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Plant Science Panel

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'The Ugly Truth'

by Tracey Brown, director of Sense About Science

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Using GM plants to ‘grow’ medicine

Dr Penny Sparrow, Professor Joachim Schiemann, Professor Julian Ma and Professor Maurice Moloney answered your questions on using GM plants to ‘grow’ medicine on Wednesday 20th February 2013. Find out more about our panellists and this Q&A here. We've compiled the tweets from the Q&A on Storify.

If you have a question on a plant science related issue then get in contact with our plant science panel via Twitter, @senseaboutsci using #plantsci, or email us at [email protected].

 

30. "What are the disadvantages of producing medicines in this way?" Alisa Prise

JM: Not all medicines would benefit from being made using plants. The manufacturing systems we use currently are very high quality and perfectly adequate for the majority of medicines we need. The industry has invested enormous money and time into fine tuning the manufacturing of medicines, and we have all benefited in terms of product quality, safety and reliability.  Plant biotechnology is very new, and the manufacturing details have not yet been fine tuned. There are many areas of improvement required, before it can become as robust a manufacturing platform as, for example, cell platforms such as E. coli or CHO cells.

An additional issue is that once a medicine has been tested, and received a commercial license, you cannot simply use another manufacturing system to make the "same" medicine. If you make it in a different way, it is regarded as a different medicine and would need to be tested extensively again. That would be hugely expensive and a difficult commercial investment decision to make.

 

29. "Biological containment is likely to be critical in the case of open-air growth of plant-made pharmaceutical crops, but I understand that such “terminator technologies” are currently outlawed by EU legislation. What is being done to promote EU rules that would allow Molecular Farming?" Martin Stocks

JS: Yes, biological containment/confinement might be critical for several cases of open field growth of plant-made pharmaceutical crops. Fortunately, there are physical and biological means available to reduce or prevent gene flow besides molecular technologies known as “terminator technologies” – a misleading term! The COST (European Cooperation in Science and Technology) Action FA804 “Molecular Farming” aims at providing a virtual coordination center at a pan European level to address issues related to Molecular Farming (http://www.molecularfarming.org/) including aspects of risk assessment and regulation. The outcome of the Action, including experts from 23 signatory countries, is expected to be a sustainable European Plant Molecular Farming community with clear frameworks for regulatory, biosafety and IP issues.

 

28. "Would people attempt to steal #gm medicinal plants?" Rebecca Nesbit

PS: This was a consideration when we were doing the EU Pharma Planta programme, as one option was to use maize to produce our product (anti-HIV antibodies) grown in South Africa. These plants if eaten would not benefit those people eating them (see also answer to Q21 also ‘risk of eating plants’); but I can imagine desperate people, unaware of the full facts may think that they would be beneficial. Obviously something like that would need to be considered in the risk assessment and risk management scenarios. High fencing of fields may be an option.

 

27."Is there any point in carrying on GM research in Europe if the public wont accept the products?" Kyle Purkiss

JS: GM technology is an indispensable part of basic plant research. Though the cultivation of GM plants in Europe is limited to a few Member States like Spain, we are importing large amounts of GM commodities, mainly for feed purposes. To be competitive in the international arena European plant breeders have to use molecular breeding technologies, including GM. The actual data on the Global Status of Commercialized Biotech/GM Crops 2012 (http://www.isaaa.org/resources/publications/briefs/44/executivesummary/default.asp)  released today (Wednesday 20th February 2013) show that 170.3 million hectares of biotech crops were grown globally in 2012, at an annual growth rate of 6%, up 10.3 million from 160 million hectares in 2011. Products from “red” (production of pharmaceuticals in GM microorganisms) and “white” (production of e.g. enzymes in GM microorganisms) GM technology are well accepted by the European public. There are also examples for consumer acceptance of products from GM plants, for example plant-made growth factors and other recombinant proteins produced in barley seeds in large greenhouses in Iceland (http://www.orfgenetics.com/).

 

26."Is there a plant/plants that can prevent or cure aids. I have read about this and could not come to firm conclusion." Alistair Griffiths

JM: No. Researchers are investigating using plants to manufacture pharmaceuticals that could be used to prevent HIV infection, but this work is still only in early clinical trials. The main problem is that we still don't understand the best way to prevent HIV or cure AIDS with vaccines or other medicines. If such a vaccine were to be discovered, plant biotechnology would be an important manufacturing option. This is mainly because the vast majority of people in the world who would need that vaccine are in resource poor, under-developed regions. 

