A Review of the Agri-Food Presentations from the Biotechnology Industry Organisation (BIO) 2002 International Convention

 

Liz Morris and Gwilym Williams

National Agricultural and Veterinary Biotechnology Centre, University College Dublin, Belfield, Dublin 4, Ireland.

 

The annual Biotechnology Industry Organization (BIO) meeting is the premier event of its kind in the world, with an estimated attendance this year of about 15,500 international delegates from 52 countries (Metro Convention Centre, Toronto, Canada, June 9^th – 12^th).  A choice of 15 parallel breakout sessions and symposia were complemented by a trade exhibition of truly enormous proportions (comprising over 1,000 exhibitors), and the usual line-up of high profile plenary speakers. 

 

Perhaps understandably dominated by North American presentations, BIO nonetheless continues to provide a useful barometer on emerging biobusiness trends for the European entrepreneur, at once representing a powerful opportunity to network and also to benchmark progress against the world’s leading biobusiness economy.  The agri-food track focussed primarily on the next generation of biotech innovation, and attempted to anticipate the likely socio-economic and regulatory climate against which such products will be judged. Interestingly, in contrast to the 2001 conference, which focused heavily on plant science innovation (reviewed by Williams, 2001), the emphasis this year was on animal biotechnology strategies for agricultural applications.

 

Review of Sessions

The agri-food theme was divided up into 9 sessions, conducted over three days, and covered a diverse range of topics as discussed below.

 

 

Working to enrich the landscape: a collaborative model to regain the American chestnut

In an opening presentation, entitled ‘trees of tradition, trees of technology’, Session Chair Steven Burke (North Carolina Biotechnology Centre, USA; www.ncbiotech.org) reviewed the challenges and opportunities facing forestry in North America and around the globe.  Burke articulated as a singular imperative the need to more efficiently increase tree production for lumber and derivative products in response to a growing world demand. Featuring quite targeted, consumer-led characteristics, such trees will also need to be grown using less land and with a diminished environmental ‘footprint’.

 

Burke proposed that biotechnology affords the opportunity to effect appropriate changes in key harvested tree types, while also permitting the preservation of existing forests by development of

altered species. An additional potential relates to providing a means to strengthen or regain key species that are important to landscape, culture, and economies. He articulated that there are good prospects for achievement of this goal within a commercially relevant time-line. From a technical feasibility standpoint, with the exception of some horticultural species, the undomesticated nature of many tree species lends itself to more amenable genetic transformation. Countering this, he acknowledged that forestry is also a conservative and traditional sector, and emphasised the importance of acknowledging the concerns of people on the issue of modified trees.  He therefore foresaw a need to balance the inevitable ensuing social tensions with a requirement to grow altered/transgenic trees, and advocated a reflective stance regarding the loss of natural forests. 

 

The question of phenotype is an integral component of forestry biotechnology, and Burke acknowledged that the ‘trees of technology’ will not necessarily look the same as traditional trees. Variations in shape and size relative to the wild-type are a possibility, as biotechnology strives to effect control over such features as flowering and crown development, increased fungal and insect resistance, and reduced lignin content. 

 

Many of these issues are being investigated under the auspices of the Institute of Forest Biotechnology, formed in North Carolina in early 2001 as a non–profit organization to develop this technology (www.forestbiotech.org). For example, the Institute’s Heritage Trees programme is deploying biotech strategies to help threatened tree species such as elm, American chestnut, dogwood, Frazer Fir and oak.   

 

Extending the debate in a commercial direction, Charles Michler (USDA Forest Service, Purdue University, USA) focused on the use of biotechnology to add value to the area of fine, decorative hardwoods, typically used in furniture production (such as figured walnut, black walnut, red oak and black cherry).  An array of techniques, spanning classical breeding, molecular marker-assisted selection, advanced propagation techniques and plantation management are now being complemented by genetic modification strategies (to be used “when the genes are not in the natural population”). Using such technologies, Michler highlighted that it is possible to cut as many as 10 years from the conventional breeding cycle, with genetic modification techniques facilitating the creation of targeted mutations. 

 

For example, black walnut is being developed for improved disease resistance, control of heartwood formation, selection for fast juvenile growth and also herbicide tolerance. A separate walnut breeding programme is targeted at the isolation of genes from heartwood, sap and the sap-heartwood transition zone in order to determine which genes control ‘figured’ (decorative) traits. Breeding for less sapwood in walnut and less heartwood in maple is also being pursued to add market value to these species. 

 

Confirming Burke’s assertions regarding alterations to phenotype, Michler outlined that tree domestication strategies often result in many radical modifications to plant appearance, such as changes in shape, size and structural architecture. This is usually accompanied by a significant gain in productivity attributes (such as increases in the size of usable parts) and improvements in yield and product quality.  Success in such intensive management systems requires that the trees do not compete with each other, produce maximum stem growth, possess shorter but thicker stems, and demonstrate maximum light interception in the crown. Flowering must also be controlled to inhibit gene flow to natural relatives; such trees are unlikely to survive in the wild without human intervention, and Michler conjectured that they may therefore represent less of a policy issue for governments.

 

John Pait (CellFor Inc., Vancouver, Canada; www.cellfor.com) predicted a significantly elevated US demand for wood, with an estimated 43% increase in this market over the period 1995 to 2020. This growth is currently most marked in loblolly pine and spruce. In global terms, current wood demand requires the use of 40% of the world’s natural forests, with managed plantations contributing to only 4% of this requirement.  Against a declining forest land base, there is therefore an urgent need to generate ‘more-from-less’. Pait proposed that somatic embryogenesis and transgenesis applied to elite clonal forestry represent a viable solution to this challenge.

