GENOMICS: WHOLE GENOME, TOTAL CONTROL

GENOMICS: WHOLE GENOME, TOTAL CONTROL

The birth of the science of genomics has sent the race to appropriate and exploit the genes of humans, animals and plants into high gear. Genomics is the study of all the genes of a given species and the way in which they interact in order to generate the characteristics of that species. Genes are the future currency of both the pharmaceutical and agricultural industries, and genomics is the tool researchers are looking towards to help develop new drugs, foods and industrial products. Companies involved in genomics research are not shy in their predictions. "Death is a series of preventable diseases," claims the head of Human Genome Sciences.

Genomics research began in earnest with the launch in the US of the Human Gene Project (HGP) in October 1990, a public sector initiative to map the whole of the human genome. Hyped as the greatest endeavour ever undertaken in the field of biological medicine, the HGP has been funded to the tune of $US 2.2 billion. Since then, at least 18 countries have established human genome research programmes: mainly industrialised nations, but also Brazil, China and Mexico.

HGP findings were intended to be made public in order to support further research efforts. However, one of the scientists from the project left to set up his own private company, Celera Genomics, in direct competition with the HGP. Because the company used a different (and more crude) technique from researchers in the HGP, Celera claimed that it could sequence the whole genome in less than three years and at a fraction of the cost ($US200 million). Celera’s challenge to the HGP signalled the start of the race for the human genome, and it was soon joined by numerous other start-up companies looking to capitalise on this new source of potential wealth.

Pharmaceutical companies have been eager to enter into agreements with these start-ups in order to appropriate genes involved in profitable illnesses. They have collectively invested more than US$1.8 billion in such alliances, excluding in-house efforts. Research activity has been translated into a wild frenzy of patent applications as companies try to gain proprietary control of the genome. Celera and Human Genome Sciences have filed for preliminary patents on 6,500 and 6,700 human gene sequences respectively, while Incyte has filed patent applications covering an estimated 50,000 individual human genes. In most cases, the companies have little or no idea about the gene or gene fragment’s function, which should automatically result in the applications being turned down. But the companies are undeterred, since plenty of patents have already been awarded for products lacking the inventive step and evidence of usefulness.

Competition between private and public concerns has accelerated sequencing efforts. Celera claims to have sequenced almost three quarters of the genome and the HGP is planning to release its ‘first draft’ this spring. Concern is rising in scientific and political circles that privatisation of the human genome will hamper medical research and the benefits thereof. In September 1999, the UK and the US governments announced that they were drawing up an agreement to prevent patenting of the human genome. But this has not yet translated into action, and it seems highly unlikely that the US in particular will follow through, having already granted some 1,500 patents on human DNA and being the home of all the leading genomics companies.

Research in plant genomics has been much lower profile than human genome research, but many scientists believe that practical results of genomics research will be manifested in the agricultural field long before those in the field of human health. Industry, with its myopic view of the future of agriculture being rooted in genetic engineering, sees a genomics approach as essential. The modifications that can be introduced into a plant through genetic engineering are currently very limited: only those traits regulated by one to three genes can be engineered with some effectiveness. But such traits are the exception, rather than the rule. Researchers are finally taking notice of the fact that gene relationships and interactions are as important as their individual effects. Genes operate together as a system, and their effects are more than the sum of their parts.

Most of the traits of economic relevance for industrial agriculture – such as yield, stress tolerance, salinity tolerance, nutrient content – are the result of complex interactions between a number of genes and their environment. The single gene approach to genetic engineering is already reaching the end of its short life, and a genomics approach is seen as the natural next step. Although the endeavour is huge, fortunately for the researchers it has been found that plants are genetically very conservative, meaning that the genes that code for plant traits and processes are nearly identical across a wide range of species. This makes their task a great deal easier.

The model plant that has received greatest attention so far is Arabidopsis thaliana or wild mustard, a dicotyledonous plant with one of the smallest known plant genomes. Rice was the obvious choice amongst monocotyledons, because it is not only economically very important, but its genome size is six times smaller than corn and 37 times smaller than wheat.

