How the hell do you do a science PhD?!

In a state of desperation after weeks of failed and broken lab experiments, I asked my friend who is allowed to use the title 'Doctor:'

"How the hell do you do a PhD?!  Because I just don't seem to be getting it!"

He replied,

"I guess when you've done every possible mistake, [there] remains the beautiful truth..."

(followed by some sarcastic comments about how "beautiful" is relative).

Well, fine.  I understand that there is meant to be beauty and simplicity underlying all of the faff of spilled fluids and scribbled equations.  But why, then, do my current experiments seem to involve finding the most complex way to do something that should be obvious?!

Immune interaction optimises foetal nourishment during pregnancy

My first PR written for Cambridge University Science Communications Office!
Published here: 
http://www.admin.cam.ac.uk/news/dp/2011020801
© 2010 News, University of Cambridge, The Old Schools, Trinity Lane, Cambridge, CB2 1TN 



Paternal genes advise maternal immune cells on how to build the best womb for developing foetuses.

Mouse placental cells (red) and uterine natural killer cells (green). Note the close
intermingling of placental cells with maternal immune cells at this early developmental stage - 8.5
days after conception. Credit: Myriam Hemberger and Francesco Colucci

Researchers at the University of Cambridge and the Babraham Institute have identified a mechanism by which specific combinations of genes can lead to miscarriage and other complications in pregnancies.

The research revealed that paternal immune genes (MHC) in the placenta provide information to uterine natural killer (NK) cells to ensure that the foetus receives sufficient blood supply. Unlike their blood counterpart NK cells, which kill infectious and cancerous cells, uterine NK (uNK) cells actually help placental cells adapt the blood vessels in the womb to nourish the foetus.

By mating mice whose only genetic difference was in the MHC genes of the mother and father (1% of the genome), the researchers found that uNK cells would sense the difference in highly variable MHC genes. When faced with mismatched MHC genes from the father's immune system, uNKs were presumably not switched off and could focus on optimising the blood flow of the womb.

Francesco Colucci of the University of Cambridge Department of Obstetrics and Gynaecology had previously identified the particular genes expressed by mouse uNK cells and Ashley Moffett of the University of Cambridge's Department of Pathology had pioneered the research relevant to human uNK cells and MHC genes. But up until now, it was not clear which paternal MHC genes were expressed by mouse placentae.

"What is most exciting," Colucci says, "is that by revealing the similarities between human and mouse immunology of pregnancy, the [teams] lay new foundation for using mouse genetics to test new ideas and hypotheses informed by human genetics data."

The interaction of MHC and NK genes is also key in foetal programming of adult diseases such as diabetes and hypertension which are known to have early developmental origins

Colucci's work, published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) yesterday, was funded by the BBSRC and the Wellcome Trust, along with the Centre for Trophoblast Research, Medical Research Council, and NIHR Cambridge Biomedical Research Centre.

Colucci describes the next steps of where this research is leading, saying, "We are now well positioned to explore how the inherent variability of these immune system genes affects reproductive success by comparing NK receptors and MHC in normal pregnancy to those with disorders."

In the future research, the 'good' and 'bad' combinations in humans will be mimicked in mice to examine uterine blood vessels and foetus/placenta growth. The results of these experiments should help provide an understanding of how to prevent pregnancy disorders.

"This paradox has puzzled scientists for decades and understanding how the foetus evades rejection, except in severe pregnancy complications, has remained elusive," said Dr Myriam Hemberger of the Babraham Institute, the senior co-author who is an expert in mouse placental development. "Our findings show that paternal antigens on foetal trophoblast cells, which form the placenta and are therefore in direct contact with maternal tissue, help to transform the uterus for robust placental and foetal growth. This is essential for reproductive success."

Questions on genetic engineering

Scientists have recently been able to genetically engineer chickens to render them unable to transmit avian flu.

This all sounds good for the poultry industry, but it brings to mind a few questions about genetic engineering, to which I certainly don't have any good answers.

What are the ethical implications of human beings trying to genetically change a creature with a central nervous system, whether genetically engineering chickens to avoid avian flu, or engineering pigs to synthesise omega-3 rather than omega-6 fatty acids thus providing healthier pork?

Would the ethics of the situation be different if these genetic changes were done with the goal of providing a better life for the birds/pigs themselves, rather than the goal of more profit to the people that were doing the genetic engineering?

What about the evolutionary side?  Genetic traits evolve over time.  Is human beings' interference with other species' genetics changing the course of evolution, or is our ability to do this simply a product of evolution and thus completely natural?

Suppose a family member had an incurable disease such as chronic leukemia or diabetes.  If this individual's parents had, before birth, chosen to have their offspring's genes engineered so that this disease would not have been able to happen (if the technology were available), would this be a different case to genetic engineering in chickens or pigs?  Would there be anything wrong with that?