 

25. "What treatments are out there already?" Julian Walker

JM: There is only one plant-made pharmaceutical used at present; an enzyme called glucocerebrosidase for a rare condition called Gaucher's disease. There is also a cosmetic product available, a skin cream that contains a compound made by plant biotechnology.

 

24. "I know next to nothing about the pros and cons of the process used in developing medicine from GM plants, although at face value I would consider it a more ethical means than the use of live animals. Is this a factor in the consideration of using GM plants?" Bob Dawson

JM: Yes, there is an opportunity to use plants as a low-cost replacement manufacturing platform for medicines that are currently produced in animals, for examples medicines against rabies that are currently produced by immunising horses. However, there are not many of these examples. If you are thinking about the development path for medicines, then I'm afraid that all new medicines, whether produced in plants or not, still need to be tested (where appropriate) in animals.

JS: No, this is not a central issue. Most pharmaceutical proteins that might one day be produced in plants are currently produced in single cell systems like bacteria, yeasts or animal cells. A well known production platform is the Chinese hamster ovary (CHO) cell. A cell line has been derived from the ovary of the Chinese hamster and used in research and also commercially in the production of therapeutic proteins. Plant Molecular Farming might offer a convenient way to produce molecules of interest on a large scale at low cost, allowing rapid scaling up and convenient storage of raw material (e.g. in seeds), and is linked with less concern over human pathogen contamination. Also, some necessary processes after the production of the protein itself, like folding or glycosylation, are performed better in plants than in other cell systems.

 

23. "Are there any potential benefits in terms of delivering drugs in food - for instance increased compliance?" Catherine de Lange

JS: Yes, increased compliance might be a good argument. But delivering drugs in food will not become reality in the short- to mid-term, it might be in the long-term. Two decades ago we were discussing ideas like the “vaccine banana” produced for and in developing countries. But we realised there are too many unsolved problems around dosage, stability, labeling. Drugs should be clearly separated from food and feed throughout the production chain, from seed production via farming to processing and selling. But this interesting idea has not been buried – the future will show whether the problems mentioned above, as well as others, might be solved.

 

22. "With all these considerations about biosafety how much cheaper is this method of production? Is it worth it?" Ailsa Prise

PS: Under the current regulatory requirements – it may be questionable.  It was calculated that it takes on average 7-10 million euros to approve a GM crop for cultivation. Whether this would outweigh the cheaper production costs, I can’t say. What we do, however, argue is that the current regulations are not really applicable to 'molecular farming' which would be conducted on a relatively small scale, under licence by contract farmers. As such the GM crop regulation (part C of the EU 2001/18 directive) may not be appropriate. By better understanding how these regulations could be amended for molecular farming, it would enable the balance of costs and benefits to be fully weighed up.  


21. "Is the potential of people accidentally eating plants which contain medicine the greatest danger?" @RebeccaNesbit

PS: All measures would be taken to ensure this was avoided – but let's take the ‘what if they did’ attitude. For most of the proteins that would be considered for field production, there would be a minimal risk associated with consumption (remember the plants need to be harvested, processed and the protein purified and formulated to be most effective) therefore, the amount you would be exposed to would be minimal. If the level in the plant was such that it would trigger a response in humans and animals by eating them, they would be unlikely to be granted approval and such proteins would be produced in glasshouse conditions.

 

20. "Is the regulation of pharma medicine sufficient for regulating GM grown medicine or will it require more or less stringent regulation?" Martin Pearce

JS: Pharmaceuticals and GM plants to produce them are regulated in the frame of different regulations and by different authorities. For example in Europe, EMA is involved in risk assessment and regulation of pharmaceuticals, EFSA is performing the risk assessment of the GM plants to be grown under open field conditions. A lot of efforts have been spent to clarify who is responsible for what, to define areas of overlapping responsibilities and to harmonize the regulations. The regulations for plant molecular farming are stringent both in Europe and US.