From the start, plant genomics initiatives have been influenced greatly by the private sector agenda. In 1995, the first high-profile corporate call for public investment on plant genomics was the US National Corn Initiative (NCI). Heavily backed by industry and carrying the slogan "The future of the corn industry is written in the genetic code," the NCI is being touted as the way to ensure continued US dominance of the international corn market. Industry’s strategy has been to obtain government funding to sequence the entire corn genome. The results would be protected under patents owned by the US government, which would make them available to the US research community – that industry itself dominates.

Industry has also welcomed the US National Plant Genome Initiative (NPGI), an inter-agency strategy to fund plant genomic projects. Among its goals are participation in international genomics collaborations – mainly the sequencing of Arabidopsis and rice genomes – and the development of genomics technology. The NPGI was funded to the tune of US$40 million in 1998, US$50 in 1999, and is projected to reach US$145 million in 2000. Virtually all the projects funded so far have been granted to universities and non-profit research institutes, although these include also Venter’s Institute for Genomic Research, which is closely tied to Venter’s for-profit Celera Genomics. The bulk of the money has gone to functional and mapping projects, and corn has been the main target crop, with 13 projects approved and US$55.5 million awarded. The NPGI has also funded four projects focusing on the functional genomics of Arabidopsis, and three on mapping the rice genome.

The US government has also activated in-house genomics capacity. The US Department of Agriculture (USDA) announced in January 1999 that it was to establish a new Center for Bioinformatics and Comparative Genomics at the Cornell University, and it was also to acquire eight state-of-the-art automated machines to speed gene sequences. These new capacities were to convert the USDA’s Agricultural Research Service into "the single most powerful force in genome sequencing within the public agricultural research sector."

The intellectual property policy of the NPGI is somewhat unclear. The adopted policy is that "All resources, including data, software, germplasm, and other biological materials should be openly accessible to all." But, rather feebly, it only promises "not to patent early-stage research tools and to discourage plant genome initiative grantees or contractors from doing so." It is obvious that the US public sector is too entangled in patenting itself and feels much too obligated to the private sector to establish a clear non-patenting policy. However sound its intentions, the NPGI will probably end up subsidising industry’s work and hammering a few more nails into the coffin of public research.

In the last decade, the European Union has invested EURO 40 million in genomics research. Most of this money has gone towards Arabidopsis, the EU having financed the sequencing of 25% of its genome. Some European member states are also undertaking their own genomics initiatives. France has laid its public research sector at the feet of industry through its controversial Génoplante initiative, whose goal is to privatise as a large part of our crop genetic heritage as possible, before other countries do so. The French government is about in invest US$158.9 million in this blatant subsidy to its transnational corporations (see Seedling Vol 16, No 3, p17).

Japan’s main priority in genomic research has been the sequencing of rice, which it began in the late 1980s. Initially, the involvement of the private sector in the Japanese Rice Genome Research Program (RGP) was so strong that it had to be shut down and set up again. By 1998, the RGP had an annual budget of US$5.5 million for gene sequencing, and a further US$17 million for other genomic research. In 1997 Japan was made permanent chair of the International Rice Genome Sequencing Project (IRGSP), which aimed to map and to sequence all the rice genome by 2008. Current members of the IRGSP are Japan, the US, the EU, Taiwan, Thailand and South Korea. This supposedly open access initiative was to keep all data in the public domain, but has not been free from industry pressure. In order to ensure funding from private companies for the second phase, the Japanese Ministry of Agriculture, Fisheries and Food has deliberately excluded genetic data on the roots and flowers from being released.

