Under the Microscope: Kinesin Motors and Cancer

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This post was contributed by Jill Faircloth, an alumna of the Birkbeck Structural Molecular Biology MSc

There are many different types of cancer but each is caused by the failure of a cell to control its normal healthy cell division.  Uncontrolled proliferation produces a cluster of cancerous cells, a tumour, often the first indicator of many cancer types.  Several prevalent cancer drugs target microtubules, which are used by the cell to orchestrate the intricate ballet of cell division, but disabling this machinery provokes various unpleasant associated side effects.  In this lecture, which was part of Science Week, Dr Carolyn Moores, of the Department of Biological Sciences at Birkbeck shared some exciting recent developments in her work which pave the way for new cancer drugs which are less toxic to the rest of the body.

To understand the size of the machinery under discussion, if a human body were amplified to fill the whole of Buckingham Palace, each cell would be approximately the size of a single grain of sand.  These cells need to replicate, both to grow and to repair normal wear and tear and this replication is a delicate and highly regulated process.  Dr Moores showed a video of a dividing cell, taken from a remarkable online library of cellular images.  This process starts with the separation of the chromosomes, the familiar four legged bearers of our DNA, of which there are 23 pairs in humans.  The chromosomes arrange themselves in the centre of a spindle-like framework, which then retracts in opposite directions, separating each chromosome into halves and grouping them into two new nuclei centres, ready for the division of the rest of the cell. 

The dynamic spindle framework at the heart of this incredibly accurate mechanism is primarily composed of microtubules along with associated proteins including members of the kinesin family of molecular motors, which organise them.  Microtubules are made up of pairs of tubulin molecules, or dimers, each of which has a polar structure.  The dimers bind to each other both longitudinally, with opposites attracting so that the overall polarity is maintained, and laterally so that long thin stable cylinders are formed.  These cylinders can grow and shrink with great flexibility and at all lengths the cylindrical structure provides a frame which can withstand the tension required in pulling chromosomes apart.  Drugs that block the dynamics of microtubules can therefore block the ability of cells to proliferate, which is why they are used in chemotherapy.  Unfortunately, microtubules are also critical in healthy cell repair, as well as providing frameworks essential for cellular structure, organelle positioning and vital transport networks within the cell.

Kinesins are highly attractive as potential targets since each appears to operate primarily in support of one of the major microtubule functions, in which case an inhibitor could be designed to attack the cell’s ability to divide without affecting its other vital processes.

Kinesin proteins comprise several domains, one of which is the motor domain, responsible for the protein’s movement.   This motor binds to a microtubule and uses it as a track with a directionality given by its polarity.  It also binds ATP, the universal cellular fuel, which provides the energy required to move along the track.  This has been particularly well studied in kinesin 1, whose function is to transport cargo along the microtubules.  In a mechanism that Dr Moores compared to a child walking on his hands, each unit of cargo is transported by a linked pair of kinesin 1 molecules.  The molecules alternate so that one will bind to the microtubule and the energy source, ATP, and then its partner will displace it so that the motor effectively steps hand over hand along the microtubule track.  Structural studies of kinesin 1 bound to a microtubule show that a small linker region of each kinesin reacts with the polarity of the track to point and presumably inform the direction of travel.

Dr Moores’ group are studying kinesin 5, which combines into oligomers of four molecules and forms crosslinks between microtubules.  This has been shown to be essential to cell division in humans.  The structural studies have involved cryo electron microscopy which has given a 3D model of the motor domain of kinesin 5 bound to a microtubule, both binding ATP and without ATP present.  Electron microscopy is a technique much like ordinary microscopy except that an electron beam is used instead of visual light and this gives images at a molecular level.  The fact that a fast freezing method is employed is extremely useful since biological samples are effectively viewed in solution, as they are in their natural state.  By fitting x-ray crystallography models, which give atomic level detail of smaller molecular configurations, into the 3D cryo electron microscopy models, an enormous level of detail is obtained.

Drugs that target kinesin 5 are currently in clinical trials and appear to be successful so far.  It would appear that the drugs interact with an on/off switch elucidated by Dr Moores’ team but at the moment the precise function of the on/off switch is not known.  Work continues in this rewarding area of study with the aim of understanding the purpose of the on/off switch and consequently being able to design future cancer drugs which have even higher specificity and consequently better outcomes.

More details of Dr Carolyn Moores’ work are available on her staff page.

Representing Players in Sport: Bargaining for A Fair Deal for Athletes in an Olympic Year

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This post was contributed by James Brown, from Birkbeck’s Department of External Relations.

In the week that former darts champion Jocky Wilson passed away, it was fascinating to hear the Birkbeck Sport Business Centre discussion about the welfare of athletes both during and after their sporting career on 27 March 2012.

