Medical implications of this years Nobel Prize (telomere end maintenance)

This years Nobel Prize in Physiology and Medicine was awarded for findings that revealed the crucial role telomeres play in maintenance of linear chromosomes. A recent review in NEJM covers the medical implications of these discoveries. It always gets tricky when alteration of a single molecular mechanism underlies a wide range of pathological conditions but we already seem to have some critical knowledge. The review covers some examples of telomere associated diseases, namely Bone Marrow Failure, Dyskeratosis Congenita, Acquired Aplastic Anemia, Pulmonary Fibrosis and a sometimes associated Liver Diesease. All of these show mutations in genes responsible for certain functions in telomere end maintenance like DKC1 which codes for the telomerase complex stabilizing protein dyskerin, TERC coding for the telomerase RNA component or TERT the telomerase reverse transcriptase itself.

Again there is the major drawback that we have no idea how to make use of this knowledge. We know that telomere end maintenance affects ageing, induces tumors and plays an important role in the above mentioned diseases, yet we do not fully understand why and how we can interfere. Yet.

The Mystery of Swine Flu

Since the Leading Edge Forum published last summer in Cell some time has passed. Back then it was considered obvious that the number of severe illnesses or deaths linked to this specific virus strain did not necessarily lead to the assumption H1N1 could be worlds next pandemic. 6 months later not much has changed. A constant hiss of imminent danger accompanies most news broadcasts covering swine flu and people are waiting in lines to get vaccinated. Fact is, H1N1 viruses are circulating constantly in human population since the ‘70s and are a component of standard annual influenza vaccines. No molecular markers of pathogenicity have been discovered in the current flavor (H1N1 swine influenza) yet. One might even add that most of the deaths resulting from infection with Spanish flu in 1918 were caused by secondary bacterial pneumonia, a complication we would be able to tackle, considering we live in the era of antibiotics and antiviral medication.

Are we missing a quality indicator for physicians wellness?

A recent review in Lancet reminds us that a working health-care system is directly linked to the well-being of its practitioners. What might seem rather intuitive on first glance reveals a rather unpleasant truth. Most health-care systems couldn’t care less about physicians wellness. The review covers in detail the risks associated with fatigued, overworked or stressed physicians trying to cope with superhuman workloads. The persistence of this problem is widely known (and not exclusive to American health-care) and if we are unable to improve this conditions, we should at least keep an eye on the consequences. A first step could be the mentioned “quality of work competence survey” and linking the physicians own perception of well-being with observed efficiency and risk of medical errors. Since we are aware of the potential consequences of unwell physicians I agree that health-care systems could benefit from actually paying attention to it.

Looking for interesting people to follow on Twitter, I got informed that Twello is kind of a Yellow Pages for Twitter accounts since you can search by topic.

Well. Doesn't work too well tho.

Person hosting an astrology website #1 hit when searching biology?? :D

Maybe a sign ...

Good science blogs #1

An awful lot of people blog on science. Most of these blogs give clear evidence why their authors became scientists and not writers. So it's rather difficult to find some readable science around here. I emphasized both words, 'cause you also encounter it the other way round.
From time to time I stumble over a real gem, that surprisingly combines these features and becomes one of the blogs who become honoured by me following them :-p

Thanks to the Sandwalk (I'll give an introduction to this one later) I found this:

http://blogs.discovermagazine.com/loom/

That's EXACTLY what I mean. Real discoveries, aroused from the papers where they were hiding and herded on a single site.

Only drawback: too many flash commercials for my taste.

Fresh approach

Has been a long break and, well, I don't think it works out like this. I mean, posting some comments to single articles is no real help. Maybe I should try making a more general overview over a set of publications on a defined topic. Like a minireview that tries to aggregate key findings across different field. Just more holistic and a few steps back from the naked research results.

Another tumor repressing microRNA controls angiogenesis - and recovers tissue!

