Le Dossier de l'environnement de l'INRA n°22    
D22 : INRA faced with Sustainable Development : Landmarks for the Johannesburg Conference

The Appropriation of Living Organisms: from Biology to Social Debate

Introduction
1. The long march towards the "control of generation"
2. The emergence of a social debate: fate or an opportunity to seize?

Conclusion


[R] Introduction

Ownership of living beings, whether animals or plants, has always been considered as a limited right since it applies only to the individuals themselves and may be cancelled in certain cases (1), beside not being systematically extendable to the progeny. Indeed, in case of a straying male domestic animal, the animal's owner cannot claim ownership of the progeny.
The claim for a more comprehensive right of ownership over living organisms that would extend to an undefined number of individuals and their descendants, only appeared at the end of the XXth century and gained considerable momentum with the growth of biotechnologies. This claim arose out of the conjunction of new technical possibilities and globalised economic stakes.
We will first consider the scientific and technical genesis of the "control of generation", by showing that methods which are nowadays being challenged by society, such as transgenesis, cloning, the "Terminator" gene, are in fact the result of a long process of seeking to understand and master the process of life transmission. These studies have made the "appropriation" of living organisms possible in two senses, by achieving mastery over the dissemination of living organisms and second by acquiring the ability to confer "appropriate" characteristics to it. We will then examine the various legal, economic, political and ethical facets of the social debate which is developing about the practical implications of this control.
Our examples are based on animal and plant species used in agriculture. Issues more specifically linked to the human being will be discussed in other lectures.

[R] 1. The long march towards the "control of generation"

Compared to inanimate things, living beings possess two apparently contradictory characteristics. On the one hand, they are self-reproducing, i.e. able, without human intervention, to generate similar new individuals and on the other hand, apart from a few exceptions, they do not reproduce totally identically, in other words, no individual is strictly identical to its parents or close relatives.
Up to XXth century, these two characteristics were a challenge for anyone aiming to lay hands on living organisms and appropriate it, that is to say to master the progeny, forecast the progeny's characteristics and take advantage of it. A century or more of research has at last provided the keys to achieving this ambition. We will consider three particular aspects of this long march:
- the definition of the laws commanding the transmission of characters, which led to the progressive discovery and manipulation of the supports of genetic information;
- the understanding of the laws of character recombination and achievement of reproduction true to type;
- the control of reproduction to create "unreproducible" living beings.

1.1 From Aristotle to transgenesis: a brief history of genes
The study of similarities and differences between parents and children is undoubtedly one of the most common and ancient human activities. Nevertheless, it seems that despite this people were unable for a very long time to formulate general laws that accounted for the complexity of the process of character transmission. Indeed, the very existence of a contribution of both genders to the genetic heritage of the progeny was long disbelieved. Following Aristotle, some people viewed the mother only as a nourishing support, supplying the "matter", while the father alone contributed the "form", which determines the progeny's characteristics: "As generating principles, we could rightly consider the male and the female. The male possesses the driving and generating principles while the female possesses the substance"(2). We will return later to the importance of the distinction between "form" (which in modern words could be viewed as "information") and matter.
Others considered sperm only as a "vital fluid" that stimulated the development of the egg in which the embryo was "pre-formed". This was for instance the opinion of the Swiss naturalist Charles Bonnet. He founded this opinion on his meticulous observations in 1745 of the breeding of elder tree aphids. He had isolated some aphids at birth and noticed that these insects were able to give birth to new aphids, a proof that the male's intervention did not play an essential part and could be replaced in these insects by "a special liquor extracted from their own blood".(3).
The first observation of spermatozoids with a microscope, at the end of the XVIIth century, gave rise to contradictory interpretations: the Dutch naturalist Anton Van Leeuwenhoek thought at first they were "parasite animals" which lived in the semen. On the other hand, his colleague Nicolas Hartsoeker thought he detected in it a miniature man, and in 1694, published a drawing of this homunculus, which popularised his theory. It was only in 1876 that the meticulous observations of Hertwig and Fol on fertilisation in sea urchins demonstrated that the nuclei of the spermatozoid and ovum merged to produce a new individual.
Another aspect of the uncertainty on the issue of generation was that, up to XVIIth century, the potential existence of spontaneous generation in many living beings, such as rodents, amphibians, fish and insects, was considered a fact. This theory was, however, progressively confined to the genesis of primitive organisms by some experimentators such as the Italian Spallanzani, and was finally refuted by Pasteur for micro-organisms only in 1865 following famous experimental and verbal debates with several eminent scientists of the time, such as Pouchet.
