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New drugs need old logic

The bonanza of innovative drug discoveries that was meant to follow the sequencing of the human-genome hasn't arrived, argues Dr David C. Swinney.

Investment in drug research and development has substantially increased since the beginning of this century. But the number of truly innovative new medicines resulting from human-genome sequencing has not increased.

Many drugs don't make it past the initial research stage.

This means that a broad variety of diseases are not being treated effectively, in the developed or the developing worlds.

So why is the production of new medicines so frustratingly low?

Advances in molecular sciences, corresponding to the sequencing of the human genome in the 1980s, allowed scientists to identify all the human proteins — large, complex molecules necessary for many of the body's functions.

Understanding the proteins' roles then led to greater knowledge of the underlying causes of diseases. For example, mutations, or defects, at specific molecular locations in human DNA were found to be responsible for some cancers, raising the hope of developing successful therapies tailored to individual patients.

Identifying the defective molecular parts, known as the drug targets, should have made addressing the causes of disease easier, and would revolutionise the pharmaceutical sciences.

Scientists believed that the ability to visualise and understand human biology at a more detailed level would lead to many new medicines.

Prior to this molecular revolution, scientists discovered medicines by randomly evaluating different chemicals against phenotypes — an organism's observable physiological and biochemical traits — in authentic biological systems, such as animals or cells. But, unfortunately, this strategy is neither efficient, nor intellectually satisfying.

The molecular revolution heralded an era in which drug discovery and development would be rational, not random. Contrary to expectations, however, the increased efficiency implied by identifying target molecules has not produced a bounty of new drugs.

Efforts to address the problem have focused on how the target was selected, the candidate drugs' efficacy in humans, the risk of undesirable side effects, and the efficiency of the discovery process — all to little or no avail.

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Older and wiser

In fact, it appears that the lion's share of first-in-class medicines — those drugs that successfully establish a new class of medicines — have been discovered using the older method of phenotype screening.

In research published in a recent issue of Nature Reviews Drug Discovery, my colleague Jason Anthony and I analysed how first-in-class medicines were approved by the Federal Drugs Administration in the decade between 1999 and 2008.

We found that 75 drugs approved in this time were small-molecule first-in-class drugs. Phenotypic screening produced 28 of these new drugs, while target-based approaches produced 17 new drugs.

Considering how strongly biased the industry has been toward target-based drug discovery, that imbalance is highly significant.

This lower productivity partly reflects target-based discovery's lack of consideration of the molecular complexities of how the drugs work. Knowing the parts of an efficient machine — a watch, an automobile, or a computer — is not enough to describe how it works. The parts must collaborate in precise ways to provide accurate time, reliable transportation, or processed information.

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Complex biology

Biology is infinitely more complex. The phrase "molecular mechanism of action" describes the way that biological parts collaborate as a whole to provide an effective and safe medicine.

Addressing the molecular mechanism of action would help improve the success of target-based discoveries, because merely knowing the identity of a part involved in a defect may not be sufficient to repair a malfunctioning machine.

The target-based approach is analogous to looking for your keys in the dark: if they are under a streetlight, they're easier to find. Many hoped the molecular revolution would amount to more streetlights for drug discovery. Unfortunately, it appears that this new light, in most cases, is too dim to illuminate the molecular details of the dynamic human biological machine with sufficient specificity to rationalise the design of new medicines.

The random phenotypic process, though less efficient, will ultimately identify medicines that are effective and work to repair disease. The target-based approach, on the other hand, creates only the illusion of greater efficiency.

The way forward is to find a method that combines the efficiency of target-based approaches with the authenticity of phenotypic research.

About the author David C. Swinney is at the Institute for Rare and Neglected Diseases Drug Discovery and previously was Director of Virology Biochemical Pharmacology at Roche, Palo Alto.

© Project Syndicate, 2011.



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