A new report by “The Economist” laments the lack of innovation in the biopharma sector

On “The Digital Biologist” a couple of months back, I published an article about a troubling trend in the pharmaceutical industry in which R&D investment costs are soaring even as the approval rate for new drugs actually declines. One of the reasons I posited for the apparent stagnation in this sector, was the inability of corporate leaders to abandon old practices and embrace innovation and new methodologies. “Do what you’ve always done and you’ll get what you’ve always gotten”.

Now a new report from “The Economist” (sponsored by Quintiles) provides some real numbers to back up this idea – and while it may not be a strictly scientific or comprehensive survey of the sector, it does provide real evidence of a kind of corporate inertia at the highest levels, with regard to embracing new ideas and changing course from the rocky road that the industry currently finds itself on.

I would encourage you to read this interesting and well written report in full, but here are some of its major findings in summary …

Less than half of industry executives even have faith that their own R&D programs currently in place, are adequate to meet the needs of their companies.

As much of 70% of the global R&D budget for the sector may actually be wasted in fruitless programs.

Barely half of all companies who responded to the survey say that they are prioritizing change and innovation and this includes the companies who admit that the programs they do have in place are largely inadequate.

An inflexible corporate culture that fears change is cited as the leading impediment to improved innovation.

In a sector that is seen as being driven more by fear than by ambition, the companies that are doing well are those in which life science innovators are able to create a culture that recognizes and rewards effort rather than penalizing failure.

You can download a full copy of this report here

The author Gordon Webster, has spent his career working at the intersection of biology and computation and specializes in computational approaches to life science research and development.

© The Digital Biologist | All Rights Reserved

Getting the green light for metastasis

metastasis-networkIn their habitual zeal for the next hot story, the press have done something of a disservice to the important research of a couple of scientists at the University of East Anglia in the UK. The work of Soond and Chantry that appears in the January 24th issue of Oncogene is an important step forward in our understanding of the path that a cell takes from normality to neoplasia. The preliminary nature of these published findings however, did not inhibit some in the popular press to claim that it heralded an imminent cure for many types of cancer, based upon the notion that this research has succeeded in isolating “the rogue gene” that is responsible for the spread of cancer in the body. Having heard this kind of hype from the press before (remember how in 2000, the Human Genome Project was being predicted to yield a cure for most cancers within two years?) it is easy for such fanfare to have the opposite effect and to foster cynicism. Somewhere between fanfare and cynicism however, lies the kind of cautious optimism with which most researchers in the field would view these findings and this would seem to be an appropriate response to them. What the authors describe is indeed a fundamental pathway by which cells make the transition from the kind of neighborly and cooperative way of life that is necessary to maintain the integrity of tissues and organs, to the kind of every-man-for-himself maverick cell that wants to blaze its own trail, regardless of the consequences to the organism that it was hitherto a working part of.

Through their communications with their surroundings and with neighboring cells, most cells in the body have a pretty good sense of where they are at all times, and will continue to do their thing so long as these signals are all present. Remove such a cell from its normal context however and it will invariably pursue a new course of action, often involving its own self destruction through apoptosis. For example, the signaling pathways involving cell-to-cell adhesion are generally inhibitory to apoptosis when their receptor ligands (furnished by contacts with neighboring cells) are present. Remove these contacts however, and the cell will rapidly initiate a program that leads to apoptosis. Sometimes however, it is necessary for a cell to be able to migrate from one place to another (as in wound healing for example), thereby requiring it to have (at least temporarily) the ability to exist as a free-standing cell. The carefully regulated process by which this occurs is know as the epidermal to mesenchymal transition or EMT.

So why are we talking so much about EMT?  Because EMT plays a pivotal role in the progression of many cancers. A cancer cell that can bypass the regulatory controls that maintain the epidermal state and undergo EMT, becomes a cell that is capable of metastasis and the invasion of other tissues – the hallmark of a malignant tumor cell.

