic testing acquiredin the framework of health care is possible only for health purposes or for scientific researchlinked to health purposes, nowithstanding the free contractual relationship. An Article,restricting not only the performance of such tests, but also the communication of their results,is urgently needed. I therefore propose to maintain the corresponding amendment formerlyaccepted by the Parliamentary Assembly, ie. to insert a second paragraph of Article 12 asfollows:

"The communication of results of genetic testing outside the health field may only be allowedin accordance with the provisions of Article 26 paragraph 1 of this Convention and inaccordance with the national legislation about data protection".

20. On the other hand, the individual who has knowledge of his or her genetic constitutionmight try to use this unduly, in particular in the case of private insurance contracts. It is leftto national law, taking into account especially the notion of good faith and the generalprinciple forbidding the abuse of law, to specify the appropriate solutions.

B. UK monitoring and regulation

In the UK human embryo research is regulated by the Human Fertilisation and EmbryologyAct 1990. This Act allows research on the human embryo only until fourteen days afterfertilisation. It forbids alteration of the germ line. This is discussed in greater detail inResearch Paper 97/43 "Cloning".

There has been widespread discussion in the UK over the last ten years of the implications forsociety of the new genetics and a number of committees and organisations have beenidentified by the Government as dealing with aspects of genetic science. Amongst these are54:

54 "Human genetics - the Government's response. 3rd Report Science and Technology Committee 1995-96 HC 231 –1, 3 April 1996


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• Gene Therapy Advisory Committee• Local Research Ethics Committees• Advisory Committee on Genetic Testing• Occupational Health Advisory Committee• The Advisory Group on Scientific Advances in Genetics• Medicines Control Agency• Medical Devices Agency• Nuffield Council on Bioethics.

1. Gene Therapy Advisory Committee

This non-statutory non-regulatory body, was established in 1993 on the recommendation ofthe Committee on the Ethics of Gene Therapy55. It is responsible for

• assessing case-by-case individual protocols for gene therapy trials;• reviewing more general issues related to such therapy; and• providing advice to UK Health Ministers on developments in this field and on their

implications.

2. Nuffield Council on Bioethics

The Nuffield Council on Bioethics was set up in 1991 as a non-statutory body to considerethical issues presented by advances in biomedical and biological sciences. The Councilundertook a detailed consideration of the ethical issues of genetic screening56. The reportaddressed the difficulty of assessing individual health risks exposed by genetic screening; thecomplexity of the issue of confidentiality; the demands made upon professional and healthresources by the required ethical procedures; and the broad framework provided as asafeguard against eugenic abuse.

3. Science and Technology Committee

Parliament addressed the issues of the new genetics in the wide-ranging report of the Houseof Commons Science and Technology Committee "Human Genetics: the science and itsconsequences"57.

55 Cm 1788 Report of the Committee on the Ethics of Gene Therapy (January 1992) ,a non-statutory body set up in1989 under the Chairmanship of Sir Cecil Clothier KCB QC

56 "Genetic screening ethical issues" Nuffield Council on Bioethics 199357 HC 41-1 “Human genetics: the science and its consequences” 3rd report of the Science and Technology Committee

1994-95 6 July 1995


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This Committee investigated UK participation in the Human Genome Project, the value andextent of genomic research, medical applications and industrial implications including thepatenting of genetic material. Human rights aspects arising from the new genetics, includinggenetic discrimination, confidentiality and disclosure of information, and employment andinsurance issues were also discussed.

A proposal for a Human Genome Diversity Project (HGDP) was endorsed. Its specificpurpose is to study variations in the human genome as an insight into human populationstructure and evolution. As an example, genetic variations have shown that the hypothesis onwhich the KonTiki expedition was based is wrong. Although it may have been theoreticallypossible for the Polynesians to have colonised the Pacific from the Americas they happen topossess the same thalassaemia mutation in haemoglobin as the Melanesians, from Papua,New Guinea.58

The possible exploitation of indiginous peoples through patenting of material or therapiessupplied by them was addressed59:

To avoid any compromise of the Project's principles or controversy over the uses to whichtissue samples may be put, we recommend that participants in the HGDP ensure thatsamples supplied for the HGDP be used for the project alone.

The Committee recommended that a body should be set up to advise in the area of genetictesting services, and to take an overview in policy matters related to the new genetics.

