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the average tumor contains 15 or more altered genes that are responsible for its unchecked growth and metastasis. Other diseases may arise simply from a combination of what turns out to be an “unhealthy mix” of genetic variations acting in concert, or in combination with environmental factors. Finding effective treatments for these types of diseases is much more difficult than those caused by single genetic alteration (not that these are necessarily easy to treat either).
The various molecules that exist within our cells don’t function independently of each other. There are numerous interconnections between them, the study of which has spawned a recent approach referred to as systems biology. The complex nature of these interactions makes them extremely difficult to study. It’s obviously simpler to design a drug that affects a protein that operates within a single defined pathway than one that functions at the intersection of numerous metabolic junctions. Drugs that are directed at proteins that function at biological intersections may affect any and all of the pathways that lead to and away from the target.
It’s important to have a clear understanding of the drug discovery process if we hope to accelerate the pace of creating new medicines. Prior to the past 120 years or so, virtually all medicines were derived from naturally occurring plant materials. These eventually gave way to chemically synthesized molecules, which ruled a large share of the market for the better part of a century. Drugs these days may still come from these sources, but many of the newer medicines are biologics (purified recombinant proteins, including monoclonal antibodies). Insulin, the first protein drug, was originally purified from cadaver pigs, but bacteria growing in brewery-sized stainless steel tanks now generate most of it. Biology has usurped chemistry as the dominant force behind many of the newest drugs, even though most biologics are incredibly expensive compared to small, chemically synthesized drugs. Some of the newest types of medicines (most of which are still in development) are comprised of various types of DNA or RNA, and they may be packaged in viruses, liposomes, or as nanoparticles for administration to people. Various medicines require distinct routes for drug delivery: they can be swallowed, inhaled, sniffed, injected, or supplied via a skin patch.
This tremendous degree of biological diversity and complexity demands that pharma and biotech companies devise new and pioneering approaches in both research and development. This will take guts, which some feel many of these companies are lacking. Sequencing of the human genome was a great milestone in biology, but it only served to underscore just how much work remains to be done in solving biological problems. The “innovation intervention” approach mentioned at the beginning of this article was actually targeted at business models, not drug discovery. What is abundantly clear is that the industry needs to change its modus operandi, and several new initiatives have been launched.
One popular approach that a number of Big Pharma companies have adopted is to align themselves financially with university researchers to take advantage of the expertise contained within academia. If properly done, this tactic should undoubtedly be helpful. Many of the most innovative drug development papers that I’ve seen recently originated in academia. Another approach has been for Big Pharma to re-align and narrow the focus of their internal research programs; some companies have made significant cuts in their research and development spending. This can be successful if the aim is to focus on fewer research areas, but increased spending, not less, will be needed going forward to support the remaining avenues of investigation.
I believe that all of these changes are necessary, but I have doubts as to whether they will be sufficient to reinvigorate Big Pharma’s drug discovery efforts. As novelist Ellen Glasgow put it “All change is not growth, as all movement is not forward.” I have no doubt that “bushels of fruit” remain to be picked from the medicinal tree, although reaching those higher branches will require the industry to wisely adapt a long term perspective. They need to establish an innovative culture, correctly employ new technologies, reward smart thinking, and have a brave heart. Though many are loath to admit it, the truth is plain to see: there will be no shortcuts on the long and difficult journey towards the medicines of tomorrow.
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