 

19. "What condition areas would be the most likely recipients of future treatments from this area?" Alistair Kent

JM: There are many types of medical conditions that could benefit hugely. At the moment, target products are chosen on the basis of the advantage that production in plants might confer. In previous answers we have spoken about the cost advantage. Another advantage is scalability, where plants offer the potential of production on agricultural scale. So there, you could be thinking about drugs that are needed in massive quantities. Insulin was one example, HIV microbicides is another. Antibodies against infectious diseases such as rabies and HIV are being developed, because these are products that are important for under-developed countries and are required in large volumes. Pandemic vaccines such as flu are being produced in plants, because of the volume issue, but also because making these vaccines in plants can be incredibly quick. So you can respond to new outbreaks very rapidly. Then there are the specialty needs, like Gaucher's disease, again mentioned earlier. Finally, there is one fascinating product under development  - a vaccine against a cancer called non-Hodgkin's lymphoma, where every patient needs a specific vaccine, but made very quickly.

 

18. "What are scientists doing to change public opinion on GM?" @DanKagan1

JS: Scientists tend not to behave in the same way. There are scientists (I guess the majority) supporting molecular breeding technologies including GM technology, scientists not interested in the debate and scientists opposing GM technology. We have to provide objective information and have to try to do it in an understandable way. There are many examples where this has been done, such as unbiased presentations of GM (biosafety) research data (www.gmo-safety.eu/), or the transparent and impressive debate on experimental field trials at Rothamsted Research. Another main issue is to improve people's understanding of agriculture in general and plant breeding. A very successful approach to this was the establishment of the Fascination of Plants Day by EPSO last year, to be repeated as a worldwide event this year.

PS: Developing traits with clear consumer and environmental benefits. Participating in web chats like this. Promoting an evidence-based approach to forming opinions and making policy. Helping to correct misleading claims. Independent scientists are guided by the evidence and the evidence shows the benefits of the technology, otherwise it would not be pursued. All they can do is share that independent view. If the evidence pointed to harm, then they would share that too.

 

17. "GM insulin/safflower: the company behind it said there was no need for clinical trials as the same insulin has already been tested. Is this true? Are people reassured?" Jo Brodie

MM: No this is not true. I was the Chief Scientist at SemBioSys and we actually conducted a rigorous phase II trial in Manchester with this material. The trial was reviewed and permitted through EMA and MHRA. The results were very encouraging in that they proved, using the Agency statistical models, that plant-made insulin is bioequivalent to the standard of care Eli Lilly's Humulin, which is one of the widest used recombinant human insulin throughout the world.

It would be inconceivable at this time to suggest that a new plant-made  pharmaceutical would not be subject to clinical trials. They are treated exactly like pharmaceuticals from any other source and follow the same regulatory path.


16. "Will it one day be possible to eat the plants in order to extract the drugs?" Flavia Lyons

JM: 20 years ago, when we first started thinking about using plants to manufacture vaccines, that was a vision - to deliver vaccines as food.  But we rapidly realised that was never going to happen. Quite apart from having to keep food completely separate from medicine, one of the most important things to control is dosage. It would be impossible to control the exact quantity of medicine that you take if you deliver it within a plant or a fruit.

However, that is not to say that oral vaccines are not possible. There are many industrial scale food process technologies that could allow you to perform a simple processing step, say pulping fruits into a paste with a preservative. It would then be possible to produce packaged portions with defined qualtiy, dose and shelf-life. That is not going to happen quickly, but 20 years from now, I could see giving oral medicines being a possibility.

 

15. "Why is it more beneficial to use plants to produce medicines than bacteria?" @DanKagan1

PS: It should be clear that we are not saying plants are the only way forward, instead we are simply advocating plants as another production platform to be explored. However, for some proteins, bacteria such as E. coli have their limitations in not being able to make some of the more complex proteins that could be made in plants. If comparing culture systems – then plants potentially offer cheaper input costs (feeding the cells to make them grow for example) than bacterial and mammalian cell cultures. But cell culture systems also have their limitations, in terms of scaling up, and for high demand, low value therapeutics (e.g. where global demand exceeds 10 tonnes/ year) the ability to grow plants out in the field is an exciting prospect to achieving affordable drugs.

