Prof. Dr. Christoph Wittmann from the TU Braunschweig is a partner in the Biopolymers/Biomaterials cluster. He is developing mathematical models of metabolic processes to optimise microorganisms for use in biotechnology. In an interview with Christoph Bächtle, Wittmann talks about systems biology, ”drawing-board” organisms, biobased plastics and biotechnology’s capacity to complement existing large-scale methods.
Classical polymer chemistry has been hugely successful for many years. What kind of contribution can biotechnology be expected to make?
The strength of biotechnology is that it opens up possibilities to establish new, sustainable production processes. Petrochemical resources are getting scarcer and more expensive. On top of this, the processes involved in the product cycle generate increased levels of carbon dioxide that have an impact on the climate.
Biotechnology can use alternative renewable resources for manufacturing the same products. The use of renewable resources enables the refixaton of carbon dioxide that is released during the products’ life cycle, thus closing the carbon cycle, which is a huge advantage in the combat against global warming. Biotechnology also addresses the issue of the increasing scarcity and price of natural resources.
Biotechnology opens up production methods of the future, biological chemistry so to say, that will lead to the production of chemicals, materials and fuels using alternative resources.
When you look at the overall balance of a biotechnological process, i.e. the production of media, heating and stirring of fermenters, the purification of biotechnological products, and so on - how do biotechnological processes compare to petrochemical processes, in terms of both efficiency and costs?
Biotechnological processes are often considered to be very attractive in terms of ecological efficiency. However, it must be pointed out that many petrochemical processes are also very efficient - they are carried out in depreciated facilities and are tailored to the production of large volumes. This economy-of-scale has a massive positive impact on product price. Petrochemistry has thus set the barrier very high and it remains to be seen whether biotechnological methods can live up to our expectations.
Having a ‘bio-label', i.e. being seen as sustainable, is not the only important factor in the launch of a new product. Biotechnological production methods also have to be efficient and inexpensive. This is one of the big challenges that we have to overcome. Biotechnological processes, cell factories, tailor-made biocatalysts and processing methods must be efficient enough to make biotechnology competitive.
What is the price difference between petrochemical and biotechnological processes?
It is difficult to compare the two processes. Petrochemical processes are currently being used in large-scale production whereas biotechnological methods are still at the stage of being tested in the laboratory or on the pilot scale. But I think it is realistic to envisage that biotechnological methods will eventually also be used for large-scale production, which will enable them to compete with petrochemical methods. We think this is likely to be the case particularly for high price products.
Will this relate specifically to high-tech plastics in the first instance, or will biotechnological processes also be able to compete with petrochemical processes in the production of bulk products such as polyethylene, polypropylene or PET?
Polylactide is a biobased plastic in the low-property polymer class, i.e. bulk plastics. I believe that the USA currently produces huge quantities of polylactide, in excess of 100,000 t per year. Polyhydroxyalkanoates, PHAs, are another example of biobased polymers used for bulk production. It appears to me that biopolymers are starting to play an important role in the production of bulk plastics.
High quality, top of the price range plastics are also very attractive in my opinion, because they offer a broad range of applications that could potentially tap into huge markets. Polyamides are one example of plastics of this kind.
A decisive factor in the competitiveness of biotechnological methods is the yields of the basic substances that are used for the production of polymers. What is the best way to increase these yields?
It depends on the new systems biology strategies used to optimise production strains. Progress in this area will make an even greater contribution to increasing yields. Systems biology methods will provide us with a very comprehensive picture of genome sequences, substance flows and metabolites in the cells. This will help us to discover how to alter organisms in order to obtain the sought-after properties.
In the past, organisms were optimised through trial and error, random mutagenesis and the subsequent selection of those that were best suited to the required processes. Nowadays, optimisation can be efficiently achieved by tailoring a strain to a desired purpose and by introducing a range of positive modifications into the bacteria in order to optimise them. These strategies open up possibilities that far exceed what was possible several years ago.
This optimisation will be the decisive factor in the development of tailor-made cell factories, which enable the efficient production of metabolites, etc. and which are able to compete with petrochemical methods.
What kind of improvements will the new methods bring?
It is difficult to express any potential improvements in percentage terms. But it is clear that strains optimised with traditional methods will be inferior to the strains produced with the new methods. Although traditional strains have thousands of mutations, only a few contribute to higher yields. Many of these mutations even make development more difficult as the bacteria do not grow well enough, are more susceptible to stress and require additional nutrients.
However, detailed analyses can provide me with information as to what needs to be switched off or added. I can ‘design the sought-after cell on the drawing board’ and use genetic engineering to alter the cells in a specific way. Cells that are optimised in this way, grow faster, produce higher yields and there are fewer requirements on the culture conditions.
Does this imply that virtually any strain can be used? Or do you need to take already existing efficient bacterial candidates and develop them further?
