Saturday, June 30, 2007

Prognostic markers in Bournemouth

Several people have asked me about getting prognostic markers done in Bournemouth. I should first say that I no longer work at Bournemouth and have no financial interest in the tests. The tests are carried out by the same scientists who performed the tests in my publications, and the laboratory is the one that I use when patients come and see me. It is possible to do the tests on samples that arrive within 48 hours of the blood draw, and they have successfully tested samples from as far away as New Zealand, sent by courier.

It is first, necessary to het a blood sample taken. They need at least 10 ccs taken into Lithium Heparin anticoagulant (for many manufacturers this is a tube with a green top.)

Then it is necessary to organise an international courier to send the sample (which courier doesn't seem to matter - FedEx, DHL, TNT etc)

The sample should be sent to Dr Rachel Ibbotson, Department of Molecular Biology, Department of Pathology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK.

Please contact me beforehand so that I can tell them about a sample being due. Try and arrange that the sample arrives during the working week, Monday to Friday.

The tests that are offered and their prices are:
IgVH genes - £156
CD38 - £42
FISH for del 11q and del 17p - £115
Full Karyotyping - in addition to FISH £75, but if separate without FISH then £100.
A new assay for ZAP-70 is being tried, but at tehy moment no charge is made for that.

I will interpret the results without charge. You must make your own arrangements to pay the laboratory for the tests. Some people send a check that cane be negotiable by a British bank, but I am sure that some sort of bank tansfer is possible.

Friday, June 29, 2007

How the bombers have failed

Another bomb in London is successfully defused. This one was left in a car in Haymarket outside the Tiger, Tiger nightclub around 2 am this morning. There was no warning and no intelligence suggesting an attack was imminent. Suspicion points to Al-Qa'eda - giving no warning and aiming to maim as many as possible, especially the irreligious folk who go to nightclubs is an Al-Qa'ida trademark. The likelihood is that they were British Muslims and that they timed the attack to coincide with the start of Brown's premiership.

Apparently there are now over 2000 Al-Qa'ida suspects under surveillance by the police and security services. This compares with the 700 or so who were interned in Northern Ireland at the start of the 'Troubles'.

In view of the threat it is worth considering what the terrorists have failed to do in England. We do not have imprisonment without trial. Indeed despite the wish of the police and government to detain suspects for 90 days without charging them, our democracy has not allowed it. We do not allow suspects to be tortured. We have interned nobody. Attempts to deport foreign suspects are rare and strongly opposed by civil rights groups. We are going about our business normally. The City of London is thriving. Tourism is more affected by the terrible weather than by the threat of terrorism. Immigrants are still dying to get to London. The Judiciary are independent from the Executive. The Press is free. Broadcasters are not intimidated by the government. We have free elections. People are allowed to go on strike (indeed the mailmen are on strike today). We do not allow phone-tap evidence in court. Bid sporting events (like Wimbledon) continue to be held in London. Arabs are not attacked in the street. The police do not carry guns. The public have accepted being searched and X-rayed without demur. We are not forced to carry Identity Cards. The trains, the buses, the airplanes and the roads are full. No-one is intimidated. Mosques remain open.

London withstood bombs from Zeppelins in 1914-18. London withstood bombs from Heinkels and Messerschmidts in 1940. London withstood the V1 flying bombs in 1943-44. London withstood the V2 rockets in 1944-5. London withstood the IRA bombers in the seventies, eighties and nineties.

Here is a message to Islamist bombers: London is not a soft touch.

Later: A second car bomb has been found. This one was illegally parked and was towed away. The thought is comical. A terrorist plants a car bomb to do maximum damage to partying infidels. But along comes a traffic warden. "Hey you can't park there." So it is towed away and only later does a council employee smell petrol.

But Wimbledon continues (all those naked female limbs), a Gay Pride march takes place in London today and tomorrow a concert in memory of Princess Diana (the hussey - and died dating a Muslim too). What do you expect, London, is that not provocation?

Thursday, June 28, 2007


Smoking in buildings used by the public is about to become illegal in England. The Celtic parts of the British Isles have already taken this path, and indeed it was the popularity of this measure in the Republic of Ireland that finally persuaded the government to take the plunge. I will be glad that this is finally to the law. At last we will be able to eat in a restaurant an emerge without clothes and hair smelling foul. However, the punishment for smoking will not approach what happens in Sunni areas of Iraq where Al Qaida punish smokers by cutting off the two 'smoking fingers'.

I have been convinced of the evils of smoking ever since my grandmother took me on her knee and pointed out my cousin who was smoking away. "Look how green he is going" she said, and I'm sure he went as green as Shrek.

Nevertheless, my father smoked, lighting one cigarette with the but of the last one. He died young of a pulmonary embolus while suffering from smoker's polycythemia.

When I attend King's College Hospital we have an X-ray meeting where we review around 50 chest X-rays and chest CTs. The pulmonary radiologist is first class. He tells you straight away whether your patient is a smoker by viewing the state of the lungs on CT. A couple of weeks ago he astonished me by pointing out that the patient smoked cannabis. Only cannabis smoking can produce this degree of emphysema in one so young. Today he made the diagnosis of AIDS in a Nigerian Health Tourist. He had enlarged lymph nodes beneath his chin and nowhere else. "This is a picture pathognomic of HIV infection," he said

Wednesday, June 27, 2007

The silver ring thing

Much fuss about a little girl taking her school to the High Court over not being allowed to wear "Christian jewellry" in school. Obviously an attempt to trump the hijab and veil. My problems with it are 1. The silver ring has never been a part of Christian iconography - it sounds to me like some commercial enterprise is trying to cash in on the publicity. 2. My brand of Christianity has never been one to go in for symbols to be worn for show. The demonstration that one is a Christian should come from how one behaves, but from what one is wearing. Remember what Jesus said about whited sepulchres. 3. Even if one wanted a symbol of Christianity, it would be the cross, not a silver ring. 4. The reason schools have an objection to jewellry is nothing to do with religious persecution, but with an undremarkable wish not to be sued if the jewellry goes missing. 5. Schools are for education, not this silly sort of religious battle. 6. This goes for all the other religions too. The girl with the veil was set up by her parents who used her as a propaganda pawn. I should not be at all surprised to discover that the same sort of thing was going on here.

Monday, June 25, 2007


After the warmest April we now have had the wettest June. The rain is coming down in stair rods and people have been killed by the floods. Of course, it is the first week of Wimbledon, so what should we expect? All those hats at Royal Ascot got soaked and Glastonbury turned into a mud bath. The English summer has returned.

The book on CLL that I was writing for doctors has been abandoned. My co-author who was writing the myeloid side has not been able to find the time to do his part, so I have abandoned my part with 6500 words already written. I feel a strange relief at the release. Perhaps I didn't really want to do it.

Most of today I have been kicking my heels doing killer sudokus and reading a detective story. Is this what retirement is going to be like? Frankly I am bored.

There are things I could do, but I realy can't be bothered. I have recorded the talk that I should have given in Niagara Falls onto my computer and am trying to send it to Canada. It takes about 500 megabytes of storage and has to be sent via a special website for large files. At this rate it will take about ten hours to send. I have alrady tried once, but after nothing arrived after 2 hours I thought there must be something wrong and abandoned it. This time I have kept track of its progress. So far only 15% has gone.