MM: It is not always more beneficial. In some cases bacteria do very well. However, bacteria are prokaryotic organisms and they have many differences from humans which are eukaryotic organisms. Plants are also eukaryotic. This means that plants can carry out most of the biochemical instructions encoded in human DNA and are often capable of producing an authentic "humanised" pharmaceutical. Occasionally, bacterial fail to do this and produce a variant which is biologically inactive, or they sometimes degrade the human protein, because to the bacterium it has an aberrant shape. Plants generally recognise human proteins as being "eukaryotic" and allow for the production of an authentic bioactive molecule.

 

14. "Is the primary benefit of 'growing' medicines cost or is this approach likely to be able to produce medicines that we cannot easily produce in other ways?" William Nelson

MM: There are three major advantages: The first is direct cost of production. This is particularly important for medicines used at a large scale or in large volumes such as insulin. The second is cost of capital. The cost of building a new pharmaceutical facility is in the hundreds of millions of dollars. When plants are used, the front end of the process (called fermentation or cell culture) is replaced by relatively cheap plants in a field or greenhouse. This can halve the cost of capital and make it realistic for less rich economies. Finally, plants have been shown to allow the production of medicines that have been hard to produce in more conventional systems due to incompatibilities with the host cells. These are very important cases.

It should also be noted that many medicines are currently grown in hamster cells. These cells are fairly reliable, but can carry mammalian viruses. Plants eliminate the risk of cryptic mammalian viruses and mammalian prions, both of which have been issues over the years using mammalian cells.


13. "Since insulin (or other drugs) are designed to be introduced into the human body, albeit in a different manner to food, why shouldn't they be held to the same regulatory standard?" Daniel Callaghan

PS: They would be. All new biotech drugs have to adhere to the same EU regulations. These regulations have been developed with mammalian and bacterial cell culture systems in mind, and need to be adapted to fit with plant cell or whole plant production in mind. The European Medicines Agency (EMA) has issued guidance notes for plant-derived proteins made in stable transgenics – but as yet there are no guidance notes that apply to proteins that are only expressed some of the time.

 

12. "How much space does it require? Does it take away from resources for growing food?" Carolyn Tregidgo

MM: It is interesting to note that you could produce the world's entire supply of insulin on about 10,000 hectares. In North America that would be 3 or 4 farms. Thus the scale is such that it would not even be noticed against the hundreds of millions of hectares used to grow food. The space required is minuscule in contrast to food production. You could produce the entire world's supply of Erythropoeitin (a multibillion $ pharmaceutical) in a 20,000 sq ft greenhouse. The British tomato industry alone employs hundreds of greenhouses of this size just to grow  vine-ripened tomatoes.

 

11. "What would you say are the current top ten plants that plant-made pharmaceuticals are derived from?" Alistair Griffiths @botanyrocks

JM: There is no top 10!  The choice of plant species comes down to what it is that you want to achieve. (This is one of the advantages of biotechnology.) Many groups are working with tobacco, because it is easy to grow, produces a lot of biomass and is not used for food. Some are working with small plants like duckweed or moss, which can be grown in sealed plastic bags. Carrot cells were used (again grown in plastic bags) by one company and gave an advantage in terms of the way the cells assembled the drug product. Other species that are under investigation are maize, rice and potato because scientists are seeking to find ways to deliver vaccines orally, rather than by injection. Oral vaccines would be a significant step for new vaccines, not just because they do not hurt, but because they are cheaper and would be much easier to deliver in under-developed areas.

 

10. "If this science is 'prohibitively expensive' why is it being pursued?" Natalie Hogg

PS: Demand for drugs and industrial proteins will continue to grow.  Plants offer a number of potential benefits in terms of low manufacturing costs and production scalability, low early stage capital investment, low technical expertise etc. The first approved plant-derived product – a therapeutic enzyme for the treatment of Gauchers disease made in carrot cell culture by the company Protalix in concert with Pfizer – showed a 25% reduction in production costs compared to the mammalian cell culture system. The big expense will be taken by the first companies to road test and challenge the regulatory systems to make them applicable to plant-derived proteins.

 

9. "Please explain the science behind the idea? How does a safflower yield insulin exactly?" Natalie Hogg

MM: Human DNA and plant DNA follows exactly the same rules and so if we put the human insulin gene into a plant and make it active in the seed of the plant, the seed can produce insulin very cheaply. There are special refinements to make the levels of the protein economic and to make sure that the seed doesn't 'reject' the human protein. But essentially it works quite well.

