Biotechnology - The Next Frontier

The euphoria of the lucrativeness of dot.com companies has evaporated. Many such companies are now more appropriately called 'dot.gones'. The next big thing is the commercialisation of biotechnology. Its significance is fuelled by the current bandwagon mentality of advanced nations to spur its growth domestically and its prominence received a boost at the recent discovery of the human genome. Looi Teck Kheong explores some fundamental issues arising from ongoing controversies in the industry.

Broadly speaking, biotechnology is defined by the Encyclopaedia Britannica as 'the application to industry of advances made in the techniques and instruments of research in the biological sciences'. It could also mean 'using living organisms or parts of them to provide goods or services' according to a report prepared by Darryl Macer for the Sub-Committee on Food, Plant Bio Technology and Ethics of the UNESCO International Bioethics Committee.

The recent breakthrough in the mapping and sequencing of the human genome is a critical phase in the development of biotechnology. The information is crucial in accelerating research into genetic disorders and the identification of genetic strands that are responsible for various diseases. One result is the improvement in DNA based gene tests which enable early detection of genetic disorders. Patients are now able to seek treatment and adjust their lifestyles in anticipation of their diseases, such as Alzheimer's disease, hereditary nonpolyposis colon cancer, cystic fibrosis and various other disorders, which were previously not detectable by prior testing but can now be tested for and detected early.

Gene therapy is another benefit arising from biotechnology. This includes the prevention of disease through the alteration of a person's genetic makeup. Although this is still at a preliminary clinical trial stage, the potential is enormous.

Biotechnology also enables more effective drugs and vaccines to be created, such as improved human insulin which enables diabetics to be better treated. It also gives hope to heart patients, sufferers of Parkinson's and Alzheimer's disease of receiving a cure one day. Such drugs may be enhanced and tailor made to suit the genetic makeup of patients. This science of doing so, also known as pharmacogenomics, maximises the effect and enhances the chances of the patient responding positively to drugs related treatment.

Apart from research on the genetic sequencing of human beings, biotechnology also extends to agriculture and farming. Animals can be genetically designed to produce more milk or genetically enlarged so that more meat per animal can be obtained. Genetically enhanced or modified crops can be designed to withstand pests, diseases and harsh weather conditions more readily than traditional crops and to contain more nutrients per stalk. Also known as transgenic crops, these plants contain genes which are artificially inserted.

Does biotechnology really offer fresh hope to the world in its quest to end hunger, malnutrition and disease amongst people, especially those in Third World nations? Whilst genetically enhanced crops can survive pest attacks and live under extreme weather conditions and drugs may be enhanced to optimise and enhance prospects of treatment, it does not follow that employing these new found technologies would necessarily lead to the eradication of hunger and disease or even to increase agricultural output and improve health in these countries.

Malnutrition, global hunger and disease are a consequence of a variety of socio-political and economic factors. The interplay of factors such as equitable systems for food, land and wealth distribution, stable and incorrupt political systems, availability of cheap agri-credit, sound population and healthcare policies and the absence of natural catastrophes are pre-requisites for ensuring that the fruits of the life sciences will be deployed successfully for combating global hunger and disease. Jonathan Robinson in Ethics and Transgenic Crops: A Review was of the view that 'the dilemma is that food shortages generally occur in areas characterised by poverty, high population growth rate and political instability, if not war itself. In addition, the environment sets natural limitations.' He asked, 'Is it therefore likely that [genetic engineering] can make a positive contribution to the relief of hunger where it occurs?'

Looking at the problem from a First World perspective, the lack of genetically enhanced crops and drugs have not prevented advanced nations from producing sufficiently or providing adequate healthcare for their populace. This observation necessarily shows that any reliance on such lofty ideals, ie to eradicate world hunger and disease, by proponents of increased public funding for research in biotechnology must be viewed with a fair degree of skepticism. The industry of biotechnology is fraught with controversies. There are lobby groups that strive for the alternative of not pursuing or perhaps a limited pursuit of the commercialisation of the biological sciences.

Does Man have the right to interfere with the genetic integrity of humans, animals and plants?

There are two principal objections to Man's interference in the genetic makeup of life on earth. The first is the belief that Mother Nature knows better. The second is the belief that Man should not play God. Both necessarily entails Man leaving the genetic makeup of life alone.