 

The use of somatic embryogenesis, combined with the establishment, storage and testing of clones, and systems for mass clonal development, will all enable breeders to circumvent the limitations of seed orchards, while this technology also acts as a viable platform for transgenesis. These advantages are reflected in terms of reported yield improvements from such systems: 30-60% with clonal forestry, versus 8-13% with a seed orchard, while the crop is also of more uniform quality than traditional forests/plantations.  Indeed, Pait proposed that such improvements in quality control may some day enable forestry products to rise above ‘commodity’ status, predicting higher value branding in this area in the future. 

 

In closing, Pait recognised potential problems regarding the public acceptance of biotechnology in forestry, as trees are very personal to the general populace, who remain sensitive to changes in this area. Indeed, due to “outstanding ecological issues” and current social resistance, he estimated that it may be a while before transgenic forestry is fully developed.

 

Countering the commercial perspective, in a talk entitled ‘new trees yield responses and responsibility’, Michael Fernandez (Pew Initiative on Food and Biotechnology, USA;  www.pewagbiotech.org) foresaw possible risks as well as benefits pertaining to tree biotechnology. While acknowledging that the “technology is too valuable to abandon”, he also pointed out that “controversy has been a constant companion of forestry” in this area. Primary among the concerns he articulated were the difficulties in reversing any potential environmental damage and the practical challenge of tracking transgene “escapees”. His projections for wood demand were also more sober, opining that at present the overall demand for wood is flat, but he did recognise an increase in growth in certain market sectors. 

 

Fernandez stressed that the public have quite strong emotional ties to forests (“people chain themselves to trees”), and opined that existing regulatory processes do not adequately factor in such emotions.  He also felt that numerous questions exist about the capacity of the US regulatory structure to effectively incorporate a consideration of forestry biotechnology; indeed, in his view, the regulators need help in knowing the relevant questions to ask.  Perhaps central to the debate is that society currently has divergent values, and nobody has yet taken ownership of this topic.  The public need assurances, while the industry must learn from the GM debate that has taken place to date. There is still room for dialogue regarding this particular application of biotechnology, but he warned that the developers of the first GM forest must be able to demonstrate a clear value to the public.

 

Biotechnology for developing countries: an important tool in sustainable development

Targeting the debate on new technologies of benefit to the poor in developing nations, Session Chair Sakiko Fukada-Parr (United Nations Development Programme and lead author of UN Human Development Report 2001, ‘Making New Technologies Work for Human Development’) outlined the current UN philosophy on this challenge. Addressing her message to the developed world, she advocated a war on poverty, rather than a strategy for profitability, and urged caution on the issue of globalisation. While acknowledging that biotechnology is a very hotly debated issue, she opined that “in many regards, the debate has been captured by extremists”. The seriousness of the real life situation is borne out by the statistics: there are currently greater than 2 billion people living on less that $2 a day, while a total of 800 million go hungry. Although wheat and rice yields in Asia have increased, yields of sorghum and millet have actually fallen in Africa.  She highlighted that the responsible use of biotechnology can form part of the armoury to tackle such challenges.

 

Although the world has the means to address the problem of basic poverty, many political problems remain, and the technology has not spread to the areas where it is most needed. Fukada-Parr therefore recommended the use of incentives by governments to offset such factors. She further maintained that it is clear that if new technology is to work for human development, the wealthy countries need to adopt a different model to the one presently used by industries.  For every $100 of agricultural GDP, public investment in R&D is currently $2 in the developed world;  in poor countries this investment is only about 60 cents. In closing, she called for more consideration to be given to potential environmental health and socio-economic risks emanating from agri-biotechnology, and for more debate on the capacity of developing nations to address such issues.

 

Robert Horsch (Monsanto, USA; www.monsanto.com) reviewed the advantages of GM crops (Table 1), and stressed the significant potential of this technology for developing countries (“more food, on less land, with fewer inputs”).

 

Table 1.   Agricultural biotechnology: why it matters

Weeds, pests, diseases and environmental stresses drastically reduce crop yields Ploughing, pesticides, and irrigation all consume resources and produce wastes, adding substantial costs for farmers Huge opportunity to substitute information for materials, energy and capital costs Increasing yields per acre, per gallon and per barrel Large, un-served or under-served markets Growing concern and mandated regulation of toxic, persistent, mobile and bio-accumulative pesticides Growing support for soil, water and land conservation initiatives, practices and technologies Waste, cost and risk reduction opportunities

(Horsch, R. 2002. BIO 2002, Toronto, Canada, June 9 – 12th).

 

Horsch outlined that within the developed world, there have been significant decreases in pesticide usage patterns since the introduction of transgenic cotton: the decrease was about 46 million pounds of pesticide in the US during 2001 alone.  Other crops, such as BT corn, have also delivered extra value for the farmer, with a dramatic increase in acreage. He advanced the thesis that such successes can be transposed to developing countries, where pests and environmental stresses have dramatically reduced crop yields. Older practices, such as ploughing and pesticide usage, all consume resources and produce waste, which in turn, add to increased costs for farmers. Erosion of soil and soil degradation is still a significant problem in the developing world, and a reduction in tillage practices is currently being actively promoted, allowing less soil disturbance. Trends have shown that GM-mediated herbicide tolerance of crops has aided this conversion from tillage to non-tillage practices.

 

Horsch outlined the required bespoke commercialisation route for biotechnology in developing countries, based on a ‘commercial – transitional - non-commercial cooperation’ strategy.  According to Monsanto’s experience, the way forward is the improvement of the agricultural environment for subsistence crops, introducing plant biotech products to the small-holder, and thereby encouraging reduced tillage, seed and fertiliser use. The company has undertaken to assist farmers and conservationists in aiding best practice. Currently, their programme reaches 283,000 small-holder farmers on 290,000 hectares world-wide. 