Part of the boredom is the state of politics in this country. Ms H. Harman was elected as deputy leader of the Labor Party. In order to get elected she took an anti-Iraq stance. I guess she thought that she might become deputy Prime Minister like Prescott was, but Brown put her in her place by making her Party Chairman, a post of monumental insignificance. In doing so he proffered the sack for Hazel mini-Blears who had occupied that post. Harman has infuriated the country by suggesting that she ought to be elected because she was a woman and there were enough men in top jobs. She also sent her children to schools that selected academically when it was part policy to phase out such schools.

Most impressive of the candidates was John Cruddas who was the only back-bencher and the only one who did not see this election as a stepping stone to power. He was the leader after the first ballot. On a decent first past the post electoral system he would have won. These foreign proportional representation systems only lead to fudges. Look around at what they lead to: Israel, Italy and the European Union. And Northern Ireland, Heaven help us.

Sunday, June 24, 2007

Mark 12 continued

Not all the Pharisees are condemned by Jesus. One, impressed by how Jesus dealt with the Saducees, asked a serious question; not a trick one. "What is the most important commandment?"

Jesus's answer was bound to impress a teacher of the law; he quoted from the Torah.
From Deuteronomy Ch6, the shema: The LORD is one. Love the LORD your God with all your heart and with all your soul and with all your mind and with all your strength.

In neither the Hebrew nor the Greek of the Septuagint does the word 'mind' appear. Some commentators make nothing of this, but it seems to me that this is at the very heart of the Christian Gospel and I will return to it.

Jesus quotes again, this time from Leviticus Ch 19: The second is this: Love your neighbor as yourself.

The reaction of the scribe is to agree: Well said, Teacher.

Jesus commends him: You are not far from the Kingdom of Heaven.

In Luke's Gospel there is a similar story, but here the scribe tries to trick him and when he receives the same answer seeks to justify himself by asking, "Who is my neighbor?" which prompts the story of the good Samaritan.

However, in Mark we need not follow that path, but instead look back to the Levitical text. Chapter 19 is an expansion of the Ten Commandments. Neighbors first appear with the injunction to judge them fairly. Then 'Don't do anything that endangers your neighbor's life.' The 'Rebuke your neighbor frankly so that you will not share in his guilt.' Then 'Do not seek revenge or a bear a grudge against one of your people, but love your neighbor as yourself.'

In Luke's Gospel, the parable of the Good Samaritan takes away the option of regarding as neighbors merely our kith and kin, those that live in our town or even in our country. The Samaritan was a heretic in Jewish eyes. The principle of neighborliness extends even to people not of our religion.

Most people know about the good Samaritan, and draw from that story our need to be concerned about the sick and suffering, the persecuted and the hard done by wherever they are in the world. That is part of neighborliness, but it is not all of it. If it were then Christians would be a soft touch for any crook and con-man. Christians are not expected to roll over for any kind of abuse. They are not to be milk-sops.

We are to 'judge our neighbors fairly' but we are also to 'rebuke our neighbors frankly so that we will not share in their guilt'. 'Fairly and frankly' that is the watchword. We do our neighbor no favor by turning a blind eye to his misdemeanors.

How do we love God with all our heart, soul, mind and strength? To love him we have to know him. We know him from studying Scripture.

You shall have no other Gods before me. It seems to me that modern Christians are in danger of worshipping the God of Tolerance. Now it is true that God is patient.
'Slow to chide and swift to bless' as the hymn says. We must not mistake that for tolerance. He abhors wickedness, cruelty, dishonesty and all manner of sinfulness. His reluctance to punish us here and now is evidence of his patience, not his tolerance. He gives us time to repent and turn. To tolerate what is evil is a parody of Christianity. We are instructed to judge our neighbors fairly and rebuke them frankly, but to do nothing that endangers our neighbors life. In this we would be loving our neighbors as ourselves; for we would not want anyone to tolerate what was evil in our lives nor to refrain from warning us against mistakes.

"To love your neighbor as yourself is more important than all burnt offerings and sacrifices", answers the scribe and in the opinion of Jesus, wisely. It is not our attendance at church, our baptism or our taking communion that provides evidence that we are Christians, but our love for our neighbor. This is why it is so important to love God with our minds. It would be easy to lay back and let the emotion of the hymns sweep over us; to lean back into a warm glow of beautiful music, great buildings, incense and art; but this would be to deny our understanding of the instruction love your neighbor. Loving your neighbor may be neither beautiful nor artistically satisfying. It is often excruciatingly hard and unpleasant. It may cost us money and time. It may upset our plans.

I left out part of verse 18 of Leviticus Ch 19. The full verse reads: Do not seek revenge or bear a grudge against one of your people, but love your neighbor as yourself. I am the LORD.

This is often the hardest part. Much of the weight we bear on our shoulders is made up of grudges. They are often the hardest things to dispose of, yet unless we do we will be ground down into despair and depression. So put your pride in your pocket and love your neighbor.

One last thing: evangelicals have reacted against the 'social gospel' ever since it became the only gospel of liberals who discarded Scripture. CS Spurgeon had nothing against giving his neighbor tracts, but he suggested we wrapped them up in a sandwich. By all means get your doctrine right, but Jesus commended those who saw the least of his brothers hungry and fed them, thirsty and gave them drink, naked and clothed them, without shelter and took them in, sick and looked after them and in prison and visited them. For those who failed to do these things, no matter how good their knowledge of doctrine, whether they were four or five pointers on the tulip scale, whether they had been baptized, confirmed or communicated, he said,"Depart from me, you who are cursed, into the eternal fire prepared for the devil and his angels."

Pretty intolerant of him wasn't it.

Saturday, June 23, 2007

Tony Blair retires

Well, not quite. He has a few days to go, but his all nighter at the EU summit was his last strut upon the stage. An interesting article in the Grauniad today attempts to assess his place in history.

Martin Kettle recalls a conversation between Dick Morris and Bill Clinton which ranked American presidents in the following way: In his first rank of presidents, Morris placed George Washington, Thomas Jefferson, Abraham Lincoln, Woodrow Wilson and Franklin Roosevelt. His second comprised Andrew Jackson, James Polk, Chester Arthur, Theodore Roosevelt, Harry Truman and Ronald Reagan. For his third rank, Morris nominated James Madison, Andrew Johnson, Grover Cleveland, John Kennedy, Lyndon Johnson, Richard Nixon and George Bush Sr. Clinton himself, Morris suggested, was "borderline third tier" - though this was a pre-impeachment conversation. The rest were nowhere.

In a similar way Kettle has attempted to rank British Prime Ministers: Since the 1832 Reform Act - and we have to draw a starting line - this country has had 30 prime ministers up to and including Blair (but excluding the Duke of Wellington's brief caretaker government of 1834). In chronological order, the following 16 have some claim, on various criteria, to be counted as outstanding PMs: Grey, Peel, Palmerston, Disraeli, Gladstone, Salisbury, Asquith, Lloyd George, Baldwin, Churchill, Attlee, Macmillan, Wilson, Heath, Thatcher and Blair. That means excluding (again in chronological order) the following 14: Melbourne, Russell, Derby, Aberdeen, Rosebery, Balfour, Campbell-Bannerman, Bonar Law, MacDonald, Chamberlain, Eden, Douglas-Home, Callaghan and Major.