As mentioned previously in the section discussing Down's syndrome and its effects on tumor growth the suppression of angiogenesis proofs to be a rather powerful tool in cancer medicine. Fast growing tumorous tissue is in the need of sophisticated supply hence inhibiting growth of new blood vessels through inhibiting division of endothelial cells and thus starving the tumor is a strikingly functional strategy. Here I want to point out a new microRNA investigated by the team around Stefanie Dimmeler and recently made public in Science (http://www.sciencemag.org/cgi/content/abstract/324/5935/1710) being capable of controling angiogenesis. The role of miR-92a in angiogenesis has so far been unclear but the team could demonstrate now that overexpression of miR-92a suppresses angiogenesis. Different approaches can take advantage of this finding. One has already been mentioned above (and in my post concerning therapeutic potentials of miR-26a). It would appear plausible to slow down tumor growth by overexpressing inhibitory microRNA. Another approach, and this has actually been done in this work, is doing exactly the opposite. It has been observed that during ischemic injuries miR-92a expression is significantly increased. Applying antisense RNA against miR-92a, a so called antagomir, leads to neovascularization and reduction in toe necrosis. At least in a murine model. Yet hope rises to functionally recover ischemic tissue through application of an antagomir. Potential molecular targets of were also identified and the action of miR-92a might not be limited to endothelial cells.

I think these findings might add some new features to the already wide-ranging applications of microRNA in developing future therapeutic strategies.

Therapeutic microRNA

Therapeutic potentials of microRNA have often been discussed and several functional studies explore strategies using antisense RNA against tumorigenic microRNA or replacing it. One recent publication in the magatine Cell shows the power of gene therapy utilizing inhibitory microRNA (http://www.cell.com/abstract/S0092-8674(09)00446-2). A characteristic feature of common tumor models is upregulation of specific and downregulation of general miRNA levels. Using a murine model for inducible liver tumors and human Hepatocellular carcinoma (HCC) cells the team around Joshua Mendell took advantage of the fact, that abundance of microRNA miR-26a is almost twice as high in unaffected tissue than in tumorous liver tissue. Through retroviral vectors it is possible to force expression of miR-26a and thus increasing its endogenic concentration leading to cell cycle arrest of tumor cells. Cellular proliferation is inhibited because miR-26a directly represses the expression of cell cycle control proteins Cyclin D2 and Cyclin E2 which also induces tumor-specific apoptosis. All this sounds pretty impressive to me but as the authors stated it is still the beginning. More than likely several powerful tumor repressing microRNAs will be discovered in close future and once clinical studies investigate toxic consequences of therapeutic microRNA treatment we will be close to making a great leap in curing cancer.

Down's syndrome involved in tumor suppression

It has already been observed that individuals affected by Down's syndrome show reduced tumor growth and speculations arised that the additional copy of Chromosome 21 could feature the genes leading to this effect. Now a study published in Nature (http://www.nature.com/nature/journal/v459/n7250/abs/nature08062.html) proofed one of these genes to be coding for a protein inhibiting the VEGF-Calcineurin pathway, the so called Down’s syndrome candidate region 1 (DSCR1). In mouse models for lung carcinoma and melanoma the a tird copy of the DSCR1 encoding gene was sufficient to reduce angiogenesis and thus significantly slowing down tumor growth. As already mentioned in the part concerning Immunotherapy, the VEGF is a rather prominent target for anti-tumor drugs. A naturally occuring negative regulator of the VEGF pathway opens the way for a completely different set of therapeutic tools to control tumors.

Immunotherapy - applying antibodies against critical molecular targets in tumor cells

Among them you can find some of the most profit-making drugs on earth, like Avastin or Rituxan, selling for around 700 Mio $ each in 2008 (http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11767). So why are we not done yet? If you look at the websites for Avastin (http://www.avastin.de/) and Rituxan (http://www.rituxan.com/) you encounter the main problem. Avastin for example targets a variety of cancers in breast, lung and kidneys, and in all applicable forms of tumor the target is VEGF, the vascular endothelial growth factor (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=micad&part=Bevacizumab111In). The target for Rituxan is the membrane protein CD20. This explains why Avastin or Rituxan can be applied for different types of tumor and why we are still lacking pharmaceutical agents that target all types of breast cancer or all types of lung cancer. There is no common marker expressed in all types of breast cancer that can be targeted without afflicting serious damage to healthy tissue as well. Antbodies against specific surface molecules on tumor cells is still something to open a business.

Getting started

Whew, that was more work than anticipated. But I still don't know where to begin. How about a gene responsible for alcohol resistance? (well, everybody talks about that anyway...) Or how targeted breast cancer therapies work on molecular level? Choices ...