The first objection is based on the need for man to respect Mother Nature. Any interference with how Mother Nature works is deemed disrespectful and when applied to humans may even be deemed to be 'dehumanising'. This is based mainly on the need by Man not to disturb the delicate balance of nature. However, the fallacy of this 'respect for nature' objection is easily debunked by the retaliation that if Mother Nature does indeed know what is best for Man, there would be no need for Man to interfere in Her work. The fact is that there is a very long list of human genetic disorders. To bypass the opportunity of discovering the causes and cures for these disorders and thereby helping those afflicted would be unethical and, perhaps, even unnatural.

The second objection, which is theologically based, is founded on the notion of God, which is a controversy in itself. However, on the assumption that God is a certainty, there is also an ambiguity as to what His message is in relation to Man's relationship with animals and plants. Genesis 1:26-28 of the Bible - 'Increase and multiply and dominate the Earth' - may be interpreted to mean that He intended human beings to dominate the Earth and, hence, to do whatever they wish with animals and plants. If that is the message, the objection that 'Man should not play God' is of little relevance.

However, assuming that the religious view is that animals and plants are not subservient to humans, then, can Man, with new found knowledge in the mapping of DNA sequencing, interfere with their genetic makeup, ie play God? In an article entitled 'Seeds of Disaster' in The Daily Telegraph (8 June 1998), Prince Charles was reported to have said that genetic engineering took mankind 'into realms that belong to God and God alone'. This objection is fraught with two major difficulties.

The first hurdle is the question of how one determines where the role of God ends and that of Man begins? This issue of the extent of Man's role and when Man should stop playing God inevitably leads us down a slippery slope: if one allows Man an inch, why not a foot?

The second difficulty with leaving it to God is the issue of whether He is doing a good job, as a major reason for Man's interference in genetics is to find the cause and cure to genetic disorder. The achievements in the human genome programme in identifying genetic defects associated with various specific diseases offer hope to a segment of humanity afflicted with these diseases which would otherwise have been unavailable if Man had not taken the courage to 'play God'.

An obvious and major issue in biotechnology, especially in the light of its recent advancements and discoveries, is how genetic information can be stored and used without manipulation, discrimination and exploitation by interested parties.

A government could use genetic information in its effort to distribute the nation's talent appropriately to various segments of its economy. The information would also be useful to achieve an optimum allocation of funding for public health purposes. Some governments may even encourage the proliferation of genetically enhanced human beings over those who may be less genetically endowed in efforts to maximise the resources of the country. Businesses may want to know the genetic background of their potential employees for the purpose of hiring, firing and promotion. Such information is especially important to certain industries such as the insurance and reinsurance business, which may enhance its actuarial assessment of the business with more information. Genetic information would also be useful and relevant to individuals faced with reproductive and marital decisions. It would be important data to those generally responsible for their own and their family's health.

The US has not implemented any federal legislation relating to such genetic discrimination in the workplace or for individual insurance coverage, although some 13 states have done so. However, an Executive Order protecting federal employees has been signed early this year prohibiting federal departments and agencies from using genetic information in any hiring and promotion action. A model genetic privacy bill was introduced in the US senate sometime in November 1995 and parts were incorporated into the Genetic Confidentiality and Non-Discrimination Act in June 1996. A revised version was introduced into the 105th Congress.

Should Singapore follow suit? Or should a different path be followed? A lot of it would depend on the philosophy of the government of the day and its belief in the reliability of genetic information and the various political agenda that it has to meet at the material time. The Human Genome Project Information website on 'Genetic Privacy and Legislation' offers reasons why legislation is required to deal with genetic information, for instance,

Whilst all individuals should be treated equally under the law as provided for under Article 12(1) of the Constitution of the Republic of Singapore and no citizen will face discrimination on the basis of 'only of religion, race, descent or place of birth' as provided under Article 12(2), there does not appear to be any provisions prohibiting discrimination based on genetic information of individuals. However, one may make the argument that discrimination based on genetic traits that are closely associated with a particular race or ethnic group may constitute unlawful or racial discrimination, which is expressly prohibited under the Constitution.