 

Horsch highlighted that virus resistance is more important in developing countries than in the developed world. Reflecting this, current Monsanto Technology Cooperative Projects include those aimed at developing virus resistances in sweet potato (Africa), papaya (South East Asia), potato (Mexico), and cassava (Africa). Monsanto has also recently donated their data on the rice genome sequence to the ten-member International rice genome project for use in completion of the sequence.

 

On the issue of biosafety, Horsch recounted that many developing countries are well advanced in developing their own regulatory programmes for GM crops.  In Africa, biosafety regulations are in place in Uganda, Kenya, Zimbabwe and South Africa, while such regulations are actively being formulated in Nigeria, Malawi, Zambia, Namibia, Ghana, Burkina faso, Cameroon and Ivory Coast.

 

Vibha Dhawan (Tata Energy Research Institute, India; www.teriin.org) concentrated her presentation on the challenge of ensuring effective technology transfer to the developing world. She highlighted that the ‘Green Revolution’ focused on only a few grain crops, such as wheat, rice and maize. Encouraging the use of high input fertilisers and pesticides, and appealing to the high resource farmer, the major focus of this drive has been on increased yield and food production.

 

Dhawan surmised that perhaps the most formidable challenge facing future agriculture will relate to the increasing world population, with an additional 90 million people being added each year.  At this rate of growth, an additional 2 billion people are expected to inhabit the Earth by 2025.  Unfortunately the growing world population will not be evenly distributed, with the highest increases concentrated in the developing world, an aspect that is likely to continue to nullify most conventional technological improvements and developments. Within the developing world, such factors as reductions in available arable land area, the shortage of water and labour, land degradation and the effects of global warming, will all increase over the next 25 years. Additionally, an important and much overlooked problem in developing countries is that many farmers are illiterate, and therefore knowledge exchange and development of agriculture is mainly by word of mouth.  Indeed, a lack of availability of pesticide-handling information has sometimes resulted in the wrong pesticide being used for specific situations, and has also posed a direct toxicity risk to farmers.

 

Dhawan advocated the responsible use of biotechnology to tackle some of these challenges, and outlined a priority list of research needs for developing countries (Table 2). However, she pointed out that the major bottleneck in biotechnology within India is currently the issue of public acceptance. Biotechnology therefore needs to be managed responsibly, effectively and affordably.

 

 

Dhawan viewed biotechnology as holding out the promise of improving food and nutrition security, enhancing production efficiency (post-harvest quality control through an increased shelf life of fruit and flowers and increased stress tolerance), promoting sustainable agriculture, reducing environmental impact, and empowering the rural sector through income generation and the reduction of economic inequity. 

 

On the issue of agriculture in developing countries and globalisation, Dhawan opined that global competitiveness will be judged on the basis of the ability to produce food and fibre of international quality at comparatively lower cost.  Biotechnology should therefore ensure that farmers can produce competitively and are able to export. 

 

Roger Beachy (Donald Danforth Plant Centre, USA) further developed the theme of biotechnology aiding less developed countries (LDCs).  Reviewing the activities of the Danforth Plant Science Centre (established in 1998; www.danforthcentre.org) in achieving this goal, Beachy proclaimed that “agriculture is the foundation of economic growth and stability”, but said that this is not recognised within the US.  He echoed Dhawan in highlighting the issue of increasing world population, with his short-term projections indicating about 150 million more people in less than 5 years. He pointed out that malnutrition has been responsible for 50% of childhood deaths within developing countries, with 150 million children under 5 years suffering from malnourishment. Additionally, two billion people world-wide suffer from anaemia due to folic acid deficiency (the most common dietary ailment).

 

Elaborating on the research being conducted at the Danforth Plant Centre that will benefit LDCs, Beachy highlighted the areas of nutritional enhancement of foods, plant protection (pathogen resistances), and the use of plants for human health applications (edible vaccines) as priority targets. Ten percent of the Centre’s research currently directly benefits LDCs, with intellectual property (IP) policies that recognise the specific needs of these nations. Preservation of IP rights for humanitarian purposes is a core component of this, with an agreement covering the interaction of the Centre and any commercial research partner to preserve the availability of IP for meeting the needs of the Third World.  On this issue, Beachy pointed to a need to reformulate IP policies within the public sector of developed countries towards such aims.

 

Near term product innovations from genomics research

In his introduction, Session Chair Gary Miller (Paradigm Genetics, USA; www.paragen.com) briefly reviewed the progression to date of genomics, functional genomics, metabolomics and systems biology.  While he affirmed that agri-genomics has the potential to produce improved products and processes, better food and health, and to deliver important environmental advances, he emphasized that the non-technical barriers to agribiotech progress remain significant, and centre on consumer confusion and poorly defined business models. 

 

The application of genomics for the improvement of livestock was discussed by Sue Denise (MMI Genomics, USA). While current research programmes focus on the genetics of similarities through interrogation of public and private databases, thereby allowing comparison to be made across species, she felt that future approaches will be targeted at the “genetics of differences”. A priority will be the production of integrated maps for proteome and protein expression, which are currently difficult to handle in a high throughput situation. 

 

Denise summarized the current mission as being to “drill down to the genes”, thereby circumventing a reliance on conventional phenotype-driven animal breeding. Dense Single Nucleotide Polymorphism (SNP) maps and whole genome associations with specific traits of interest can be used as diagnostic tools for selection and prediction of the phenotype. The short-term targets for the use of SNP diagnostics in livestock production remain better feed efficiency, improved disease resistances, better meat quality and superior reproductive capacity. Metabolomics remains a long-term technology target.