 

8. "Why use crops that are consumed by humans e.g. food crops and tobacco, to produce medical chemicals? Are there no alternative plants that are not subject to human consumption?"

JS: The choice of the plant production platform (e.g. plant cell culture, non-food/feed plant, food/feed plant) and the containment (bioreactor, greenhouse, open field) for a plant-made pharmaceutical depends on several factors, including biosafety issues. Food/feed crops provide several advantages like high productivity, long history of safe use, established good agricultural practice. For example, growth factors and other recombinant proteins are produced in barley seeds in large greenhouses in Iceland. The company ORF Genetics (http://www.orfgenetics.com/) is a pioneer in this kind of manufacturing and its human-like growth factors produced in the company’s proprietary Orfeus™ system are successfully marketed as ingredients of cosmetic products and for various medical research, cell culture media and diagnostics. Examples for alternative non-food/feed plants are the wild tobacco Nicotiana benthamiana and the safflower. Vaccines can be produced cheaper, safer and in much shorter production time in the wild tobacco by exploring the Transient Gene Expression method (http://www.fraunhofer-cmb.org/). Genetically modified safflower plants can be explored to produce human insulin as the global demand for the hormone grows (http://en.wikipedia.org/wiki/Safflower).

 

7. "Would these GM plants be grown in a protected environment or in the open air? (Given concerns about cross pollination with natural plant stock.)" Rose Cook

JS: The decision on the plant production platform and the necessary containment (bioreactor, greenhouse, open field) depends on the nature of the product, its value and the amount to be produced. This will be a case-by-case decision, mainly based on biosafety considerations. Most of the plant-made pharmaceuticals envisaged will be produced under containment/protected conditions, but for some products there might be a preference for open field production. For example, therapeutic or diagnostic antibodies will require different considerations.

MM: They have been grown in normal fields, but isolated from other crops. Safflower does not outcross very much and so very low potential of cross pollination with natural plant stock. In fact even if you were to eat the seeds with insulin it doesn't matter as insulin
 is only active when injected and cannot survive stomach acids and digestive enzymes.

 

6. "How will introgression (gene flow between species) with food crops be prevented when this is scaled up commercially?  What will the evolutionary consequences of such introgression be? Can they be foreseen?" Chris Banks

PS: It will be vitally important for industry to show that these crops can be segregated from the food and feed-chain (that is not to say their presence would necessarily be a risk – but it is an avoidable potential issue). Measures such as limited acreage for growing these crops, grown by specialist farmers under licence, completely separate and distant to agricultural farms. Furthermore, farmers would use dedicated farm equipment and extra clean-down measures between harvest would be taken (similar to the rules set out by APHIS in the US). The choice of crop to grow will also be considered to minimise any perceived risk – this could be using non food crops, such as tobacco, or plants with heavy pollen to avoid wind pollination etc. All risk assessments for GM crops take these points into consideration. The EU takes a precautionary approach to risk assessment – and would consider the ‘what if’ scenario of introgression, if it was considered a risk, approval would not be granted for cultivation (containment may then be the alternative option). 

JS: Several confinement measures (physical and or biological) are available and will be further developed and validated to reduce the probability of gene flow. Biological confinement measures include e.g. cytoplasmic male sterility (no production of viable pollen), cleistogamy (flowers do not open), apomixis (no sexual reproduction). Nevertheless, accidental gene flow has to be considered in the risk assessment. The possible consequences have to be considered case-by-case, in the same way as for GM plants with modified input traits (like insect resistance, improved pathogen resistence, resistence to biotic and abiotic stress).

 

5. "What are the risks? Perceived or otherwise." Ken Pearce

PS: I think the biggest concern people have is not production in cell culture or plants grown in containment, but concerns with growing such plants in the field. Cultivation of GM commodity crops is already a contentious issue in Europe and plants modified to produce proteins not intended for the food chain, but for medicinal or industrial use, may appear alarming. The biggest perceived risk is ‘what if these crops accidentally end up in the food chain?’ Regulatory oversight would mean that a zero tolerance threshold would be in place to ensure the likelihood of such occurrence did not happen (as opposed to GM agricultural crops where there is a minimum threshold level for inadvertent mixing - as these crops have been evaluated as safe for the food/feed chain). The additional requirements APHIS have made for Molecular Farmed Crops, to the standard USDA permit requirements for growing GM crops, would be a good starting point for the EU. These include additional training for growers, dedicated farm equipment, specialist cleaning of farm equipment post harvest, no food crops to be grown in subsequent years on the same site, increased separation zones from agricultural crops etc.

