Each industry has to reinvent itself from time to time in order to survive. Energy production transits tot sustainable sources. Automotive industries prepare for the electric car and self drive. But the pharmaceutical sector is scrambling to develop a clear vision on its future. We suggest they need to develop better precision and higher success rates through nature based medicines stemming from modern synthetic biology.
The strategy of major pharmaceutical companies still consists of developing synthetic medicines, straight from the lab; but their heydays are over. Then there was the suggestion for ‘rational design’ of new drugs, based on modern knowledge of the functioning of our bodies; that proved to be a bridge too far. Plant based medicines are too rare and lack systematics to serve as a basis for a new future. The promises of genetic modification and synthetic biology are just a little too vague. And yet, these ingredients taken together will serve to revive pharmaceutical industries. The many takeovers and mergers in the sector testify to an industry that is doing its utmost to secure a better future.
Nature provides us with many medicines
In the past few decades, although chemists were leading in the development of new medicines instead of biologists, still a number of important plant based drugs has come to the market. Either nature could do better, or chemical structures proved to be too difficult to reproduce successfully in the lab. Examples are digoxin (a medicine for the cure of Alzheimer’s disease) from the foxglove plant, quinine from the kina tree, and artemisinin (an antimalarial drug) from the mugwort plant. And of course the important antibiotics, based on penicillins. Up to the present day, the base structure of penicillin is too difficult to synthesise in the lab. Nature (yeasts, moulds, bacteria and plants) can do better. Biology and horticulture make great strides in this field, and as a result we will see more natural medicines coming. Nowadays artemisinin is being produced by yeast cells, and a Dutch horticulturalist is preparing for growing a foxglove variety with an enhanced amount of digoxin.
But chemists do not give up easily
Still, the majority of new medicines in the past few decades were developed by chemists. They provided us with better antibiotics, antihypertensive drugs, beta-blockers and cholesterol-lowering drugs. The most important step in chemical drug development is the identification of new chemical structures with likely beneficial biochemical activity in our bodies; discovery of ‘lead compounds’, in technical terms. For a short period of time, researchers thought they could design such structures on the basis of our knowledge of bodily functions. They coined the term rational design for this. But this proved to be a bridge too far. The sheer number of parameters, and the many interactions between them, is too large, even for very large computers. And a guided search into natural compounds proves to be difficult as well. We have far too little systematic knowledge of chemical formulae of natural products in relationship with their function in the microorganism or the plant. We do not know why and when a plant or a bacterium produces a substance, we just find it doing so, and if we are lucky we can find an explanation. Far too little for predictions. And the far majority of phenomena in living nature we have not investigated yet. The best chemists could do in their search for new medicines, particularly through the development of informatics and automation in the lab, was to generate huge amounts of chemical structures and synthesise them quickly, in very tiny amounts. A random search, in fact, hoping that some lead for a new drug might come up. At present, this is the dominant procedure in the search for new medicines.
Resulting loss of precision
Such random searches have resulted in the discovery of many new medicines, but they did not come up with block busters. All too often, the result was more of the same, or piecemeal improvements on existing pathways. All in all, these procedures produced a major race among pharmaceutical companies to be the first to introduce a new product on the market, however flimsy the amelioration. Consequently, they do not have the time for a proper design of industrial production. The original pathway towards the chemical structure becomes leading for large-scale production. Such processes were intended for the development of many chemical structures as fast as possible, not for doing so as efficiently as possible for each individual structure. The motto is: let’s get the structure first, test it for any medicinal properties, and then we’ll see what to do.
But that opportunity never comes. If good physiological activity is found, speed (time-to-market) is all that counts. There never is the time for the proper development of a precise, catalytic and efficient production pathway. And once the product is on the market, regulation stands in the way of improvements in the production process. Each change needs to be registered and approved for reasons of product safety; a costly process, and frustrating to all chemists who know very well how to improve the existing production process. The impurity profile might just change slightly, with possible consequences for the action of the drug in the body. Therefore: no more risk taking, stick to what we have. Rather purify the end product again a few times, and accept major materials losses as a consequence, than reserve funds for the development of a dedicated and efficient production process. As a consequence, the production of modern medicines may incur the production of hundreds of kilos of chemical waste per kilo of end product. There are cases in which waste production exceeds a ton of waste per kilo of product. This does not pose major problems yet, as these substances are produced in small volumes, hundreds of kilos to several tons, but it is a shame on industry and a disgrace to process engineers and producers. A lot of unnecessary work has to be done to clean up all waste.
Bringing the best of both worlds together
We judge a new direction for pharmaceutical companies to be found by bringing together the achievements of synthetic chemistry and the prospects of modern synthetic biology. Although we cannot yet establish a system of relationships between structures and functions of naturally occurring compounds, synthetic biology does supply us with the instruments to generate purposefully a wealth of chemical structures identical or closely related to naturally occurring chemical structures. We can transfer genetic codes from plants to microorganisms, like from the mugwort plant to yeast cells in order to produce artemisinin. And any other code from any other plant or organism can be transferred. This supplies us with the means to produce any substance found in nature and a range of related products, from modified microorganisms, once we have assembled the genetic codes for its production in a suitable microorganism. With modern techniques like CRISPR-Cas9, we can transfer and modify codes very efficiently and with great precision. Moreover, we do not have to confine ourselves to genetic codes found in nature, we can also enlarge or modify these codes with artificial ones from the lab – this is in the heart of the field of synthetic biology and widens up considerably the field of nature based medicines.
Towards nature based medicines
These procedures open up a large field of prospective medicines, waiting to be investigated. The major advantage of this procedure over the chemical one is that the factory for large-scale production is already there at a mini scale – it is the microorganism that produced the first batch. Reproducing microorganisms is a standard procedure, as is the enhancement of the microorganism’s productivity. And in this case of nature based medicines, regulation will not stand in the way of process improvements: regulation does not go into the way in which the organism does its work (in fact, through natural processes), but targets waste production and ensures that no traces of the intermediate organism will end up in the final product. And in this procedure, waste production is a completely different story. It is very small in volume or readily biodegradable. It may consist of simple salts, like ammonium sulphate as a side product, a substance that can be sold as a fertilizer.
Now, if these nature based medicines produced through microorganisms would not fulfil their promises, chemists can still come along and perform their tricks. They can use the molecule from the microorganism as their feedstock and produce an endless array of modifications to its chemical structure. The entire body of knowledge they have acquired so far will be at their disposal. They will have let the microorganism do the bit that was too complicated for chemical synthesis. Successful examples of such nature based medicines from the past are the well known semi-synthetic antibiotics (penicillins, cephalosporins). Their development could serve as the blueprint for the pharmaceutical industry of the future, building upon the discoveries by Fleming in 1928 (penicillin) and Abraham in 1955 (cephalosporin), and the subsequent development of many great drugs by major companies (or formerly so) like Beecam, SKF, Bristol-Meyers, Glaxo, Squibb, Lily and Gist-Brocades. The future is to nature based medicines.