In response to the Committee's report, the Conservative Government felt that existingsystems and bodies in place provided an appropriate level of coverage and control, except inthe area of genetic testing, where it proposed a UK Advisory Committee on Genetic Testing.Proposals for a body to oversee policy were initially rejected. 60

4. Advisory Committee on Genetic Testing (ACGT)

This Committee was set up in 1996 as a non-statutory body under the Chairmanship of Rev.Dr John Polkinghorne, following the recommendations of the Select Committee on Scienceand Technology. Its terms of reference in the area of policy issues are:

58 “The Book of Man: The Quest to Discover our Genetic Inheritance”. Walter Bodmer and Robin McKie London,1994 pp. 166-168

59 HC 41-1 1994-95 p xxix 6 July 199560 Cm 3061 “Human Genetics: the science and its consequences”. Government Response to the Third Report of the

House of Commons Select Committee on Science and Technology 1994-95 January 1996


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• To provide advice to ministers on developments in testing for genetic disorders;

• To advise on testing individuals for genetic disorders, taking account of ethical, socialand scientific aspects;

• To establish requirements, especially in respect of efficacy and product information,to be met by manufacturers and suppliers of genetic tests.

Following wide consultation, the ACGT issued a “Code of Practice and Guidance on HumanGenetic Testing Services supplied Direct to the Public" in August 1997. (See page 14)

5. Human Genetics Advisory Commission (HGAC)

The Science and Technology Select Committee felt strongly about the need for a HumanGenetics Commission. It therefore revisited the subject and took further evidence61.Subsquently, the Conservative Government announced its decision to set up a non-statutoryHuman Genetics Advisory Commission, to oversee the new genetics, especially the use ofgenetics tests in insurance, employment and public health.62

While functions already being performed by existing more specialist technical committeeswill continue, the explicit terms of reference of the Commission are as follows63:

• to keep under review scientific progress at the frontiers of human genetics and relatedfields;

• to report on issues arising from new developments in human genetics that can beexpected to have wider social, ethical, and/or economic consequences, for example inrelation to public health, insurance, patents and employment;

• to advise on ways to build public confidence in, and understanding of, the newgenetics

The Commission will also establish contact with people in different sectors in the UK, keepin touch with public views on human genetics and keep abreast of developments in othercountries.

61 HC 231-1 “Human genetics: the Government’s response” 1995-96 3 April 199662 Cm 3306 Human Genetics: The Government's response June 199663 Cm3306 Govt. response to the third report of the House of Commons Select Committee on Science and

Technology 1995/96 Annex 1


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C. Specific issues

Several issues have received particular attention. Cloning is discussed in Research Paper"Cloning" (97/43 March 1997).

1. Germ-line modification

The temptation to alter germ-line cells, ie. reproductive cells, so that an inheritable conditionwould not be passed on to future generations, would seem great. (Somatic cell gene therapy,by contrast, affects only the individual treated.) The possibilities and ethical dilemmas raisedby germline therapy have been examined by many groups world-wide. The consensus atpresent is that our level of knowledge is insufficient to allow alteration of geneticcharacteristics that can be inherited. Attempts at germ-line modification could do more harmthan good. We have very little understanding of how genes interact with one another, but weknow that genes responsible for one trait can be associated with resistance to another. Anexample here is that individuals who carry the gene for sickle cell disease are relativelyresistant to malaria. In malarial areas of the world this characteristic is a genetic advantage.Thus there exists a risk of adversely affecting the germ-line, causing undesired hereditaryside-effects, which might be difficult to undo. In order for germ-line therapy to work, thegenes would have to be expressed in the right way, in the right tissues of the body;unsuccessful germ-line therapy could cause lasting damage in disrupting the operation ofnormal genes.

Alternative methods of bearing a child who does not carry the genes for a serious geneticdisorder are available in in-vitro fertilisation, embryonic diagnosis and selective implantationof an unaffected embryo. However, it has to be acknowledged that these techniques arecumbersome and have a high failure rate.

Although there is at present an international moratorium on germ-line intervention, it is worthnoting that, in 1992, The Clothier Committee on the Ethics of Gene Therapy recommendedthat64:

Because there is insufficient knowledge to evaluate the risk to future generations, geneticmodification of reproductive cells, or the germ cells which give rise to them, should not atpresent [italics added] be attempted.