 

Denise felt that the consumer needed to be educated about this technology in order to assure acceptance. She emphasized that molecular markers are only an adjunct to natural breeding (affording “more accurate selection”), thereby allowing breeders merely to change gene frequencies. 

 

In the area of plant science, Steven Briggs (Syngenta, Torrey Mesa Research Institute, USA; www.nadii.com) concentrated on the sequencing of the 420 Mb rice genome, which he recounted is now 99% complete and estimated to be 99.8% accurate. The sequence analysis has revealed in the region of 45,000 genes distributed over 12 chromosomes. Illustrating the extent of progress in the area of plant functional genomics, Syngenta have produced a ‘Rice GeneChip’ which in 2001 could screen for expression across 23,700 genes. Furthermore, this chip can function as a 'universal cereal genechip':  91.3% of rice genes match those of corn, while 81.3% match barley. 

 

 

Lawrence Schook (Pyxis Genomics Inc, USA; www.anigenics.com) delivered a talk entitled ‘near term innovations in animal genomics’. He discussed at length a business model centred on the identification of performance trait genes as representing the maximum value proposition. From a producer perspective, the major cost drivers remain reproduction, nutrition and growth, behaviour (confinement in high intensive systems) and environmental tolerance, and disease resistance. Conversely, consumer opinion generally seeks to replace/eliminate growth promoters (antibiotics and hormones), provide uniform product quality and ensure food safety and security. Food animal business trends indicate an industry consolidation and market pull directed at delivering consumer requirements.

 

Schook described a “genome positioning system” using SNP markers and differential arrays to select for traits of value, in effect a “marker to market” strategy that can be commercialised in a number of different ways. Examples include parentage testing of cattle, country-of-origin identification of animals, testing for meat quality traits, and selecting for growth and yield characteristics. In the area of animal nutrition, it can enable the matching of genotype and diet, while a further use in animal health extends to breeding for disease resistance and identification of novel drug targets for animal medicines via pharmacogenomics.

 

Biosecurity represents another market opportunity, as well as tracking affected animals for Bovine Spongiform Encephalopathy (BSE), Foot-and-Mouth-Disease (FMD) and anthrax. Developing this theme, Schook outlined that early detection and containment of suspect animals would be facilitated by microarray profiling (using the proprietary CattleArray3800™ gene chip) to analyse gene activation profiles from different tissues. The ‘early activation’ host gene expression profile would then be matched with a ‘known agent’ reference pattern in a proprietary database, prior to the appearance of a classical immune response. This would facilitate the early initiation of a containment plan and provide early warning signals for local, regional, state and federal authorities.   

 

In closing, Schook envisioned a time when beef cattle will be produced as a branded product, based around such traits as growth and body conformation. However, he articulated that the greatest challenge remains consumer acceptance, but also felt that the application of molecular genetics to companion animals, such as the dog, may represent a gateway for greater public understanding. 

 

Food safety in a time of uncertainty

Session Chair Ron Meeusen (Dow Agrosciences, USA) emphasised that while the human food supply has never been so well protected, lingering fears about food safety continue to run high, especially in the light of recent concerns over natural and manmade threats. He explained this as a natural human tendency to balance quality and availability when it comes to food.  In the developed world, food scarcity does not exist.  Additionally, food is not viewed rationally – it is personal and tied up with culture and taste factors.  However, he expressed a belief that there is an urgent need for new tools and methods from biotechnology to “raise the bar” on the security of the food supply.

 

Roy Curtiss III (Washington University, St. Louis, USA) discussed vaccines and vaccination strategies to enhance food safety. At present, about 3 million people world-wide die annually due to enteric pathogens; most of these are in the developing world.  However, this is also a significant problem for industrialized nations, with such pathogens as Campylobacter jejuni, Escherichia coli 0157, Listeria monocytogenes, Enterococcus spp., and Salmonella serotypes all representing serious threats.  In the US, the main food-borne risk is from Campylobacter jejuni, which causes diarrhoea in an estimated 2.5 million people (Table 3).

 

Table 3.  Human food-borne bacterial infections in the US     Pathogen                     Total cases                  Total deaths                 Food-borne deaths   C.  jejuni                       2,453 x 103                    124                               99   S. enterica                    1,412 x 103                    582                               553   L. monocytogenes          2.5 x 103                       504                               449   E. coli 0157                   110 x 103                       91                                 78     Original data from Mead, P.S., Slutsker, L., Dietz, V.  et al. Food-related illness and death in the United States. Emerg. Infect. Dis. 1999, 5: 607 – 625.   (cited by Curtiss, R. 2002. BIO 2002, Toronto, Canada, June 9 – 12th).

 

 

Curtiss highlighted that while all of these pathogens could be removed through improved personal and food hygiene practices, “inevitable lapses” in hygiene standards would make this strategy untenable. Vaccination of animals against these organisms therefore represents a more viable way forward.  Such vaccines should ideally be avirulent and highly immunogenic, retaining tissue tropism without causing disease or impairment of normal host physiology and growth, and possess two or more attenuation deletion mutations. 

 

Using this strategy, a Salmonella typhimurium–based vaccine, UK-1 strain c3985 (with Dcya and Dcrp mutations), has been used to induce good cross-protective immunity in young chickens against infection by S. typhi and S. enteriditis. The UK-1 (‘universal killer’) strain has the lowest LD50 among salmonella species. Attenuation is effected by mutations in adenylate cyclase (Dcya) and cAMP receptor protein (Dcrp) genes, affecting the catabolite regulatory system.  The vaccine is administered to the chicks through a coarse spray, with a booster given in water after 2 or 3 weeks, to give a potentially Salmonella free-life.  It is now marketed as a live vaccine in the US for poultry and swine. Curtiss is extending this work, focusing on attenuation strategies involving mutations in the phospho-mannose isomerase gene (Dpmi), needed for bacterial lipopolysaccharide synthesis. 