If we use Morris's three ranks to sort the 16 survivors, then Peel, Gladstone, Asquith, Churchill, Attlee and Thatcher have claims to be in the first rank, doing great things in great times. In the second rank, I would place Grey, Disraeli, Baldwin, Macmillan and Heath (achieving great things in less compelling times). My third rank (great but mixed) would contain Palmerston, Salisbury, Lloyd George, Wilson and Blair.

As you might imagine, responders in subsequent comments had much to disagree with, but most surprising for a left wing newspaper there was almost universal condemnation of Tony Blair, in the view of some incomparably the worst British Prime Minister ever.

The views of Amery encapsulate the feeling.
1. Causing the death of 100,000s in wars of aggression.
2. Making Britain hated around the world, a curse handed down to our children, our children's' children, and probably longer.
3. Elevating lying, spinning and obfuscation to the central form of government
4. Destroying the health service and lying about it.
5. Taxing us by stealth, relentlessly and in ever-increasing amounts to fund his wars and incompetent schemes.
6. Corruption, the sale of honours and the "reform" of the house of Lords in favour of an appointed, not elected body so as to remove the last vestiges of independence.
7. The erosion of civil liberties - SOCPA, the anti-terrorist legislation (we are all terrorists now), the civil contingencies bill - a perfect legal framework for totalitarianism.
8. Fawning obedience to the catastrophic US foreign policy.
9. Fawning deference to Mr Putin and sundry dictators.
10. Fomenting the housing bubble and promoting the culture of debt.
11. Allowing the ultra-rich to pay no taxes while the rest of us pay more and more.
12. Laying the foundations for civil strife in the UK by giving Wales and Scotland their own elected bodies, but allowing none for England.
13. Welcoming the mafia to run casinos to leech the poor even more.

It might well be expected that Guardian readers would hate Tony Blair. There is no doubt that he has compromised the ideals of the left in order to get a left wing government elected.

Let's take the points in order:
1. Is he responsible for 100,000 deaths? Certainly not in the way that Hitler, Stalin, Mao Tse Tung or Pol Pot were responsible for millions of deaths. His interventionist foreign policy saved lives in Kosovo, Bosnia and Sierra Leone. In Afghanistan virtually every country in the world approved of the policy of getting rid of the Taliban. As for Iraq, there is a tendency to look back on Saddam era with rose-tinted spectacles. A case can certainly be made for the removal of Saddam on humanitarian grounds. The major failure has been in the lack of any effective plan for the reconstruction of the country after the war. It has to be remembered that the responsibility for this is primarily George Bush's rather than Tony Blair's but in his continued support for his ally he has certainly diminished his current reputation.
2. Now that is pure exaggeration. There may have been some anti-British feeling in the Eurovision Song Contest voting, but that will be temporary.
3. There is some merit in that charge. Manipulating the media was something that Sir Bernard Ingram, Lady Thatcher's press secretary, was was famous for, but Alistair Campbell took the art to a new low. I am not convinced that all his untruths were mendacious. The justification for the Iraq war was an exaggeration, but perhaps one deriving from genuine lack of knowledge rather than a deliberate lie. More telling has been the dissembling over tax increases. He criticised the Tories over stealth taxes, but his Chancellor has become the unchallenged king of the subject.
4. This is certainly not true. The NHS performs better than when New Labor came into government, but still suffers from the same problems that it had under the Tories - lack of funds. Billions have been invested but not enough. Expenditure per head has just about reached the level that it was in America in 1980. More tellingly, despite a promise to increase funding to the European average, as a proportion of GDP it has only just reached the level that Germany was at when Tony Blair made the promise 10 years ago. Undoubtedly the money is better spent than in any other health service, but nevertheless a lot has been wasted, on PFI, on management consultants, on endless rounds of reorganisations, on computer systems that don't work, on top-down regulations and on MTAS.
5. I have already mentioned stealth taxes. Until someone has the courage to raise income tax, surely the fairest type of taxation, all taxes will be stealth taxes. What is more worrying is the proportion of our money taken by the government to do their things which might not be our priorities.
6. Sleaze? This was why the Tory Government fell. New Labor has been far worse. It started with Bernie Ecclestone and has gone from bad to worse. Blair's biggest failing is his failure to sack people. Prescott should have gone. Blunkett and Mandelson should never have come back. Byers stayed too long.
7. Civil liberties is a very difficult problem. Most people feel that their liberties are being eroded, but undoubtedly the threat is much greater than it was, even when the IRA was active. I don't particularly mind that we have more CCTV cameras than the rest of Europe and I am quite happy for my DNA to be on record. I would happily have an ID card. I am not so sure about someone locking me up for 90 days without charge as the government wanted. Some of the problems are of the government's own making. Buying into the Human Rights Act without quibble and accepting unrestricted immigration and tolerating the growth of an unreformed Muslim community under the guise of multiculturalism have made matters worse.
8. A misjudgement surely. He thought he would be able to influence George Bush, but there is little evidence that this is so. I imagine that the Middle East has not worked out as he intended, but had he taken the attitude of say, Chiriac would anything have been different?
9. I'm not sure that this charge sticks. Putin is at the head of a state with vast oil wealth and nuclear weapons. He can do pretty well what he likes.
10. This one is off the wall. Immigration has been one great driver for this, but the other side of the coin is a vibrant economy. Fewer marriages and more singles - but how is that his fault? Low interest rates? Surely a good thing.
11. Again a product of a vibrant economy, and anyway down to the Prime Minister-in-waiting rather than TB.
12. I'll agree with this one.
13. And with this one.

All this has to be set alongside other things in his legacy.
1. He made Labor electable.
2. He sorted or helped to sort foreign wars in Kosovo, Bosnia, and Sierra Leone. After the disgrace of Rwanda this was crucial.
3. He contributed greatly to the peace in Ulster, though John Major deserves some of the credit.
4. He prevented the undoing of much of the Thatcher legislation that has been responsible for Britain's healthy economy. Many on the left were baying for this.
5. He introduced a minimum wage.
6. City Academies may not be perfect, but at least they go some way to address the problem of education.

It is too close for now to assess his long term legacy. Churchill would certainly not have been counted a success in 1939 and even in 1945 was unpopular enough to be thown out of government.

Borderline mutated

Although the difference between CLL with mutated and unmutated immunoglobulin variable region heavy chain (IgVH) genes is well established and this distinction is recognised as one of the most important prognostic variables, the choice of 98% as the limit of the unmutated subset was arbitrary, based on possible polymorphisms that might produce that degree of variation.

What is a polymorphism? Everybody is different. The difference between you and me is the sum of the polymorphisms in all our genes. The classic polymorphism is the difference between normal haemoglobin and sickle haemoglobin. A single amino acid switch from glutamic acid to valine at position 6 in the beta chain of haemoglobin is enough to cause a devastating disease. But every protein in the body is subject to such polymorphisms, though most of them are completely silent. Some will determine whether you are blood group A or O, or whether you have blue or brown eyes, or how long your ear lobes are. The immunoglobulin genes are no exception, but it presents us with a problem. How do we know whether a variation from the accepted sequence in a particular IgVH gene is a somatic mutation (as part of germinal center induced variation to improve antibody-fit) or a simple polymorphism. The obvious answer is to sequence the IgVH genes in a different tissue that isn’t subject to somatic hypermutation such as the neutrophils or skin fibroblasts. But that is a time consuming business and as a short cut scientists decided that it probably didn’t matter very much and decided that up to 2% sequence variation might be due to polymorphisms, so patients with more than 98% sequence homology would be regarded as unmutated.

