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.

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.

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

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.

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.

We are increasingly conscious of the need to recycle waste products, but it is never quite so easy as rinsing and sorting your waste into the appropriate bins, especially when it comes to plastic.

Despite our best intentions, only around 16% of plastic is recycled into new products — and, worse, plastics tend to be recycled into low quality materials because transformation into high-value chemicals requires substantial amounts of energy, meaning the choices are either downcycling or prohibitively difficult. The majority of single-use plastics end up in landfills or abandoned in the environment.

This is a particular problem when it comes to polyolefins such as polyethylene (PE) and polypropylene (PP), which use cheap and readily available raw materials. Approximately 380 million tonnes of plastics are generated annually around the world and it is estimated that, by 2050, that figure will be 1.1 billion tonnes. Currently, 57% of this total are polyolefins.

Why are polyolefins an issue? The strong sp3 carbon–carbon bonds (essentially long, straight chains of carbon and hydrogen atoms) that make them useful as a material also make them particularly difficult to degrade and reuse without intensive, high energy procedures or strong chemicals. More than most plastics, downcycling or landfill disposal tend to be the main end-of-life options for polyolefins.

Polyethylene is used to make plastic bags and packaging.

Now, however, a team of scientists from MIT, led by Yuriy Román-Leshkov, believe they may have made a significant step towards solving this problem.

Previous research has demonstrated that noble metals, such as zirconium, platinum, and ruthenium can help split apart short, simple hydrocarbon chains as well as more complicated, but plant-based lignin molecules, in processes with much lower temperatures and energy.

So the team looked at using the same approach for the long hydrocarbon chains in polyolefins, aiming to disintegrate the plastics into usable chemicals and natural gas. It worked.

First, they used ruthenium-carbon nanoparticles to convert more than 90% of the hydrocarbons into shorter compounds at 200 Celsius (previously, temperatures of 430–760 Celsius were required).

Next, they tested their new method on commercially available, more complex polyolefins without pre-treatment (an energy intensive requirement). Not only were the samples completely broken down into gaseous and liquid products, the end product could be selected by tuning the reaction, yielding either natural gas or a combination of natural gas and liquid alkanes (both highly desirable) as preferred.

Polypropylene is used in bottle caps, houseware, and other packaging and consumer products.

The researchers believe that an industrial scale use of their method could eventually help reduce the volume of post-consumer waste in landfills by recycling plastics to desirable, highly valuable alkanes — but, of course, it's not that simple. The team says that more research into the effects of moisture and contaminants in the process is required, as well as product removal strategies to decrease the formation of light alkanes which will be critical for the industrialisation of this reaction.

However, they believe the path they're on could lead to affordable upcycling technology that would better integrate polyolefins into the global economy and incentivise the removal of waste plastics from landfill and the environment.

More about the study can be read here:
https://pubs.acs.org/doi/full/10.1021/jacsau.0c00041

The Organisation for Economic Cooperation and Development (OECD) has published its Science Technology and Innovation Outlook 2021: Time of Crises and Opportunity report.

Published at the beginning of 2021, the report focuses on the ‘unparalleled mobilisation of the scientific and innovation community’ in response to the covid-19 pandemic. The report indicates that newly funded research initiatives have been established by public research agencies and organisations, private foundations and charities, while the health sector has similarly invested in an array of research programmes worth billions of dollars in record time.

The pandemic has led an unprecedented mobilisation of the scientific and innovation community

However, the report also exposes gaps in overall system resilience to future crises. ‘It’s a wake-up call that highlights the need to recalibrate science, technology and innovation (STI) policies, so that they better orient research and innovation efforts towards sustainability, inclusivity and resiliency goals,’ the report asserts.

Highlighting the rapid response by governments around the world, the report indicates that in the first few months of the pandemic, national research funding bodies spent around $5 billion on emergency financial support. This includes $300 million in Asia-Pacific, excluding China, over $850 million in Europe and more than $3.5 billion in North America. At the same time, research efforts led to around 75,000 scientific publications on covid-19 being released between January and November 2020, the report says. The largest share came from the US, followed by China and the UK. Research databases and scientific publishers removed paywalls so that covid-19 related information could be quickly shared.

Research efforts led to around 75,000 scientific publications on covid-19 being released between January and November 2020

‘These developments mark important changes that could accelerate the transition to a more open science in the longer run,’ the report says. It is also noted that not only have researchers continued their work with more than three quarters of scientists indicating that they had shifted to working from home at some point in 2020, but almost two thirds experienced, or expected to see, an increase in the use of digital tools for research as a consequence of the crisis. The report also mentions the contribution of the general public, with so called ‘frugal innovations’ in response to shortages of medical equipment and emergency supplies.

Looking to the future of the research community, the report says that postgraduate training regimes require reform to support a diversity of career paths. ‘The crisis has shown that the need for STI expertise is not limited to the public laboratory; it is also important for business, government and NGOs […] Reforming PhD and post-doctoral training to support a diversity of career paths is essential for improving societies’ ability to react to crises like covid-19 and to deal with long-term challenges like climate change that demand science-based responses […] There has been a 25% increase in the number of people with PhDs in OECD countries over the past decade with no corresponding increase in academic posts. The pandemic is expected to make matters worse, more than half of the scientists participating in the OECD Science Flash Survey expect the crisis to negatively affect their job security and career opportunities,’ the report says.

Post-graduate training regimes require reform to support a diversity of career paths

While still in the midst of the pandemic, the report stresses that STI policies now need to be reoriented to tackle the challenges of sustainability, inclusivity and resiliency. ‘In the short-term governments should continue their support for science and innovation activities that aim to develop solutions to the pandemic and mitigate its negative impacts, while paying attention to its uneven distributional effects. Science for policy will remain in the spotlight as governments seek to strike the right balance in their response to covid-19. This will effect public perceptions of science that could have long term implications for science-society relations.’

The report concludes that governments now have the task of developing public sector capabilities to deliver more ambitious STI policy. This will require engagement from stakeholders and citizens in order to capture a diversity of knowledge and values.

DOI:10.1787/75f79015-en