In his winning essay in SCI Scotland’s Postgraduate Researcher competition, Alexander Triccas, postgraduate chemistry researcher at the University of Edinburgh, explains how the tiny shells produced by marine algae protect our natural environment.

Each year, SCI’s Scotland Regional Group runs the Scotland Postgraduate Researcher Competition to celebrate the work of research students working in scientific research in Scottish universities.

This year, four students produced outstanding essays. In the fourth of this year’s winning essays, Alexander Triccas explained how coccoliths provide a valuable carbon store and could play a key role in keeping our bones healthy.

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Why tiny shells produced by marine algae are important for both global carbon stores and repairing bones

Although humans can engineer complex and eye-catching structures that help us navigate through our daily lives, they are nowhere close to the design and functionality of natural materials.

These mineral structures are specifically grown to provide support, protection, or food for many organisms. Humans would not exist without them. Indeed, our bones and teeth are made of calcium phosphate. But when grown in a lab, calcium phosphate forms as simple rectangular crystals, which is vastly different to how our bones and teeth look.

This is because our bodies use organic molecules to precisely control how minerals grow, producing materials that can fulfil very specific tasks. Biominerals can even be produced inside single cells. Coral reefs are held together by calcium carbonate minerals made by marine invertebrates. Elsewhere in the ocean, carbonate shells produced by small algae cells are buried on the ocean floor, over time forming the chalk rocks that make up coastal landmarks such as the White Cliffs of Dover.

Advances in microscopy are shedding new light on the composition of coccoliths.

This process is incredibly important to the environment. It takes carbon dissolved in seawater, turns it into solid material, then stores it at the bottom of the ocean. It is concerning then that we don’t know how ocean acidification and rising CO2 levels will affect coccoliths, the name given to these carbonate shells.

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We’re still unsure how coccoliths are produced, particularly how organic molecules are used to give them their unique shape. Proteins and sugars decide where and when the first carbonate mineral forms; then the growth of the coccolith is controlled by sugar molecules.

But how exactly do these organic molecules control the mineral that is produced? We struggle to answer this question because we don’t know how the composition of the coccolith changes as the structure grows.

Composition of the coccolith

Our research focuses on imaging coccoliths in an attempt to observe these changes. We used a technique called X-ray ptychography to map coccolith composition over the course of its formation. This revealed that coccoliths are not entirely made of calcium carbonate, instead having a hybrid structure containing mineral and organic molecules. But this isn’t all.

We revealed that the composition of the coccolith changes during its growth. We think this could represent a transition from a disordered liquid-like state to an ordered crystalline state. While this is common in other biomineral-produced organisms like corals, no evidence of this transition has been reported in coccolith formation before.

>> Read Rebecca Stevens’ winning essay on PROTAC synthesis.

This is incredibly important because it tells us how the cell is controlling the first calcium carbonate mineral that forms. The transition enables the cell to control exactly how it wants the mineral to form, meaning coccoliths can be made faster.

It might also lessen the impact that more acidic seawater has on mineral formation. This could mean coccoliths will not be affected by ocean acidification as much as expected, which is good for the planet’s long-term carbon stores.

However, this is only a prediction. Improvements to the microscopes used to analyse coccoliths will help us know if the transition occurs. Electron and X-ray microscopes are extremely useful in industry – from drug research and medical imaging, to data storage and materials analysis – but their use in these fields is still relatively novel.

Coccolith analysis could give us a better idea of how bones are produced.

Most advancements in instrumental procedures are done in academic research. Our work, therefore, helps us understand the benefits and limits microscopes may have, making them more suitable for industrial use.

Bone research also relies heavily on these microscopes. Our findings could be important in understanding how bones are produced, benefiting not only pharmaceutical and medical industries, but also improving human healthcare by providing better treatments to patients.

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In her winning essay in SCI Scotland’s Postgraduate Researcher competition, Rebecca Stevens, Industrial PhD student with GSK and the University of Strathclyde, talks about the potential of PROTACS.

