Monday, July 31, 2006


Sarah Harris was my mother’s mother’s mother. She was Jewish. My sister used to pass for Jewish when she worked in the rag trade. Sophie Harrod was my wife’s grandmother. We believe that she was Jewish too. Although I am tallish, fair and blue-eyed, I could be admitted to settle in Israel, as Jewishness is carried down the female line.

Both our families are Christian. It was common for British Jews to convert – Benjamin D’Israeli is the best known example.

Many of the best haematologists in the world are Jewish. Most of them are my friends.

Leith Samuel was a famous Christian preacher. He became a friend when I had the great privilege of looking after a member of his family. His name tells you he was Jewish.

Jesus Christ was Jewish. So were St Paul, St Peter, St John, St Matthew, St Mark, St James, the virgin Mary, Mary Magdalene, Moses, Joshua, Isaiah, Jeremiah, Daniel and the rest.

Mel Gibson made a film about Jesus called The Passion. At the time it was derided as anti-Semitic. I must say it didn’t seem so to me. Almost all the characters were Jews apart from Pilate and a few Roman soldiers. True, the Jewish high priests are shown in a bad light, but it would hardly be true to life if they had been shown as misunderstood heroes. I thought that most of the film was Biblical, though there were some interpolations from Roman Catholic mythology that didn’t fit with my understanding of the gospels. The St Veronica story, for example, is extra-Biblical. The scourging of Jesus was particularly vivid and I think was overdone. As I understand it Roman law limited the strokes to 39. I guess the point was to exaggerate the physical suffering because although Christians believe that the greatest suffering came from the dereliction as son was separated from father, it is hard to portray that in a film. Gibson had Satan (was it Tilda Swinton who played the Archangel Gabriel in Constantine?) flitting around among the crowd and merging with them. I didn’t object to that. It might have been dramatic license but I took home the message that all of us are responsible; there is no-one who would not have been baying for his blood. I certainly did not see it as getting at the Jews.

Now Gibson has been arrested for drunk driving and responded by insulting Jews in a foul-mouthed and aggressive manner. It has been a signal for more accusations of anti-Semitism. In vino veritas. Perhaps. There has been a long history of the Roman Catholic Church blaming the Jews. God-slayers, they were called. It is one of the things I have against them. As if Italians would not have been in the crowd egging on the soldiers, or the Boston Irish, or Spaniards, or South Americans, or Australians. Or Church of England old ladies for that matter.

The teaching of Christianity is, “All have sinned and fallen short.”

On a more serious matter the bombing of Qana produced a brief hiatus in the bombing. I was wrong last week to think there might be an early end to this war. Israeli public opinion is right behind their government. Hezbollah are not going to stop fighting, and they are winning the propaganda battles. Eventually, the Israelis will win militarily unless the US starves them of supplies, but even that might take some time, and at present there is little evidence that they will try. Israel might well think that they might as well be hung for a sheep as a lamb. They are pretty immune to world opinion, care nothing for the Arab street, will soon be secure behind their wall, so why should they worry?

On BBC2 tonight there was a discussion between three London Jews. One concentrated on the suffering of Palestinians in Gaza and of the Shiite children in Qana. One concentrated on the danger to Israelis in Haifa. The other felt that the activity of the IDF in Gaza and the West Bank was indefensible, but could understand the reason behind the Lebanese incursion. It may be tactically wrong but it is understandable. You can always rely on the BBC for ‘balance’.

Would the RAF have been stopped from bombing Germany had pictures of children dying in Hamburg been broadcast around the world?

Would the Nazis have sent V2s on London had pictures of mutilated schoolboys been published in Berlin?

Leaving aside the geopolitical ambitions of Islamofascists, it seems that there is a serious point of dispute at the bottom of this. There are some farms of about 40 square kilometres occupied by Israel, which were part of Syria before the 1967 war. Hezbollah wants them to become part of Lebanon.

Can you imagine the negotiations?

I know we said that we wanted to wipe every Jew from the face of the planet, but if you let us have our farms back we will cease hostilities.

No? How about half the farms?

OK! Final offer. A third of the farms and green stamps.