 

In closing, Curtiss emphasized that live attenuated bacterial vaccines represent safe, efficacious and inexpensive approaches to tackling food safety. Typical manufacturing costs for such vaccines (involving bacterial cultivation, harvesting, lyophilization, filling into vials, labelling and packaging) range from $0.001/dose (poultry) to about $0.10/dose (human). Additionally, the system obviates the need for refrigeration (they can be reconstituted in the field), and permits oral/intra-nasal administration (no needle costs and associated hazards).

 

Frank Heppner (Institute of Neuropathology, Zurich, Switzerland) spoke about the pathogenesis of diseases caused by ‘infectious’ prion particles, and reviewed current theories on transmission.

Bovine Spongiform Encephalopathy (BSE) was first reported in cattle in 1986, with disease incidence peaking between the years 1989 and 1995, and declining thereafter. This fatal neurodegenerative brain disorder is characterised by spongiosis, gliosis, neuronal loss and the formation of amyloid plaques, and is thought to have been originally caused by infection with a scrapie-like agent derived from meat and bone meal used in feedstuffs. Although a ban on such feed has been effective in blocking BSE transmission, the long incubation period of the disease has meant that cases are still being seen. BSE is mainly associated with the EU, with 4 cases found in Japan (Table 4).

 

 

The current wide interest in BSE is due mainly to the development of a link between BSE and a similar disease which has been reported in humans, called ‘new variant Cruetzfeldt-Jakob Disease’ (nvCJD).  The first cases of nvCJD were diagnosed in the UK in 1995 (3 cases), while there have been 120 cases to date (as of 30 May 2002) (Table 5).

 

 

Table 5.  CJD deaths in the UK

Year        Referrals                 Sporadic                  Iatrogenic             Familial                     GSS†       nvCJD      Total   1990        [53]                          28                            5                              0                              0              -               33 1991        75                            32                            1                              3                              0              -               36 1992        96                            44                            2                              5                              1              -               52 1993        78                            37                            4                              3                              2              -               46 1994        116                          51                            1                              4                              3              -               59 1995        87                            35                            4                              2                              3              3              47 1996        134                          40                            4                              2                              4              10            60 1997        161                          59                            6                              4                              1              10            76 1998        154                          63                            3                              4                              1              18            89 1999        169                          61                            6                              2                              0              15            84 2000        178                          48                            1                              2                              1              28            80 2001        172                          50                            3                              2                              2              20            77 2002*       57                            9                              0                              1                              0              9              19     †Gerstmann-Sträussler Syndrome  * data as of 30th May 2002  (Heppner, F.  2002. BIO 2002, Toronto, Canada, June 9 – 12th).

 

Based on the incubation period typically witnessed for BSE in animals, Heppner hypothesized that the nvCJD incidence may have peaked, but also pointed out that there is no data regarding the incubation period in humans. 

 

At the cellular level, prion diseases are thought to be caused by the interaction of a normal body protein, PrP^c, with the infectious particle, PrP^sc, a process that sets up a ‘chain reaction’ of protein aggregation (termed the ‘protein only’ hypothesis).  This model is consistent with the fact that PrP^c knock-out mice are resistant to prion infection.  It is now thought that the port of entry of the prion to the body is through the Peyer’s patches, immunological tissue located in the mucosa of the small intestine. Particle amplification within the follicular dendritic cells then occurs, followed by transmission to the brain via the peripheral nervous system. 

 

Prion protein ‘vaccines’ are unable to immunise against the protein, as it is a natural part of the body’s own system.  However, passive and active immunization strategies are being devised around transgenic expression of PrP^c antibodies, and this has been experimentally found to prevent accumulation of PrP^sc infectivity in the spleens of mice, after intraperitoneal inoculation.

 

Jim Richards (National Research Council of Canada, Institute for Biological Sciences) affirmed the priority of tackling the global resurgence of infectious disease. He identified further challenges as the development of antibiotic resistance in bacteria, the emergence of new pathogens (such as E. coli 0157:H7), and the recognition of the role of new microbes in disease (Helicobacter pylori and its association with ulcers and cancer).  Additionally, in the wake of the September 11^th 2001 terrorist attacks, bioterrorism must now also be added to the list of concerns for nations.

 

Richards highlighted that many human disease microorganisms, such as Campylobacter, Salmonella, E. coli 0157:H7 and Listeria, are transmitted mainly through farm run-off and from meat and dairy products. Increasing incidences of food poisoning from these microbes has led to elevated public concern over the quality control and safety of drinking water and foods.

 

Targeting the immunochemistry of bacterial cell surface carbohydrates, Richards expanded on vaccine strategies based on developing a better understanding of antigen identification and characterisation, using in vivo and in vitro virulence and infection models. The short-term research goal being pursued by Richards’ Group is to reduce the risk of food-borne illness caused by E. coli 0157:H7, through elimination at source (cattle, animals) by vaccination. The strategy is based on a molecular understanding of the protective antigens on the outer membrane (lipopolysaccharide) of Gram negative bacteria, and has shown encouraging results in cattle trials in Western Canada during 2001. The vaccine is based on a natural isolate of Salmonella landau, which is a ‘friendly’ version of Salmonella.  S. landau naturally expresses the 0157 antigen (a tetrasaccharide repeating unit that can comprise up to 100 units). This organism is not known to cause disease, and therefore provides the possibility of deploying it as a vaccine. Results have shown that oral vaccination of cattle with S. landau yields good cross-protective immunity against E. coli 0157 isolates, and markedly decreases faecal shedding, while cattle can also tolerate large doses of this vaccine. 