In April 1999 Celera (whose non-profit arm, the TIGR, is a part of the IRGSP) offered to sequence the whole rice genome in six weeks for any company willing to pay its price of US$30 million. No company has yet taken the company up on its offer, but the announcement raised concerns all over the world about the proprietary control of plant genetic material, just as Celera’s voyage into the human genome had done. The announcement scared the IRGSP into advancing its calendar by almost four years (to 2004) and stepping up its budget. Japan pledged to inject extra funding: in 2000, the country’s annual rice genome research budget is to reach US$ 67 million, a threefold increase from 1999.

The other large plant genomics international programme is focused in Arabidopsis, which is known as the Arabidopsis Genome Initiative (AGI). The AGI’s steering committee comprises representatives from the EU, Japan, US – including both University consortiums and the private sector – and France. It is now estimated that the entire sequence of Arabidopsis will have been sequenced by the end of 2000.

While plant genomics is given an increasing priority in the main economic nodes of the North, the South remains almost completely marginalised. The science of genomics will polarise even further the haves and have-nots in agricultural research, because of the astronomical cost of seqencing machines and technologies to interpret the data they produce. At the moment, the only large sequencing project that directly involves countries from the South is the IRGSP, of which Thailand is a member country. Only three of the International Agricultural Research Centres (IARCs) of the Consultative Group on International Agricultural Research (CGIAR) are planning any involvement in genomics: ILRI intends to use genetic markets of disease resistance for selection of breeding stock to develop improved high-resistant livestock; ICRISAT is setting up an Applied Genomics Laboratory to develop molecular strategies, techniques and analyses to enhance the use of the accessions stored at ICRISAT’s germplasm bank and to investigate pathogens; and IRRI is about to hire a bioinformatics specialist to integrate molecular and genomic data with the information generated through more traditional approaches to the study of rice.

As for developing countries themselves, Brazil is the first country in the South to have completely sequenced a species' genome. It has been working on the bacterium Xylella fastidiosa, which it claims is be the first crop pathogen to be fully sequenced.

In 1998, India invested US$250,000 in a Plant Genome Research Centre at the Jawaharlal Nehru University in New Delhi. In March 1999, the Indian government announced an initiative to sequence the entire genome of chickpea there, with a budget allocation of US$4 million. The Indian government stated its interest in this particular crop because it considers that no other government will be interested in it – perhaps somehow underestimating the interest that Australia has clearly shown in it. However, difficulties have already been reported as Indian scientists are drawn towards Monsanto’s US$ 25 million genomic research centre in Bangalore, which offers better salaries and rosier job prospects.

Pioneer Hi-Bred International, which is being bought up by DuPont, was the first seed company to venture into the genomics arena. Having failed to convince the US government to invest in genomics research, it decided to go it alone. In January 1996, it teamed up with Human Genome Sciences (HGS). In exchange of US$16 million, HGS was to sequence the genes in Pioneer’s corn gene bank. Pioneer would own all the gene sequence information and intellectual property rights resulting from the collaboration. In this way, ‘lord of the gene’ Pioneer had set itself on the path to becoming ‘lord of the genome.’ Meanwhile, it continued to encourage the US government to undertake its own corn sequencing programme, hoping to have free access to the results of public research, while holding its own cards tight to its chest.

The next significant move came when Monsanto announced an strategic alliance with Incyte Pharmaceuticals in October 1996. Monsanto would have exclusive access to Incyte’s plant genome database – presumably generated from samples provided by Monsanto, but remaining under the control of Incyte – with Monsanto paying Incyte part of any future royalties gleaned from sales of products developed through the agreement. These two basic approaches to the control of genomic information – owing and patenting sequences or paying user fees for accessing value-added information without actually owning the sequences – now characterise most joint ventures in this field.

In the last three years, the agricultural genomics scene has changed dramatically. Access to and control of complex genomic information is now perceived as the cornerstone for the future development of transgenic plants, and the leaders of the agroindustrial genetic complex have entered a race for being the first to identify – and hopefully own – the genes involved in the regulation of commercially interesting traits and their interactions. Private sector investments in the last four years have already greatly exceeded the investments made by public sector on model plants. These companies are now courting genomics start-ups just like the pharmaceutical industry has been doing since the early nineties (see Table 1). The situation is reminiscient of the early nineties, when a number of biotechnology start-up companies (such as Plant Genetic Systems and Calgene) serviced their genetic engineering needs. The start-ups ended up being ingested by the transnationals, a move that may well be played out in the genomics field.