Sunday, July 30, 2006

On the water

Another book to try is "On the water" by HM Van Den Brink. Really, its a short story of only 130 pages. Set in Holland in 1938 and 1939 it tells the story of working class teenager who joins a rowing club and is partnered with another young lad called David. Together they train and improve under the guidance of their gruff and idiosyncratic German coach.

Of course, we realize that middle-class David is Jewish and that war is on the way. there will never be a 1940 Olympic Games. But young Anton, the little Dutch boy, doesn't read newspapers or listen to the radio. This is a rites of passage book beautifuly told in terms of the young rowers. The descriptions of the boat, the water, the rigor of the training, the excitement of the competition; are all used to flesh out the growing relationship between the two boys.

It is not an easy read, but it repays the effort.

Saturday, July 29, 2006

Freddie Trueman

I've had a chance to watch the cricket this week. Despite being without Michael Vaughan and Freddie Flintoff England are doing well. What I particularly noted is how the young cricketers are emerging. Tim Bell and Alec Cook have appeared hard on the heels of Andrew Strauss and Kevin Pietersen. And this is how it should be. I think that international teams rely too much on a settled side.

The England football team continued to pick Michael Owen and Frank Lampard when they had clearly lost form. Form is temporary, they say, class is permanent. Nonsense! These are all well trained, excellent athletes. Especially in cricket, technique is most important and then confidence. Loss of form is usually due to loss of one or the other. Loss of technique is usually best sorted out by a spell in the nets with the coach. It can be as simple as a slight change in grip or a new movement of the head. They can learn from golfers how exercise to strengthen a particular muscle can put it right. Confidence comes from character. Some have it; some haven't.

I have been impressed by Tim Bell. Last year he seemed to have no self-confidence. This year, having regained his place in the team because of Freddie's injury, he was determined to take his opportunity. Yesterday's innings showed he had the class; now he has the confidence.

I was impressed with Alec Cook's century for a different reason. His innings wasn't the most fluent you will ever see, and he should have been out LBW twice had the umpires had the use of the electronic media, but he seems to have taken the advice of Gary Player. I heard him on the radio saying that there is no past and no future on the golf course, only the present. What he meant is that there is no point in brooding over the last mistake or setting your sights on a future good score. You must play every shot for itself. Cook did this in a way that Jones, the wicket keeper, did not. He needs a spell on the bench to find his game. There are others who deserve a chance.

I think in the past players have felt that once they achieved a place in the team they had become a privileged player. They became over cautious, afraid to make a mistake for fear they would lose their place. If there were more fluidity, then fear would be less of a factor. Selectors need to be able to pick a team for particular oppositions, venues and climatic conditions, without being afraid of upsetting an incumbent. The best football teams at the recent World Cup weren't afraid to change their teams. Josee Mourinho has success with Chelsea because players have to fight for their place in the team.

The recent death of Freddie Trueman reminded me of the England team of the 1950s: Richardson, Cowdrey, May, Graveney, Bailey, Evans, Trueman, Lock, Laker, Statham.

Fifty years ago Jim Laker took 19 Australian wickets in the Manchester test. Perhaps England are due for a similar period of cricket supremacy.

I guess for most cricket fans Trueman was best known as a curmudgeonly commentator on the radio, with his Yorkshire vowels and his contempt for the pampered young of today. Those of us who saw him bowl remember a fiery thoroughbred in full flight, eyes flashing, black mane strung out behind him in the wind with a perfect side-on action. They remember an athletic snapper-up of chances in the leg-trap. They remember a no-nonsense hitter with a true eye. Here was the bulldog Englishman, afraid of nothing, blunt and forthright. He was the first to take 300 wickets in Tests. When asked if he thought anyone would beat his record, he replied, "If they do, they'll be bloody tired."

He had a famous Northern wit. "That was a very good ball, Mr Trueman," said the defeated batsman from Cambridge University. "Ay; wasted on the likes of thee, lad," was the reply.

He continued playing until the age of 38. His pace had slowed, but he was able to swing the ball either way and his knowledge of tactics was second to none. He could think you out.

He was appalled by the modern game. He detested limited overs cricket played in colored pyjamas. He was one of the last of the flannelled fools who played the game for love not money. He was also a muddied oaf, but his version of football was soccer not rugby; he played for Lincoln City while he was doing his national Service. A strange coincidence as his great successor, Ian Botham (who certainly did not see eye to eye with Fiery Fred) also played soccer for a Lincolnshire club, Scunthorpe United.

