Nature’s Miracles in our Midst
A different approach to identifying new drugs: Dolphins and zebrafish
The classical model of small molecule drug discovery and development typically follows a set process that starts with either target-based screening or phenotype-based screening for novel disease candidates. Once a potential compound is identified, it is validated in cell-based and animal models (if available) prior to investigational new drug application enabling studies that are the gateway to clinical trials. This well-known process can take anywhere from 8-12 years and cost up to US$2.6 billion dollars. Consider this – launching a space shuttle mission costs about the same as getting a drug to market with the difference being that space shuttle launches have a 98% success rate while getting drugs to market have a 5% or less success rate! So it is clear that a significant investment of time and money does not guarantee success. The drug discovery process for small molecules is heavily dependent on computer-aided modeling and synthetic chemistry and if corners are cut during the compound creation process, the chances of failure in downstream efficacy and toxicity studies are high.
Are there alternative methods? Yes— say a few savvy scientists who look to Mother Nature for inspiration. Dr. Michael Zasloff from Georgetown University has researched the miraculous healing capabilities of dolphins. In the open ocean, dolphins fall prey to killer whale attacks and sometimes escape with severe injuries. By current medical standards, these wounds should be fatal but marine biologists have observed that not only do these dolphins show no sign of hemorrhage or sepsis or pain but actually make a complete recovery in ocean waters where microbes and dirt abound. Clearly, these animals have extraordinary healing powers and natural pain suppressants and their blubber is being investigated as a source of antimicrobial and pain management compounds.
More recently, Dr. Kevin Strange from Novo Biosciences amputated zebrafish tails to find that the tails grew back correctly. The tail regrowth involved the regeneration of bone, blood vessels, connective tissue and skin in the exact orientation and amount. This suggests that there are in-built stop signals along with the go signals for tissue regeneration. Dr. Strange with Dr. Viravuth Yin from MDI Biological Laboratory, then went on to identify a new candidate (MSI-1436) that shows exquisite sensitivity and specificity to regrow amputated zebrafish tails 2-3x faster and also regenerates heart tissue. MSI-1436 also showed good efficacy in reducing cardiac infarcts in mouse models and is now headed to clinical trials; MSI-1436 is thought to promote regeneration by inhibiting phosphatase activity, thus driving protein phosphorylation.
However, to my mind, there is more to this story. Several phosphorylation drivers have been studied but there has to be something special about MSI-1436 that involves a stop signal. How else would a tailless zebrafish treated with MSI-1436 stop responding when the tail has been correctly rebuilt? There is no doubt that the identification of this molecule opens up a fascinating new approach to small molecule drug discovery and while this area is young it shows a great deal of promise in reducing costs and time associated with finding new therapeutic compounds. The take home lesson is that perhaps the time has come that we should look to Nature to do exquisite chemical synthesis for us!