Each year, SCI’s Scotland Regional Group runs the Scotland Postgraduate Researcher Competition to celebrate the work of research students working in scientific research in Scottish universities.

This year, four students produced outstanding essays in which they describe their research projects and the need for them. In the third of this year’s winning essays, Rebecca Stevens discusses her work in developing a multistep synthetic platform for Proteolysis Targeting Chimeras (PROTAC) synthesis and the potential of PROTACS in general.

Pictured above: Rebecca Stevens

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A ‘PROTAC-tical’ synthetic approach to new pharmaceutical modalities

PROTACs are a rapidly evolving new drug modality that is currently sparking great excitement within the pharmaceutical and biotechnology industries.

Despite the first PROTAC only being reported in 2001, 12 of these potential drugs have already entered phase I/II clinical trials. In fact, a handful of new biotechnology companies have launched in the last two decades with a primary focus on these molecules. So, what’s so special about them?

Traditional drug discovery relies on optimising small-molecules to inhibit the action of a protein target and subsequently elicit a downstream effect on cellular function. However, many proteins are not tractable to this approach due to their lack of defined binding sites. This is where PROTACs offer a unique opportunity to target traditionally ‘undruggable’ parts of the proteome; instead of inhibiting the protein, PROTACs simply remove it altogether.

PROTACs are heterobifunctional molecules made up of two small-molecule binders attached together via a covalent linker; one end binds to the protein of interest and the other to an E3 ubiquitin ligase.

Rebecca is working on a multistep platform for PROTAC synthesis.

By bringing these two proteins into close proximity, PROTACs exploit the body’s own protein degradation mechanisms to tag and degrade desired proteins of interest in a method known as ‘targeted protein degradation’.

This different mechanism of action offers some revolutionary advantages over small-molecule drugs. Alongside potentially accessing ‘undruggable’ targets, PROTACs can overcome resistance mechanisms from which other drugs suffer, as well as acting in a catalytic manner, ultimately requiring less compound for therapeutic effects and maximising profits.

>> SCI’s Scotland Group connects scientists working in industry and academia throughout Scotland.

Problems with PROTACS

While great in theory, the reality is that with two small-molecule binders and a linker, PROTACs are typically double the size and complexity of normal drugs, so their synthesis is far from simple.

Classic drug discovery programmes often make many bespoke analogues alongside their use of library synthesis, using a design-make test cycle to optimise hits and find a lead molecule. With PROTACs, linear synthetic routes are much longer for bespoke compounds, underlining an even greater need for new PROTAC parallel synthesis platforms.

>> Read Marina Economidou’s winning essay on palladium recovery

Additionally, the design of PROTACs is more challenging as there are three separate parts of the structure to optimise, and small changes can have a large impact on their biological activity. As such, very simple chemistry is used to connect the three parts of the molecule, resulting in limited chemical space for exploration, causing potentially interesting bioactive compounds to be missed.

A platform for PROTAC synthesis

My PhD project seeks to develop a multistep synthetic platform for PROTAC synthesis, using modern chemical transformations such as C(sp2)-C(sp3) cross-couplings and metallaphotoredox chemistry.

Starting from already complex intermediates in the synthetic route, methods for late-stage functionalisation are under development to complete the final synthetic steps. By making elaborate changes at a late stage, a variety of structurally diverse PROTACs can be synthesised from a single building block, offering an economical and sustainable approach to optimisation for the industries involved.

Furthermore, the purification step prior to testing will be eliminated, with crude reaction mixtures taken into cells in an emerging ‘direct-to-biology high-throughput-chemistry’ approach. This removes a key bottleneck associated with hit identification and lead optimisation, delivering biological results in very short turnaround times.

The synthetic methods developed in the project will offer new capabilities for efficient and sustainable synthesis of PROTACs and other related modalities. Increasing the pace of data generation could accelerate the exploration of structure-activity relationships and deployment in large parallel arrays could provide a significant quantity of data to inform new machine learning models.