I have on my study wall a signed photograph of the Australian tourists of 1938. the team included Bradman of course, but also Fingleton, Fleetwood-Smith, Barnes, O'Reilly, McCabe and Hassett. The picture was given me by Captain Thorpe who captained the Oriana, the ship that brought them to England. Lindsey Hassett captained the 1953 Australians, Richie Benaud's first tour and a side that included Lindwall and Miller as well as Neil Harvey and Alan Davidson. I had a signed photo of them too at one time but my little brother destroyed it. For a while about this time Freddie Trueman was displaced from the side by Frank Tyson, an even faster bowler, but he didn't have the staying power.

Friday, July 28, 2006

Matthew Hervey

My relaxing time has enabled me to read two books by Allan Mallinson. Brigadier Mallinson is a serving cavalry officer in the British Army (nowadays the cavalry drives around in tanks and other armored vehicles). He originally trained for the Anglican priesthood before pursuing a successful military career. He has seen action in Cyprus, Malaya and Northern Ireland, and more recently piloted a desk.
"A Regimental Affair" and "A Call to Arms" follow the career of Matthew Hervey (pronounced Harvey) whom we first met at Waterloo. We follow him through a period with the Prince Regent in Brighton, then facing the Luddite uprising in Nottinghamshire and on to the aftermath of the Canadian war with America. We see him as a civilian again in Italy and then joined up once more in Bengal.

Mallinson has a feel for the early nineteenth century. We meet historical figures like Shelley in Rome, Henry Hunt, the radical politician and presider at Peterloo, and John Keble, the founder of the Oxford movement. We understand what it meant to belong to a regiment. We see the Christian virtues of loyalty, respect, self effacement and continence. We learn about leadership and tactics.

I learnt new words. Glebe - land going with a clergyman’s benefice; orlop - the lowest deck on a three deck ship; vidette - a look-out (from video, I see.)

The blurb says he is the natural successor to Patrick O'Brian.

He is certainly a refreshing change form Bush and Bin Laden.

Destruction of the UN outpost

Why did Israel continue to attack the area around the UN outpost in South Lebanon? Apparently the UN warned the IDF on 10 occasions that they were getting very close to destroying it. Eventually four UN Observers were killed. Kofi Annan was furious. The Israeli PM apologized. But this outpost was well sign posted. It was prominent. It had been there for about 30 years. Israel has very sophisticated weapons. Sorry, I just don't buy it as a mistake.

Reframe the question: why would the IDF want to destroy the UN outpost?

Possibility #1. Hezbollah were using the outpost as a shield. This would fit with what we are told about their tactics. It is said that they fire their rockets from civilian areas; that they store them in the basement car parks of apartment blocks; that they use schools, hospitals and mosques to hide behind. Why not a UN outpost?

Possibility #2. The UN was complicit in the Hezbollah attacks. One of the UN soldiers was from China. The rockets are purportedly made in Iran from a Chinese design.

Possibility #3. The IDF are not as good as their reputation suggests. Like the US army they have become too reliant on technology. If NASA can make an error in putting a satellite on one of Saturn's moons, surely laser guided bombs can hit the wrong target. After all did not the US 'mistakenly' take out the Chinese embassy in Belgrade?

I take no sides over this. On the whole 'cock-up' is to be preferred to 'conspiracy'. But perhaps conspirators take advantage of that.

Tuesday, July 25, 2006

Holiday thoughts

I'm on holiday. I have spent most of today sitting in the sun in my garden reading a novel. It is a reward for yesterday's activities which were physical. I had to repair a water-damaged ceiling and paint it. Then I had to sand down and repaint an upright on our porch. A break from being hunched over a keyboard being spent on physical activity was welcome. Today I have been lost in the nineteenth century British army fighting smugglers, Luddites and American Indians, as they used to be called. But I shall save my thoughts on Alan Mallinson until I have completed the two books I am reading back-to-back.

There is an interesting paper on familial CLL in the most recent Blood to arrive. It implicated the ATM-CHK2-BRCA2 pathway, which I have mentioned before.

The weather now is very pleasant. Warm and sunny without the oppressive heat of last week; this is about perfect.