 

Richards’ Group is also investigating plastic wrap applications that incorporate pathogen-specific antibodies as an early warning system for microbial contamination. To date, a single chain Fv version of a monoclonal antibody which is specific for the E. coli 0157 antigen has been produced, and this can be used to detect whether a toxin or the bacterial pathogen is present.  Recombinant plant expression provides the most cost-effective way of generating the antibodies, and research is ongoing to examine the potential of tobacco plants for this application. Finally, in collaboration with Dow Agro Sciences, a project is ongoing to reduce the risk of E. coli 0157 at source, through bioengineering cattle feed in order to express 0157 antibodies, thereby reducing the incidence of E. coli from the digestive system of cows. 

 

Agriculture’s New Horizons: Engineered proteins from plants and animals

Session Chair, Thomas Vilsak (Governor of Iowa) opened the session by expressing excitement at the prospect of biotechnology.  He briefly overviewed the ‘Biotech Partnership’, where the Governors of 28 US states have formed a biotech information initiative, and he encouraged people to use this resource.

 

 

 

 

David Faber (Trans Ova Genetics, USA; www.transova.com) described how activities such as in vitro fertilization and embryo transfer in cattle for agricultural applications are now being translated into higher value business models.  The latter include production of medicines in the milk of transgenic animals. Expressing the Company’s mission to “lead the application of agricultural cloning and genetic technology”, their Genetic Advancement Centre intends to extend transgenesis to farm animals in the future, initially focusing on disease resistance and other production aspects.

 

Faber reviewed the inherent advantages of transgenic animals, which can yield improved production, better disease resistance and enhanced carcass growth. Cloning for medical protein production may be achieved within 13 to 48 months (Table 6). Faber expressed a desire for an “open house” and transparency on this issue with the public, and believed there would be an accepting consumer, provided that education was available.

 

 

Table 6.  Time required from starting cloning to protein production                                                   Bovine                                       3 mo induction   13 mo induction             nat lact G0        nat lact 2nd Project months              13                     23                                 34                     48 Kg                                0.17                  1.8                                41.0                  49 Cumulative Kgs                                      1.8                                54                     706   (Faber, D.  2002. BIO 2002, Toronto, Canada, June 9 – 12th).

 

 

An alternative animal biotechnology business strategy was described by James Robl (Hematech Inc., USA; www.hematech.com). Hematech produce bovine-derived human polyclonal antibodies, which find a number of uses in human medicine. For example, intravenous immunoglobulin-replacement therapy for immune deficiencies is used in the management of

inflammatory and autoimmune disease, and also in many ‘off-label’ applications. Hyperimmune immunoglobulins (Igs) are used in the prophylaxis and treatment of infectious disease, and also as antitoxins.  At present, there is a global 6 million gram shortfall per annum in such polyclonal sera (22 million grams are actually required). Such a deficit can only be partly addressed by the more widespread availability of monoclonal antibodies (MAbs): there remain significant limitations relating to the production, scale-up and facilities cost associated with these reagents, while there is also a limited efficacy for treatment of infectious disease with MAbs, and variable patient responses due to polymorphisms. Further novel applications of polyclonal antibodies will be in the areas of antibiotic resistance and anti-bioterrorism.  Robl recounted that two million people in the US acquire infections during hospital stays, and such pathogens are frequently resistant to anti-microbial drugs, while reoccurring respiratory and ear infections represent the single largest use of antibiotics in the US.

 

Hematech’s proprietary technology approach has been to develop a human polyclonal production system through a ‘transchromosomic’ (Tc^TM) cow. The technique involves insertion of the human Ig gene into the cow genome, accompanied by simultaneous bovine Ig gene inactivation. The system thus allows a theoretically unlimited production of human polyclonal antibodies (with scale-up being straightforward), the possibility of making antibodies against any human infectious disease organism, and the manufacture of antibodies against human molecules and cells.  On the issue of public acceptance of such production systems, Robl identified ignorance of the technology as being the main hurdle. 

 

Allan Kramer (Sioux Pharm, Inc., Iowa, USA) recounted the experience of a company involved in the isolation, purification, characterisation and marketing of proteins and carbohydrates derived from animal tissue.  Examples given included the production of such compounds as follicle stimulating hormone (for use in embryo transfer), chondroitin sulfate (from bovine cartilage, used for pain relief in rheumatoid arthritis), trypsin and chymotrypsin (enzymes for industrial use) and phosphatidyl serine (produced from soybean by-products and used for age-associated memory loss and control of attention deficit hyperactivity disorder in children). Current research is focusing on the development of new technologies to isolate proteins and enzymes from transgenic grain, where the goal is to achieve high volume/low cost extraction processes.

 

Regulatory policies for adventitious presence in crops

Session Chair, Terry Medley (Dupont Agriculture and Nutrition, Wilmington, USA) summarised the critical aspects of the (GMO) adventitious presence (AP) debate, where such elements as the precautionary approach/principle, intellectual property/identity preservation (especially for second generation products with enhanced traits) and public policy, are now being actively discussed by regulators around the globe in an effort to balance public concerns with regulatory requirements.