Ultimately, for industry, this ‘PROTAC-tical’ approach offers a huge opportunity for rapidly progressing PROTAC projects and discovering novel PROTACs with clinical potential.

>> Our Careers for Chemistry Postdocs series explores the different career paths taken by chemistry graduates.

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In her winning essay in SCI Scotland’s Postgraduate Researcher competition, Marina Economidou, first year PhD Student at GSK/The University of Strathclyde, talks about palladium recovery.

Each year, SCI’s Scotland Regional Group runs the Scotland Postgraduate Researcher Competition to celebrate the work of research students working in scientific research in Scottish universities.

This year, four students produced outstanding essays in which they describe their research projects and the need for them. In the second of this year’s winning essays, Marina Economidou explains the need for palladium recovery and making it more efficient.

Pictured above: Marina Economidou

U-Pd-ating the workflows for metal removal in industrial processes

Palladium-catalysed reactions have great utility in the pharmaceutical industry as they offer an easy way to access important functional motifs in molecules through the formation of carbon-carbon or carbon-hetero-atom bonds.

The superior performance of such reactions over classical methodologies is evident in modern drug syntheses, where Buchwald-Hartwig, Negishi or Suzuki cross-coupling reactions are frequently employed.

However, the demand for efficient methods of palladium recovery runs parallel to the increased use of catalysts in synthesis. The interest in metal extraction can be attributed to several reasons.

Cross-coupling steps are usually situated late in the synthetic route, resulting in metal residues in the final product. In addition to possessing intrinsic toxicity, elemental impurities can have an unfavourable impact on downstream chemistry.

Hence, their limit must be below the threshold set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

The need for palladium recovery

However, the importance of palladium recovery does not only arise from the need to meet regulatory criteria. The volatility of palladium supply as a result of geopolitical instabilities has been a focus of attention this year, with Russia producing up to 30% of the global supply and prices reaching an all-time high of £81,179 per kilogramme.

Therefore, aside from the need to remove metals from the product for regulatory reasons, there is a desire to recover metals from waste streams as effectively as possible due to their finite nature and high costs.

The sustainability benefits of recovery for circular use are an additional incentive for an efficient extraction process, as catalysts can be regenerated when metal is returned to suppliers.

The increasing pressure for greener processes and more ambitious sustainability goals – such as GlaxoSmithKline’s environmental sustainability target of net zero impact on climate by 2030 – also contribute to the need for further refinement of working practices.

>> SCI's Scotland Group connects scientists working in industry and academia throughout Scotland.

Palladium has many uses including in catalytic converters, surgical instruments, and dental fillings.

Improving extraction processes

It is essential to have well-controlled and reproducible processes for pharmaceutical production, as redevelopment requires further laboratory work and additional time and resources.

With several industry reports on the inconsistent removal of palladium following catalytic synthetic steps, there seems to be a knowledge gap as to which factors affect the efficiency of extraction and why there can be significant differences between laboratory and plant conditions.

The focus of my PhD is investigating the speciation of palladium in solution in the presence of pharmaceutically relevant molecules, to offer an insight into the efficiency of metal extraction at the end of processes.

By understanding the oxidation state and coordinative saturation of the palladium species formed in the presence of different ligands, a better relationship could be established between the observed performance of metal extraction processes under inert and non-inert conditions.

With the wide breadth of ligands and extractants that are now commercially available for cross-coupling reactions, my ambition is to generate a workflow for smart condition selection that not only achieves selective metal recovery, but is scalable and can be transferred to plant with consistent performance.

The cost and preciousness of metal catalysts are both factors that prohibit their one-time use in processes. Understanding how palladium can be extracted and recovered in an efficient manner will not only deliver reliable processes that meet the demands of the market in the production of goods, it will also lead to economic and environmental benefits.

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>> Read Angus McLuskie’s winning essay on replacing toxic feedstocks.

>> Our Careers for Chemistry Postdocs series explores the different career paths taken by chemistry graduates.