Soond and Chantry focused their research on a family of ubiquitin ligase proteins that modulate the cellular machinery that degrades proteins, and which itself has far-reaching consequences for cell metabolism. In particular, they studied the protein WWP2 whose function is to tag other proteins in the cell with ubiquitin, thereby targeting them for degradation in the proteosome. WWP2 turns out to be one of those proteins that is produced as isoforms of different lengths, there being a full length isoform WWP2-FL and two shorter variants WWP2-N and WWP2-C. The authors were interested in understanding how the interactions of these various forms of WWP2 with other cellular proteins could influence the ability of a cell to migrate – a hallmark of cells that have undergone EMT.

One big “needle-in-the-haystack” question that confronted the authors was to figure out which other proteins in the cell interact with the various isoforms of WWP2. An immunoprecipitation experiment showed that WWP2 interacts with the SMAD family of proteins – a finding of particular relevance for the regulation of EMT. Under the control of TGF-β, the SMAD2 and SMAD3 proteins act in a stimultory fashion with regard to EMT, pushing the cell towards a migratory phenotype, whereas SMAD7 is currently believed to be an inhibitor of EMT. Interestingly, the authors discovered that WWP2-FL, the full length form of WWP2, interacts with all 3 SMAD proteins whereas WWP2-N interacts only with SMAD3 and WWP2-C interacts only with SMAD7. Furthermore, they found that the presence of the WWP2-N variant in the cell, increased the activity of the WWP2-FL protein.

So what was happening?

The overarching finding was that increasing the amount of WWP2 in cancer cell lines known to undergo EMT, inhibited a cell’s progression towards the mesenchymal state. Increasing the amount of WWP2-FL reduced the ability of TGF-β to switch on the SMAD2 and SMAD3 genes. As a control for this experiment, they were also able to show that silencing the WWP2-FL gene using siRNA reversed this effect in the treated cells, restoring the ability of TGF-β to switch on SMAD2 and SMAD3 once more. WWP2-FL was also shown to enhance the ubiquitination of SMAD2 and SMAD3, thereby targeting them for degradation and reducing their levels in the cell. This ubiquitinating activity of WWP2-FL was further shown to be enhanced by the presence of the WWP2-N isoform. And while the presence of WWP2-FL also increased the removal rate of the EMT-inhibitory SMAD7, it was found that WWP2-C seemed to be able to act in opposition, increasing the activity of SMAD7 in the cell.

While these findings are preliminary, what they point to is an interconnected network of enhancers and inhibitors that are able to subtly modulate the equilibrium of the cell between the epidermal and mesenchymal states, based upon the relative abundances of the 3 WWP2 isoforms. This network includes interactions between these WWP2 isoforms and the SMAD family of proteins that are under the control of TGF-β, but there are also interactions between the WWP2 isoforms themselves that modify their activity. This is a system that cries out for a good computer model, although it may be necessary to do some more quantitative experiments in the lab first, in order to be able to provide a realistic set of parameters for such a model.

The system of protein interactions described in Sood and Chantry’s article are an important step forward in our understanding of EMT and with further research and accumulated knowledge, a fuller understanding of them could well lead to new approaches for combating invasive cancers. Such a system is also a potential poster child for a digital biology approach to understanding the complicated equilibrium between rival cell phenotypes and perhaps even for helping us along the road to new cancer therapies.

The author Gordon Webster, has spent his career working at the intersection of biology and computation and specializes in computational approaches to life science research and development.

© The Digital Biologist | All Rights Reserved

 

Digital Biology group on LinkedIn

LinkedIn-Logo-02For those of you who are interested in the future of digital biology or who are already working in this new field, there is an active group for digital biology on LinkedIn. You will need a LinkedIn account to access the group but if you do just so happen to be one of the few professionals on the planet who is not already on LinkedIn, you can set up an account for free in just a few minutes and applications to join the Digital Biology group are normally approved the same day. Clicking on the LinkedIn logo above will take you to the LinkedIn homepage if you need to set yourself up with an account.

linked-digitalbiology-group-logoIn addition to the benefits of networking with an active group of people who share your interests, more and more members are posting jobs and announcements for upcoming conferences and workshops, making the group an excellent professional resource for those who are pursuing careers in this exciting field.

Already on LinkedIn? Just click on the Digital Biology group logo to go directly to the group’s homepage.

 

The author Gordon Webster, has spent his career working at the intersection of biology and computation and specializes in computational approaches to life science research and development.

© The Digital Biologist | All Rights Reserved