Each year, The Institute of Cancer Research encourages our researchers and students to hone their science writing skills by offering a prize - named after Professor Mel Greaves, one of our most eminent scientists and skilled communicators. The winner of 2014’s Mel Greaves Science Writing Prize was Dr Rohan Bythell-Douglas, for his illuminating piece Using Crystals to Cure Cancer.

Advocates of alternative medicine have long touted the healing effects of strategically placing crystals on parts of your body or around your home. “Ah yes,” they say, “if we place some amber around the bedroom, it will absorb all of the negative energy and transform it into healing energy”. Crystal healing, as it is known, is nothing more than bunk pseudoscience that does not stand up to scientific inquiry or peer review. However, crystals of another, much smaller variety have been used to develop some very effective cancer treatments. These crystals are very different to the beautiful examples you will see at a holistic healing center or in the geology section of a museum (where they belong). For a start, they are far smaller. Even the largest examples are only just visible to the naked human eye. They are also very fragile, breaking on even the slightest of contact. The vast majority of these crystals don’t even come in pretty colours, like jade or sapphire. Instead they are generally clear and colourless. So what is so special about these tiny, fragile, rather plain crystals? These are not crystals of minerals. These are crystals of proteins.

Protein crystals are not a naturally occurring phenomenon. They are produced under highly controlled conditions in a laboratory. Scientists intentionally set out to make a crystal of a specific protein they are researching for a very good reason. A wonderful property of crystals is the way that they interact with light. When light is shone on to a crystal, the light is reflected into a pattern that directly relates to the composition of the crystal. By analysing the pattern of reflected light, scientists can determine what the components within the crystal must look like in order to produce the observed reflection pattern. The method is known as X-ray crystallography because the light used is the same energy as X-rays.

The father-son scientist duo William Lawrence Bragg and William Henry Bragg won the Nobel prize for discovering this property of crystals. The real power of their discovery is that if you can generate a crystal of the substance you are interested in, you can then determine the structure of the substance you are interested in. So when the crystal is made out of protein, scientists can figure out what the crystallised protein looks like. Knowing the structure of a particular protein can be very useful indeed. Once scientists have identified a certain protein involved in a disease, knowing the structure of that protein makes it far easier to design a drug to bind to the target protein to treat the disease.

Scientists will try to crystallise a protein with a candidate drug to see how the drug binds to the protein and to determine how they can make the drug interact more strongly and specifically. If protein crystals don’t already sound science fiction enough, scientists often use a type of particle accelerator called a synchrotron to produce the specific type of high-energy light they need for this experiment. Why don’t they just use a microscope to look directly at the protein without worrying about making a crystal in the first place? This method involving crystal-reflected light patterns provides a far higher resolution structure of the protein than even the most advanced microscopes and has done so for the last 50 years!

A brilliant example of a cancer-causing protein successfully targeted by this crystal-mediated process is the Bcr-Abl fusion protein. Bcr and Abl are two different proteins that are separate from one another in healthy cells. In some people, there is a rare genetic event that causes the two proteins to fuse together to form the Bcr-Abl fusion protein. When these two proteins are fused together, the cell loses the ability to regulate the activity of these proteins, which causes chronic myeloid leukemia.

Armed with this knowledge, scientists targeted the Bcr-Abl fusion protein for drug design. Researchers carried out an iterative drug design process, where they generated crystals of the Bcr-Abl fusion protein that had been incubated with candidate drug-like compounds. After much research carefully analysing the structure of the protein in the presence of various drug-like compounds and further optimisation, the project eventually yielded the drug imatinib (marketed as Glivec or Gleevec).

Clinical trials demonstrated that imatinib was an effective drug against chronic myeloid leukaemia caused by the Bcr-Abl fusion protein. Some 98% of patients showed complete haematologic response after five years of imatinib therapy. This essentially means that their white blood cell count had returned to healthy, non-cancerous levels. Staggeringly, imatinib increased the survival rate of patients with chronic myeloid leukemia from 30% to 89% five years post diagnosis. Such was the success of the drug that imatinib made the cover of Time magazine in 2001 as the ‘magic bullet’ to cure this type of cancer. A life-saving discovery had been made through the use of protein crystals.

Protein crystals have played an essential role in the development of several other drugs for the treatment of numerous diseases, including swine flu, HIV and hepatitis C. The development of imatinib to treat chronic myeloid leukemia is a brilliant example of how we really can use crystals to cure cancer.
 

References

Druker, B. J., et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia, New England Journal of Medicine 355, 2408–2417 (2006)