Finally, the eventuality of the first sire having a lasting influence on the subsequent characteristics of the progeny of a female, even born to other sires, was long considered to be an experimental truth, especially in horses. This "heredity by impregnation", known as telegony, led to asserting that mares mated with a donkey would subsequently systematically produce foals having mule characteristics, even if they had been impregnated by horses. This theory was also sometimes applied to humans to justify some surprising characteristics in the descendants!
Thus there existed at the end of XIXth century, a great number of theories on generation. A turning point occurred with the emergence of two approaches seeking to quantify the laws of heredity (4). Although purely formal since the nature of the material support of heredity was unknown at that time, these two methods have proved operational and keep on inspiring the creation of new animal and plant species.
The first approach is due to the English mathematician Sir Francis Galton, who was surprised by the fact that the progeny of parents that were "extreme" for a character such as weight or height, seemed to inherit only part of this difference and were therefore fairly close to the population average. In order to describe this phenomenon, Sir Galton formulated in 1889 his "law of universal regression", thus laying the foundations, still used nowadays, of the regression coefficient calculation which allows to statistically predict the performances of the progeny of a given couple. Unfortunately, this notion of regression also led Galton to develop some regrettable eugenic theories (he also used to describe his law as "the law of regression towards mediocrity"). Nevertheless, it has enabled the improvement of many agronomically valuable characteristics, such as fertility and growth, whose determinism is still poorly understood nowadays. Moreover, Galton tried to formalise the influence of distant ancestors through a "law of ancestral heredity", which implicitly implied both a progressive mixing of the genetic influences of these various ancestors and the persistence of these influences in a given individual. Indeed, he considered that an individual transmitted to his progeny a genetic contribution expressed as H =1/4 p + 1/8 pp + 1/16 ppp + …, (p, pp, ppp… representing the total genetic contribution of all the ancestors of the individual). However, although the underlying genetic model was erroneous, this law keeps a degree of predictive potential at the population level.
The second approach, which at the time went unnoticed, enjoys greater fame nowadays. It was devised by the Austro-Hungarian monk Gregor Mendel who, between 1854 and 1868, explored the "laws of hybridisation" with the help of green peas. This expression reflected two questions that up to then had found no satisfactory answer. The first was the appearance and disappearance of certain characters along the generations, which was defined, but not explained, by the word "atavism". The other was the ability of some characters to associate in an individual and then to split up among his/her descendants. In a report published in 1866, Mendel asserted that the pollen and ovum of a plant both contributed to the characters of the descendants (an issue that was still being debated at that time). He then went on to affirm that these descendants retain the characters contributed by both parents - even if the characters of only one parent are expressed - and split them up independently in their descendants. These principles led to simple and verifiable proportions (3/4-1/4 for one character; 9/16-3/16-3/16-1/16 for two characters) in the various types of individuals among the descendants.
This concept of "hereditary units" that may be conserved and transmitted in an independent and intangible way conflicted with the prevailing concept of heredity through mixing. It excluded in particular any residual influence of a distant ancestor who had not transmitted his/her characters to the direct parent of an individual.
This is probably why the concept was long considered to be applicable only to specific characters (5) . Nevertheless, this approach to the genetic heritage as a mosaic of autonomous characters opened the way to the search for the material support of heredity. In 1910, work carried out at the school of the American Morgan made it possible to attribute to the chromosomes the role of support for these hereditary units, the genes. Later, in the 40's, the work of Ephrussi and Avery, among others, led to identifying DNA as the molecule carrying the genetic information.
What followed is well known: it is coupled with the extraordinary development of molecular biology. I shall recall only two significant consequences. Once the chemical nature of the genes and their transmission laws were identified, it became possible to detect the presence of some of them in an individual and to predict and even alter their future. Genetic diagnosis was born: it was first limited to the detection of recessive genetic anomalies in humans, such as haemophilia and myopathy. Nowadays it is also used for valuable domestic animals (bulls used for insemination, stallions...). Then, owing to advances in genetic engineering, isolation of a gene and its introduction into an individual of a given species could be envisaged, given the universality of system of genetic information coding and deciphering. This introduced the vast domain of transgenesis, which opened in 1973 with the work of Chang and Cohen on a bacterium and is now possible in almost every living species.
The gene, initially a purely formal concept, has now become an autonomous item that can be conserved, multiplied, modified and even synthesised independently of the organism from which it comes. The first key to the appropriation of living organisms, the mastery of its "elementary particles", is now available.