Table 1. Some agreements between agbiotech companies and genomics companies and institutions

* Fund is co-managed by Makhteshim-Agan Industries of Israel, one of the world's main generic pesticide producers.
** Savia is the name of the company formed by the merger of Empresas La Moderna and Seguros Comercial America.
Source: Compiled by GRAIN

One of the highest bidders for plant genomics is Novartis, which is investing about 10% of its agricultural R&D budget on genomics. In 1998, the company invested a breath-taking US$600 million in a brand new genomics research centre in La Jolla, California: the Novartis Agricultural Discovery Institute (NADI). NADI is focusing on "understanding the basis of crop performance and finding genes outside plants that could improve health and nutrition," and is collaborating with academia and genomics companies. Aventis is also investing heavily in genomics, mainly via Rhobio, a joint venture between Rhone Poulenc and Biogemma (co-owned by Limagrain). It is no small significance that this joint venture between the largest French agrochemical and seed business was launched just five months after the birth of Gènoplante, in which France offered up its public research to these very companies. Pioneer Hi-Bred, and its new owner-to-be, DuPont, are positioning themselves as the leaders in corn and soybean genomics respectively. According to Doyle Karr of Pioneer, the companies’ combined efforts have already "identified more than 90% of the DNA sequencing in corn genes." And Monsanto, of course, which hates to be left out of anything, has bought up Millenium’s sequencing technology, created a genomics subsidiary, set up a genomics research centre in India and started working with IBM in the field of bioinformatics.

As interest in genomics gears up, the interface between the private and public sector is becoming increasingly blurry: in fact, France’s Gènoplante initiative seems to remove it altogether. NADI’s agreement with the genomics section of Berkeley’s Department of Plant and Microbial Biology is almost as blatant. Berkeley is to own all patents arising from the US$25 million agreement, and to collect royalties from them. Meanwhile, Novartis will receive first rights to negotiate for 30-40% of the discoveries (the company gets to select which) made in the department, since it provides 30-40% of the funding. Novartis also has rights to review scientific manuscripts 30 days before they are submitted for publication, in order to assess potential business applications. The UK’s John Innes Centre and Sainsbury Laboratory have struck up long-term research alliances with Zeneca and DuPont, and Germany’s Max-Planck Institute has teamed up with AgrEvo (Aventis).

The rationale industry has for investing in plant genomics is to extend the technological and legal frameworks for genetically engineered crops to economically interesting traits that are controlled by the interaction among a large number of genes. It is therefore unsurprising to find that, as in human genomics research, agroindustrial companies have been eager to claim intellectual property on every gene sequence they stumble across. But unlike the pharmaceutical industry, companies are largely limiting their patent applications to whole genes rather than sequences. As yet, only a few patents have been awarded, but many companies are building up quite a library of patents pending. Companies are unwilling to disclose exactly how many patents they have applied for or have been awarded, but some, such as Pioneer Hi-Bred and Aventis, have been particularly aggressive in this realm. Novartis appears to be favour a more open-access approach to early stage research, but is equally eager to gain proprietary control of anything that looks potentially lucrative (see Table 2).