In their discussion of germ-line therapy, a report of the Catholic Bishops' Joint Committee onBioethical Issues 65states that:

64 Cm 1788 Report of the Committee on the Ethics of Gene Therapy January 1992


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“We believe that, like other parts of the body, the genome may in principle be altered, to curesome defect of the body. If a person's reproductive potential is in some way faulty, to amendthat potential, is, in principle, an acceptable way of promoting the health of that person, andhis or her descendants. We can imagine situations in which to choose this kind of treatmentwould be, not simply a right of the person choosing it, but morally required. Granted thatpeople should not be deprived without good reason of the genes which would otherwise haveinherited from their parents and passed on to their children, the real possibility of eliminatingfrom a family some serious disease - for example, Huntington's Chorea - would appear to begood enough reason to improve on a person's genetic makeup and reproductive potential".

They go on to say, however, that:

“the current risks to the embryo of germ-line interventions - whether on the embryo or thegametes [eggs and sperm] which form it - go beyond what is reasonable."

2. Insurance

In the light of the increasing numbers of genetic tests becoming available, there has beenmuch concern that insurance companies might use the information derived to deny insuranceto an individual, or to raise premiums.

The Association of British Insurers (ABI) issued a statement on the use of genetic tests inFebruary 1997. This requires that people applying for insurance reveal the results of anygenetic tests they have had. Most insurance companies have pledged to ignore test resultswhen they are disclosed by someone applying for life insurance of up to £100,000 linked to anew mortgage.66 However, the Data Protection Registrar has told the ABI that this policymay breech the 1984 Data Protection Act. Under the Act personal data held for any purposeshould be "adequate, relevant and not excessive". Insurers would therefore be in danger ofbreeching the Act if they recorded on computer test results that they did not use. Thissituation will not change when the European Union Data Protection Directive67 isimplemented in October 1998. The ABI has said it will publish a new code of practice byJanuary 1998, which will advise insurers not to ask for genetic tests unless they intend to usethem.68

The Human Genetics Advisory Commission has just completed a consultation exercise whichposes certain questions69:

65 "Genetic Intervention on Human Subjects' The report of a working party of the Catholic Bishops Joint Committee

on Bioethical Issues London 1996 p3266 "It’s none of their business" New Scientist 4 October 1997 p1367 95/46/EC68 footnote 6569 Department of Trade and Industry press notice P/97/448, "Commission invites views on Genetic Tests and

Insurance" 9 July 1997


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• whether or not insurers should be allowed to use a genetic test at all;• how they plan to use genetic tests;• how they will protect confidentiality of medical information;• what grounds they will use for directing how a test result might affect an individuals

application for insurance.

A report will be submitted to Ministers and published by the end of 1997.


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V European Directive on the Legal Protection ofBiotechnological Inventions

Inventions are generally patentable70 if they are industrially useful, new and involve aninventive step. The grant of a patent does not give the owner an automatic right to exploit aninvention. If it clashes with product, environmental or employee safety regulations, forexample, it cannot be made.

DNA patenting has been allowed under European, US and Japanese law since the first DNApatents were filed 20 years ago. To date thousands of DNA molecules, cells and proteinsproduced by genetic engineering have been patented. Many medicines using patented DNAare on the market. These include G-CSF for cancer; erythtopoetin for anaemia; humaninsulin for diabetes and recombinant surface antigen vaccines for hepatitis B71.

An amended proposal for a European Directive on the Legal Protection of BiotechnologicalInventions72 was passed by the European Council of Ministers on 27 November 1997. Thepurpose of the Directive is to harmonise national laws of member states in this field. Nowthat a common position has been reached it will be returned to the European Parliament for asecond reading under the co-decision procedure.