1.2. Recombination: the myth of Sisyphus
While Mendel's work opened the way to the identification and manipulation of genes, it also pointed out the inevitability of their recombination. When two characters are controlled by two different genes possessing each a number of variants, or "alleles", that control for instance the colour and shape of a flower, recombination enables the plant breeder to rationally create new types associating the desired alleles of both characters. On the contrary, if a given character is ruled by a significant number of genes possessing each many alleles, each breeding couple will give birth to individuals that are all different. For instance, in the case of a character controlled by twenty genes for which both parents possess different alleles, one may potentially obtain 1,000 billion (420) individuals, each of them genetically different regarding this character. Nevertheless, as seen above, many characters that are interesting in agronomic terms are not determined only by one, but certainly by many genes: statistically, the descendants of an exceptionally performing individual will therefore obey Galton's harsh regression law. Moreover, these descendants will display great heterogeneity, which will compel breeders to repeat their work generation after generation (for a given character, 3 to 5% progress per generation is deemed significant progress). This is the reason why breeders have long searched for the possibility of exactly replicating an exceptional individual, that is to say replicating exactly its genetic make-up.
However, from a biological viewpoint, the process at the basis of recombination, meiosis (a type of cell division that produces the sexual cells, spermatozoids and ova), governs the reproduction of most species and produces perfect replication only in particular cases, the best-known being that of plants reproducing through self-fertilisation (or "autogamous" plants such as wheat, pea, potato...). In this case, this reproduction mode, when strict, has produced over the years individuals that display no diversity in their alleles: these individuals are known as "homozygotes". Their descendants will all be genetically identical and identical with their parents. This is called a "pure line": most wheat varieties for instance are propagated in this way.
It was of course tempting to extend this approach so as to avoid cross-fertilisation among hermaphrodite plants (6) which disseminate their pollen, such as for instance maize or rape.
In most cases, this is relatively easy. But as these plants usually possess a fairly great diversity of alleles, self-fertilisation needs to be repeated over many generations in order to obtain "pure lines". Moreover, the resulting line is often less performing than the original population: this is the well known "inbreeding depression", which goes with the progressive increase of homozygosis and is thus a serious drawback in using this method. On the other hand, these lines may be crossed together to obtain homogeneous "hybrid" lines, composed of identical individuals. Furthermore, such hybrids may display higher performances than the original population: this is known as the "heterosis effect", which was widely used in maize in the USA and then in Europe after World War 2 and is currently being extended to a range of arable plant species such as rice and rape, or vegetables such as cabbage and tomato.
However, these approaches based on pure lines or their crossing involve lengthy processes and are costly, although some methods that use plant organ culture nowadays make it possible to reduce the time needed to obtain pure lines. But their use is limited to plants (7), hence the interest for direct cloning methods that produce a clone, i.e. an individual genetically identical to another individual, in one single operation.
The first step, also confined to plants, was "vegetative" reproduction from a fragment of plant organ (stem, root, leaf...). In the 1940's, this practice, long used by gardeners, progressed significantly with the development of plant tissue culture, particularly owing to work by the French botanists Roger Gautheret and Georges Morel. Plantlets can be regenerated from these cultures, which makes it possible to quickly and exactly replicate and multiply an interesting new plant variety. Roses, orchids, palm trees, fruit and forest trees may profitably benefit from this cloning procedure known as "horizontal cloning", because all the individuals obtained belong to the same generation as the tissue donor (in terms of sexual reproduction).
In animals on the other hand, such horizontal cloning could be performed only in very simple invertebrates, the best-known example being Hydra vulgaris. Although the indefinite culture of animal tissues has been possible since the beginning of the XXth century, thanks in particular to the work of Alexis Carrel in 1912, we have never been able to regenerate a living being from such cultures. This is why the birth of Dolly the ewe in Scotland in July 1996, performed by Ian Wilmut's team by transferring a cell issued from the culture of mammary gland tissue culture into an enucleated ocyte, had been given immense media coverage. This is called "vertical" cloning, as all the individuals may be considered as the offspring of their mother. Such cloning had already been performed in amphibians as early as 1952 (work by Briggs and King) and then in 1980 in various mammals (sheep, cow, goat, rabbit...), but the method used the nuclei of embryo cells at the initial stage of their development; these were considered to be able to regenerate a whole individual. But since embryo cells were rare and difficult to obtain, this cloning method remained mainly a research tool.
The use of cells originating from differentiated tissue, which is easier to create and thus opens the possibility of large-scale production, paved the way to the perfect replication of adult individuals whose characters have been previously examined. The second key to the mastery of generations, i.e. the possibility of exactly replicating a high-performing individual, is now potentially available for all living beings.

