Transcript

NARRATOR: No drug is perfect. Cisplatin had side effects. Apart from nausea, it could also cause kidney damage. It didn’t work against all cancers. And, most of all, there was a huge gap in understanding. How did it work? And why didn’t the trans form of the same chemical have the same effect? Better understanding could possibly lead to better drugs, and this interested top chemical research teams across the world, including a group at the Massachusetts Institute of Technology (MIT) led by Professor Stephen Lippard.

STEPHEN LIPPARD: We were primarily a chemistry group, beginning to learn something about macromolecules – proteins and nucleic acids. And we were particularly intrigued, in the case of cisplatin, with the fact that the cis isomer, with the chlorides on the same side of the square plane, was active. And the trans isomer was inactive. And I’ve always been fascinated by problems in inorganic stereochemistry. And so it seemed that there would be a structure or function relationship that we ought to be able to sort out as chemists.

NARRATOR: This is one of the tools the research chemists can use to discover details of the structure of molecules. It’s known as nuclear magnetic resonance spectroscopy, or NMR. The large shiny vessels are cryostats. They store the liquid helium which cools superconducting magnets. These magnets generate huge magnetic fields and are so heavy that NMR facilities, such as this one at MIT, are usually housed in the basement.

Test samples are lowered into the magnetic field, and radio frequency energy is fired into them. Some atomic nuclei, such as the 195 isotope of platinum, possess a property known as ‘spin’. And the combination of the two fields can make such nuclei jump from one energy state to another. This in turn produces electronic signals unique to those particular atoms, giving information on their immediate environment in the molecule.

NMR proved to be an immensely useful tool in helping to determine how cisplatin gets into the cells and what happened to it once it was inside. These chemical formulae show what the NMR results meant. Cisplatin hydrolyses stepwise to produce positively charged ions. First, one chloride ion is replaced by water to form a species with a single positive charge. And then, the second chloride ion is replaced by another water molecule to form an ion with two positive charges.

STEPHEN LIPPARD: And when that happens, the platinum becomes positively charged. The platinum complex becomes positively charged. And there would be a natural attraction then for it to bind, migrate to and bind to DNA, which is a polyanion.