The rise and fall of Wilson is one of the more extreme that sport has known. In his eighties pomp, he was an ever-present in the latter stages of the World Championship, winning the title twice. With the sport regularly attracting 8 million views, Wilson became a folk hero with his large frame betraying the pub lineage that darts was trying so hard to leave behind. Never flash, the extent of his largesse was to splash out £1200 on new dentures following his 1982 title triumph. Yet within seven years of his second and final World Championship in 1989, Wilson was living in a council flat, aged 45, surviving on the disability benefits that were granted to him after his lifestyle brought on diabetes. When he was elected to the Darts Hall of Fame in 1996, it took a further two years for him to be informed of the honour, so far had he retreated from the game he had once dominated.

I was reminded of his story in listening to Barry McGuigan talk at the Birkbeck Sport Business Centre. In managing athletes, he was keen to emphasise that they should be prepared not just for their sporting career but also for what happens after their career has ended – or if it never happens at all. By his calculation, 85% of boxers don’t make a career out of the sport, and only 5% make any real money. Television holds most of the power in the sport, because it provides most of the money. McGuigan counted five boxers in the UK who would draw an audience big enough to attract television coverage – for the rest “it is a very tough business”.

McGuigan, like Wilson, was hugely successful in the Eighties, his fights attracting huge television audiences. He became WBA Featherweight Champion and was voted BBC Sports Personality of the Year, both in 1985. But his career since retiring from sport has been no less successful. A boxing pundit and commentator across most British broadcasters, he’s also had stints as a chat show host and won Hell’s Kitchen in 2007. But more importantly, and perhaps borne out of an eventually fractious relationship with his own manager, he founded the Barry McGuigan Boxing Academy in 2009. Its aim is to target people who are enthusiastic about boxing, but who have fallen out of love with education, and use the sport as a hook to get them back to learning: “It is so laudable to see students going back to college no matter how old they are – I’m into lifelong learning”.

Encouraging boxers back into education is difficult, said McGuigan. The nature of boxing in particular, where bravado is a key element of the boxer’s makeup, means that those attempting to make a career out of the sport have to believe in their ability to be the best, or that lack of confidence will soon be found out. But in doing so, trying to persuade aspiring boxers that they may not be a success can be a thankless task. And even if you do get them to college, they are naturally suspicious of spending time in class with other boxers who they may well be fighting in the ring next week.

But his Boxing Academies are helping to overturn some of that negativity. Now working with five further education colleges across the country, and there are hopes of extending the arrangement to more. “If you can invest 20% of the energy you put into sport, you can succeed in other areas of life”. It’s safe to say that, on McGuigan’s induction into the International Boxing Hall of Fame in 2005, it didn’t take two years for him to find out about the honour.

Which brings us back to Jocky Wilson. “I don’t want anyone feeling sorry for me,” he said in 1996. “There’s only one person to blame for the situation I’m in, and that’s me.” Here’s hoping that future sportsmen will also invest the 20% that means they won’t have to say the same thing.

Military Economics: defence choices for the UK

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The Inaugural Ronald Tress Memorial Lecture by Professor Ron Smith

 This blog post was contributed by Betty Low, a Birkbeck alumna who graduated with a MSc Economics in 1975.

The last time I had seen Ron Smith he was a lecturer, it was in the old Gresse Street Building (don’t ask) and he had dark hair. Gresse Street is long gone and, well, my hair isn’t dark any more either.

I say this not to be glib, but to emphasise that Ron’s lecture was never going to be an ordinary economics lecture. The inaugural Ronald Tress Memorial Lecture was launched to commemorate the 40th anniversary of the establishment of the Birkbeck Economics Department by the eminent economist and one-time Master of Birkbeck.

So the audience that had gathered to listen to Professor Smith’s “Military Economics: defence choices for the UK” was understandably an eclectic cocktail of alumnae, old (such as myself) and new (such as my daughter), current students, fellow academics and a contingent from the Tress family. Like all good writing Ron’s words were accessible and meaningful on many different thought levels. He used the lecture to reflect on the past and the future and how looking back always helped one to understand how to look forward.

Ron overlaid MOD spending behaviour with a layer of rigour and structure to explain both to the knowledgeable and to the neophytes the context and consequences of military personnel making commercial decisions.

Procurement practice at the Ministry of Defence was affected by three biases of which observers should be aware: “optimism bias”, “certainty bias” and can-do bias”. The first results in habitual under-estimation of the cost of projects and by the time this is obvious, those involved have moved on so there is no accountability. The certainty bias is the habit of Whitehall to treat everything as more predictable than it in fact can ever be. The “can-do bias” is another word for misplaced confidence; not to accept what our military tells us is tantamount to not believing in motherhood and apple pie.

The biases seem to be well understood and accepted but inescapable.