1.3. Inhibiting reproduction: an avatar or an end?
The fact that some beings are unable to produce a progeny, and the consequences of this fact have long been observed. It opened the way to castration practised in many domestic species (pigs, cattle, horses, poultry), although probably more in order to improve their taste or submissivity than to inhibit the reproduction in itself.
In practice, these traditional methods could only be applied to large animals(8) and the operation had to be carried out on each individual and thus remained rather artisanal. However, the possibility of breeding easily great numbers of sterile individuals has certainly been a long desired objective of many farmers and animal holders, long before this became feasible less than a century ago.
The first pathway that was explored in depth was that of hybridisation between species (both animal and plant species). There were innumerable attempts to cross different species, by having them live together or by direct intervention in their mating, with some surprising results. Around 1780, the Italian priest Lazaro Spallanzani, well-known for his studies on reproduction, is said to have tried to cross a cat and a dog! Nevertheless, despite many enthusiastic attempts, these trials on animals remained anecdotal. The mule, the mule duck (9) and some ornamental pheasants are the main examples of hybrids sufficiently viable to be of practical use, although their sterility (10) was judged secondary to the interest of having succeeded in combining the parent species. Things are quite different in the plant realm since hybridisation between species was, and still is, one of the main tool for creating new varieties both in ornamentals (roses, rhododendrons...) and in food plants (cereals such as rice or triticale, wheat and rye hybrids, citrus fruits, coffee). In that case, sterility is not systematic and is also not the primary aim of the plant breeders.
In the case of fertile hybrids, however, their descendants are highly diverse and do not replicate the characters of the parent plant. They are therefore "practically" non-reproducible. This high segregation faculty of the parental characters has been exploited in species such as maize in order to create hybrids by crossing pure lines. Although these hybrids produce abundant seed, they cannot be grown from these seeds and, consequently, the farmers must buy new seeds each year. This dependency on the plant breeder was acceptable to farmers only if there were clear yield or homogeneity improvement (11). This is probably the reason why maize remained for a long time a relatively isolated example of a clear success in this field. In particular, the results of attempts to adapt this method to small domestic animal species (poultry and fish) were not as efficient as conventional selection methods.
The second pathway, mainly investigated in plants, was that of chromosome multiplication or polyploidisation. This method, which uses mainly plant substances such as colchicine, a cell division inhibitor, most often enables the doubling of the chromosome numbers. This produces a shift from the classic diploid state (12), in which each chromosome is paired, to a tetraploid state (four sets of each chromosome), and even to hexa- or octoploid sets of chromosomes if the operation is repeated. This change produces increased plant vigour and organ size, and has been widely used in ornamentals as well as in food plants (cereals, tomatoes, aubergines). These tetraploid plants, which possess an even number of chromosomes, are usually not sterile: by crossing them with diploids, triploid individuals may be obtained, which have three sets of each chromosome. This situation considerably disrupts the forming of sexual cells and induces a considerable fertility decrease, with seeds that are few and abortive. The absence of seed in bananas or in some varieties of watermelons is a good example of the interest of triploids.
In animals, a great many attempts have been made since the early 1930's to adapt this approach, based on the pioneer work of the Jean Rostand. Some simple physical methods (brief exposure of eggs to low or high temperatures or even to high pressures just after the fertilisation) were developed to produce tri- and tetraploids, but it was soon realised that only invertebrates and low vertebrates (fish and amphibians) could produce viable polyploid individuals. The trout and oyster, in which inhibition of sexual maturation avoids the weakening of the animals and the alteration of their taste during the breeding period, are concrete applications of triploidy to produce sterile animals.
In brief, hybridisation and polyploidy appear to have a limited sphere of application and only partial efficacy in inhibiting reproduction. Moreover, as mentioned previously, these methods have generally other objectives than controlling the propagation of an original variety. Indeed, we can say that until recently, sterility was viewed much more as a means than as an end (13).
The advent of molecular biology made it possible to contemplate methods with far wider applications, in which the expression of fertility could be closely tied to treatments with specific external molecules that activate or inhibit the expression of certain genes. The most (in)famous technique was named "Terminator" by its detractors and was developed in the USA in the framework of a co-operation between a seed firm and the US Department of Agriculture (USDA). It is a genetic construction, which associates three genes. In the absence of any treatment, the plants are normally fertile and the construction remains dormant. On the contrary, treatment of the seeds with an antibiotic activates a reorganisation of the genetic construction, allowing the expression of a gene that secretes a substance which inhibits the forming of the embryo. With this treatment, seeds will produce normal plants with normal seed production, but these seeds will have no embryo and are therefore sterile.
Even though use of the Terminator technology is no longer envisaged for the time being, many alternatives are possible and are probably being developed. The essential information is that the third technical key to the appropriation of living organisms, that which allows full control of the production of progeny, is now potentially available for a wide number of animal and plant species.

