Thursday, July 7, 2011

The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, by Brent R. Stockwell--A Review

The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines   The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, Columbia University Press, ISBN 9780231152129, June 2011

The great advances in medicine over the last century have been to a large degree advances in the creation of new and more effective drugs to combat diseases that were previously untreatable. Stockwell tells the story of these advances, how they were achieved, and why--a fact not widely recognized by the general public--the rate of new drug discovery has slowed dramatically, raising the spectre  in the medical and pharmaceutical industries of an end to new drugs.


We are first introduced to the basics of how disease and drugs work. Disease, at its simplest level, is caused by proteins in our bodies malfunctioning--whether due to the effects of infection with bacteria or viruses, or due to the mutation of a gene, in the protein itself or in a kinase that attaches to the protein. A drug is a small molecule (usually) that attaches itself to a small open spot in a protein molecule, preventing that protein from engaging in the malfunctioning behavior that creates illness. Stockwell gives us a fascinating introduction to the early waves of drug discovery, the testing and screening of small molecules that will attach to proteins and affect their functioning, for better or for worse. Interestingly, the invention of the dreaded mustard gas of the two world wars was a side product of early drug discovery research--and there are in fact legitimate and beneficial uses for some of the "mustards" produced by that research!

The drug discovery history is compelling in itself, but it leads to a more discouraging reality: Not all proteins are "druggable." Their structures don't provide suitable spots for small molecule drugs to attach themselves, or their functioning is such that "breaking" the function of the protein by a small molecule drug leads to the very disease process you want to prevent. Consider a protein that in its "on" position causes cell growth, and in its "off" position stops it--and the "broken" position for this protein, if you attach a small molecule drug to it, is the "on" position. Other proteins are involved in protein-protein reactions rather than protein-kinase reactions, and the two proteins, both being relatively large molecules, attach and interact over much larger areas than in protein-kinase reactions.

Why is this a problem? Because small molecules are better drugs in a number of ways. They are more stable than most large molecules, so they are easier to work with. They are easier to make. And they can almost always be administered orally. Large molecules are sufficiently hard to work with that they have long been considered unsuitable as drug candidates.

Taken all together, the proteins with lack of suitable attachment sites, the disease mechanism being such that attaching a small molecule won't help, the protein being involved in a protein-protein reaction rather than a protein-kinase reaction, only 15% of proteins are considered "druggable," and only 2% of proteins have actually been successfully targeted with drugs. The rate of drug discovery is slowing down, and unless there is a major change, pharmaceutical companies and academic researchers see drug discovery slowing even further, or even coming to an end within the next couple of decades. If that happens, many human diseases will remain untreatable. It's a grim realization.

But the last part of the book is about potential solutions to this problem. It's about building artificial peptides and even artificial proteins, and making the stable with carbon stapling. It's about learning to image the structures of proteins, to find potential drug attachment sites in proteins currently considered "undruggable." It's about creating libraries of not just small molecules but large molecules that can be tested. It's about some really exciting developments that, if pursued and funded, can potentially completely change the current prospects for drug discovery. It holds out the prospect of personalized medicine--learning how to identify which patients will respond to a particular treatment, so that only those who can get the benefit need to endure the side effects.

I'm not doing justice to how exciting this is; you need to read Stockwell's book to get the full benefit of that! This is a book fairly heavy on science, but explained in clear, readable language that should be accessible to any layperson who is interested in the subject, and for those who want to dig more deeply into the science, there are extensive notes and references at the end. And for those readers who do expect to dig into the science, I would recommend getting the print edition, not the electronic edition, because the figures and charts included in the text will be, as is common, more readable in the print edition than the electronic edition.

Highly recommended.

I received a free electronic galley of this book from the publisher via NetGalley.