Bone remodelling- lessons from bioengineering

It is increasingly clear that to understand the complex processes that regulate the human body, it is no longer sufficient to rely entirely on a single approach. There has been a drive over the past decade to enhance co-operation between different academic disciplines such as biology, medicine, engineering, mathematics and informatics to improve understanding of disease and thereby develop novel therapeutic approaches.

An example of the promising results such an integrated approach can yield is the paper published by shih et al. in Proceedings of the National Academy of Sciences which elucidates an important osteogenic mechanism. This study used engineered calcium phosphate (CaP)-rich synthetic matrices to investigate the in vitro differentiation of human mesenchymal stem cells into osteoblasts, the main cell type involved in bone growth and homeostasis. The researchers found that dissociation of calcium and phosphate ions occurred freely from the matrix, but the phospate ions were key to stem cell differentiation. Briefly, the SLC20a1 transporter enabled uptake of extracellular phosphate. In turn, phosphate increased ATP synthesis via mitochondrial metabolism prior to ATP being exported from the cell. This extracellular ATP was degraded to adenosine via a number of enzymes. Adenosine, through binding its cell-surface receptor in autocrine/paracrine fashion was able to activate osteogenic signalling pathways.

As well as highlighting the importance of inter-disciplinary research this study has key implications for a variety of diseases where defects in bone homeostasis occur, including osteoporosis, osteoarthritis and osteomalacia. By surgically implanting such bioengineered matrices it may be possible to induce a switch from catabolism to anabolism and discover new receptors or enzymes involved in osteogenesis that are amenable to pharmaceutical intervention. Further studies investigating the in-vivo stability of such matrices must be carried out as well as any issues that may arise due to interaction of these materials with host immune cells. Nevertheless, the age of revolution in biosystems engineering draws ever closer.

References

shih et al. Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signalling Proceedings of the National Academy of Sciences January 2014 (vol. 111, issue 3)

Internet monitoring to predict infectious disease outbreaks

A review  to be published in The Lancet reveals that for the outbreaks of infectious disease to be accurately predicted, monitoring of search queries in popular search engines may be the best method. Milinovich and colleagues compared data across a number of studies and found that for diseases such as Influenza, H1N1 and Dengue it was possible to predict disease outbreaks weeks in advance using digital data analysis. Analysis of posts on social media is also a useful predictor.


The Office for National Statistics found that 83% of households in the UK have access to the internet, and data in the US suggests that almost half of patients seek medical advice online prior to visiting a doctor and  up to 8 million health-related searches are generated per day in the US. Such a large quantity of data is useful for assessing risk in large populations. Moreover, access to the internet is relatively high in some developing countries compared to access to healthcare. For example, In Ghana 2009 data reveals that there is one doctor per 11,500 people (Oxfam) while one in nine people have access to the internet, meaning that for many the internet is the only source of information. The numbers of Africans having internet access is rising rapidly. Approaches using monitoring of internet search habits within populations may be key to preventing serious disease  in the 21st century

Reference

Milinovich et al.- Internet-based surveillance systems for monitoring emerging infectious diseases The Lancet Infectious Diseases February 2014.

Role of p53 in overcoming tumour therapy resistance

Since the discovery of p53 by David Lane and colleagues in the 1970's, this tumour suppressor gene has emerged as one of most important molecules in suppressing cancer development and progression. There is little surprise therefore that p53 undergoes loss-of-function mutations in over 50% of solid tumours including lung, colon and breast cancers. mutations in p53 alone or in combination with loss-of-function in other tumour suppressors can confer resistance to chemo- and radiotherapy, the main mechanisms of which are to induce a DNA damage response that leads to cell death and senescence.

 The role of p53 in mediating apoptosis and cell cycle arrest following DNA damage and cell stress is well established but a recent paper has highlighted an additional mode of action. p53 activation in normal (non-tumour) cells resulted in suppression of UACA, a molecule involved in the sequestration and degradation of PAR-4. The release of pro-apoptotic PAR-4 from these p53-proficient normal cells was able to act in paracrine (local) and systemic fashion to induce selective tumour cell death for in vitro and in vivo models of p53-deficient prostate and lung cancers (1).