Not everybody agreed on the 98%. A German group chose 97% and a British group 95% as a more appropriate cut-off. However, when David Oscier from our lab in Bournemouth decided to investigate this by looking at IgVH gene homology in leukaemic cells and granulocytes from the same patient, it became apparent that even small numbers of mutations were caused by somatic hypermutation rather than polymorphisms.

Individuals whose IgVH genes have only a few somatic mutations comprise a small proportion of CLL patients and until recently it has not been possible to study enough patients in this group to distinguish a different prognostic impact of choosing the threshold for unmutated status at >97% or >98% homology. A final difficulty is the discovery that the use of the VH3-21 gene is associated with a poor prognosis whether of not there are somatic mutations. This is especially problematic because such cases frequently have between 96 and 99% sequence homology.

In order to resolve these difficulties we have made a retrospective survey of 310 patients with CLL who have passed through our hands in the past 30 years and who have had their IgVH genes sequenced. We have compared outcomes of patients with different degrees of sequence homology. There were only four whose tumor used the VH3-21 gene, none of which fell in the disputed area of 97-98% homology; two had > 99% and two <97% sequence homology. Patients were observed until treatment was indicated because of symptoms or evidence of progression, and then treated according to best practice of the day; largely with chlorambucil prior to 1990 and increasingly with purine analogues or combinations including purine analogues since then.

There were 99 patients with 100% sequence homology, 22 with between 98 and 99.9%, 22 with between 97 and 97.9%, 24 with between 96 and 96.9%, and 143 with <96% homology with germ line genes. There have been 139 deaths of which 79 were determined to be unrelated to CLL. Survival curves are shown in figure 1. The median survivals, censored for unrelated deaths, were 102 months for patients with 100% IgVH gene homology; 132 months for those with 98-99.9%, 184 months for those with 97-97.9% and not yet reached for those with 96% or <96%. The difference between 100% and 97-97.9% was statistically significant (p=0.002) as was the difference between 97-97.9% and <97% (p<0.0001). However, the differences between 100% and 98-99.9% and between 98-99.9% and 97-97.9% did not reach statistical significance. The survival curves for those with 96-96.9% homology and <96% were virtually identical.

Using treatment-free survival as an alternative end-point gave very similar results. Median times to treatment were 35 months for 100% homology, 36 months for 98-99.9%, 156 months for 97-97.9%, and 272 months for <97%. The difference between 100% and 97-97.9% was statistically significant (p=0.001) as was the difference between 97-97.9% and <97% (p=0.0003), but the differences between 100% and 98-99.9%, between 98-99.9% and 97-97.9%, and between 96-96.9% and <96% were not.

The pattern revealed by this study is not a continuous gradation with survival increasing with increases in the number of mutations. Those with 97%-97.9% homology comprise a mixture of benign and malignant cases rather than a homogeneous group with moderate malignancy.

It is not understood how accumulations of somatic mutations affects prognosis in CLL. The initial explanation that in those with mutated IgVH genes the cells had passed through the germinal centre while the cells of those with unmutated IgVH genes had not seems unlikely to be true. Tumour cells from both types of patients most closely resemble memory B cells; both express CD27 and both are now thought of as antigen-experienced.

An alternative possibility is that the mutator mechanism is impaired in CLLs with unmutated IgVH genes. The anomalously high expression of activation-induced cytosine deaminase (AID), an enzyme necessary for somatic hypermutation and Ig class switching, in cases with unmutated IgVH genes may be implicated. It has been suggested that high levels of AID may result in loss of substrate specificity and the development of mutations in c-MYC, PAX-5 and RhoH genes which are associated with more aggressive forms of the disease. It would be interesting to see whether the level of AID correlates with the degree of somatic hypermutation.

Tuesday, June 19, 2007

Each to his own gout attack.

Bernard Manning the Manchester comedian is dead. He was a fat man of Jewish origin with a pudding basin haircut and long sideburns. His popularity peaked in the 1970s but he has been off television for past 20 years because his jokes were considered too racist and insufficiently PC for modern taste. Although, some have praised his comic timing, if you click on the Guardian Unlimited website you will find as much invective heaped on his memory as he unleashed upon 'Pakis', 'homos' and Guardian readers.

His act was a series of one liners that always shocked. One particular joke dates from the time of the Falklands war. "I see we have a couple of soldiers in tonight who fought bravely at Goose Green." The audience breaks into spontaneous and prolonged applause. Then he names them, "Carlos del Santos and Manuel Reyes."

He was undoubtedly offensive to many. But then, I find Billy Connelly offensive and Little Britain and Ben Elton and a whole host of 'alternative comedians'. Comedians by their very nature challenge the accepted norms. Staying in fashion is difficult. For years Benny Hill topped the TV audience ratings, but he suddenly fell out of fashion. Chasing semi-naked young women with Keystone Kops jerkiness was suddenly not funny. I watched a recording of Peter Cook doing his EL Whisty act the other day and I couldn't imagine how I found it amusing.

For me Yes Minister and Fawlty Towers have stood the test of time but precious little else has.

Bernard Manning? Well I remember laughing at him 30 years ago, but I hadn't seen hime recently. With comedy it is a matter of chacun a son gout. (with accents).

Sunday, June 17, 2007

Mark 12

Modern people, the worldly-wise, the smart set, fashionable icons, those in the know, power-brokers, the Establishment, they all have a little time for Jesus Christ. Notice the indefinite article. They don't dismiss him out of hand, but they have no time for his church, which, they believe, has misjudged him, mixed him up with mumbo-jumbo and been seduced by a narrow Pauline view of life. Paul is a great villain, a self confessed Pharisee who usurped Jesus's teaching of love and tolerance and substituted a legalistic, anti-sex, anti-feminine code that simply induces guilt where there should be none. Guilt is the great imprisoner of the human spirit. Jesus was a great and charismatic teacher, but he was honestly mistaken about many things, being a child of his time. One wonders how Jesus would confront these people today.

Actually, we know. The Sadducees were exactly that. They were the powers that be in Jerusalem. They hated the Pharisees. They lived for the moment. They believed that this life is all that there is, and while they would say that they believed in God, they believed that God's favor was shown by earthly rewards. Their very position in society was evidence that they were pleasing God. They thought a lot of Jesus; not that they believed all this stuff about miracles and the supernatural, but he was terrific at self-promotion. Look at the crowds following him. He was building up a power base to threaten their own. He had celebrity status. But they knew how to puncture his popularity; they saw his very belief in the supernatural as his Achilles' heel.

Although the Sadducees had no time for those mystical books like Isaiah and Daniel, they did believe in the Pentateuch, the first five books of Moses. They sought to catch him out with a question about the resurrection taken from Deuteronomy Ch 25, about the Mosaic Law that if a woman is widowed while childless, her brother-in-law must marry her to sire children on her in his brother’s name. They envision a situation whereby seven brothers all rise to this particular task and all are childless. “At the resurrection,” they ask, “whose wife will she be since all seven have married her?”

They seek to ridicule the idea of life after death. Jesus is short with them. “You are in error because you do not know the Scriptures or the power of God.”

They knew not the Scriptures because they had ripped great chunks out of the Bible, and their view of God was of a remote force who took little interest in the ways of men.