John Battle, Minister for Science, Energy and Industry, commented on the need for theDirective73:

"Greater harmonisation of national laws on the patenting of inventions with abiotechnological component is needed to remove the current uncertainty which acts as adeterrent to investment. Biotechnology is already driving the medicines of the future. It willbe the key to national well-being and quality of life"

An earlier version of the Directive74 was rejected by the European Parliament in March 1995because of ethical concerns. Disagreement centred on the patentability of living things, inparticular the human body, which many MEPs consider an "unalienable heritage".75

70 Under the Patents Act 1949, Patents Act 1997 and Copyright, Design and Patents Act 198871 "Patents ethics and improving health care” George Poste, David Roberts and Simon Gentry, SmithKline Beecham,

Bulletin of Medical Ethics no.124, January 1997 p3072 EC DOC 1050/9773 Press Statement DTI 9 July 1997 P/97/452A74 95/0350 (COD) Proposal for a European Parliament and Council Directive on the legal protection of

biotechnological inventions75 "European Parliament votes for protection of inventions" europe Environment July 24 1997


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In July 1997 MEPs voted 388 to 110, with 15 abstentions, in favour of a modified proposal topatent new inventions involving biotechnology or technical processes with an industrialapplication76. Parliament endorsed many of the amendments put forward by the legalcommittee and designed to strengthen ethical provision regarding the exclusion of patentinghuman genes or parts of the human body.77 The European Commission has accepted 65 ofthe 70 amendments voted in the Parliament on July 16 1997. An amendment which sought toprovide a system of safeguarding consent procedures for those providing genetic material wasnot passed. The Commission takes the view that this would not comply with therequirements of Directive 95/46 for the protection of personal data.78

The intention of the MEPs is that no patents can be taken out on genes, sequences of genes orindeed new discoveries with a therapeutic application. Importantly, Amendment 78 (article9a) of the draft directive requires that an Ethics Committee "shall be set up to assess allethical aspects of biotechnology and its utilisation, in particular with regard to patents. TheCommission shall submit proposals for the composition and terms of reference of theCommittee before this Directive comes into force"79 According to the text endorsed by theParliament80, the following are not patentable:

• Plant varieties, animal breeds or essentially biological procedures for obtaining plantsor animals;

• The human body at any stage of its constitution or development, or the discovery ofone of its elements, including the sequence or partial sequence of a gene;

• Inventions the application or publication of which would be harmful to public orderand morality; application as such cannot be considered unacceptable solely because itis prohibited by a legal or regulatory provision;

• Procedures for human cloning or procedures for modification of the germinal geneticidentity of a human being;

• Procedures for the modification of the genetic identity of animals that cause themsuffering or inflict physical handicaps without substantial medical benefits for man oranimals, or animals produced using such procedures;

76 EP DOC A4/222/97 Report on proposal for a Council Directive on the legal protection of biotechnologicalinventions. Amendments and summary of debates of the European Parliament on 15 and 16 July 1997

77 "Green light for biotechnology and patents" Strasbourg notebook 16 July 1997 Editors Roy Wensley and TimBoden

78 "Commission amends inventions proposal" europe environment September 5 199779 Proposal for a European Parliament and Council Directive on the legal protection of biotechnological inventions

(EP Doc A4/222/97)80 "European Parliament votes for protection of inventions" europe environment July 24 1997


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• Methods requiring the use of human embryos or methods producing human embryospossessing the same genetic information as another human being, whether living ordead (cloning).

The following are patentable:

• Inventions relating to plants or animals, if the technical feasibility of the invention isnot limited to a plant variety or a specific animal breed;

• An isolated element of the human body or one produced by a technical procedure,including the structure or partial isolation of a gene, even if the structure of thiselement is identical to that of a natural element;

• Industrial application of a sequence or partial sequence of a human gene, which mustbe explicitly described in the patent application;

• Under certain strict conditions, an invention using biological material of human, plantor animal origin.

There are, however, two exceptions from this protection. The first concerns the sale ofreproductive material to a farmer. Farmers are authorised to use the product of their harvest(“farm-saved seed”) for reproduction or multiplication within their own operation. (The PlantVarieties Bill ensures a payment mechanism). The second concerns the sale of patentedlivestock to farmers. Farmers may use the patented animals for reproduction on their ownfarms to maintain their own herds. These authorisations include resale for agricultural use,but not sale within the framework of or for the purpose of commercial stock breedingactivity.

A. Views on the Directive

Those in favour of the directive argue that patents are intended as a means of rewardinginventors for their discoveries; patents foster technical innovation while guaranteeing theprofitability of investment in research and the industrial application of the results obtained.Thus the pharmaceutical lobby has been heavily in favour of the Directive. Others feel thatwithout the protection offered by patents, research will become a closed shop in which it isno longer possible to follow the progress of research and openly discuss biotechnology.(Patenting requires full publication of the innovation).


