The 3D Printer Drug Discovery Search Engine

The 3D Printer Drug Discovery Search Engine

By Lee Cronin – Gardiner Professor of Chemistry

Inspired by developments in technology I am often wondering how chemists who make molecules, materials and formulations could do things differently. This is because if you look at the impact technology has made in a modern physics or molecular biology laboratory, the difference would be rather dramatic; but if you looked in a chemistry laboratory you would see not much has changed, certainly in terms of glassware and the way reactions are done, at least for the discovery of new molecules. Inspired by the technology of 3D printing, I wondered if it was possible to use a 3D printer, not only to construct a test tube for a chemical reaction, but also deploy the chemicals into the test tube for the reaction and also customize the test tube to allow certain reactions to happen in different ways. One could even imagine printing a test tube out of biologically relevant materials and using the test tube as a way of fusing chemistry experiments with cell biology experiments. Born was the idea of 3D printing of chemistry.

At the heart of the idea was the realization that organic chemists make complicated molecules step-by-step in the lab with a lot of know-how and many unit operations. Conceptually, organic chemists often work out how to make their target molecule by working backwards and reducing the complex molecule to simpler ones step-by-step on paper, only to reverse the process in the laboratory and build the molecule up. Thinking about this approach, and the way chemists make things, I asked my research group if we could make a version of this chemistry set and use a 3D printer to make the molecules. I then wondered if we could use common building blocks in different ways to make different molecules—i.e. have software control over the molecular assembly. In essence, could we “app” chemistry?

Now what would this mean, and how would we do it? Well to begin, we took a 3D printer and started to print our beakers and our test tubes on one side and then print the molecule at the same time on the other side and combine them together in what we call reactionware. By printing the vessel and doing the chemistry at the same time, we were able to do a range of different chemical reactions, but also we were able to both purify the new molecules by a process of crystallization. By changing the volume of the reactor space, we could change the outcome of the reactions and make different molecules. At the heart of this idea is a 3D printer used in two different ways: i) a test tube builder and ii) as a liquid handling robot to place the chemicals in the right place at the right time for the chemistry to work. As the whole thing is computer controlled, the software blueprint could act as a new way to control chemistry as a type of app.

Today we are at the very early stages of this technology and many colleagues are excited and some are concerned. Those who are excited see the vision of moving chemistry beyond the laboratory; and those who are concerned doubt that the idea is feasible and cite the potential problems of chemical compatibility, inefficiency of the reactions, problems with purification, product verification and so on. I do not doubt these issues for a second, but rather I see the potential spin-offs from attempting to solve the problems. It may be possible to discover new molecules and materials by manipulating the chemicals in a new way exploiting my reactionware idea (reactor architecture and function), to do reactions in new environments (for example in model 3D cell-printed structures as tissue or organ models), and perhaps even to app the recipe once the new molecule has been found in the 3D printer system. I think the 3D printer for new routes to chemical discovery can be thought of a bit like a molecular search engine and in the laboratory this could become a new tool for professional scientists to make and characterize molecules. This is probably where the technology could stay for many decades but, if it indeed proves possible to use such approaches to discover new molecules, then the leap to use the systems to build drug molecules out of the laboratory from a fixed set of ingredients could also be possible and perhaps even be easy. This is exciting since it could allow fast access to molecules with the recipe simply downloaded. If the printer had a common set of chemicals or inks, then it may be possible not only to build the molecule by doing the right chemistry in the device, but also to purify the molecule and even verify that the correct molecule was made before realizing it from the device.

Today we are far away from the out of the laboratory vision; but in the laboratory we are developing routes to show that in principle it could be possible to build organic molecules like simple drugs, and also show how these methods of chemical synthesis could be made into an app. This could ultimately mean that you could print your own personalized medicine. But first we need to take baby steps to get there, and it is important that we can demonstrate the value of this approach to our colleagues, and demonstrate the feasibility of our big vision. However, as with all big ideas, there are critics and we have found that a lot of the criticism has helped us clarify our approach and ensure that we aim for the big wins that will allow us to build a new field. Right now we are busy solving many of the technical issues but there would seem to be no intrinsic barrier. The key issue is not only if it will catch on, but if we can discover more interesting molecules using this approach than using other approaches, and how robust the approach is. This is because the real excitement is the possibility that we could go from discovery to manufacture very quickly and allow deployment anywhere. This could even mean you would not need to go the pharmacy anymore. One could literally imagine printing drugs at point of need—although this would require a radical overhaul of our regulatory approaches, not to mention robust product verification protocols. But one of the most immediate uses could be for chemical or biological diagnostics that could allow the development of new threats to be monitored. Perhaps futuristically hybrid hard, wet, and bio-devices could be used in synergy with the chemical search engine to rapidly develop new drugs and allow a type of on-the-fly molecular assembly to combat super-resistant bacteria as a defence of last resort.

I wonder if, in the end, the barriers are not really the technical issues in doing chemistry in an unfamiliar way, although they are great, nor the amount of funding required to achieve the vision, but perhaps our attitudes to radical new things and not considering how drug discovery should change in future—especially the regulatory issues. However, in a world where access to the most basic resources is going to become tougher, I think we owe it to humanity to consider how we could make life-saving chemicals available to all as quickly as discovery and safety testing will allow. As futuristic as it may sound, perhaps aiming for the universal matter fabricator rather than the drug-3D-printer could be the way to light up our imagination to the possibilities . . .