As most Christians know, CS Lewis has dismissed the idea that Jesus was ‘honestly mistaken’. You can only think that if you have never read the Bible. Read the Scriptures and it is plain that the Jesus of the Bible is either mad, bad or Lord. Either he knew what he was saying and was deceiving thousands of people in a most wicked way or he was a crazy as a man who thinks he’s a poached egg. Or else He is God Almighty.

“At the resurrection there will be no giving and taking in marriage. They will be like the angels in heaven.”

I am afraid that modern Christians are confused about life after death. They talk about heaven and see this as a sort of disembodied future, floating on clouds, singing hymns. No wonder, cynics think of hell as a much more interesting place, as a sort of lower pleasure gardens.

But the Bible teaches of a new heaven and new earth. It talks about a general resurrection. It talks about new bodies.

Now eschatology is not my specialty and I think that there are so many different interpretations of what the Bible says about the last things that I would hesitate to be support any definitive program of eventual happenings. But the Bible is very definite about a general resurrection. What our resurrection bodies will be like is not clear but both Paul (in I Cor ch 15) and John (I John ch 3) testify that it will be like Jesus’s resurrection body and that is good enough for me.

Belief in a future resurrection makes a lot of difference to the way you live. It makes you better able to bear the trials and tribulations of this life. We know of a certainty that our sufferings will end and a future is coming which is better by far. We know about laying up treasure in heaven. We know that we matter to God and He will vindicate us. We know that nothing, absolutely nothing, can separate us from the love of God. Without the hope of the resurrection we might curse God and die (as Job’s wife suggested). There are times in this life when God seems distant; when the enemies of God seem to have the upper hand. As we see the sufferings of Christians in Turkey, in Iraq, in Indonesia and many other countries, we can’t imagine why a loving God would allow it to happen. That’s because we are shortsighted. We do not see the bigger picture. We forget about the resurrection.

Don’t envy the rich and powerful; pity them. Pray for them. Remember that God takes no pleasure from the death of the wicked; rather he is pleased when they turn from their ways and live. Jesus was willing to die that the wicked might live. It seems that believers must continue to suffer to give them time to turn.

Some might be rather miffed that there is no marriage on this new earth. No marriage; no sex. What will be there is better by far. CS Lewis tries to picture it in his short book, The Great Divorce. He sees our new bodies as so much more substantial than our earthly ones. In one episode he traces the difficulty of an old earth body walking on new earth grass. The grass is so much more substantial it penetrates the old earth feet making walking there painful and next to impossible. It’s only a picture. I am content to leave the future to God, but I am reassured that he wants the best for me, because he sent his son to die for me.

Saturday, June 16, 2007

Two very short men

What to do on an overcast breezy Saturday? We decided to take a trip into deepest Dorset to learn about two very short men.

Cloud's Hill is the cottage owned by Private TE Shaw, the name chosen by Colonel Thomas Edward Lawrence in his attempt at obscurity following his World War I Middle Eastern exploits. Most people's knowledge of Lawrence has been gleaned from David Lean's famous film, Lawrence of Arabia. Lawrence was nothing like Peter O'Toole. First of all he was very short, only five foot five. He was also very strange. Believed to be a closet homosexual with sado-masochistic tendencies, he had a great affinity for service life. Before going to University (Jesus College, Oxford) he had run off to join the Boy Soldiers, so that his father had to come along and buy him out. He then joined up on three further occasions, rising to the rank of colonel as an intelligence officer in the war against Turkey, and post-war joining the RAF as Aircraftsman John Hume Ross and latterly the Tank Corps as Shaw.

He was a very clever man. A first in history at Oxford and a fellowship at All Souls are not easily come by. From the age of 12 he supported his own academic tuition by winning scholarships. He was also extremely well read. At Cloud's Hill the walls were lined with over 2000 books.

The cottage is still a primitive place, though it stands in large grounds overrun with rhododendrons and wild foxgloves. Lawrence never slept there - he slept at nearby Bovington Camp (where Prince William sleeps now) but the role of a private in the Tank Corps was hardly arduous and he found plenty of time to nip off on his Brough Superior motor bike to spend time at Cloud's Hill reading and entertaining friends. There was even a tiny guest room there with a bunk bed and a porthole window, that perhaps reminded him of life on board ship. EM Forster, a frequent visitor, used sometimes to sleep there.

There is some evidence that Lawrence was doing it up for his retirement. He was 46 when he died, and his life as an army private must have been close to being time expired. With his own hand he had laid on water to the cottage with a pump from a nearby spring. He had installed a bathroom (though no lavatory - he presumably used the army camp and the rhododendrons) with a modern bath and walls lined with cork. He clearly liked bizarre wallpapers - the walls of the bunk bedroom were lined with aluminium foil. His main living room was upstairs with a fine log fire. The downstairs rooms were the bathroom and a large reading room, which contained a large (unused) leather bed and a reading chair of his own design, with flat arms to hold a cup of tea. His tea set was of black local pottery.

If not ugly he was a very plain man, but also very vain. He kept changing his name to avoid the attention of the public yet he sought attention. There are many portraits of him (including one by Augustus John). The cottage contains an impressive bronze of his head. His biographers were famous friends, Robert Lowell, Robert Graves and Liddell Hart, George Bernard Shaw (a frequent visitor to Cloud's Hill)wrote a play based upon him, Too True to be Good and gave him a copy inscribed 'to private Shaw from public Shaw'. and Terence Rattigan wrote a play about him called Ross, and WH Auden's The Ascent of F6 was based on his character.

We climbed to the top of the hill overlooking the cottage. It is an unusual segment of British history, hard to find in the Dorset countryside, but worth the effort.

The second very short man we sought was George Loveless. A farm laborer, but despite the outside life and the hard work, he was only five foot four. It was not his cottage that we had come to see but the Martyr's Memorial Museum at Tolpuddle, a mere 3 miles from Cloud's Hill. On the main A35 Bournemouth to Dorchester road the Trades Union Congress has erected 6 cottages in memory of the six 'martyrs' and the block also houses an exhibition and a shop. Everything in the shop is incredibly overpriced, but I suppose with Union membership so low now, they need every penny they can get. Despite their being called martyrs, nobody died, and indeed one lived to the age of 90.

The story is well known. Beginning in 1770 the common land began to be enclosed by the gentry. Removal of their grazing rights impoverished the working man. The Enclosures Act appears in Patrick O'Brien's Captain Aubrey novels. Aubrey, a landowner, magistrate and MP as well as a sea-faring captain and scourge of Napoleon's navy, detested the Act and thought it oppressive to agricultural workers. As more and more soldiers were discharged from the Army after Napoleon was defeated labor became plentiful and wages fell. Enclosures meant more land to farm for the rich landowners and more employment, but still the wages offered of 9 shillings a week were insufficient to provide for a family. Men began to form Unions to demand more money, but the landowners, mindful of the French revolution reacted spitefully.

With the connivance of Lord Melbourne the Home Secretary local magistrate Frampton used an arcane Act against giving of oaths to convict Loveless and the others and sentence them to 7 years transportation to Australia. There was a national outcry against this misuse of power and following the suggestion that the King's own brother was guilty under the same Act (He was a member of the Orangemen who swore oaths that were similarly illegal), Lord Russell the prime minister eventually gave the men a pardon.