 

Stanley Abramson (Arent Fox Kintner Plotkin & Kahn PPLC, Washington D.C., USA; www.arentfox.com) invited the assembly to “get real about crop production and biotechnology” regarding the issue of AP, and pointed out that there are no textbooks available on this topic. He advocated the establishment of reasonable, science-based standards and procedures on AP that acknowledge the realities of growing food, feed and fibre, and further stressed that biological systems are inherently imperfect and dynamic. Movement and dissemination of GM seeds and pollen would be inevitable in such systems, while transfer of gene material is both normal and natural, especially since some plants are genetically quite promiscuous. Along the production chain, unintentional commingling of seeds and grains occur routinely in agricultural processes. Regarding the application of analytical techniques for detecting AP, he opined that if one looks hard enough, contaminants and imperfections will be found in many foods.  Historically, the presence of unintended impurities has been recognised in US law.  For example, the seed of a particular hybrid may contain up to 5% of a different hybrid without the need for identification (USDA), while decaffeinated coffee may contain up to 3% caffeine (FDA).  Similarly, ‘corn’ must consist of at least 50% corn, and no more than 10% of other grains for which standards have been set (USDA), while ‘number 1 grade corn’ may include up to 2% broken corn and ‘foreign materials’ (USDA). 

 

However, while not a single incidence of harm has been reported for GM crops, proactive product stewardship requires assurances to the public. Without the operation of a transparent national policy, the AP standard becomes zero by default. Abramson opined that as each country is tending to go its own way on the issue of standards, consumer confidence is being undermined, precipitating unnecessary trade disputes, adversely impacting growers and undermining investor confidence in the agri-biotechnology sector.

 

In closing, Abramson called on the various players to build on the existing US regulatory system for early (field stage) safety assessment of GM crops, a process which should also involve the input of trading partners to establish workable standards. 

 

Tony Van der haegen (European Commission Delegation, Washington D.C., USA) provided the current European Commission (EC) perspective on the regulation of GM crops, food and feed. Leading off with the opinion of the EU consumer, he cited the Eurobarometer December 2001 poll, which indicated that 70.9% of the EU population do not want this type of food, while 85.9% want clear labelling information and 94.6% believe it is their right to be informed. Succinctly summarised by Van der haegen,  the “EU consumer, rightly or wrongly, does not accept GMOs”.

 

He opined that an appropriate mandatory labelling system for GM foods was essential; if this is not accepted by the biotechnology industry then “(agri)-biotech is dead in Europe”.  He emphasised that this requirement for labelling is not science-based:  its purpose is not to inform the consumer about the safety of a food, because unsafe products cannot be placed on the EU market. Part of the difference of opinion between the US and EU on this aspect was cultural: “in the US, labelling is often a warning, while in the EU it is part of the information content”.  He felt that this stance would withstand critical examination by the World Trade Organization (WTO).

 

The EC's new proposals therefore reinforce the labelling of GM foods, irrespective of whether DNA or protein of GM origin is detectable in the final product.  This will extend to such foods as starches, flour, highly refined oils and products composed thereof.  Additionally, all GM animal feedstuffs will require labelling (for example, the case of soya meal, and also corn gluten feed produced from GM corn). 

 

The proposed EU regulations pertaining to AP of GM material recommend a 1% threshold for minute traces of approved GM components in food or feed. In the case of seeds, a new Directive is still under active discussion, with suggested threshold values for authorized GM seeds varying according to crop type as follows: 0.3% for canola and cotton, 0.5% for tomato, beet, corn and potatoes and 0.7% for soybean.  The threshold for unauthorized GM seed will likely be set at 0.1%.  Applicants must provide a method for detection of such contamination, including sampling protocols. It is proposed to establish an EU reference laboratory so that sampling and testing standards will be assured and the Joint Research Centre (in Northern Italy) has been suggested to carry out this task. 

 

With regard to the lifting of the current moratorium on new crop approvals in the EU, Van der haegen placed the blame squarely at the door of the national states (“we do not know what the Member States are up to”). He emphasized that such countries will only resume the review process if labelling and traceability regulations are in place.  He confirmed that the EC is doing its utmost to have a resumption of the approval process, and admitted that the EU position on this issue was untenable and unlikely to withstand a complaint by the US and Canada to the WTO. 

 

In closing his presentation, Van der heagen highlighted the issue of segregation of GM products with special traits (nutraceuticals, medicines), emphasising the importance of deriving a workable threshold figure.  On the issue of GM crops and organic farming, he provocatively posed the question, “should biotech not be (a) part of organic?” 

 

Adelaida Harries (National Seed Institute, Secretariat of Agriculture, Livestock, Fisheries and Food, Buenos Aires, Argentina) reviewed regulatory policies in Argentina regarding AP of GM material in seeds, a process which has evolved over the past 7 years.  In Argentina, a variety of GM crops are approved (Table 7) and about 11 million hectares in total are sown with GM corn, soybean and cotton. 

 

 

 

The Argentinian threshold for the AP of GMOs in non-GM varieties is 1%, and this was decided

from tests conducted within Argentina. Policy formulation decisions have been derived on the basis of such factors as Argentinian consumer opinion, GM products that may possess special characteristics (such as Golden Rice) and the recommendations of the UN Cartegena Protocol on Biosafety. Harries was not convinced regarding the future GM segregation policies of trading blocs such as the EU, feeling that the European consumer will not be willing to pay the increased cost of product segregation in the long-run. She also pointed out that countries such as Argentina would find it too difficult to adapt to such requirements: “we have no money to change our rules/system for export”. Finally, she highlighted as a special case the challenge of effectively monitoring the movement of GM crops across frontiers, citing examples from other areas of agriculture, such as the movement of Foot-and-Mouth Disease from Paraguay to Argentina. 

 

Cliff Gabriel (Office of Science and Technology Policy, Executive Office of the President, Washington D.C., USA) opined that AP as defined in one country might be “approved variety” in another.  Providing an insight into the US Administration’s view on this area, he recommended that international players should stick to a science and a risk-based approach (the US citizen trusts the regulatory process), but was open to questions regarding the adequacy of current field testing procedures. He also indicated that there may be room for discussion on the point at which developers of new crops would approach the FDA to discuss the salient issues. 