Given that Singapore's plans are not centered only on setting up a regional centre for clinical trials, but also to attract at least 15 world class biological sciences companies by the year 2010 and to manage a Singapore Genomics Programme (Asiaweek, 6 October 2000), the establishment of a comprehensive legal framework which addresses concerns over the use of genetic information should be of utmost importance.

An inherent difficulty which is the subject of much legal debate is the extent and scope in which discoveries arising from biotechnology may be patented. Prior to the 1980s, it was not legal to patent life forms as these were considered a part of nature. Diamond v Chakrabarty changed all that with a 5-4 US Supreme Court decision and paved the way for genetically engineered bacteria (in that case, an oil dissolving bio-engineered microbe) to become patentable. Patents were thereafter filed with regard to both whole genes and less than whole genes (ie fragments of DNA).

Patenting of genetic DNA sequences are generally justifiable. The usual arguments in support are that it encourages research by rewarding novel and useful discoveries. Moneys obtained can be used for further research. The system of patenting avoids duplication of research in similar areas by making public the methods or secrets of scientific discoveries. These 'secrets' may be employed for a commercial purpose or further research provided a licence is granted.

However, the main objections with patenting for profit is that the creative and inventive synergies that the patent system originally seeks to protect or encourage may in effect result in its retardation. In the case of gene patenting, the granting of patents to fragmented or partial DNAs or uncharacterised DNA sequences may reward scientists who merely make routine discoveries but substantially penalise those who commercialise the function. The patenting of fragmented or partial DNAs also discourages those researching into complete DNA sequences which contain partial DNAs as the licencing costs may be prohibitive, especially when several fragmented DNAs (which are patented) comprise the whole. In such cases, the courts will have to consider whether the second inventor may obtain a patent without the permission of the inventors of the composite DNAs sequences. Hence, patenting for profit may result in prohibitive costs, thus dampening further diagnostic and therapeutic development by other researchers as profits are being shared by patent owners to downstream products.

The costs of patenting and licensing will eventually be passed on to the final consumer. These costs are further increased by allowing patent stacking, ie a process whereby the genomic sequence of any micro organism may be patented in its several manifestations, such as an expressed sequence tag (EST), a gene and a single nucleotide polymorphisms (SNP). An EST comprises 300 to 500 base gene fragments and comprises 10% to 30% of the average DNA. SNP are DNA sequence variations in a genomic sequence that take place when a single nucleotide (A, T, C or G) is rearranged.

Whilst the purpose of patenting is to avoid the duplication of research, the pre-filing stages to the granting of a patent need not necessarily result in this goal. Pending patent applications are normally secret and similar research may be ongoing elsewhere. Hence, the granting of such patents may result in the escalation of costs of this concurrent research aimed at developing a product, thus affecting the sponsor's original cost projections.

Major biotechnology conglomerates may monopolise certain patents relating to gene testing or even the DNA sequence of transgenic crops. This may lead to the danger of increased corporate control of world food and medical supplies. Considering the billions that are being invested in biotechnology, it is a foregone conclusion that such corporations will jealously guard the fruits of their labour through patenting laws and the imposition of restrictive conditions on the purchase of these genetically modified seeds.

Other objections offered against patenting are that patent filing may have the effect of replacing academic and research journals as sources of public disclosure of knowledge. There is also the highly controversial issue of whether it is right for one organism to own the genetic sequence of another. Considering that the DNA sequence of each individual is unique, one necessarily wonders whether it may be prudent for owners of such unique strands to start filing patent protection of a sequence before somebody else makes a claim for it.

Perhaps a critical debate on the impact of genetic information and its reliability in determining the predisposition of an individual to behave in a certain manner is the issue of whether free will exists for the individual, so as to justify the law which holds each individual accountable to the effects of his own action.

The idea of personal responsibility is diametrically opposed to the belief in behavioural genetic determinism, which proposes that genes are the major predeterminant in human behaviour. The controversy surrounding this issue is not new and will continue to absorb the various segments of society interested in the answer to this issue. Its significance has far reaching effects which goes beyond the imposition of liability for criminal behaviour in any legal system and extends to highly controversial issues such as the nature of intelligence and religious truths.