They returned home after 4 years, but felt unwelcome and 5 of the 6 eventually emigrated to Canada. The only one who stayed was eventually honored by the Trades Union movement in his old age. At this celebration he admitted that he never actually took the oath. He took the rap for his brother who was expecting his first child.

While reading about this I realized why there had been such an outcry recently about a proposal to house surplus prisoners in a ship moored off Portland. The Tolpuddle martyrs had been housed in the Prison ship, York, off Portsmouth before their deportation. History casts a long shadow.

Tuesday, June 12, 2007

Popular Culture

While my wife is reading Alistair MacLean for the first time I have been sampling Harlen Coben. These writers make no claims to literary excellence, but they certainly know how to get the reader to turn the page over. The problem with these books is that they tend to be formulaic. Take Dick Francis for example. His books feature a hero is an expert in some arcane field. He might be a photographer, a sculptor, a pilot of small airplanes, a diamond merchant etc, etc. Something in his job brings him into contact with the horsey world. Then there is a beautiful woman, also has horsey connections. For some reason she is vulnerable. Then there is a villain - usually a crooked bookie, owner or trainer. Our hero tries to rescue damsel in distress and gets beaten up for his troubles. However, using his arcane knowledge he understands the mystery, overcomes the villain and rescues the girl, with whom he is by now romantically involved. Story over, next time the hero can be a jockey.

In the Alistair MacLean books there is always a false friend, someone who appears to be on the side of the hero but all the time working for the opposition. There is also always something that isolates the characters, like a sabotaged radio. In the few Harlen Coben books I have read, the hero is unjustly accused of a crime. He is attacked by the villains but shows superhuman resource to fight his way out and then fight his way through a complicated plot that has baffled the police (who are at least in part corrupt).

So it is; popular authors hit on a formula that works and then replay it over and over again. When they step outside their genre disaster often beckons, as with John Le Carre's book The Night manager. John Grisham therefore is to be commended for The Painted House and Stephen King for stories like those filmed as Stand by Me and The Shawshank Redemption.

There is no reason that thrillers cannot be works of art. Raymond Chandler's books will always bear re-reading and I enjoy James Ellroy for more than just the plot.

I have just finished watching the first series of Lost on DVD. This television series embodies the same characteristics as the thriller. There is an overwhelming need to know what happens next. All the characters are stereotypes apart from the central character - the Island itself. The Island is allowed to step outside the expected, and this is what makes the series watchable. I mean, Polar bears?

Last night I watched Antonioni's Blow up on TCM. I first saw it 30 years ago in the middle of the 'Swinging London' era. At the time I was puzzled as to what it all meant. It got rave reviews at the time and a couple of Oscar nominations. Even Halliwell gives it two stars. Swinging fashion photographer, David Hemmings, takes some atmospheric shots in a fairly deserted London park, but one of the few people in shot, Vanessa Redgrave, demands the film. Fascinated by the lengths that she goes to, to retrieve the film Hemmings enlarges his pictures and sees what appears to be a murder taking place. Eventually, he returns to the park and finds a dead body there. The story is punctuated with episodes of sex and pot smoking, which at the time I thought irritating; something to justify the swinging London reputation thrown in gratuitously. Now I'm not so sure. It is these distractions which prevent Hemmings from doing anything about the murder. His studio is broken in to and the pictures stolen and when he returned to the park the body had been removed.

The film ends with a group of students in the park miming an imaginary game of tennis. One of the 'players' knocks the 'ball' outside the court. All the students look at Hemmings who obediently runs over and throws the 'ball' back to them. The metaphor is clearly to ask the question, "What is real and what is just in the imagination?"

But the movie says more. This lifestyle of sex, drugs and rock'n'roll is a blind alley which blurs the distinction between reality and non-reality and ends up in apathy. The bigger mystery is how this slim and boyish Hemmings turned into the fat and bloated Governor in Gangs of New York.

Sunday, June 10, 2007

Ps 82; G8; Mk 12

The meeting of the G8 gives Psalm 82 a particular resonance.

God presides over a great assembly; he gives judgement among the "gods".

The "gods" referred to here are the world's leaders.

How long will you defend the unjust and show partiality to the wicked?

Isn't this just how it is now? All over the world the rich line their pockets at the expense of the poor. In the news at the moment is the sale of warplanes to Saudi Arabia by BAC systems. It has been suggested that over the past 20 years this deal has meant that "backhanders" of 1 billion pounds have been paid to a Saudi prince in order to secure the deal, and that Tony Blair has quashed an investigation into the deal for fear of prejudicing the current phase of the deal.

Leaving aside the morality of selling arms to an autocratic regime, the notion that some matters and some people are above the law is extremely distasteful.

Last night, at long last, I got to see Martin Scorsese's movie, "Gangs of New York". Despite his obvious immorality, Bill the Butcher, at least as played by Daniel Day-Lewis was an engaging character, far more attractive than Leonardo Di Caprio's Amsterdam. He was entertaining and a natural leader, generous to his followers and intelligent. Yet his blatant and brutal murder of the newly elected Sheriff (Brendan Gleeson) in front of many witnesses displayed his arrogant contempt for the law. I don't care how many of these little people see me, I am above the law. The law in New York at the time of the Civil War was certainly corrupt, but no leader should set himself above the law.

Defend the cause of the weak and fatherless, maintain the rights of the poor an oppressed. Rescue the weak and needy; deliver them from the hand of the wicked.

In one sense Bush and Blair were trying to do that when they invaded Iraq and Afghanistan. I know that many other reasons both good and bad have been imputed to them. The best that can be said of them is that they were naive. The worst, that they were venal and woefully unconcerned for the lives of both our soldiers and their civilians.

But go back a term and we see Blair and Clinton intervening in Kosovo and eventually in Bosnia. They were commended for these interventions and blamed that nothing was done in Rwanda and earlier in Bosnia. Even now some are calling for armed intervention in Darfur.

Both Bush and Blair and even Clinton declare themselves as Christians. They will not have been unaware of the thrust of this Psalm, which is a common theme throughout Scripture.

There were many lessons to learn from the G8 meeting on the Baltic. Both Bono and Geldoff were disparaging about the results of the last commitment to aid the poor of Africa. Paradoxically it was the 'bad boys', the UK and the US, who were meeting their commitments while the 'good guys', Canada and Italy, under the socialist Prodi who were welshing on the agreement. (Interesting also that those who gave aid in the wake of Katrina were mostly Christian groups headed by the Salvation Army, with the secular humanists nowhere.) I can understand an argument that says that aid to Africa is wasted because it goes straight into the pockets of corrupt rulers and stunts the people's need to work hard to get themselves out of the mess; but to promise to give aid and then fail to keep your promises is particularly creepy.

The 8 richest nations naturally want to compete with one another to increase their market share. The whole point of a meeting like this is to define areas of truce. The developing (what a euphemism!) world can't compete and needs help. If the rich can do anything for the poor then number 4 needs to know that number 5 will not steal a march on him while he is being kind to number 174.

Sadly, verse 5 of Psalm 82 all too aptly describes the world's political state:

They know nothing, they understand nothing. They walk about in darkness; all the foundations of the earth are shaken.

Pop stars judge them. Newspapers judge them. History will judge them. Tony Blair has been touring the world seeking to secure his legacy. In the next couple of years, he, Bush and probably Putin will all leave office. It is not the judgement of history they should fear.