This prompted a non-practising economics alumna such as myself to think, “If you were charged today with creating a system for defence procurement, would you recommend that which now exists?” No.

As if to answer the question Ron deftly compared the British experience with the French.  They were similar – both had difficulty in financing their strategic objectives and both let arms exports determine foreign policy – yet different – the French resisted reappraisal while the British had regular defence reviews in response to economic crises. It was scarce comfort to hear Ron point out that the British experience is no different from the American but that they just had more money to throw at the problem.

The defence community is not just the MOD officials. It is comprised of representatives of the armed services, politicians, civil servants, science and industry. To quote Professor Smith, “Each of these groups face incentives that generate outcomes that, while rational in terms of the objectives of each group, are severely dysfunctional for MOD as a whole.”

In the private sector measuring output is simple; it is the bottom right-hand corner. The public sector has different challenges. There are no easy measures of output. As Ron said, “A good result for the Ministry of Defence is no activity. Defence is like an insurance policy. If it works you deter and don’t need it at all.” Not an easy one to benchmark.

Those of us who work in the private sector often fail to grasp how challenging and different it is to work in an environment of conflicting and often illogical agenda. At the risk of sounding like Yes, Minister, it is important to remember that decision-making is being made in an atmosphere of constant, inherent tensions between bureaucrats and politicians and that the public sector does not celebrate innovation. Introducing any change in Whitehall is like turning around one of the MOD’s biggest submarines.

In introducing the Inaugural Ronald Tress Memorial Lecture Birkbeck College Master David Latchman had reminded us that the founder of the Economics Department had been “a sound bastion of common sense”. What successive generations of British defence planners sometimes lack, the erstwhile Master had in spades.

For it was Ronald Tress who almost 40 years ago appointed Ron Smith.

Damage assessment of heritage objects and methods used in their preventive conservation. A talk by Dr Marianne Odlyha.

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This post was contributed by Bryony Stewart-Seume, a Senior Administrator in the School of Science.

Science Week continued with a lecture given by Dr Marianne Odlyha, concerning ways in which heritage objects can be damaged over time, and recent research into the methods which can be employed to minimise risk and decay. The lecture was well attended and well received.

After being introduced by Professor Nick Keep, the Dean of the School of Science, Dr Odlyha gave some background to the project on which she has been working for some time; “Measurement, Effect Assessment and Mitigation of Pollutant Impact on Movable Cultural Assets – Innovative Research for Market Transfer.” Essentially this research looks at the different environments in which moveable cultural objects (paintings, artefacts, tapestries, etc…) are displayed, stored or transported and to what pollutants these conditions may subject the objects.

Dr Odlyha began by explaining that the research is an interdisciplinary area; it encompasses many academic fields ranging from Art History to hardcore Science. The key objective of the work is to retard the degradation and decay of objects as much as possible. A description of the corrosion found in the organ pipes in the St James Church in Lübeck, Germany was given as a case study, and as an example of a situation that could have benefitted greatly from better environmental monitoring systems.  The organ is now sadly in a terrible state, and is unplayable.

It is of course unfortunate that the material of choice for the construction of organs (oak) is a high emitter of damaging gases. This issue is exacerbated by the fact that organs (and other such items of cultural worth) are often located in places with central heating, which is there for the comfort and convenience of the audience.

I was surprised that, despite being a method of display for many years, even something as apparently innocuous as the wood from which a case is built can cause damage over time. Plywood, for example, gives off very strong emissions; of course the cases in which paintings are kept in storage (Dr Odlyha used the example of the Tate’s store to highlight her point) are primarily built from this material. There is a legitimate economic reason for this, but perhaps this is offset against the damage potential?  While showcases will keep out much of the outside pollutants, it seems that it is just as important to be aware that the climate on the inside will also have a noticeable effect on the item on display.

Similarly, the practice of using varnish on a painting is an old one, and was originally thought to do some good. It does have the effect of darkening the image and enhancing colour saturation; however, as Dr Odlyha told us, over time the painting may start to yellow. It is not only the varnish itself that can inflict damage on the painting, but also the method of cleaning employed. It is also important to know that when we find a solution that minimises the damage potential of one polluting factor, we may have merely introduced another. The cycle of material selection/damage dealt is apparently perpetual, and it is only through cutting edge, up to the minute research that we can hope to do what can be considered best for our heritage.

There are options, though, for mitigating the risks to movable objects; one of those being a so-called ‘Micro-Climate Frame’. The conditions on the insides of the frames are measured using custom-made dosimeters and compared with the ambient atmosphere. Fluctuations in the surroundings have proven to be far more severe than within the frames themselves. Of course this is good news, and what is expected, but Dr Odlyha admitted that there is still much research to be done in this area.

You can find out more about Dr Odlyha’s research at http://www.memori-project.eu/memori_project.html