Basel, Switzerland
23 May 2000

In response to consumer concerns, a novel marker gene system called Positech^TM is being hailed as a breakthrough for plant biotechnology. Pioneered by Novartis and collaborators, the Positech system offers a novel and efficient alternative to antibiotic resistance or herbicide tolerance marker genes in many genetically enhanced crops.

Novartis is currently working with Positech in several crops, in particular maize and wheat. Regulatory dossiers for the first commercial release of these crops with novel traits, which have been introduced using Positech, are expected to be submitted to regulatory authorities within 12-24 months.

Novartis plans to make the technology widely available to both the biotechnology industry and the academic scientific community through simple licensing procedures. Positech has already been licensed to more than 100 advanced academic and industry research laboratories around the world that are developing more productive and healthier food crops.

Novartis will provide Positech royalty-free for subsistence farmers in developing countries, through local institutes or companies, where appropriate regulations are in place to confirm user and consumer safety, and protect local environments for crops modified using Positech.

Dr. Johanna Puonti-Kaerlas, of the Swiss Federal Institute of Technology, who has been using Positech in her research, reported, "The positive selection system based on mannose has been used successfully in cassava, a crop of significance to the developing world, and this may eventually be useful as a replacement for antibiotic resistance marker genes in the future."

Marker genes allow scientists to select cells that can express improved traits. Other marker selection systems employ antibiotic or herbicide resistance marker genes and a chemical to eliminate unwanted cells. Positech provides a selection system based on a marker gene that enables plant cells to use a simple sugar (mannose) to grow and form new plants.

Positech is an alternative to antibiotic resistance genes as markers in future genetically enhanced crop varieties and will likely be welcomed by regulatory authorities responsible for assessing GM crops worldwide. Antibiotic marker systems do not create a risk to farmers or consumers but such systems are often confused with antibiotic use in healthcare. Novartis has pledged to phase out such antibiotic resistance markers in developing its future products, as alternative selection systems such as Positech become available.

Wally Beversdorf, Head of Research and Development at Novartis Seeds, said: "By developing Positech and making a firm commitment to phase out the use of antibiotic resistance marker genes wherever possible, we have shown how good science can address public concerns and offer innovative solutions."

Novartis is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 1999, the Group (including Agribusiness) achieved sales of CHF 32.5 billion and invested more than CHF 4.2 billion in R&D. Headquartered in Basel, Switzerland, Novartis employs about 82 000 people and operates in over 140 countries around the world. The Group recently announced plans to spin off its Crop Protection and Seeds sectors and to merge them with the agrochemicals business of AstraZeneca to form a new company, Syngenta, in the second half of 2000.

Positech^TM is a genetic marker system that offers scientists a novel and efficient alternative to using antibiotic resistance markers in GM crops, based on a positive selection scheme. Marker genes allow scientists to confirm the uptake of new genes by cells because they can identify the transformed cell.

While we stand by the safety of other marker genes that are used in genetically modified crops, Novartis is committed to phasing out their use in favour of Positech wherever this is technically feasible.

Novartis will provide the technology at no financial cost to subsistence farmers in countries that have a credible regulatory framework in place.

• A selective marker gene is required in the early stages of developing genetically modified (GM) plants. In the process of inserting new genes into plant cells, called transformation, not all the plant cells are transformed. To identify cells that have been transformed a marker gene is used.
  
• Commonly used marker genes function as negative selection markers in that they give transformed cells the ability to survive treatment with antibiotics or herbicides, whereas the non-transformed cells are subject to growth inhibition or are killed. Therefore, if the plant cells are grown on a medium containing a specific antibiotic or herbicide, only the transformed cells will grow.
  

• Certain simple sugars such as mannose cannot generally be utilised as an energy source by many plants like maize, potato or sugar beet, when grown in tissue culture. However, transformed plant cells containing the gene that encodes for the enzyme phosphomannose isomerase (PMI) are able to convert mannose-6-phosphate to fructose-6-phosphate and use it as an energy source. When grown on a medium containing mannose as a sole sugar source, only transformed cells that produce - or express - the PMI enzyme will grow.
  
• When the gene that encodes for the PMI enzyme, called ‘manA’, is used as a selectable marker, the end product is a common sugar.
  
• This system, called ‘Positech’, is currently being used in research on maize, wheat, barley, sugar beet and vegetables. Positech offers an effective alternative to antibiotic resistance or herbicide tolerance marker genes in many crops.

• The manA gene is naturally present and expressed in mammals. Therefore, the metabolites produced by the Positech system are already widely present.

• There have been no observed agronomic differences, such as yield, compared with equivalent conventional maize varieties.
• As part of the ongoing safety assessment of the Positech system, the following results were found:

• No measurable allergenic potential was found.
• Glycoprotein profiles remained the same in transformed plants.
• Transgenic maize using Positech was indistinguishable from conventional maize when analysed for moisture, ash, fibre, fat, protein, beta-carotene, xanthophylls and vitamin C.
• No adverse effects of the PMI enzyme were found during an acute oral mouse toxicity study.

• The safety of the existing marker genes has been comprehensively tested and proven over years of use.
• For example, the results of extensive study concludes that the antibiotic-resistance marker gene used in Novartis Bt-176 maize poses no health risk or threat to the effectiveness of antibiotics used in humans or animals. This is supported by the opinions of some of the world’s leading experts¹ on antibiotics and micro-organisms, who have concluded that the possibility of DNA transfer from Bt-176 maize to bacteria living in the gut of animals is virtually zero. Bt maize has been extensively tested and over 30 independent scientific committees around the world have examined its safety and concluded that it is as safe as conventional maize.