36

It is recognised that patenting will stimulate the development of new therapies anddiagnostics by the private sector. Some patient groups and many of those involved inresearch into genetically inherited disorders have welcomed patenting as they see it as a spurto promote research into rare inherited diseases and because it puts the newly acquiredgenetic information in the public domain.

There has been opposition to the draft Directive from those who consider the European PatentConvention provides sufficient harmonisation of patent laws across Europe.81 The House ofCommons Science and Technology Committee concluded in their 3rd Report82 that "There ismanifestly no consensus on a Directive to harmonise patent law and we consider that theimposition of a Directive could be more harmful than the differences in the criteria forpatentability in different countries under the current system." The Committee did, however,recognise that continued uncertainty might damage pharmaceutical investment in Europe andfelt that the criteria of novelty and utility were being applied too loosely.

Matthew Taylor, speaking in an adjournment debate on genetic patenting has said83:

“a recognition of the potential that genetic engineering offers must not lead us to set asideconsideration of the possible pitfalls. Above all, we should not encourage faster developmenthere – as the Directive will do in practice – in order simply to protect the United Kingdom’scompetitive position at the cost of long-term risks.

..The draft directive would allow human body parts, including DNA, genes and cells, to bepatentable outside the human body, even though they have an identical structure to theirnatural counterparts. The directive would also cover cloned animals and geneticallyengineered food.

..We are moving further into the commercial development and patenting sector than ourability to control the issues yet allows us. That is the imbalance about which I amconcerned.”

In common with others, Matthew Taylor felt that patents in the US are granted too widely,and that the European directive “appears to be drawn too widely in its potentialapplication”84.

Others hold the view that research undertaken with public funds and in the initial stagesthrough scientific co-operation is being exploited unfairly by those patenting the end result.Speaking in the same debate, Mr Alan Simpson asked85:

81 HC Deb 28 July 1997 c. 12282 HC 41-1 1994/95 para 21883 HC Deb 28 July 1997 C. 12084 ibid c. 12185 ibid c. 122


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“Does the hon. Gentleman think that it would be helpful for the UK to make two specific submissions?First, that perhaps there is a case for less rather than more patenting. Secondly, that we ought to beexploring the notion of public goods. Where there has been a financial contribution to researchschemes – direct or indirect – either by Governments, charities or voluntary participants, that should betranslated into a public stakeholding in goods which cannot be patentable.”

There are also concerns that creation of monopoly rights over genes and the royalties payableto patent holders, may lead to prohibitive cost for users of screening services. This hasconsiderable financial implication for providers of health care.

In 1994 attempts were made by a Toronto-based company to collect royalties for cysticfibrosis screening tests from the North West Regional Genetics Centre (based in Manchester).The company demanded a licence fee of $5,000, and $4 for each test performed. This wouldmake provision of the service prohibitively expensive, and health care providers would needto negotiate terms with any company requiring royalties. In the event it transpired that thepatent was not valid in the UK. It remains, however, a valid concern, as these problems willsurely recur.

The US company, Biocyte, has a patent on the use of all human blood cells from theumbilical cord of a new-born. The immature cells have many potential uses in research andtreatment (for example they may be useful in bone marrow deficiencies) This patent is beingdisputed by US and European medical groups because it threatens the free use of such cells.

Much opposition to the Directive has focused on ethical issues. The Genetics Forum86 hasconsistently argued against the extension of patent protection to living organisms includinghuman genetic material. They feel also that patenting may undermine public acceptabilityand confidence in genetics-based medicine.87 Many argue that patents do not provideincentives for research, they merely act as a brake on initiatives by other laboratories.88

They feel that allowing patents on human material will direct research and developmenttowards commercially exploitable products. Patenting in this case will not help patients withrare inherited disorders that form too small a market to provide commercial incentive.

86 a non-profit organisation that campaigns against patents in genetic engineering87 Bulletin of Medial Ethics no. 124 January 1997 p16 -1788 "A matter of life and death -The patenting of living material is in disarray says Maggie Grace" New Scientist 27

July 1996


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1. The Government's view

The Government sees this as primarily a harmonising and clarifying Directive, which wouldremove discrepancies which could interfere with the operation of a single market. Its view onpolicy implications is stated in a DTI explanatory memorandum89:

The harmonisation of patent law would ensure that exclusions from patentability are nogreater throughout the EU than they are in the UK.