[R] 2. The emergence of a social debate: fate or an opportunity to seize?

While the development of tools to master the generation process occurred over a long period of time, the justification of their use started being questioned only recently. Initially, these questions related to our own species only. The production of hybrids and polyploids, the development of cell culture and in vitro plant propagation, the first successes of transgenesis do not seem to have raised much debate. Indeed, the Asilomar congress, organised in 1975 by the biotechnology pioneers in order to discuss a possible moratorium on certain manipulations, was an initiative that remained within the boundaries of the scientific community (14) and essentially focused on evaluating technical risks.
Awareness of the collective stakes involved in the control of generation progressively arose around two main questions that were pure speculation 50 years ago but have become very concrete nowadays:
- To whom do living organisms belong? Is it the common and inalienable heritage of all mankind or can individuals be allowed to claim exclusive ownership of some part of this heritage?
- To what extent can we alter living organisms? What boundaries should be set to the creation of "impossible" living beings, i.e. having characteristics that could never have resulted from natural evolution?
These two difficult questions can be looked at from several angles and it is not the role of scientists to decide about the answer. But given their knowledge, they should in my opinion contribute to a collective reflection on these issues and highlight the different aspects that need taking into account. I shall particularly focus on three: the legal, economic and ethical aspects.

2.1. Ownership of living organisms: the need for a legal framework
Until the 1990's, there seemed to be a clear, theoretical as well as practical distinction between "natural" genetic resources and the breeds and varieties produced by breeders.
"Natural" genetic resources included species existing in the "natural" state, as well as traditional varieties used by farmers and produced through an empirical collective breeding process. Significant collection and conservation work was done for these resources during the XXth century. This work was pioneered by the Russian scientist Nicolas Vavilov who from 1925 onwards organised expeditions around the world from which he brought back more than 150,000 varieties, that are conserved and studied at his "All-Soviet Institute of Plant Culture"(15), in the then city of Leningrad. In his wake, and thanks in particular to the creation after World War 2 of international agronomic centres specialising in the main food crops (cereals, potatoes, legumes...), considerable numbers of samples were collected. The collection of the International Rice Research Institute (IRRI), based in the Philippines, includes more than 20,000 varieties, and that of USDA over 3,000 wheat varieties. In France, INRA conserves some 93,000 plant genetic resources, representing a total of 71 different species (16). The exchange of resources of international centres is governed by a clear rule: these resources are available free of charge to any person requesting them (of course depending on stocks and mailing costs). In fact, these Centres consider themselves to be only the depositories of these resources. In 1983, the "International Undertaking on Plant Genetic Resources" concluded under the authority of FAO, the U.N. Food and Agriculture Organisation, reasserted the principle that plant genetic resources are a "common heritage of humankind".
Out of these resources, some public or private operators have developed "modern" varieties through crossbreeding and selection. The dissemination of these varieties legitimately demanded some form of appropriate protection. The protection system aimed to encourage innovation, while ensuring returns on investment for the operator via exclusive rights on the marketing of the variety; it also sought to foster emulation by allowing other operators to use these modern varieties, and not the original genetic resources, to create a new variety. The new variety will then be approved and protected, on the condition that it differs for one or more characteristics from existing varieties. Besides, no royalty fees need to be paid to the breeders of the initial variety (17). These rules governing the PBR (Plant Breeder's Rights) are much more open than those of patents (18). They were formalised in 1961 by the Paris Convention, which created the International Union for the Protection of New Varieties of Plants (UPOV) and currently includes some 40 countries. Besides, this Convention states that while the breeder conserves exclusive rights over the marketing of his/her variety, the farmer who has bought seeds is free to re-sow the produce of his crop and thus propagate the variety for his own use (in case of true to type reproduction - see. above), free of charge.
The situation is even more open in the case of animal species. Although during the last century in England, the creation of "Herd Books" for the main domestic species enabled animal breeders to have their best sires acknowledged, it did not accord them a monopoly over the diffusion of the breed. In France, under the 1996 Livestock Law, the only compulsory measure for large species and artificial insemination was the obligation to use males acknowledged by a UPRA (Breed Promotion and Improvement Unit), a collective organisation that manages the genetic improvement of a given breed. However, these organisations do not have exclusive rights on this breed: the farmers are still free to sell females, or males for natural mating.
This very open approach to the ownership of living organisms changed in the 1990's. The first warning came from the United States: in 1980, the Supreme Court changed a century of case law on the non-applicability of patent law to living beings. While in 1972 the US Patent and Trademark Office, following the above principle, had rejected a request for a patent on a hydrocarbon-degrading bacterium, the Supreme Court overturned the decision and stated (by 5 voices to 4) that the sole fact of being live did not exclude it from being patentable. Several patents on micro-organisms, then on transgenic plants and on a triploid oyster in 1987, and finally in 1988, on a transgenic laboratory mouse, confirmed this new approach to living organisms, which from now on is considered to be at least in part a real "human" invention (19). After much debate and rejection of a first Directive project in 1995, the European Union also adopted a Directive on the patentability of "biotechnological inventions" in 1998. Contrary to the US situation, plant varieties and animal breeds born through "conventional" methods are still excluded from the sphere of application, but in the future it will be highly difficult to define the legal status of a plant combining on the one hand, various transgenically introduced patented genes and, on the other hand, features that have been improved through selection and protected under the Plant Breeder's Rights system. Similarly, and contrary to the US, farmers will be allowed to re-sow transgenic seeds for their own use (20). This practice is not accepted for patented plants in North America and is closely supervised by the biotechnology firms (21)..
The second destabilising warning concerned the genetic resources themselves: in 1991, the government of Costa Rica sold the exclusivity on exploration and collection of micro-organisms, insects or plant samples to the firm Merck-Inbio for one million dollars. This "nationalising" of the common heritage of humankind was ratified in 1992 by the Rio Convention on Biodiversity. Signed up to now by 174 countries, this convention acknowledges the sovereignty of a state over the living resources of its territory. Today, as a retroactive effect, many states claim right of ownership to the resources collected and conserved by agronomic international centres, considering that these resources have often contributed to the success of agriculture in the Northern countries (22) with no compensation for the country of origin. These claims are still being debated by international bodies: they underscore the fact that farmers in Southern countries have significantly contributed to the domestication of some species. In a general approach to genetic resources, a distinction should therefore be made between, on the one hand, resources consisting of wild plants that are a produce of nature, and on the other hand, cultivated traditional varieties reflecting several hundred years of empirical domestication and representing a collective investment that should be legitimately recognised and remunerated. The debate is all the more heated as the introduction of patented modern varieties into these countries would prevent farmers from freely re-sowing plants whose main features they helped to create.
While these debates are carrying on, protection of the "living matter" with patents is gaining ground. Thus, the 1994 Marrakech agreements compel the 132 member states of WTO (World Trade Organisation) to protect intellectual property on their own territory. Under this clause, plant varieties must be protected by patents or by a sui generis system, such as, for example, the Plant Breeder's Rights defined within the framework of UPOV (see above). Five years later, no country has so far been able to set up such a system specifically adapted to living beings, and important countries like India or Thailand seem to turn to protection by patents.
From a semantic standpoint, notice should be taken of the progressive introduction of the term "living material" when referring to components of living organisms, or even living beings. This shift is significant and may refer to the Aristotelian distinction between "form" and "matter". The problem is - something Aristotle could not foresee - that we now know that contrary to lifeless matter which can take shape only through external action (the classical example is that of marble and the sculptor), living matter includes the components needed to achieve its form. Therefore, it seems that this is more a social euphemism than a relevant philosophical reference.
Over a time span of 50 years, the status of living material changed from that of a natural object, whose components could be discovered but not appropriated, to that of an invention resulting from human industry, which can be protected as strictly as any other original human creation. However, it would be overly simplistic to denounce a drift of the law, when what it simply reflects is a change in our conception of the respective roles of nature and of humans, as well as the respective roles of the various people who, along the years, have contributed to shaping today's living beings. As an emblematic example, the neem tree, or Indian lilac, which has been used in India for thousands of years for its many healing properties, is now "protected" by 65 patents on its active principles. A traditional healer who would wish to sell tree extracts would, as a result, be liable to legal action. Fortunately, the tradition is that healers often refuse to take advantage of their knowledge!