Table 2. Work and IPR agreements between some agbiotech companies and genomics partners

Key to type of work: S=sequencing, M=mapping, E=expression, F=functional genomics, B=bioinformatics
Source: Compiled by GRAIN

The practice of patenting human genes and gene sequences has already been denounced by the scientific establishment. Now, interestingly, industry is also starting to question its wisdom. As Steve Seelig, from Vysis, a functional genomics company, recently declared to Nature Biotechnology, "somebody needs to step up and say intellectual property can be an extraordinary hindrance and that patents are not always in the national interest." Seelig even went so far as to suggest that perhaps the Patent and Trademark Office should outlaw the patenting of genes! Seelig’s concerns focused on pharmaceutical research, whose industry serves a global market of US $300 billion. If the pharmaceutical industry is going to struggle to finance genomics research in an aggressive IPR environment, agroindustry will struggle even more, given that the market for agrochemicals and seeds is only one-fifth the size. In practice, the patenting of crop gene sequences could limit the playing field to only those owning enough sequences themselves to gamble with.

Granting property rights on plant gene sequences is already starting to affect the ability of researchers to do their work. A small but significant study in the US found that 48% of 86 university plant breeders who answered a survey indicated that they had experienced difficulty in obtaining genetic stocks from private companies, and 45% indicated that this had interfered with their research. Limiting access to genetic material will have even more serious consequences in the field of genomics than in traditional plant breeding. Sequencing is but the first step in genomics research, and current methods of figuring out the function of the hundreds of thousands of sequences generated in this way require the analysis of many genes at the same time. Such forms of analysis could be prohibitive not only for public sector researchers, but also for many companies if they are forced to pay heavy licensing fees.

There is a certain amount of recognition of this reality amongst researchers, many of whom recognise that it is everybody’s interest to keep early stage research findings in the public arena. Competitive advantage would be gained not by being the first to sequence, but by being the first to make sense out of the sequences through the development of proprietary bioinformatics systems. This seems the way many genomics companies, and also some gene giants, such as Novartis, seem to be pushing ahead. As Steve Briggs, head of NADI, says, "We can’t afford to patent everything – our policy is to patent useful inventions." (As if it should be possible to patent any other kind of invention!)

One aspect that makes functional genomics more straightforward in agricultural research than in pharmaceutical research is the relative homogeneity of plant genes across species. Many companies are able to file for patents on genes in one crop because the function of the same gene has been determined in another crop. How the race for the genes plays out remains to be seen, but we can be sure of two things. First, companies will do everything possible to ensure legal or biological control of any variety developed through genomics. Second, the farmers that have developed the varieties containing the genes companies are interested in will not be compensated in any way.

Marching boldly into the world of plant genomics is a risky affair for the agricultural industry. The gene giants are failing to recoup the rich rewards they were expecting to gain from the heavy investments they made into transgenic crops. While they confidently boast that consumer adversity to genetically modified crops is merely a storm in a teacup, there is little evidence to suggest that the storm is going to abate any time soon. Genomics research will require unprecedented investments and risks, and has the potential to completely strangle companies and research through legal battles over proprietary issues. Nevertheless, agribusiness seems undeterred, as its substantial investments in this arena over the last few years indicate.

Given that both the agrochemical and pharmaceutical industries are investing so heavily in the genomics approach, the natural progression seems to point towards further consolidation of these two arms of the life industry. But there are also indications that marrying the agrochemical and pharmaceutical industries may not be altogether desirable. The pharmaceutical divisions of the life science giants continue to reap rich profits, but the agrochemical and seed divisions are floundering, owing to a stagnant agrochemical market and growing opposition to genetically modified seeds. Several of the so-called "life science" companies are placing their agricultural divisions at arms length. Novartis and AstraZeneca, for example, announced in December 1999 that they would be combining their agribusiness divisions in a new joint venture named ‘Syngenta.’ Similarly, Monsanto, almost bankrupt from its insatiable urge to gobble up seed companies, has had a hard time courting a pharmaceutical partner.

One thing that is clear is that genomics research can only entertain the élite. The huge costs involved mean that the South can barely even contemplate entering the fray, and Northern public research institutions are finding that they can only participate by prostrating themselves before industry. If the IPR environment continues to tighten up, the number of players will continue to shrink and agricultural research and development will be left in the hands of a few gene giants. Centuries of work by farmers all over the world will be sucked up into proprietary databases and patented gene banks, unavailable for use by all but a handful of researchers, whose goal will be to fill corporate coffers rather than feeding the world.