Regardless of the conclusion, there is one important consideration: if genetic characteristics are accepted as playing a dominant role in determining human behaviour, then it must follow that any legal system established to impose criminal liability will have to consider the influence of the genetic makeup of accused persons on their predisposition to certain actions. The philosopher Dan Brock in 'The Human Genome Project and Human Identity' (1992) 29 Hou L Rev 7, 16 frames the issue as follows:

Some consolation may be obtained from the fact that research in behavioural genetics is still extremely contentious, according to Mark A Rothstein in 'The Impact of Behavioural Genetics on the Law and the Courts' Vol 83(3) American Judicature Society Nov-Dec 1999. Whilst correlating a specific genotype (the genetic endowment of an individual) to a specific behaviour may sometimes be statistically supported, it does not necessarily follow that correlation means causation. There is also the obstacle of defining the endpoint of a certain characteristic and the difficulty of excluding other possible causes to the condition. Behavioural genetic determinism, as it stands today, is not an irrefutable science.

Hence, whilst much can be said in support of behavioural genetic determinism from a scientific point of view, it may still be premature to consider public policy implementation of socio-economic-legal developmental goals based on present findings of behavioural genetic research. Be it as it may, the courts may well have to decide on behavioural genetic arguments put forth by defence counsel in the criminal courts once such views are more fully supportable by the scientific community. Even if it is not possible to push through the theories of genetic predisposition as an acceptable defence to criminal charges, the courts will have to consider whether such predisposition is, nonetheless, a mitigating factor in the passing of the appropriate sentence for the offence at hand.

Whilst biotechnology seems to offer much hope and promise of the brave new world that is yet to come, there are unforeseen problems. To begin with, genetic testing is often inconclusive. For example, Ari Patrinos and Daniel W Drell ('Introducing the Human Genome Projects: Its Relevance, Triumphs and Challenges' The Judges' Journal of the American Bar Association Summer 1997, Vol 36:3) points out that:

Over six hundred mutations in the gene for the cystic fibrosis transmembrane regulator can lead to cystic fibrosis. Many experts think that only seven of these mutations are responsible for 85% of the cases of cystic fibrosis seen clinically, and it is these seven for which most people are tested. However, a negative test for cystic fibrosis disease-associated alleles does not necessarily mean that a person does not have a risk for cystic fibrosis.

The usage of transgenic crops has its own risks and concerns. The first is whether it poses any health hazard to human beings who consume them. An often cited experiment which was carried out in Scotland where rats which were fed with transgenic potatoes for ten days developed internal organ damage. However, this experiment has been criticised as being inconclusive and on a small scale (Ewen and Pusztai, 1999). There is, nonetheless, some risk for those allergic to certain components of transgenic crops. An example is the negative reaction by persons allergic to nuts to a brazil nut protein gene which was inserted into soybean products (Nordlee et al, 1996) and the project for its production was halted as a result. Another potentially unforeseen problem with transgenic crops is that they may be a threat to other organisms in the environment, ie they may have unintended effects on non-target hosts (eg Bt corn, a transgenic crop containing a bacterial gene was found to produce a substance that is toxic to butterfly and moth larvae). Other concerns about transgenic crops is whether herbicide resistant types may spawn 'superweeds' through gene movement from crop to weed. There is also the concern of whether transgenic crops containing the Bt gene may expose insects to the Bt toxin, thus accelerating the development of resistance to the toxin or mutation. It has also been argued that the usage of transgenic crops reduces biological diversity as the genetically modified plants replace traditional crop varieties which may still contain useful genes.

Such concerns, which are not unfounded, have been expressed by lobby groups in the United States. The recent World Trade Organisation talks in Seattle were greeted by a demonstration organised by such groups, denouncing, interalia, transgenic crops as 'Frankenfood'.

In conclusion, the genie in the bag has already been released. It is too late to turn back the clock. Although there have been calls (eg by the Union of Concerned Scientists in Washington in 1993 in their report on genetic engineering entitled 'Perils Amidst the Promise') for a moratorium on the commercialisation of biotechnology, until there is in place a strong government programme to assess risk and control of transgenic crops, none of these calls will be heeded. Whether government programmes will be established to assess such risks and to impose the relevant and comprehensive legislative control in Singapore is yet to be seen.