In the chickens or pigs, nobody could ever explain to the chicken or pig what had happened nor why.  But in the would-have-been chronically ill person, presumably the child would grow up and understand that his parents had done something helpful for him.  The parents would have effectively provided the consent for medical treatment (genetic modification) on behalf of the child.  So effectively, there would be consent within the family.  For chickens and pigs, there's not even consent within the species.


As an afterthought:  could this ever lead to genetically engineering groups of people to fill certain roles in society?  Pre-programming the genes of, say, non-university educated groups, to be really good at farming so that they could crank out productive 14 hour-days on a farm every day?  And genetically engineering another group to be really good at truck-driving?  And another group to be really good at politics?  As though selectively breeding a certain type of dog or horse to accentuate a trait associated with that variety of animal, this would be genetically programming people to accentuate traits associated with different roles in society.  Humans trained in genetic engineering would become the ruling class and ultimately control the function of all other groups of people.  I'd hate to see what would happen.

http://www.sciencemag.org/content/331/6014/132.1.full?sid=5b36e31e-5329-41e4-927d-6e8a266bc6f3

Musings on "Cornell Dots" clinical trial and radioactive iodine

Schematic representation of a Cornell Dot, with several molecules of dye encapsulated in the center (Image (c) Cornell University)

Cornell researchers' efforts at tagging tumors has been approved by the US Food and Drug Administration for a clinical trial in humans.

"Cornell Dots" are silica spheres less than 8 nanometers in diameter that enclose several dye molecules and attach to tumor cells.  The glass-like shell is chemically inert and coated with polyethylene glycol to avoid being treated as a foreign substance by the body.  Organic molecules that bind to tumor surfaces are attached to the shell so the dots stick to tumors and flouresce much more brightly than unencapsulated dyes.

This can show the extent of a tumor’s blood vessels, cell death, treatment response and invasive or metastatic spread to lymph nodes and distant organs.  In the new clinical trials, the dots will be labeled with radioactive iodine so they're visible in PET scans and can show how many attach to tumors and where else in the body they go.

The dots will hopefully stay in the body (and attached to the tumor) during surgery, thus providing a useful visual for the surgeon.  They also may be useful for delivering radioactivity or drugs to tumors.  Other potential applications include biological imaging, optical computing, sensors and microarrays such as DNA chips.

But what about the radioactive iodine?  Is this going to be particularly relevant to the clinical trial which has five melanoma patients as subjects?

Now, to treat chronic lymphocytic leukemia (CLL), monoclonal antibodies that bind to particular structures on leukemic cells can be used to deliver payloads of radioactive iodine to the tumor cells.  The radioactive iodine-antibody combination is a drug called Bexxar.  The antibody identifies the targeted cell for destruction by the immune system, but also zaps it with radiation just to be sure.

The Cornell Dots trial seems to use radioactive iodine as a label. But given that the trial involves skin cancer patients, could the radioactive iodine not actually be used to kill the melanoma cell in the same way that Bexxar attacks CLL cells with radiation?

If the organic molecule on the dots' shells is able to identify and attach to melanoma cells, whether or not it singles out the cells for immune destruction, it seems that this clinical trial could shed new light on a possible radioimmunotherapy treatment.



Ow, Hooiswing et al., Bright and Stable Core-Shell Fluorescent Silica Nanoparticles.  Nano Letters Vol. 5, No. 1., 113-117, 2005.

http://www.newswise.com/articles/view/572923/?sc=dwhr&xy=10005433

Beethoven's 7th

When my undergraduate orchestra was rehearsing the second movement of Beethoven's 7th symphony, our rather dramatic conductor described the underlying bass rhythm as "that is the heartbeat of humanity."

Tom Hooper, director of the recent hit film "The King's Speech," may have thought of that same rhythm as the march of soldiers in a nation preparing for war.

At the end of the film, King George VI overcomes his struggle with a speech impediment in a scene of triumph but also of ultimate irony, as his victory is achieved during the delivery of his broadcast on the outbreak of Britain's declaration of war with Germany.  His words become the libretto for Beethoven's 7th symphony which accompanies the speech in the film, bolstering the heaviness of his message to the British people and the rest of the world on 3rd September 1939.

Whether heartbeat of humanity or marching of soldiers or an undying steadfastness and resolve, the rhythmic cello and bass material continues throughout the whole movement, underlying the king's words:  "In this grave hour, perhaps the most fateful in our history, I send to every household of my peoples, both at home and overseas, this message, spoken with the same depth of feeling for each one of you as if I were able to cross your threshold and speak to you myself."

The upward rising melody briefly touches on a major cadence and alludes to an effort at peace:  "Over and over again we have tried to find a peaceful way out of differences between ourselves and those who are now our enemies."