2.2. An economic viewpoint: how to favour evolution in the best direction ?
If we now examine the creation of new animal and plant varieties from the general standpoint of public economy, the following question arises: what remuneration (directly or as preferential commercial rights) should a given operator - a farmer, a breeder, a propagator - be given so as to encourage the further creation and dissemination of varieties adapted to a constantly evolving agriculture?
To answer this question, we need to consider, both in the Northern and Southern countries, that the major aim of this continuous creation, be it empirical or rational, collective or private, is and remains to enable agriculture to keep on assuming its food production mission. This has been acknowledged as there are multiple examples showing that varieties need to adapt to the evolution of pathogens, pests and environmental conditions. This viewpoint justifies that the creation of varieties be considered as a public good which requires a degree of collective regulating, and not only as just a private activity.
It is all-too easy to examine both extreme options and conclude that they are non optimal: if some form of protection is not ensured to an individual (or a group of individual) having really performed a creative activity, creation will not be encouraged, at least not in a market economy. Moreover, lack of protection may sharply curtail the diffusion of innovation, which will be exploited only in very closed systems. As a result of poor diffusion, the consumer may not take advantage of possible price decrease due to the innovation. On the other hand, excessive protection systems, that are either too long-lasting or too complex, will produce situation rents and prevent the technology from being applied in other situations. Furthermore, they risk creating oligopolies that may discourage new operators from getting involved. As a result, the profits risk being appropriated by the innovator alone, to the detriment of intermediate users (the farmers) and consumers.
In order to select or develop a relevant system for each situation, a comparative study of existing systems (UPOV, various types of patents...) should be carried out in a global and long-term perspective (23), taking into consideration the present situation. Indeed, in most Northern countries, farmers are no longer involved in the creation of varieties: this has passed into the hands of firms or specialised bodies (24). On the contrary, owing to a range of collective practices, farmers in many Southern countries are still the main operators of the conservation and adaptation of animal and plant species. It makes sense to consider, both in the Northern and Southern countries, that existing systems resulting from long standing relationships between a range of operators, are forms of organisation, though not necessarily optimal ones, that have proven their efficiency. As a consequence, any move to disrupt these systems by changing the rules of the game, which could discourage farmers from getting involved in the adaptation of varieties, requires careful consideration and solid arguments and cannot be justified solely by profit increases for some operators.
As a corollary to these considerations on the economic system, I wish to mention two questions that have recently emerged on the role of the various operators involved in food production :
- the first relates to the role of the state. Indeed, in many developed or developing countries, the state has played over the past 50 years a major role in the genetic improvement of animals and plants, either by organising the creation, evaluation and dissemination of breeds and varieties or by producing innovations as a direct operator. In France, INRA has played and still plays a central role in the improvement of large animal species, via a national system of performance monitoring. For some small species such as poultry, rabbits, fish, INRA has itself produced and disseminated new varieties. The most well-known example is certainly Vedette, a chicken at the origin of a great part of French broiler chicken production. As regards plants, INRA created varieties for many arable crop species (wheat, maize, rape...) as well as for fruit and forest species. Over the past 20 years the emergence of efficient private operators , particularly for arable crop species, has led to a progressive and voluntary withdrawal of public research. How far should public research withdraw? Should we consider that, as in the case of agricultural machinery, fertilisers and phytosanitary and veterinary products, this sector should be ultimately handed over to private operators, with the state in the role of a regulator and stimulator of innovation? Or, on the contrary, should public research remain in certain areas in order to avoid monopolies, meet unanswered needs or deal with longer-term objectives? It may be useful to mention the case of pharmaceutical drugs, where innovation is entirely in the hands of private companies and where the issue of "orphan" drugs (i.e. molecules that are necessary for treating certain diseases but whose further development or production is unprofitable for private operators) has arisen. This may help reflect on the necessary and legitimate intervention of the state in certain areas, in a market economy.
- the second issue relates to the sharing of added value: in the food processing industry, which from the upstream suppliers, through the farmers and processing industry to the retailers, amounts to a total of 1,000 billion francs (150 billion euros), each operator legitimately ambitions to increase his/her share of added value and each innovation may change the distribution of added value. For instance, the development of pest-resistant plants will shift some added value from the pesticides manufacturer to the seeds manufacturer; the development of biological control methods will reduce inputs and increase the share of added value falling to the farmer, a gain which may later be recuperated by the distributors... One could at first sight consider that these shifts in added value between the economic operators are normal market processes, and that the concentration of added value in the upstream or downstream part of the industry is neither more nor less desirable than the recapture of added value by the farmers, as long as the final food price does not change for the citizen. Nevertheless, these views are being increasingly challenged, or at least questioned, by society. When these transfers allow a concentration of activities, both up- and downstream, in the hands of a few operators only (for example companies manufacturing drugs and phytosanitary products), we may indeed worry about the resulting dependency situations for farmers, and thus for the country's food security. Similarly, such evolutions cannot be viewed as neutral when they may induce social and environmental (25) consequences which the state and citizens will have to assume.
Therefore, by defining and implementing rules allowing the appropriation of living organisms, we make an implicit choice on the future economic and social organisation. The debate has shifted from the technical to the political, as clearly shown in the debates that surrounded the Seattle conference.

