Gry Christensen was a 15-year-old year 11 student when she took part in a “citizen science” project to understand how the different crystals in mussel shells form. But unlike most school experiments, the samples that she and her 1,000 fellow secondary school pupils prepared were then blasted by scientists in a particle accelerator using X-rays 10bn times brighter than the sun.

Christensen reflects on his experience participating in the Project M study, which involved students from 110 schools. The study focused on examining diverse samples of calcium carbonate, a key component in mussel shells, using the UK’s Diamond Light Source. The goal was to advance understanding of how to generate various crystal structures from a single chemical. As a result of this experience, Christensen’s interest in chemistry increased, leading him to pursue agricultural science at Gråsten Landbrugsskole in Denmark. He credits his knowledge of chemistry with providing him a deeper understanding of the natural world.

However, although this method may be novel, comprehending the process of crystal formation is an age-old issue with significant consequences. The structure of crystals can impact the durability of steel, and it can also play a role in the effectiveness of medications designed for treating HIV/AIDS and Parkinson’s disease.

Calcium carbonate is the main compound in rocks such as chalk, limestone and marble, that derive from organic materials including shells. It is responsible for the annoying limescale stains around taps, as well as having useful applications from antacid tablets to concrete blocks. “Calcium carbonate is all around us,” says Dr Claire Murray, a chemist who led Project M in 2017 along with colleague and fellow chemist at the Diamond Light Source, Dr Julia Parker. But one outstanding challenge is controlling its crystal forms.

A crystal is a solid material that has a uniform arrangement of components in a repeated pattern. The crystal’s properties are determined by its unique structure. An example of this is carbon, which can be found in two different crystal structures: one in pencil lead where the atoms are arranged in honeycomb-shaped lattices, and the other in diamond where the atoms are arranged in a cubic lattice. The diamond structure is much harder and more costly than the pencil lead structure.

In some cases, the ability to control the various crystal structures of a substance, also known as “polymorphs,” has had critical implications. In the 1980s, a diagnosis of AIDS typically meant a life expectancy of less than two years. However, with the introduction of antiretroviral medications, such as ritonavir, patient outcomes began to improve significantly by the mid-1990s. Unfortunately, two years after its launch in 1996, the drug had to be removed from the market due to problems with the stability of its crystal structure.

The original prescription for ritonavir capsules contained a concentrated solution of the active ingredient. Unfortunately, this caused the active drug to undergo structural changes, making it less soluble and less effective. The issue was eventually resolved through further drug development. Similarly, the Parkinson’s drug rotigotine encountered challenges in 2008 when a less soluble crystal structure was discovered. This resulted in a batch recall in Europe and the drug being unavailable in the US until 2012, when a reformulation was created by drug developers.

Dr. Marcus Neumann, CEO and scientific and technical director of Avant-garde Materials Simulation (AMS), a German company that creates crystal structure prediction software, explains that although there have been numerous recent cases, not all of them have been made public. Only when a drug already on the market is impacted do examples become publicly known, which fortunately does not occur frequently.

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For more than 20 years, AMS has refined computer programming that can anticipate the potential crystal structures that may arise for a specific chemical compound. This has proven to be valuable for pharmaceutical companies in detecting problematic polymorphs before a medication is released to the market. In 2019, AMS demonstrated its programming’s ability to foresee the occurrence of a troublesome form of rotigotine. Recent updates to the algorithm incorporate the influence of temperature and humidity, and also draw upon comparisons with crystal structure data from drug companies that AMS has partnered with, including AstraZeneca, Novartis, AbbVie (which now produces reformulated ritonavir), and UCB Pharma (which produces the reformulated rotigotine patches).

Despite this, it is difficult to determine the precise experimental conditions needed to create a particular crystal. This is because subtle variations in conditions can result in different crystal structures, and a single structure can undergo transformation into another. Imagine a box of stacked oranges – when arranged in a precise grid, each orange can rest directly on the one below it and maintain balance. However, even the slightest disturbance can cause the oranges on top to settle into the lower layer’s crevices, creating a more stable structure.

Dr. Adam Raw, head of material science R&D in the life science division at Merck, acknowledges that there is a significant need for experiments in order to fully understand how to attain specific crystal structures. He emphasizes the numerous factors that can affect the outcome when introducing additives to influence the system towards a desired crystal structure, which was the main focus of Project M.

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There are three crystal structures of calcium carbonate: aragonite, vaterite and calcite. A mussel has the ability to selectively grow the ones it requires, such as the strong and durable calcite for the outer shell. Dr. Julia Parker explains that this is achieved without the use of harsh chemicals by simply adding organic molecules. In an attempt to manipulate the growth of vaterite and calcite, Parker and Murray investigated the potential of a specific additive at the appropriate concentration.

At Diamond Light Source, it was possible for the pair to rapidly identify subtle alterations in the crystal formation of numerous samples by observing the trajectories of the X-rays emitted from the synchrotron as they interacted with the lattice of each crystal. (The synchrotron propels electrons, which produce X-rays as they alter their trajectory moving around it.) The main challenge was preparing all the samples – testing various variables such as the type of additive, concentration, and mixing time – until the idea emerged to collaborate with schools in the UK, taking advantage of the similarities in the laboratory and environmental conditions.

Christensen and her peers at Didcot girls’ school, which is located near Diamond, were the initial group to test the sample preparation kits. They also assisted Parker and Murray in selecting the appropriate equipment and instructions for each kit. The necessary data to analyze each sample was collected within a single day at the synchrotron facility.

In January of this year, the findings were released, which illuminated the favorable and inhibitory circumstances for the formation of vaterite. These results also gave understanding into the creation process of these crystals. Raw states, “They have advanced in identifying the key factors that relate to biomineralization and the development of calcium carbonate crystals in biological settings.” She adds that there is still much more research to be done. Moreover, the project had not only scientific impacts but also inspired school participants to pursue chemistry and eventually apply for internships at Diamond.

Christensen says that the project allowed for the application of skills in a real-world context, rather than just a school experiment.

Source: theguardian.com