I said, "You are 'gods'; you are all sons of the Most High". But you will die like mere men; you will fall like every other ruler. Rise up, O God, judge the earth for all the nations are your inheritance.
Should Christians concern themselves with politics? That was the essence of the question put to Jesus in Mark chapter 12 verses 13-17. Is it lawful to pay taxes to Caesar? Jesus' smart reply was to ask to be shown a penny. "Whose image and inscription are there?" "Caesar's" "Render unto Caesar the things that are Caesar's and unto God the things that are God's".

Had he said no they would have evidence of insurrection, had he said yes he would have lost the love of the people. Cleverly he avoided that dilemma. But he also said more than that.

Some Christians have seen this as an order to compartmentalize their lives. You have your Christian life and you have your secular life and never the twain shall meet. Others have seen it as an instruction to strict separation. Keep out of the world. Don't vote, it only encourages them. Never get involved in politics. Stick to evangelism and worship. You should not have time for worldly things.

In my view, both attitudes are in error. The clue to understanding this passage is in the word 'image', sadly missing in the NIV. Caesar's image was on the currency, but where is God's image? You just have to look in the mirror. We are made in God's image, so when we give Caesar his currency, we give God what is carries his image, we give Him our lives, not in part but the whole. So there is no part of our lives that is off limits for God and there is no part of God's world that is off limits for God. There is no dichotomy between spiritual service and secular service. Ruth Graham reputedly had a notice over her kitchen sink which said 'Christian Services will take place here three times a day'. Billy's preaching was no more in God's service than Ruth's washing up. We can be a soldier, a missionary, a world leader, a preacher, a builder, a deacon, a carpenter, a Sunday school teacher, a mother or a floor scrubber to the glory of God. It is all God's world.

Some of the threats and persuasions that Christian leaders have used to influence politicians have given Christianity a bad name. If you are a Christian you don't have to be either right or left wing, but you do have to be honest, of good will, self sacrificing, truthfull, kind, loving, peace-loving, faithful, gentle and self controlled.

Saturday, June 09, 2007


I have discovered another site dealing with the way patients are ripped off by snake oil salesmen. Guardian columnist and doctor Ben Goldacre is a regular read for me but he has drawn attention to David Colquohoun's site. David is Professor of Pharmacology at University College, London. Recently, the Provost of UCL has cravenly asked David to remove his Improbable Science page from the University's server following a complaint from the husband of a purveyor of herbal remedies because David called her justification for her products 'gobbledygook'. For those who don't know University College is where Jeremy Bentham's body is preserved and was founded as a place where dissenters and others (those not members of the Church of England) could study.

SCAM is David Colquohoun's acronym for so-called Complementary and Alternative Medicine.

Friday, June 08, 2007

Linford Bottom

It is fifteen years since I gave up leading the Sunday School. Every year, about this time, we would take about 100 kids, aged 5 to 11, on the Sunday School Outing. Sadly, the word 'outing' now has a different meaning and taking so many kids to the beach or the country would mean that each of the leaders would have to be cleared by the police for any pedophile tendencies and we would, no doubt, have to pay a hefty insurance premium.

It used to be a day full of innocent fun. On alternate years we would take them to Studland beach and Linford Bottom. Studland beach is at the start of the Heritage Coastline which now has some sort of United Nations fame. "The World Heritage Site covers the 95 miles of cliffs and foreshore between Exmouth in East Devon and the southern end of Studland Bay in Dorset... The cliffs and foreshore contain a near complete record through 185 million years of the Earth's history in just 95 miles of coast. This is the best place in the World to see a complete sequence of rocks from the Triassic, Jurassic and Cretaceous Periods of geological time."

The area is famous for Mary Anning "the greatest fossilist the world ever knew." Anning is credited with finding the first specimen of Ichthyosaurus acknowledged by the Geological Society in London. She also discovered the first nearly complete example of the Plesiosaurus; the first British Pterodactylus macronyx, a fossil flying reptile; the Squaloraja fossil fish, a transitional link between sharks and rays; and finally the Plesiosaurus macrocephalus.

But it wasn't for this that we went to Studland; there are large sandy beaches with safe bathing and plentiful dunes for playing hide and seek. Alas, part of the beach has now been given over to nudists - not exactly the place to take Sunday School children.

Our other destination, Linford Bottom, has nothing to do with nudists. It is a site in the New Forest where a small brook meanders through what is largely grassland on the edge of an enclosure of trees. There, we would fish for tiddlers with a toy net on a piece of bamboo, start a continuous pick-up soccer match with coats as goal posts, take part in a treasure hunt in the undergrowth and eat hot dogs for tea.

Diane and I decided to try and find it again yesterday.

There is an easy way that the coach used to take, but I always used to drive there carrying food, primus stove, balls and hoops in my car. The way I took was shorter, but involved narrow country lanes, steep hills, blind corners and the occasional tractor. After one or two detours we found our way.

It was a warm and sultry day with an overcast sky. We walked for about an hour and a half, following the stream. There was much evidence of neglect. The banks of the stream had been eroded so that the path disappeared and in places the stream had taken an entirely different course. At one stage we left the stream and crossed into the forest. The style was impassable as it had been overgrown with brambles. An old oak had fallen and decayed with no attempt by the park rangers to clear up the mess. Everywhere the sward was encroached upon by fern, holly and bramble.

We used to walk up to a small wooden footbridge that crossed the brook and then we would walk back on the other side. We found it again, but the bridge now spanned a dry stream bed. The new brook was fifty yards to the right of the bridge.

We walked back by a slightly different route keeping to our side of the stream. The trees were mainly oak and holly. Although it hasn't rained here for ten days, there were deep puddles and mud churned up by mountain bikes, motor bikes, quad bikes and galloping horses. We felt that the place had lost the sparkle that we remembered. Perhaps without the children it had became a dead, decaying wasteland. Then in one tangled thicket a rabbit scooted across our path and we found ourselves in a dark clearing surrounded by the most fantastic and grotesque trees. One particular holly had so many different stems, twined and twisted around each other, like one of those metal puzzles we used to get in Christmas stockings. An old oak had sent out dead, grey arms, bare of leaves at the height of our heads, but growing briskly above us. Here we felt the trees were a conscious, ominous and sinister presence, like glowering Ents, angry at being disturbed. There was no welcome here, but a chilling hostility.

In the distance a smear of pink and we hurried towards it. Caught up in a holly bush was a dog rose, simple, single rose flowers, then another, then a whole dog rose tree; suddenly there were wild flowers everywhere - daisies, buttercups, celandine, violets and then a small bright blue flower that we did not recognise. (At home we thought it resembled 'Alkanet' when we looked it up.) From death into life: our mood was instantly raised.

There were several other cars parked next to ours when we returned, but still no children. You can never go back.

Tuesday, June 05, 2007

Once a path through the woods

One of the joys of living in Bournemouth is the proximity of the New Forest. As most people know, the 'New' is an affectation. It has been there at least since William the Conqueror - indeed his son William the 2nd, was killed (murdered?) there in a hunting accident.

On Saturday, after a tough week for both of us, we decided to go for a walk. We really had no idea where we were going, but we drove off in the general direction of the forest. After about 20 minutes we parked in a little bay called Broomy Walk and started walking. It was a shirtsleeves day and the broadleaved trees provided welcome shelter. Oak, holly, birch, oak again and again and again; you can imagine what a resource this was when King Alfred was building a navy to defend against the invading Danes.