2.3. The ethical debate: foundations for a bioethics of the "non-human"?
Strictly speaking, ethics refers to the legitimacy of human behaviour towards themselves and their fellow humans. To guide people's acts in everyday life, they rely on a range of ethical references, based on age-old philosophies or religions, which are expressed in general principles and sometimes in highly detailed precepts.
The ethics of the relationships between humans and nature, especially when linked to the new possibilities offered by science, raises novel questions:
- on the one hand, the issue of the limits of human intervention on living species does not seem to have fostered as much philosophical speculation as in ethics in the strict sense of the word. This is particularly true the further one moves from species that are biologically or affectively close to humans. Neither the Bible nor the Koran put restrictions on the mastery of man over nature, apart from the attention to be given to useful species. The utilitarian aspect of this attention is only too obvious (26). Even the New Testament shows no indulgence for a fig tree that bears no fruit (Matthew, 21, 19)! While some oriental philosophies recommend respect towards all life forms, this is often because these forms are possible avatars of the human species, so that respect is actually issued from a kind ethics that looks "beyond appearances";
- on the other hand, conceivable behaviours towards living species are also new and their ethical dimension is not easily perceived. For instance, while it is easy to perceive the ethical aspect of vivisection, transgenesis between distant species, micro-injection of spermatozoids in an ovum or xenotransplants (27) appear as purely technical actions, with no more ethical dimension than the mending of a car engine or performing a chemical synthesis.
This total lack of references induces a wide diversity of individual attitudes, ranging from people who do not perceive the ethical dimension of the technical possibilities of modern biology, so long as the techniques are efficient and safe, to people who consider that major transgressions, altering the very essence of Man, are occurring without a possibility of opposing them or at least discussing them. Most probably, these different attitudes implicitly express contrasted representations of nature. Depending on our perception of whether nature is resilient and stable or on the contrary consists of a set of fragile balances, we will consider that nature is able or unable to tolerate and adapt to human action.
As regards the appropriation of living organisms, few texts set limits based on ethical considerations, now that the patentability principle has been accepted. The French law of July 29, 1994, states that no patent can be taken on "inventions whose publication or implementation would go against public order and accepted standards of good behaviour". However, this principle applies only to prohibiting patents on "the human body, its parts and its products". The European patent takes up this morality clause and Greenpeace, in 1995, failed in its attempt to use it in order to oppose the patenting of a transgenic plant. Greenpeace pointed out that plant material is a part of the common heritage of humankind and that it was therefore an offence to moral standards to allocate its ownership to only a few individuals. Similarly, the 1998 European directive extended regulations concerning animal pain to biotechnologies, and prohibits the patenting of "modifications of animal genetic identity able to cause pain without significant medical contribution". Note that this very limited ethical framework for the appropriation of living organisms is a European specificity. At a recent congress on the European directive (28), the American Todd Dickinson regretted these limitations (regarding man and its products and animal pain) and declared that this approach "could make standardisation between developed countries more difficult to achieve [and that] this exclusion seems to be based on ethical considerations which could be regulated outside the framework of patent legislation rather than through it".
Several approaches have been proposed to lay the foundations of this new ethics:
- the first, which may be viewed as classical and humanistic, since its ultimate goal is the future of mankind, establishes a link between impacts on nature and the resulting consequences for the future of humans in the short- or long-term. This is in particular the approach upheld by the German philosopher Hans Jonas in a book he wrote in 1979, The Principle of Responsibility (29) . This is the principle: "Act in such a way that the effects of your action are compliant with the continuation of a truly human life on earth [and] so that the effects of your action do not destroy the possibility of such life in the future". Respect for nature therefore becomes, via its possible consequences, respect for the future of humans themselves, which in some ways generalises Kant's maxim: "act only on that maxim whereby you can at the same time will that it should be a universal law." The same approach is shared by the Japanese Tomonobu Imamichi who defined the concept of "eco-ethics" (30) as an obligation for technology to ensure the creation of a "habitat" favourable to humankind and its future, with the habitat being defined as the ecological and social environment of humankind;
- the other comes from Anglo-Saxon "deep ecology" school. It elaborates on the idea that nature possesses its own proper rights that must be respected by humans, even at their own expense. Deep ecology also claims that humans have no more rights than any other living species and consequently must integrate into the ecosystem without disrupting the functioning of our planet Earth.
This standpoint views the earth as a living "super-organism": this is the "Gaïa hypothesis" (the Mother Earth of Greek mythology), developed 20 years ago the by James Lovelock (31). Philosophers like Élisabeth de Fontenay (32) defend the less widespread view that certain species have their own rights, especially domestic animal species, which are associated with humans in a "common destiny". This common destiny is the result of domestication which altered animals to suit the needs of humans, thus creating a human responsibility towards the future of these species. The notion of "animal rights" is indeed implicit in some texts (33) and the 1987 European Convention for the Protection of Pet Animals states wild animal should be obliged to suffer the life conditions of pets. Similarly, the Belgian law of 1986 obliges animal keepers to provide animals with "food, care and lodging [...] adapted to their degree of development or domestication".
In practice these various approaches may understandably lead to varied attitudes with respect to the acceptability of some interventions.
However, while scientists should not impose their viewpoint in defining this new ethics of living organisms, it is nonetheless their responsibility to contribute knowledge on two issues:
- to highlight the underlying ethical dimension of biotechnological innovations, which, as said earlier, is often not immediately obvious (34). For instance, it has been shown that xenotransplants may stimulate the expression of new pathogenic viruses in humans, with the result that the deceiver may then contaminate other people. There is consequently a possible conflict between individual profit and collective risk, which did not exist in the case of traditional drugs whose benefits and drawbacks affected only the individual. The ethical dimension, in the strict sense of the word, of such a conflict is obvious and needs to be examined. Similarly, we need insight into the complex issue of possible effects of different forms of appropriation of living organisms on cultivated plant diversity, on habitat biodiversity and therefore on the possibility of sustainable development for humankind.
- to help define what nature "actually" is in terms of reactivity to human intervention, or to indicate the limitations of science when the consequences of a phenomenon cannot be effectively predicted. A good example of this uncertainty is the impact of certain transgenic plants on the environment. From the moment that pollen from these transgenic varieties will be able to fertilise wild individuals of the same or related species, resulting in the dissemination of new genes from very different species into these wild plants, predicting the long term consequences of large-scale growing of these transgenics will be extremely difficult. Many scenarios have been proposed, ranging from progressive disappearance of these genes to the dying out of the receiver species or, on the contrary, their conversion into invasive crop weeds. They all highlight the limitations of our knowledge. This does not mean that such transgenic crops should be banned, but that our choice cannot rest on individual decision: there is a collective dimension, which regards our future and must therefore be debated.

