Friday, November 18, 2011

Two organizations with the right idea.

Tonight I am attending the Annual Kerkut Trust dinner. This charity was set up by Gerald Kerkut to fund physiology graduate students at my university. The value of these cannot be understated. There is no place else consistently offering such no strings attached money for exciting new projects and students. The foundation is extremely generous and almost always responds positively to request for extra funds and especially travel money.  They don’t ask you to lie about potential future economic impact, only that the science be solid and new. The application is short and to the point. The result is an invaluable resource for genuinely novel and new biomedical research projects that would never get off the ground otherwise. This has to be the most underappreciated charity at my university given the magnitude of the effect I have seen it have on the faculties that it helps.
Coincident with my dinner is an announcement in Science Magazine that the NSF is proposing a new initiative, Creative Research Awards for Transformative Interdisciplinary Ventures (CREATIV).It is a program to promote what Science calls out-of-the-box research. What is new and exciting is that it is all about taking risks and working between disciplinary boundaries and actually exploring the unknown rather than just being the next step sort of science. The key requirement is that it must be transformative. Such a program would never even get a hearing today in Britain with the conservative government hell bent on only funding practical and safe translational research. It is nice to see that the US still has its revolutionary spirit.

Saturday, November 12, 2011

Ode to A4 with thanks to Stephen Fry


Two of the best things in Britain are Stephen Fry and A4 paper. One of my favourite books by Fry has inspired me to honour both with an ode. The book, “An Ode LessTravelled” is a very accessible and fun way to learn about poetry in a clear and entertaining way. I now find myself walking around chanting ti tum ti tum ti tum ti tum ti tum and trying to hear the meter of words and sentences. This is not easy for someone as musically challenged as myself. One of the unfortunate results of reading his book is that he asks you write lots of poems along the way. I confess that I have not done every exercise but I have put together a Sapphic ode, anglicised like his examples by Pope. For those who want a clearer description of A4 and it’s useful properties see Wikipedia (http://en.wikipedia.org/wiki/Paper_size).



An Ode to A4
(dedicated to Stephen Fry)

The longer page allows more lines,
with extra words and lots more white
to free from letter size confines.
                          More room to write.

To make a perfect ratio
fold halfway down and when you’re through,
dividing width by height will show;
                          square root of two.

From home made cards to poster size,
your image scales with every fold.
A4 requires no compromise.
                       Your message sold.

Why two pads for different tasks?
Too long legal, too fat letter,
One size is not too much ask.
                        A4's better!

Friday, November 11, 2011

The Paradigm Shift Continues.

Sohal and Orr have seen the light! Two more giants of the old free radical theory have moved on from the death of the old free radical theory of aging.  In an in press review in FRBM, these two leaders in free radical research argue that structural based oxidative stress and the idea of accumulated damage is not the primary cause of aging, and that the effect of redox balance on signalling is likely more important. They then stake a claim to a new version of a free radical model by labelling it “the Redox Stress Hypothesis”. This review is a much more sober conservative take preserving a central role for reactive oxygen species model compared to Blagosklonny’s call to revolution back in 2008. What is clear is that the old idea that free radicals cause aging by direct accumulation of damage is being over thrown and several reasonable contenders are arising from the ashes.
Genuine Kuhnian paradigm shifts in Science are rare. It is really fun to be able to watch this one as it has been slowly evolving for the past five or so years. It seems so intuitive to think that the damage correlated with aging is the cause rather than the effect of growing old, but the opposite is being proven true. There are still many diehards out there who have not got the message. The next interesting validation of Kuhn will be to see how many of those don’t change their minds. According to Kuhn, a significant number will never be able to let the old paradigm go. At least not until their own redox signalling pathways become hopelessly unbalanced. For the laypersons who made it this far, the take home message is to not waste your money on antioxidant supplements to prevent aging.

Thursday, November 3, 2011

Some aging research progress

There have been a couple of interesting ageing papers recently. One showing how caloric restriction works through a mechanism involving hydrogen peroxide and another on flushing out old cells in mice. Some people think I am little extreme in my views about the free radical theory of aging being dead, but I am right here. We do not just burn up or wear out and both of these studies shed light on how this works. We age because we cannot maintain the fine balance to perfectly control our repair and maintenance processes indefinitely. The beauty of the connection of hydrogen peroxide (H2O2) to caloric restriction is that H2O2 is also a signalling molecule that can affect phosphorylation pathways. This helps to connect all of the known aging metabolic pathways to the balance of highly reactive forms of oxygen that can act as monitors of metabolic activity and stress. The difference between this emerging theory and the old free radical theory is that it is the balance, and not the direct damage from these reactive and unstable signalling molecules that is important. Unfortunately, the authors and the reviewers are both still hung up on the old free radical theory and seem to be missing the point by describing the process in terms of H2O2 resistance. Caloric restriction increases the expression of an enzyme that re-activates a peroxiredoxin (an enzyme that changes H2O2 to water) reducing the amount of H2O2.  The unasked question is why would lower glucose levels require a greater ability to scavenge free radicals?  The whole system is tied into a feedback loop so H2O2 levels would seem to remain elevated in the presence of normal or excessive levels of glucose. I fear that this paper is just going to add yet more fuel to the dying fire of the old free radical theory.
The other paper is also very interesting from a systems biology point of view. What they essentially did was to improve the mechanisms for removing dying cells. They made a mouse with a “kill this cell now” gene controlled by a promoter linked to a gene that tells sick and dying cells to eventually die. In these genetically modified mice, one can trigger the  ”kill this cell gene”  with a drug so that sick and dying cells are more quickly removed. The result is an improvement in overall maintenance and less age related problems for the animal as a whole. Interestingly, this shows that dying cells are not necessarily important for signalling repair mechanisms or the animals would have been less healthy.  The other good thing is that these authors noted that they only tested on one genetic background. Aging effects are notoriously dependent on all levels of environmental effects from the genetic to physiological and even social. The H2O2 study above was done with yeast which are strange in the way they age (not multicellular) and needs to be explored in much more detail in animals and across genetic backgrounds as well. So some progress, but no sign of immortality in our immediate futures.