Dr Wilks is interested in how chemical matter behaves at the nanoscale, one ‘level’ up from individual molecules and atoms. Understanding fundamental processes of self-assembly and developing new tools to control them is at the heart of what he does because having such tools will enable incredible leaps in our ability to design and make advanced materials. Molecular diagnostics, ‘smart’ therapeutics, artificial cells: underpinning all these exciting, emerging technologies is a deep knowledge of how molecules, large and small, interact on the nanoscale. Under this broad umbrella, his work is split into three themes.
New Methods for Controlled Polymer Self-Assembly
Nanoparticles are extremely interesting materials, with many potential applications ranging from medicine to energy generation and storage. As well as its basic chemistry, the size and shape of a nanoparticle has a huge impact on its properties.
For example, rod-like particles behave very differently in cells and the circulatory system than their spherical counterparts. However, there are currently only a handful of methods that allow size and shape to be tuned with precision, and expanding this toolbox is one of my main research focuses. Doing this requires working across multiple disciplines: Dr Wilks collaborate with physicists to understand the fundamentals of self-assembly, and biologists to ask questions about the cellular processing of nanomaterials.
His main tools for this job are hydrogen-bonding (H-bonding) mediated assemblies, which have for many decades been employed as surrogates to mimic the nanostructures formed as a result of nucleobase pairing within RNA and DNA. We have recently shown that assembling nanoparticles with nucleobase functionality sequestered in the core allows us to easily and selectively control the shape of the particles simply by adding a diblock copolymer bearing the complementary nucleobase.
We are now exploring how this method can be used to generate nanoparticle libraries in which size, shape and chemistry are varied independently. This will enable us to answer fundamental questions about the effects of these parameters on biological processing, ultimately enabling more rational design of nanoparticles for therapeutic applications – an area that has huge potential, but which is yet to be fully realised for want of this basic understanding.
There is a pressing need to find new molecules capable of meeting challenges in energy generation and storage, catalysis and human health, but chemical space is vast and it is never going to be practical to synthesise every possible molecule that could exist. One solution to this problem is to use the principles of evolution by natural selection, i.e., develop a system where instructions are translated into products, these products are exposed to a selection pressure (for example binding to a target), the ‘fittest’ products survive and their instructions are replicated, mutation diversifies the instructions, and the process is repeated many times.
This way, it is possible to search a large chemical space efficiently without the need to make every possible molecule. At the foundation of this system is some method for translating a set of instructions into a chemical product. In living organisms this function is fulfilled by the ribosome, but this is limited to making peptides from 21 naturally occurring amino acids. How can we get around this? One solution is DNA-templated synthesis (DTS), which controls chemical product formation by using the specificity of DNA hybridization to bring selected reactants into close proximity, and which is capable of the programmed synthesis of many distinct products in the same reaction vessel. By making use of dynamic, programmable DNA processes, it is possible to engineer a system that can translate instructions coded as a sequence of DNA bases into a chemical structure – but without the constraint of using only amino acids. It is also possible to ensure that each product molecule is tagged with its identifying DNA sequence.
Compound libraries synthesized in this way can be exposed to selection against suitable targets, enriching successful molecules. The encoding DNA can then be amplified using the polymerase chain reaction and decoded by DNA sequencing. More importantly, the DNA instruction sequences can be mutated and reused during multiple rounds of amplification, translation and selection.
My research is focused on developing autonomous DTS systems that can reliably synthesise large combinatorial libraries with high efficiency. This involves developing new templated chemical reactions, investigating novel solvents to improve the efficiency of existing DTS chemistries, and designing new DNA mechanisms.
DNA is a fascinating material, best known for its ability to encode genetic information but with a wide variety of other uses in nanotechnology. For example, DNA can be folded into intricate shapes and patterns on the nanoscale (DNA ‘origami’) to produce a huge variety of 2D and 3D structures, with potential applications in drug delivery, diagnostics and electronics. Synthetic polymers, meanwhile, are cheap to make and can be easily tailored to specific applications.
For example, temperature- and pH-responsive polymers, which change their solubility in water in response to an environmental change, are straightforward to make. By combining the unique properties of DNA and synthetic polymers, it is possible to create new materials that exhibit unique behaviour. We reported the first example of a DNA-polymer hybrid in which the DNA was used to form a 3D structure (in this case a tetrahedron, see above). We also developed a way of non-covalently modifying double stranded DNA with polymers by making use of intercalation interactions between the DNA base pairs. I am currently working on new methods for the synthesis of DNA-polymer conjugates and their self-assembly.