[R] Conclusion

Advances in biology and the possibilities they offer for appropriating living organisms have induced society to scrutinise and sometimes critically examine these advances and, most of all, their applications. Some may regret the time when biology stood far less in the limelight, and even more the times when its achievements raised only admiration.
I personally rejoice about this attention. In my opinion it demonstrates that the adventure of research is not an individual quest only, but that it also participates in building our future society, a process that necessarily involves dialogue with those who consider they have a say in the matter, in short the citizens.
Jean Rostand wrote: "man has become too powerful to permit himself to play with evil. His excessive strength compels him to virtue"(35).


Bernard Chevassus-au-Louis is head of research at INRAand chairs the Board of the Agence française de sécurité sanitaire des aliments (French Agency for Food Sanitary Safety).
I would like to thank particularly Philippe Colas, Yvette Dattee, Jean-Stéphane Joly, Hervé Reverbori, François Rodolphe and Xavier Rognon for their help in documentary research for this paper.

This article is taken from the "Courrier de l'environnement de l'INRA, n°40", by B. Chevassus-au-Louis.
Translated from French by Nicole Scott.

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Notes

(1) For example, if pigeons leave their pigeon cot or fish their lake, they become the property of the owner of the new place where they have elected to "stay" (article 564 of the French Civil Code).[VU]
(2) Aristotle, On the Generation of Animals, quoted in "Histoire de la notion de vie". Gallimard, 1993 by André Pichot,.
see especially pp. 106-116 [VU]
(3) See André Pichot, ibid., pp. 409-414 on the work of Bonnet and ovism.[VU]
(4) On the genesis of the Mendel and Galton's ideas, Cf. in La Recherche, the articles by Marcel Blanc (1984, n° 151, pp. 46-59) and Jean-Louis Serre (1984, n°155, p. 1072-1081).[VU]
(5) Characters displaying a finite number of variants, which were called "Mendelian characters". The other characters, displaying continuous variation, were assumed to be ruled by heredity through mixing. In 1918, the Englishman Fisher showed that continuous variation could be interpreted on the basis of Mendel's law [VU]
(6) Having male and female reproductive organs on the same plant, which is the most frequent situation. [VU]
(7) In animal, true-to-type reproduction phenomena through systematic self-fertilisation or parthenogenesis (development of the ovum with no genetic contribution of a spermatozoid) are known in invertebrates and a few lower vertebrates, but does not concern any of the species bred by man. [VU]
(8) In the case of plants, manual castration has only limited applications, such as elimination of male ears in maize in order to produce hybrid seeds. [VU]
(9) Crossing of a common female duck with a Muscovy duck, used in the production of foie gras. [VU]
(10) Which is not systematic in the case of mules. In the case of mating with a horse, the descendants of fertile mules would probably look like horses.[VU]
(11) At least as long as the farmer had a choice between conventional varieties, which could be resown, and hybrids. Moreover, other aspects (guaranteed sanitary quality and germination rate, treatment of seeds against pests…) often motivate the farmers to buy seeds, even of resowable species. [VU]
(12) Most animal and plant species are in this situation although there are a few naturally polyploid species especially in plants. [VU]
(13) The most discussed case is that of maize, for which the possibility of appropriation opened by hybrid varieties could have been, according to some people, the main reason for the private breeders' choice of this method (see Jean-Pierre Berlan : Quelle politique "semencière" ? Dossier Génomique et Sélection. OCL, 6(2), March/April 1999). However, it would seem that research bodies who have long worked on improving maize through conventional breeding (such as CIMMYT, International Centre for the Improvement of Maize and Wheat, based in Mexico) finally shifted to improvement through creation of hybrids. Maize heterosis, although a still ill-known biological phenomenon, is not just a mirage for commercial use! [VU]
(14) As a matter of interest, the article relating to this congress does not appear under the section "Science et politique" in the 1975 index of La Recherche but under "Biologie, médecine". [VU]
(15) Although Lenin was favourable to him, Vavilov was attacked from 1931 - particularly by Lyssenko - because the theories of Mendel and Morgan as well as neodarwinism were considered "bourgeois" and contrary to Marxism. In 1939, during a debate at the Presidium of the Lenin Academy, Lyssenko told Vavilov for instance: "I had understood that…, following your master Bateson, you believed evolution to be a simplifying process. Yet, in chapter IV of the History of the Party, it is said that evolution increases complexity". Vavilov was arrested in 1940 and died in prison in 1943 (see especially Joël and Dan Kotek, 1986, L'affaire Lyssenko, éd. Complexe, Bruxelles). [VU]
(16) Les ressources génétiques au secteur des productions végétales, ed. INRA, 1993. [VU]
(17) This system seems to be similar to that of artworks, for which replication and plagiarism are prohibited while new work which, implicitly or not, draws its inspiration from existing work, is considered to be original.[VU]
(18) In the case of patents, someone who improves a patented object or method can take out a patent on his/her own improvement. However, the user of this patent will have to pay royalties to the owner of the original patent. [VU]
(19) On this progressive evolution of law with regard to living organisms, see the paper by Bernard Edelman "Le droit et le vivant", La Recherche, 1989, n°212, pp. 966-976.[VU]
(20) This possibility is not exactly affirmed as a true right but rather only as a (Art. 10) "dispensation". [VU]
(21) For instance, the firm Monsanto established a phone number that farmers can use to denounce persons guilty of fraud (The Washington Post, 3 February 1999). [VU]
(22) Indeed, many crops grown in the Northern Countries - maize, rice, tomato, potato - originated from the South. [VU]
(23) The issue of the long-term is particularly significant in the field of genetics. Some selection methods may be very efficient in the short term, and therefore attractive for private operator in a competitive context, but progressively level off and in the long term lead to lower improvement results than with more prudent strategies. The question is therefore whether these prudent strategies, which are less competitive in the short term, should be encouraged. [VU]
(24) Except through participation in the evaluation of new varieties on the basis of multi-local trials. [VU]
(25) For instance, the comparison between crops of insect- or herbicide-resistant transgenic plants and classical varieties for which other chemical pest control and weeding methods are used should be carried out in this general environmental perspective. [VU]
(26) Nevertheless, the biblical precept "One who beats an animal to death must make restitution for it: life for life." (Leviticus 24.18) reminds us that the entire creation is the work of God and must be respected as such by humans. [VU]
(27) Organ or tissue transplant between different species. Up to now, this practice has been greatly limited by the quasi-immediate rejection of the transplant by the receiver. However, advances in the biotechnologies, in particular the appearance of transgenic pigs whose tissues would be made compatible with those of humans, make it possible to practice such transplants on a far wider scale. [VU]
(28) Brevetabilité des inventions biotechnologiques: un nouveau départ pour l'Europe. (Patentability of biotechnological inventions: a new start for Europe). Actes du colloque organisé par Willy Rothley, député au Parlement européen (octobre 1998), page 103, éd. M&M Conseil, Paris.[VU]
(29) Translated into French in 1990, éd. du Cerf, Paris. On the work of Jonas, see also the paper by Dominique Bourg in La Recherche, 1993, n°256, pp. 886-890.[VU]
(30) Described and discussed in the work of Jean Ladrière, L'éthique dans l'univers de la rationalité , 1997, éd. ARTEL-FIDES, Québec (see pp. 12, 63-64, 229-243). [VU]
(31) On these aspects, see Robert Barbault, 1994, Des baleines, des bactéries et des hommes, éd. O. Jacob, Paris (pp. 209-211). [VU]
(32) Le silence des bêtes, éd. Fayard, Paris, 1998.[VU]
(33) On this matter, see the article by Marie-Angèle Hermitte, L'animal à l'épreuve du droit des brevets, Natures, Sciences, Société, 1993, 1, 47-55. [VU]
(34) And is even eclipsed by the essentially technical dimension of the approach. This simplistic characteristic of scientific approaches is well studied by Jean Ladrière (ibid. chap. 3 et 12).[VU]
(35) Inquiétudes d'un biologiste, p. 63, 1967, éd. Stock, Paris.[VU]

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