The melody--barely more than an exercise in counterpoint from music theory class--is traded amongst the violins, violas, and lower strings; once for each time the camera cuts to a different group of people gathered round their radio.  "For we are called, with our allies, to meet the challenge of a principle which, if it were to prevail, would be fatal to any civilised order in the world."

Gradually more insistent brass join the strings, lending increasing resolve and calling the nation to arms  "for the sake of all that we ourselves hold dear, and of the world's order and peace, it is unthinkable that we should refuse to meet the challenge.  It is to this high purpose that I now call my people at home and my peoples across the seas, who will make our cause their own."

The rise and fall of the upper voices and the persistence of the bass make it difficult to decide whether melody or accompaniment is more important.  The meoldy's brief brushes with a major key further convolute the the ominous message of "dark days ahead" that "can no longer be confined to the battlefield" with a call for the hope, requisite optimism, and resolve of "do[ing] only the right as we see the right...we shall prevail."

The age of ice

The Perito Moreno Glacier, fed by the Southern Patagonian Ice Field in Argentina.  Photo credit:  Bill Onorato (Journal of the Cambridge University Mountaineering Club)

The Patagonian Ice Sheet covered all of southern Chile during the last glacial period.  Now the Southern Patagonian Ice Field, one of its remnant parts, is one of the largest non-polar ice fields in the world and provides fun and games for mountaineers and scientists alike.

Geologists have for the first time been able to directly determine the age of early Pleistocene glaciers in the Lake Pueyrredon valley in Patagonia. The extensive sequence of moraines—glacially formed accumulations of debris—in Argentine Patagonia provide a geologic record of the Patagonian Ice Sheet.   The age of sediment on outwash terraces, which are deposits that extend along a valley downstream from a moraine, shows the age of glacial advances, according to a study published in Geology this month.

Researchers at the University of Edinburgh and the Scottish Universities Environmental Research Centre measured surface exposure ages of elements (¹⁰Be and ²⁶Al) in the outwash sediments.  A cobble from the outermost glacial sequence, which marks the greatest extent of the ice sheet, dates to 1.2 million years old.  A cobble from a younger outwash terrace dates to 600 thousand years old.  This is consistent with age constraints obtained elsewhere in Patagonia via argon dating, and indicates that major glacial advances occurred at 1.2 Ma and 600 ka. Combined with existing data, there is evidence for five major advances of the Patagonian ice sheet since the early Pleistocene.

Boulders on a moraine related to the outwash terrace that yielded the 1.2 Ma cobble are significantly younger, suggesting that boulders underestimate deposition age.

How accurate is this sediment outwash dating?  Outwash terraces indicate long-term stability and original surface morphology because they become isolated after deposition when a reverse in drainage direction occurs.  Outwash sediment ages are tightly clustered, suggesting that age determination is fairly accurate.  Accuracy could be improved by increasing sampling density and pairing depth profiles within the terrace sediment.  

If the stability of outwash terraces is common throughout the Lake Pueyrredon valley, this new information would provide insight into how regional climate signal has developed alongside global trends and has implications for understanding terrestrial climate change.

Ref:  Andrew S. Hein, Tibor J. Dunai, Nicholas R.J. Hulton and Sheng Xu. Exposure dating outwash gravels to determine the age of the greatest Patagonian glaciations,  Geology, published online 5 January 2011.

9.8 metres per second per second

Climbers on Arboneum (5), Oeschinensee, Kandersteg, Switzerland.
Photo Rachel Berkowitz, Jan 2011

Gravity.  It works every time.

In day-to-day life, people don't really think about it all that much.  I doubt that many people have much concept of how fast 32 feet per second per second is.  But last week, I got a very good visualisation as a 3m x 2m x 5m-long icicle broke off from an overhanging rock several hundred metres up the side of a mountain and came tumbling down just the other side of the rock from the two climbers pictured in this photo.

The icicle shattered into watermelon-sized shards as it boomed its way down the chute.  Accelerating at 9.8 ms^-2, one of these blocks would be plenty to kill a person.  Fortunately the two gentlemen climbing that particular icefall at the time were well sheltered at a bolted belay stance around the corner of a rocky ledge.  The part of the icicle still attached to the cliff far above now exposed a gaping hole in its centre.

That day was warmer than it had been for awhile, so the booming of ice pillars as they tumbled off their perches was audible throughout the valley (and did not increase my confidence in ice climbing).  But the air temperature was increasing; a temperature inversion meant it was warmer higher up the valley walls where the hanging icicles were; the ice began to melt and solid slowly turned to liquid; the ice core was no longer solid and the structure of the icicle was compromised; then the perfect combination of thermal and fluid dynamic conditions were tugged on by gravity and the whole thing collapsed.

It makes me appreciate physics more.