This Directive does not seek to harmonise national legislation which would impinge on thecreation or use of patentable invention, such as laws concerning health, animal welfare or theenvironment. However, it does identify areas where patentability is to be excluded on ethicalgrounds and further proposes that the Commissioners’ Group of Advisors on the EthicalImplications of Biotechnology should assess all ethical aspects of biotechnology. Theseprovisions may impose specific ethical considerations into UK law, extending beyond thosecurrently taken into account.

The derogation for farmers in respect of plant propagating material is modelled on thederogation that already applies to farm saved seed of varieties protected by community plantvariety rights. Moreover, the proposal for compulsory cross-licensing between plant varietyrights and patents is based on existing compulsory licensing provisions between patentswhere the working of a patented invention which makes a substantial contribution to the artis prevented or hindered. As far as farmer's privilege in respect of breeding stock isconcerned, since a market value in genetically modified animals has yet to develop, thebalance proposed in the directive between the interests of farmers and of patent ownerscannot be assessed.

Recognition of the deposit of biological material for patent purposes would bring UK patentlaw into line with the European Patent Convention.”

2. Consultation

The European Parliament's amendments and the amended proposal have been circulated forconsultation. The DTI find that90 response from industry indicates that all sectors are infavour or can accept the present text as being a suitable balance between the need to recoupinvestment in research and development and the need to operate in an ethically acceptablemanner. On the other hand:

"Some non-industrial groups have concerns over impediments to further research, whichcould arise from broad patent rights. Others feel that the cost of patented diagnosis andtreatment could arise. Some also feel that patent rights on transgenic animals and isolated orsynthetic substances which are found in the human body are unacceptable. There are otherswho consider that patents will lead to increased monoculture cropping which could restrictbiodiversity and increase cost to third world farmers."

89 Explanatory Memorandum on European Community Legislation COM (97) 446 final Department of Trade andIndustry

90 ibid


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The revised Directive was debated in European Standing Committee on 25 November 199791,prior to the meeting of the European Council of Ministers. Some felt that public consultationhad been insufficient, and had been given little weight by the Government, and that thematter warranted further debate on the floor of the House. The Minister for Science, Energyand Industry, Mr John Battle, felt that further delay on the Directive would disadvantage UKindustry:

“Unless we achieve a common position in Europe, we are at a great disadvantage vis-à-visthe Americans, who have their own law and are blazing ahead in technology”.

Ethical considerations were addressed. The Minister stated:

“The directive deals with patent law and that, above it, there will be a series of other lawswhich will act as an ethical belt and braces. The Human Fertilisation and Embryology Act1990 will tackle some of the health matters. The Animals (Scientific Procedures) Act 1986,Genetically Modified Organisms (Deliberate Release) regulations 1995 and the GeneticallyModified Organisms (Contained Use) regulations 1993 contain safeguard that prevent theunintentional release of products into the environment. So I suspect that some harmonisationof European law may take place with regard to the environment, animal welfare and health.However, patent law would not address that; it would draw on other areas of law to act as anethical counterweight” .

A vote of the Committee supported the Government’s view (Ayes 6, Noes 1).

At the Council of Ministers meeting on 27 November, a vote to agree a common position waspassed. Only the Dutch government voted against, with Belgium and Italy abstaining. TheDutch warned of unpredictable dangers in transferring animal genes, while Ireland, Britainand Belgium had reservations about allowing patents on human gene sequences. Othercountries were concerned about the implications for developing countries92.

91 European Standing Committee B “Biotechnological Developments” 25 November 199792 "EU step nearer gene patents” Guardian Reuter textline 28 November 1997

Health Services & Medicine

Science & Technology

Recent Research Papers on related subjects include:

97/043 Cloning 20.03.97

97/008 Genetically 27.03.97

93/066 Gene Therapy 27.04.93

93/055 Genetically Modified Organisms, Transgenic Animals and 14.06.93Animal Patenting

human genome project, gene therapy and patenting€¦ · the human genome project, gene therapy and...

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