We asked three biophysics experts to share their thoughts on the current challenges and future expectations of analytical instruments. Let’s take a leap into the future with them.
Over the last couple of decades innovation in instruments for affinity measurements changed important aspects of the way we discover and develop new therapeutic molecules and other binders.
We had a chat with HexagonFab’s Advisor Peter Ball, Biophysicist Katherine Stott of the Biochemistry Department (University of Cambridge) and Nic Farrands, Analytical & Formulation Manager of the Centre for Process Innovation Limited. We asked them to comment on the present and future of analytical instruments for studying intermolecular binding.
The present: current advances and challenges
We can rely on technologies that provide greater speed, experimental choices and reliability compared to the past. Ball highlighted that “The evolution and development of label free imaging technologies allow far richer and more relevant data to be generated than was possible 10 years or more ago. Alongside label-free imaging, more traditional methods, notably high-throughput mass spectroscopy, with a capability of analysing multiple 1536 well plates per day, have advanced considerably as a drug discovery tool.”
“The advent of single-molecule methods has resulted in the development of key instruments that are now commercially available, such as optical tweezers with fluorescence microscopy and mass photometry,” remarked Stott.
We can now count on various thermal and optical methods for analysing biomolecular interactions. The first surface plasmon resonance (SPR) instruments were sold in 1990 and are still considered the top-standard for many applications. However, more recently, platforms based on new sensors are showing promising results with new binders, as Ball pointed out: “It is not clear to what extent the current label-free technologies are suitable for new types of drug molecules. Examples of these include proteolysis-targeting chimeric drugs (PROTACs), bicyclic peptides, gene silencing therapies based on antisense and other RNA molecules, and exosome-based therapies. However, early evidence from peer-reviewed publications suggest that technologies based on graphene sensors – the heart of the HexagonFab Bolt platform – are particularly well-suited to measuring interactions involving nucleic acids.”
We have plenty of choices of affinity assays to measure affinity (KD), kinetics (kon, koff), thermodynamics, concentration and binding specificity. Nevertheless, certain aspects in affinity studies remain difficult to address with the current technologies. Stott said that measuring very high or very low affinities remains challenging, and Farrands expressed concern about the reproducibility of conjugating the probe, for example an antibody against a target, as well as batch-to-batch variations of both commercially available and self-produced probes.
The future: what’s in store
The three experts gave us some interesting views into the future from both an academic and an industry standpoint. “We will see more analytics that have a small footprint, are easy to use and can analyse an array of biological targets and drug modalities. I foresee the development of instruments that require a simple sample preparation workflow, and have the ability to analyse crude and purified samples alike. Essentially, a versatile one-stop-shop approach that can future-proof a laboratory toolbox,” commented Farrands. He also explained that the growth of messenger RNA (mRNA) vaccines caused by the current coronavirus pandemic has unleashed a renewed interest in synthetic biology, such as RNA interference (RNAi) products, in the bio-pharma industry, which could potentially treat conditions like cancer and neurodegenerative disorders.
“It would be nice to see a democratisation of instruments, with better access to all, either through access initiatives and support for high-end equipment, cheaper or new versions of the current techniques. Easily portable and solid-state devices will surely contribute,” said Stott.
According to Ball, we are only just beginning to explore the potential of two key areas: Process Analytical Technology in Bioprocessing, which has been slow to develop because of the challenges of obtaining real time data, and gene silencing and editing technologies, which could revolutionise medicine by moving away from treating diseases (often imperfectly) with drugs to curing a disease by blocking the gene (or genes) behind it.
In a nutshell, our interviewees hope to see a shift to smaller, faster, more accessible and easier data acquisition platforms that work with both traditional and new binders, especially nucleic acids. In our rapidly changing society, we need to upgrade our tools to the evolving priorities, fight new viruses, find new ways to tackle complex diseases, and detect environmental pollutants. We hope to bring some solutions to the big societal challenges ahead!