VINTAGE, AUGUST 2011
Molecular biology has not achieved its potential. Why do people still die from cancer? Why are there so few effective antivirals? Where is the HIV/malaria/common cold vaccine? Why aren’t genetic diseases routinely treatable with gene therapy? Certainly we can point to plenty of successes—the papilloma virus vaccine made from recombinant pseudovirions and rapid diagnostics for many diseases are two examples—but even the optimists among us must concede that molecular biology is not where we might have hoped 25 years ago. What went wrong?
Simply put, life on the molecular scale is much more complicated than we imagined. Molecular biology roared onto the scene in the mid-20th century when James Watson and Francis Crick illuminated the “too beautiful not to be true” structure of DNA and the deciphering of the genetic code. But the simplicity and elegance ends right there. Biology at the protein level is far removed from the linear, digital code of nucleic acids. Biological organization at the cellular or organismal levels is even less linear. Understanding life on these scales is not impossible, but we have to work it out one interaction, mechanism, and pathway at a time. Making sense of the complexity will surely take the rest of this century (though I’d love to be wrong about that!). As each small piece of biology is understood, we gain something extra to work with, something tractable and, ultimately, engineerable.
The astonishing technological progress that has taken place over the last quarter century—low-cost sequencing, commonplace protein engineering, and gene synthesis, to name but a few—will precipitate a sea change in the research and development of molecular therapies. We will witness a shift from traditional small-molecule pharmacology towards engineered biological treatments. The first stages of the revolution are happening right now. For instance, many of the recent and upcoming anticancer drugs are custom-designed biological molecules. But there are still major limitations on the design and implementation of engineered protein-based therapies. Foremost of these is our inability to reliably deliver such proteins to the interior of cells—all the therapies that have made it to the market so far act extracellularly.
As a virologist, I may be biased, but I believe the greatest advances in molecular therapies in the near future will involve viruses. Compact biological entities with little more than a handful of genes and a protein coat, viruses lend themselves to engineering. That’s not to say they aren’t also complex: HIV envelope protein for instance is known to associate with 176 human proteins at the last count. But viruses know their hosts well—they can break into cells undetected, switch off alarm systems, and undermine the cell’s authority in deciding which genes get expressed. It is this acuity, acquired by trial and error over millions of years of coevolution with their hosts, that researchers are tapping to design novel therapies.
There is a certain swords-to-ploughshares pleasure in converting these murderous creatures into medicines. Twenty-five years ago, the discovery of HIV was three years old. Infection was untreatable and almost invariably fatal. Since then the virus has claimed 30 million lives and caused innumerable human tragedies. But in 2010, for the first time, WHO statistics reported a drop in the number of new infections, thanks in large part to the molecular inhibitors that constitute antiretroviral therapy. A quarter of a century from now, it seems within the realms of expectation that HIV and its ilk will be converted, by forced defections, into a new generation of therapies. Perhaps then we will be able to say that molecular biology has fulfilled its promise.
This month’s Reading Frames articles are penned by contributors to Future Science: Essays From the Cutting Edge, a compilation of writings from leading young scientists pushing the boundaries of their respective fields.
William McEwan is a molecular biologist at the MRC Laboratory of Molecular Biology, Cambridge, UK. He is interested in intracellular mechanisms that specifically disable viruses. His current research focuses on how cells use antibodies to recognize viruses and prevent infection. You can read an excerpt from McEwan's essay as it appears in Future Science.