 

Bernard Le Buanec (International Seed Federation, Nyon, Switzerland) provided the ISF perspective on AP of GM material in non-GM seed.  The ISF is a recent merger between the International Seed Trade Federation and the International Association of Plant Breeders, and comprises members in 69 countries.  The ISF is supportive of plant GM innovation, and is against labelling unless it can be shown that the product is not substantially equivalent. On the issue of AP, he emphasised that a company cannot currently guarantee that a seed lot is GM free, even after having undertaken extensive due diligence, and displayed a proposed disclaimer being discussed for implementation by the seed industry (Table 8).

 

Table 8.  Model for Conditions of Sale applicable to seed lots     ‘Seeds supplied to you are from a variety bred from parent components that have not been genetically modified.  The methods used in the development and maintenance of that variety are aimed at avoiding the presence of off-types, including genetically modified material as defined by the applicable laws or regulations. Seed production has been carried out in accordance with production rules including stipulated isolation distances.  However, in open fields there is free circulation of pollen.  As it cannot be excluded that in seed multiplication areas the growing of approved GM plants takes place, it is not possible to totally prevent the adventitious presence of GM material and to guarantee that the seed lots comprising this delivery are free from any traces of GM plants.  (Company name) has undertaken due diligence to avoid adventitious presence of GM material in the seed lot.  However (Company Name) gives no guarantee that the seed is GM free and can accept no liability arising from the adventitious presence of GM material’.     (Le Buanec, B.  2002. BIO 2002, Toronto, Canada, June 9 – 12th).

 

While the ISF opinion as of June 2002 was that a 1% threshold on AP would be a reasonable starting point, he pointed out that in the case of some crops,  this will be extremely difficult to achieve at a reasonable cost to either seed companies or growers, especially as transgenic crop cultivation increases world-wide. Le Buanec felt that it is currently unrealistic to try to achieve an international harmonization of standards, as these are not based on technical information but instead on politics.   

 

Rick Jarman (National Food Processors Association, Washington D.C., USA; www.nfpa-food.org) identified key aspects of importance to the US food processing industry as being “unintended”, “incidental” and “trace levels” of contaminants.   He affirmed that biotech has strong potential and “is here, and here to stay”.  However, there is a recognition that AP happens, and the regulatory-legal issues need resolution. 

 

In the consumer-focused companies of the food processing world, brand name is an important asset, and such companies retain a regulatory and advocacy group focus:  “a company’s reputation or brand name may be its most valuable asset, but to the frustration of many executives and shareholders, it is virtually uninsurable”.  These companies must therefore approach the GM question with caution.  At stake for them are such issues as markets (international), customer and supplier relationships, public/consumer perception and confidence in food and brands.  In terms of AP considerations, the food processing sector would like to see the emergence of an understandable and workable solution and a regulatory system that clearly removes food safety as an issue.  Prevention must be kept a priority and public concerns addressed upfront.

 

Partnership Opportunities

Chairing the session, Edwin Quattlebaum (MetaMorphix Inc., USA) described how food and agriculture biotech companies are seeking diversification through increasing their alliance opportunities. Traditional partnering, featuring a small entrepreneurial platform company entering into alliance with a large, established international player, is now being complemented by a variety of hybrid models.   

 

 

Roger Wyse (Burrill & Company LLC, USA; www.burrillandco.com) delivered a talk entitled ‘alliances and capital attraction’. Burrill and Co. is a life science merchant bank with a core business in venture capital financing across a broad spectrum of the life sciences (including biotechnology, diagnostics and nutraceuticals). They have a fund of about $350 million under management. Emphasizing the importance of partnering, Wyse stressed that companies should not be asking the question as to whether they should partner, but rather, how and with whom they should be doing it. Indeed, an entire industry has now been built up around partnering, spurred on to a large degree by Big Pharma integration and disintegration. Large international agrichemical and pharma companies have for long been trying to consolidate their R&D efforts and reduce costs, ensuring a continuity in their product pipeline. This is necessary in order to maintain desired Big Pharma business growth rates of about 10% per year. Such companies are now looking increasingly towards ‘disintegration’ as a value realization strategy, via mechanisms such as out-sourcing their R&D, and acquiring products through partnerships and alliances.  The number of new biotech – big pharma collaborations is now approaching about 400 per year. However, Wyse noted that while the number of deals are increasing, their magnitude has decreased slightly.

 

Such trends have translated into the agri-biotech sector, with their R&D strategies embracing the pharma model of alliances, and now looking to universities to spin out start-up companies. However, at present the agri-food industry is very much dependant on private equity, and Wyse pointed out that at the moment such a source of funds is relatively vulnerable. Additionally, in terms of the socio-economic climate for GM innovation, complex and unresolved issues regarding public acceptance are being exacerbated by the fact that commodities prices have fallen and are now at an all-time low. There is a lack of value capture outside of input traits, and also a disappointing number and size of partnering deals taking place within agri-biotechnology. In terms of attracting venture capital investment, Wyse pointed out that platform companies tend to look quite alike, and therefore it is important to have a competitive edge; conversely, VC-investment deals give validation to a company’s technology and business model. Consolidation has been ongoing within the agrichemical sector, and such internal distractions have diverted attention from value creation through partnerships with smaller players.  Partnering deals in agri-biotech are fewer and smaller, and there has been big decrease witnessed from 1998 to 2002.  

 

In closing, Wyse recommended vertical integration as a strategy for an agri-biotech company to create and capture more value, and also advocated diversifying into human health applications, such as nutraceuticals.

 

Andrew Baum (President and CEO, SemBioSys Genetics Inc. USA; www.sembiosys.ca) confirmed that partnering is currently critical to biotech company growth, while also providing