On the one hand, the trend is to transform established organisms such as E. coli, Corynebacterium or Bacillus into platform organisms. These platform organisms can then be used to make different products by adapting specific metabolic pathways. The advantage is that the platform organisms are well characterised and their cultivation is well established. On the other hand, it is not that difficult to analyse a newly discovered strain (isolate) and optimise it in the desired direction. The sequencing of a bacterial genome costs around 5000 euros. This means that we are now able to also assess the potential of an unknown organism for biotechnological production and optimise it.
Would a platform strategy not be better, especially with regard to the efficiency increase required? The parameters needed for this are already known. Would this perhaps enable the modification of organisms according to clients’ requirements?
Yes, in this case the organism would only be the platform and produce compound A, B, C when modified accordingly. This is certainly a very interesting strategy for the future. An added advantage is that companies would be able to use their own patents.
How would you describe the features of an ideal production strain?
An ideal production strain needs to have excellent production properties. Especially in the case of bulk plastics, ideal production strains need to be very productive; they must be able to convert a substrate into the desired product as efficiently as possible. These strains must lead to high product concentrations in order to generate large enough quantities for purification. In addition, the strains need to be genetically stable, so that the processing is reproducible. And ideally, they must be able to live on a broad range of substrates. This would mean that we could switch to other production methods if a certain substrate becomes more expensive, thus enabling us to quickly adopt alternative raw materials. In addition, ideal production strains have minimal requirements for nutrients and can easily be integrated into biorefinery concepts.
Let’ s talk about raw materials – biotechnological production uses materials that can also be used for energy and food production? How can the problem of these competing needs be resolved?
I am sure the market itself will solve this problem, it will at least partially determine what is produced from what. Of course, it also depends on the availability of resources, on price and on other available alternatives. There are many aspects that must be taken into account when using raw materials for one particular purpose or another.
But I am sure that future development will move away from using raw materials that are also used as food. This trend is already apparent and I believe that biotechnology has an important role to play in this issue. We need to tap alternative resources, for example wood, cellulose, hemicellulose or waste. We need to refrain from using starch. This will enable us to use resources other than those used for food production. Intensive research is being carried out in order to make it possible to use cellulose as a raw material. But a lot of intensive work is required to achieve a viable result. It is a difficult area of research, but it is definitely the way forward.
You mentioned the role of production strains. On a scale of one to ten, in which ‘one’ means ‘ not present’ and ‘ten’ stands for ‘excellent results’, where would you say are we on the path to developing microorganisms for the industrial production of biobased polymers?
I would say we are around half way. Research has already made huge progress, which is very encouraging. But more progress needs to be made. The prognosis for biotechnology is quite good overall, but we still have a long way to go.
Succinic acid and diaminopentane are two components used in polymer chemistry that are already produced using biotechnological methods. The two are more or less directly derived from the tricarbonic acid cycle, which is a key metabolic pathway. Will research initially focus on these key positions in the metabolisms or will scientists also look for basic components for use in plastics production beyond the major routes?
Succinic acid and diaminopentane resulted from the first attempts to produce metabolites created in the central metabolism and they were of potential interest for plastics production. However, in future it could also be feasible to go in completely the opposite direction, for example we may start looking at the characteristics of polymers that are already on the market. Then we would try to find ways to produce the required components using microorganisms, even if it proves impossible to derive the desired molecules directly from the metabolism. What I have in mind are synthetic cell factories with completely new metabolic characteristics, which may only be possible to build by combining genes from different organisms.
In the medium term, this might be the path new developments take. New products could enter the market following an analysis of sought-after substances, components and characteristics, which would allow production organisms to be designed and developed.
Biotechnology therefore attempts to partially substitute classical petrochemical raw materials with biobased molecules at the same time as looking for new basic substances for the production of new polymers with new characteristics.
Exactly, these are the two paths that we are currently going down. Diaminopentane is one example that shows that biotechnology is able to deliver new basic substances and produce new polymers. Chemically speaking, it is relatively difficult to produce diaminopentane. That is why the substance is very rarely used in petrochemistry. However, it has been shown that polyamides based on this monomer have very attractive properties. Thanks to biotechnology, these polyamides can now be used to create new products.
Does the fact that you are able to design particular production strains and hence produce made-to-measure products represent the first steps towards biotechnological material design? Will we at some time in the future be able to produce plastics according to individual customer requirements?
I think this will be possible. At the moment we produce the monomers and polymer chemists synthesise polymers. This will probably continue to be the case in the future. Polymer chemists will synthesise polymers with the properties requested by clients and biotechnology will provide the basic substances. Polymers can be composed of a broad range of different monomers. I am convinced that the cooperation between biotechnologists and polymer chemists is the right way to produce special plastics tailored to individual customer requirements.
In the very long term, biotechnology might also be able to provide complete synthesis routes. However, at present this is still a far-off vision.