The above study is interesting on several fronts. Firstly and most importantly, this study raises the possibility of using synthetic PAR-4 analogues and UACA inhibitors in the treatment of  solid tumour types in a manner that targets one of the most common genetic defects. Further studies elucidating the pathways utilised by PAR-4 when it interacts with tumour cells may help in defining cross-talk with other pathways which are deregulated, giving scope to multi-agent targeting to achieve a synergistic effect. Further studies in other solid tumour types will also help to validate these findings. A second point which the above study illustrates is that despite extensive research on p53, new modes of action are constantly emerging which demonstrate we are only at the tip of the iceberg when it comes to understanding 'the guardian of the genome'.

Reference

Burikhanov et al. Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4 Cell Reports (2014) to be found here

Three Key Challenges Facing the Pharmaceutical Industry in 2014

Background

The Pharmaceutical Industry (pharma) is one of Europe's leading high-technology sectors. Data for 2012 reveal that in that year alone the pharmaceutical industry invested almost £25 million in R&D. Indeed, R&D investment by big pharma has shown a year-on-year increase and investment is up by approximately one third compared to 2005. Over 700,000 people are employed directly in European pharma but hundreds of thousands more are indirectly employed in related occupations including transport, legal services and health and safety (1). The value of pharma to the European economy in years to come therefore cannot be underestimated.

R&D

Nevertheless, like most industries operating in uncertain financial climates over the past decade, pharma is not immune from its share of problems. The R&D process remains risky and expensive. As an example, less than one in every 10 compounds subjected to clinical clinical trials will be approved for clinical use. The time taken from initial development to final approval is approximately 14 years. Despite increased investment, the number of New Drug Applications (NDA) has seen a steady decline over the past 20 years. In the US the number of new drugs approved by the FDA has also decreased gradually, due in part to more stringent safety assessments (2). This leads to a vicious circle whereby big pharma companies spend more resources on pre-clinical testing and are more reluctant to submit applications to the FDA owing to the high costs involved if the compound fails. Biotechnology will play a key role in improving safety by enhancing the efficacy of delivery methods for the compound. One salient example where this may reap rewards is in the development of antibody-coated nanoparticles containing chemotherapeutics to improve tumour cell targeting and minimise toxicity to normal tissue.

Generics

Another major issue facing pharma is the expiry of patents on a number of recognised drugs that ultimately leads to generic drugs emerging from rival companies. These companies incur less expense in simply manufacturing a drug which has already been approved. The benefits of generics to the healthcare industry are clear: the use of generics saved the US health system $217 billion in 2012 (3). Nevertheless, a number of high profile drugs including Lipitor and Glucophage have patents that have expired in the last few years and the cost to individual companies is enormous. Moreover, the issue of counterfeit medicines in developing countries remains a problem. One estimate suggests that around one-third of drugs issued to patients in some areas are counterfeit (4). The pharmaceutical industry together with national security forces and health regulatory agencies will have a key role to play to reduce trade in illegal drugs.

Public Profile

In the UK, public perception of the pharmaceutical industry as a whole is positive with 34% of respondents in one poll saying they felt positive about the industry, despite less than 10% having familiarity with it. Although the social and economic benefits of pharma are widely acknowledged, the major concern among the public is that the pharma companies are seen as untrustworthy. Less than 20% of respondents identified the pharmaceutical industry as trustworthy. Among the concerns raised were the making of excessive profits in times of recession, the poor response of companies to drug-related adverse events and the perceived influence pharma companies have over clinicians prescribing choices (5). What would be the benefits for the pharma industry in improving their public reputation? Firstly, a good reputation would inspire more budding scientists and entrepreneurs to consider a career in the industry. Also, a good public persona would facilitate collaborations with other sectors including IT and charities. In my opinion, pharmaceutical companies should publicly emphasise the important international programmes and charitable grants they contribute towards and highlight the impact of their research in improving global health.

 References

1. Data from European Federation of Pharmaceutical Industries and Associations (EFPIA) to be found here
2. Data from Food and Drug Administration (FDA) to be found here
3. Data from Pharmaceutical Care Management Association (PCMA) to be found here
4. Data from The Guardian to be found here
5. Data from YouGov to be found here