Gry Christensen was a 15-year-old Grade 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 she and her thousand peers prepared in high school were then blown up by scientists in a particle accelerator using X-rays 10 billion times brighter than the sun.
“It was a bit of an eye-opener,” Christensen says of the study, called Project M, which involved students from 110 schools. They made several samples of calcium carbonate (the main component of mussel shells) which scientists then examined at the UK’s national synchrotron (a type of circular particle accelerator), the Diamond Light Source in Oxfordshire. The goal was to help scientists better understand how to form different types of crystal structures from the same chemical. “I was more interested in chemistry after that,” says Christensen, who went on to study agricultural sciences at Gråsten Landbrugsskole in Denmark. “Chemistry really helped me understand the natural world.”
But while such an approach may be new, understanding crystal formation is an old problem with serious consequences. The crystal structure can influence the strength of steel, and even the therapeutic activity of drugs developed to treat AIDS and Parkinson’s disease.
Calcium carbonate is the main compound in rocks such as chalk, limestone and marble, which come from organic materials including shells. It’s responsible for the annoying limescale stains around taps and also has useful uses, from antacids 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 an outstanding challenge is controlling the crystal shapes.
The results were not just scientific: school participants who were enthusiastic about chemistry later came by for internship interviews
A crystal is a solid in which components are arranged in a highly ordered and repeating pattern, and the shape of this pattern – the crystal structure – determines the properties of the material. A well-known example of the effect of crystal structure is carbon – useful for taking notes when the atoms lie in layers of honeycomb lattices in pencil lead (graphite), but much more difficult and much more expensive when the atoms are in the cubic crystal lattice that forms diamond.
In other materials, control over a substance’s possible crystal structures – or “polymorphs” – is a matter of life and death. In the early 1980s, life expectancy after an AIDS-related diagnosis was less than two years. Patient outcomes began to improve significantly in the mid-1990s, thanks to the development of antiretroviral treatments, including a drug called ritonavir. However, two years after its initial introduction in 1996, the drug was withdrawn from the market due to problems with the stability of its crystal structure.
The ritonavir capsules were originally supplied with the active component in a highly concentrated solution. Unfortunately, these conditions caused the active drug to change structure, making it less soluble than the original and therefore much less effective as a drug. Further drug development has since solved the problem. However, the Parkinson’s drug rotigotine faced similar problems, with a less soluble crystal structure emerging in 2008, leading to a recall of batches in Europe, while the drug was out of stock in the US until 2012, when drug developers had a reformulation found it.
“There are many recent examples, but not all of them are public,” says Dr. Marcus Neumann, CEO and scientific and technical director of Avant-garde Materials Simulation (AMS), a German company that develops software for predicting crystal structure. “Examples become public if they relate to a medicine that is already on the market. And fortunately that doesn’t happen that often.”
For more than two decades, AMS has been refining computer code that can predict what crystal structures might form for a given chemical compound, helping pharmaceutical companies discover problematic polymorphs before bringing a drug to market. In 2019, AMS showed that its code could predict the appearance of a problematic form of rotigotine. Recent updates to the algorithm include the effects of temperature and humidity, and also use comparisons with crystal structure data from pharmaceutical companies AMS has worked with, including AstraZeneca, Novartis, AbbVie (which is now producing reformulated ritonavir) and UCB Pharma (which is reformulating it formulated ritonavir produces) rotigotine patches).
Nevertheless, identifying the experimental conditions necessary to produce a specific crystal remains a challenge, because different structures can occur with little change in conditions, and one structure can transform into another. You can think of it as oranges stacked in a box. You can lay out a square grid of oranges and balance each orange in the layer above directly on top of the orange below it, keeping them well balanced for a while. However, a tap can cause the oranges at the top to settle into the dip between the oranges in the layer below – the more stable structure.
“There is still a great need for experimentation, as many factors are not yet 100% clear about how certain crystal structures can be achieved,” says Dr. Adam Raw, head of materials science R&D in the life sciences department at Merck. He emphasizes the “huge number of factors that can come into play” when introducing additives to push the system toward a particular crystal structure, exactly the approach Project M explored.
Calcium carbonate has three possible crystal structures: aragonite, vaterite and calcite. A mussel grows selectively which species it needs – the more durable calcite for the outer shell, for example – and “without using aggressive chemical conditions,” says Dr. Julia Parker. “Only additives, organic molecules.” Parker and Murray wondered whether the right additive at the right concentration would help them control the growth of vaterite versus calcite.
At Diamond Light Source, the pair were able to quickly discern small changes in the crystal structure of hundreds of samples by examining the paths of the synchrotron’s X-rays as they spread out from the lattice of each crystal. (The synchrotron accelerates electrons, which emit to work with UK. schools, taking advantage of similarities in laboratories and environmental conditions.
Christensen and fellow students from Didcot Girls’ School, located near Diamond, were the first to try out the sample preparation kits and helped guide Parker and Murray to the equipment and instructions needed in each kit. The data needed to characterize each sample was collected in just one day at the synchrotron.
The results, published in January this year, help shed light on the conditions that significantly promote or inhibit vaterite formation, and provide insight into how these crystals form. “I think they have made progress in showing which factors are most likely to correspond to biomineralization [living creatures making minerals] and the formation of these calcium carbonate crystals in biological applications,” says Raw. “But there is of course much more work to be done.” However, the results of the project were not just scientific: school participants who were enthusiastic about chemistry later visited Diamond for internship interviews.
“The project was like doing something for the real world, not just an experiment at school,” says Christensen.