JS: The risks of plant-made pharmaceuticals depend on the product, the plant production platform (e.g. plant cell culture, non-food/feed plant, food/feed plant) and the containment (bioreactor, greenhouse, open field) under which the pharmaceutical is produced. The risk assessment will be performed case-by-case, including health and environmental aspects. For example, growth factors and other recombinant proteins are produced in barley seeds in large greenhouses in Iceland (http://www.orfgenetics.com/) bypassing the use of bacterial or animal cell systems. The company ORF Genetics claims that the use of its unique production method ensures that its products are “biorisk-free, allowing customers to enjoy easier regulatory clearance with animal-free, serum-free and endotoxin-free growth factors”. In the case of open field production (e.g. future production of human insulin in genetically modified safflower plants) the production chain has to be separated from other agricultural production chains. Of course, the safety requirements have to be different from insulin production in bioreactors or in the greenhouse. Irrespective of biosafety aspects, intermingling of food/feed products with pharmaceuticals has to be avoided.


4. "Sounds quite good to me, but are there any ethical issues in putting plant-made pharmaceuticals into humans?" Rose O'Brien

PS: Not sure what you mean by ethical, if you mean are plant-made pharmaceuticals safe for human use, then the answer would be yes – there is no evidence that plant glycans are immunogenic in or harmful to humans. Indeed these would be fully evaluated by the standard clinical trial process to ensure that any new drug platform produces safe and effective drugs.

JM: Not for me. We have been making medicines in various ways for decades. Some of the most successful medicines are made using biotechnology, such as insulin that is made in modified bacterial cells, hepatitis B vaccine that is made in modified yeast cells, and anti-cancer drugs that are made in modified hamster cells. Using plant cells in the same way is no different, nor are any of the potential ethical issues. An important ethical issue however, is that modern medicines are extremely expensive and, therefore, not accessible by many poorer communities around the world. One thing that plant-made pharmaceuticals could do, is drive down the price of production and make these pharmaceutical more accessible.

 

3. "How far away are we from this being feasible? What trials would there be?" Carolyn Tregidgo

JM: All medicines (however they are made) are strictly regulated and controlled. There is a long process of testing for safety and efficacy, ultimately in human volunteers, before a drug can be released onto the market. Plant-made pharmaceuticals (PMP) have to go through exactly the same process. Last year, the first PMP was licensed, having been through extensive clinical trials. This was an enzyme replacement therapy for a rare disorder called Gaucher's disease, but the plant-made product is now a less expensive prescription option compared to the medicine that was previously the only option for patients with this disease. 

 

2. "What are plant-made pharmaceuticals?" 

JM: We have been extracting natural products from plants and developing them into medicines for centuries. In this context however, we are making different kinds of medicines in plants using new biotechnologies. This allows us to produce a wide variety of pharmaceuticals including vaccines, antibodies and enzymes in a plant species of our choice. Essentially, we are using plants as cell factories to manufacture these pharmaceuticals.

 

1. "Australian Aborigines have a history of finding medicines from plants. Is this similar?" Janette Hocking

PS: Man has been using plants to produce medicines for hundreds of years (taken as whole plants, crude extracts or infusions). Only around 60 years ago most UK medicines were also herbals. Modern medicine still uses bioactive compounds from nature and we are also able to synthesise them using chemistry and biotechnology.

Our modern approach to making complex biological compounds such as antibodies, antigens and enzymes is to produce them in mammalian, yeast, bacterial or insect cell culture systems (using GM). We now have the technology to add plants to this list of host cells either as cell culture or whole plant production systems. This is ‘Plant Molecular Farming’.

 

 

Our Q&As answer the questions people put, which may mean that some parts of a subject are covered well and others not. If there is an issue that you think is not tackled, you are welcome to send a follow up question to our plant science panel

"Please explain the science behind the idea? How does a safflower yield insulin exactly?
"