Even if genomics research was affordable and accessible to farmers, it still wouldn’t get them very far because of its limitations. Genomics research is an extension of existing work in genetic engineering. While it does offer the potential to develop crop traits that are dependent on a number of genes instead of just one or two, it is still rooted in a reductionist approach to agriculture. It still totally fails to recognise that gene expression is dependent not only upon the interaction between genes, but also the on interaction between genes and the environment. Genomics will merely lead to a refinement of the Green Revolution model of agriculture, which viewed crops as single-function and single-product machines and totally failed to recognise the importance of the agroecosystems surrounding and supporting them. As is clearly demonstrated in the article on vitamin A rice on p 9 of this issue, simply inserting genes coding for desirable traits into crops is going to get us nowhere in addressing hunger and other nutritional issues, and will lead agriculture further and further away from sustainability.

Industry argues that genomics research offers the promise of creating further diversity in agriculture. Even if this is theoretically possible, it will never become a practical reality. Half a century of industrial agriculture has caused agricultural biodiversity to plummet, and there is no reason to believe that genomics is about to change that. All it is likely to amount to is reshuffling an ever-decreasing pack of cards. No matter how many gene combinations to produce a given trait the likes of Monsanto have at their fingertips, they will concentrate their efforts only on the absolute minimum to gain the maximum profit. Industry does not understand the meaning or importance of biodiversity: it is merely interested in genetic resources.

The brave new world of genomics is not the answer to the world’s cries for sustainable agriculture: it is only available to large corporate concerns, whose focus is on dollar bills rather than peoples’ bellies; it is not accessible to farmers, the real motors for crop research and development; and its reductionist roots mean that research will be kept on a treadmill trying to address the problems it has created in the first place. What is needed is a new approach, which as Dr Mae-Wan Ho says, "re-affirms the ecological wisdom of traditional indigenous peoples all over the world, who have practised sustainable agriculture on the understanding that the biological nature of each organism or species is inextricably linked to the environment, and depends ultimately on the entire ecosystem consisting of all other organisms."

The South would be wise to ignore the call of the Green Revolutionaries that point to crop genomics as the way to overcome current limitations of genetic engineering, and push their farmers into the hands of future corporate-controlled, genomics-developed transgenic super-plants. Instead, developing countries would be better off to support and learn from the traditional innovation systems developed by their farming communities and indigenous peoples as the foundation for agriculture. Genomics research may provide some important and useful contributions which can be fed into this knowledge system, but to rely on it as the basis for agriculture is complete folly.

*  Human Genome Project website, http://www.ornl.gov/hgmis/project/budget.html

*  Sandy Thomas (1999) "Les brevets en surrégime", Biofutur, No 91, August 1999, pp28-31

*  Biotechnology and Development Monitor (Dec1999), Genomics: Sequences and Consequences.

*  Jeffrey Fox, "Complaints raised over restricted microarray access", Nature Biotechnology Vol 17, No 4, pp325-326

*  See the US National Corn Initiative web-page, http://www.inverizon.com/ncgi/

*  Personal communication with Steve Briggs, NADI, and Doyle Karr, Pioneer.

*  The National Plant Genome Initiative is described at http://www.whitehouse.gov/WH/EOP/OSTP/NSTC/html/npgreport.html

*  RAFI (2000), "Phase Two of Human Genome Research," RAFI Communique January/February 2000.

*  GRAIN (1998), "Japan: Genetech’s Late Bloomer", Seedling Vol 15, No 1, March 1998, pp2-11

*  KS Jayaraman (1999), "India sequences chickpea", Nature/Biotechnology Vol 17 No 3, p211, March 1999

*  Mae-wan Ho, (1997) Genetic Engineering Dreams or Nightmares? The Brave New World of Bad Science and Big Business, Research foundation for Science, Technology and Ecology/Third World Network