It was easy walking. We tried to identify the birds by their song, but even when we saw them we couldn't recognise them. We have tits and blackbirds, robins, thrushes, jays, magpies, crows, woodpeckers and doves in our garden, but these were not any of those. Blue tits have laid in our nesting box for the second year and we talked about having a larger box next year to attract larger birds. I suggested a huge one with a dead rat in it to attract vultures, but this did not go down well.

We occasionally saw a human or two. They were generally ancient specimens like ourselves seeking the solitude. We imagined what the beaches must be like only 10 miles away. Bournemouth beach is one of the most beautiful in England, but once the crowds descend the aroma of suntan oil drives us away.

We found ourselves in a grove of beech trees. We noted that the casts were green and still on the trees. It was a delightful place; the sunlight was speckling through gaps in the verdure overhead. Above all it felt a place of safety. We spoke about how fortunate we were to live in a land without predators. No snakes to bite us, no wolves or bears, though once they would have lived in this forest. No wild boar, no poisonous spiders; the New Forest is famous for its wild ponies, but their only danger is that they are unafraid of motor cars.

Just then a roe deer ran across the path in front of us. I half expected to hear the whoosh of an arrow from some past king's bow, but it pranced on unconcerned as if there were nothing to fear. And then it was gone.

We walked back to the car. Whatever weighs on our shoulders life will continue.

Sunday, June 03, 2007


DAPK1 stands for Death Associated Protein Kinase 1. Technically, DAPK1 is an actin-filament-associated, calcium calmodulin-dependent, serine/threonine kinase that promotes apoptosis in response to various stimuli including Fas, interferon gamma and TNF alpha. No, I don’t understand all that either. In layman’s terms it is one of the normal proteins in a cell that plays a part in killing cells at the end of their natural lifespans. There are very many of these and ‘apoptosis’ or ‘programmed cell death’ is a very complex process. In fact there are whole scientific journals that are devoted to it. It has been known for a very long time that in CLL there is something wrong with the apoptosis mechanism. Cells don’t die when they are supposed to.

This is not the only thing wrong with CLL cells; they also seem to divide more rapidly than they ought to – at least in those with unmutated IgVH genes. The cause of the failure to die when they should is one of the most investigated puzzles in the whole of CLL science. Most attention has been paid to BCL-2. This is a protein that opposes apoptosis and is present in increased amounts in CLL cells. We also know that in the related disease, follicular lymphoma, they increased amounts of BCL-2 are caused by the chromosomal translocation that is characteristic of the disease: t(14;18) puts the immunoglobulin promoter region next to the bcl-2 gene. (A promoter is a bit of DNA that carries the message ‘make a lot of’. Instead of saying, “make a lot of immunoglobulin” it says, “make a lot of BCL-2”). But that is not the reason for the increased BCL-2 in CLL.

There are other apoptosis related proteins that are abnormal in CLL. Other members of the BCL-2 family such as anti-apoptotic proteins BCL-XL, BAG-1 and MCL-1 are overexpressed, while pro-apoptotic proteins like BAX and BCL-XS are underexpressed. DAPK1 is a pro-apoptotic protein that previously been little studied, but a paper by Nagy and colleagues in the British Journal of Haematology in 2003, mentioned that was underexpressed in CLL patients with del 11q23.

Yesterday, an important paper appeared in Cell (all papers in Cell are important) concerning the importance of DAPK1 in CLL. The paper comes mainly from OSU in Columbus Ohio, with contributions from several other institutions in America, Germany, Sweden and England. To explain what it says I must explain about methylation.

DNA methylation is a type of chemical modification of DNA that can be inherited without changing the DNA sequence; it is one of the epigentic mechanisms that controls how DNA functions. It involves the addition of a methyl (CH3) group to DNA, usually to the carbon atom at position 5 of the Cytosine pyrimidine ring. Characteristically it occurs at a cytosine-phosphate-guanine (CpG) sequence.

The importance of DNA methylation is that it silences the gene. In Man about 1% of DNA bases are methylated, but about 60%-70% of CpG sequences are methylated. Unmethylated CpGs are grouped in clusters called "CpG islands" that are present in the 5' regulatory regions of many genes. These are the gene promoters and if they can be switched off the gene is not translated. In many cancers some of these CpG islands get hypermethylated, silencing the promoter regions for ‘tumor suppressor genes’

Previously studies have uncovered almost 200 abnormally methylated genes that are silenced in this way in CLL. In this study the DAPK1 was silenced in this way in 60 out of 62 cases of sporadic CLL.

Even more interesting was their study of a family in which multiple members had CLL. They were able to study DNA from 3 members of the third generation and three members of the fourth generation. First they identified a region on chromosome 9 which had the greatest linkage to the appearance of CLL.. This area of the genome contains 3 known genes and 11 predicted genes. Among the known genes is DAPK1, and based on what was known of DAPK1 it was decided to concentrate the study on this gene. They started by sequencing this area of the DNA from fibroblasts taken from affected and non-affected family members. Note these were fibroblasts, not CLL cells, because they wanted to look for DNA differences that they were born with rather than ones acquired in the leukemia cells.

By a series of very intricate experiments they were able to compare in an affected individual, the DAPK1 gene on the normal chromosome 9 and the DAPK1 gene on the chromosome 9 that carried the inherited CLL in this family. They found a lot of differences – 281 in fact. These differences were single nucleotide polymorphisms or SNPs. This means that one nucleotide base – an adenine (A), cytosine (C), thymine (T) or guanine (G) – is substituted for another. However, polymorphisms are extremely common. Whether you have blue or brown eyes, fair or dark hair, blood group O or A, ear lobes or not and many other physical characteristics are cause by SNPs. Generally, they are harmless and they are well known. In this case, almost all the 281 SNPs could be eliminated as well known ones that had no malign affect, but there were 4 possibles that could be the reason for inheriting CLL. One of these, and A to G switch at position c.1-6531, was not found in 383 control samples from the US and Northern Europe, but among 263 cases of CLL from the US and Northern Europe one patient was found with the same polymorphism. This patient from Scandinavia had the SNP in both CLL cells and T cells, so presumably this was something he or she was born with, but there is no suggestion that thispatient is related to the American kindred nor any other familial cases. However, no-one knows whether they have long lost cousins back in Europe.

An important control was to look for this SNP among patients with familial CLL. They looked at 75 patients with CLL who had at least one other family member with the disease, but they didn’t find it. This means that although in this particular family this particular polmotphism predisposes to the development of CLL, and although the gene is aberrantly switched off in CLL cells in sporadic cases, it is not implicated in the majority of cases of familial CLL.

They next investigated how the A to G switch manages to reduce DAPK1 expression and it turns out that this switch increases the affinity of DAPK1 for HOXB7, a transcription factor that normally opposes the expression of DAPK1.

To summarize: John Byrd and his colleagues at OSU have identified a gene that is mutated in one family with CLL. The mutation inactivates this gene. But this is not the abnormality in most families with CLL. However, most cases of sporadic CLL also have this gene inactivated, but by an epigenetic mechanism rather than by a hereditary mutation. There is a plausible hypothesis how inactivating this gene could lead to CLL, but it is only one of 200 epigenetically silenced genes in CLL. Several other genes involved in apoptosis are also switched on or off in CLL, sothe full picture has yet to emerge.