I am slowly working my way through the BBC Sherlock Holmes starring Jeremy Brett (remember him from My Fair Lady?) and Edward Hardwicke. The sense of period is delightful, and Brett plays the part like a dancer; studied mannerisms and delicate footsteps.

I have a terribly guilty feeling that I ought to be doing something.

Saturday, July 22, 2006

Monoclonal antibodies 4

George Weiner from Iowa also took as his beginning the fact that polymorphisms of the Fc gamma III receptor (which for ease I will now call CD16) influences response to rituximab in follicular lymphoma and Waldenstrom’s macroglobulinemia and also active immunization with idiotype. NK cells with the high affinity polymorphism are better at ADCC.

Weiner’s group demonstrated that antibody-coated tumor cells modulated CD16 on NK cells, and activated the NK cell as indicated by the upregulation of CD54 and production of interferon-gamma (CD54 is ICAM-1; it mediates cell adhesion by binding to integrins). All these activities are greater for the high affinity polymorphism. As well as mediating ADCC these changes might enhance other immune effects on the target.

They next used molecular means to vary the structure of anti-CD20 antibodies. AME-B showed higher affinity to CD20 and AME-D showed higher affinity to both CD20 and to CD16, (AME stands for Applied Molecular Evolution, a company founded to do just this.)

They demonstrated that AME-D performed better than AME-B or rituximab in the following ways: it induced CD16 modulation, upregulated CD54 on NK cells, and more effectively induced ADCC at lower concentrations of antibody, irrespective of the CD16 polymorphisms of the NK cells. Moreover, this superiority was seen when CLL cells were used as targets (rituximab was unable to induce ADCC of CLL cells under the same conditions). Alas in a mouse xenograft model where Raji cells were grown in immunodeficient mice, no difference was seen between the efficacy of AME-D and rituximab in inhibiting the growth of the cell line.

A second section of the talk dealt with the immunostimulatory effects of CpG oligodeoxynucleotides (ODN). Bacterial DNA is known to be stimulatory to the immune system. Bacterial plasmids are utilized as DNA vaccines. Arthur Krieg from Iowa noted that synthetic ODN containing CpG dinucleotides are even more immunostimulatory.

Weiner’s group demonstrated that incubation of CLL cells with CpG ODN upregulates CD20 and antigen presenting and costimulatory molecules like CD40 and CD80, and enhances expression of both ligands and receptors from the TNF family including Fas, FasL, TRAIL, and TRAIL receptors, which are necessary for the non-mitochondrial pathway of apoptosis. In some samples apoptosis of the CLL cells was induced. Finally, the IL-21 receptor was upregulated.

IL-21 is a regulatory cytokine that increases the activity of NK cells and cytotoxic T cells (CTLs) in killing tumor cells. In vitro analysis of combination treatments demonstrated.

Weiner has demonstrated that IL-21 plus CpG ODN are synergistic in their ability to induce apoptosis of CLL cells. CLL cells treated with IL-21 plus CpG are able to kill untreated bystander cells. They can induce CLL cells to produce functional Granzyme B that is responsible in large part for the observed bystander effect. Antibodies against the B cell receptor plus IL-21 are also synergistic in CLL cells for their ability to induce Granzyme B production and apoptosis and they can induce Granzyme B production by other B cell populations including lymphoma lines, EBV lymphoblasts, and benign B cells.

Granzyme B is a 32-kDa serine protease that is a constituent of the cytotoxic granules in NK cells and CTLs. It is one of the fastest and effective executioners of apoptosis known.

Clearly, the idea of making CLL cells their own executioners is very exciting. CpG and IL-21 are very exciting molecules for CLL patients.

I have delayed writing about this presentation, in deference to George Weiner, as much was unpublished. However, the last of the papers is now e-published in Blood here and here.

Some of the other details have already been published at

Jahrsdorfer et al. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol. 2005;77:378-387.

Jahrsdorfer et al. Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity. Leukemia. 2005;19:759-766.

Jahrsdorfer et al. Serum alters the uptake and biologic activity of CpG oligodeoxynucleotides in B cell chronic lymphocytic leukemia. Oligonucleotides. 2005;15:51-59.

Jahrsdorfer et al. B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res 2005;11:1490-9.

Finally, finally we had an excellent presentation from Chaya, which I don’t need to summarize because she has already posted a full version of it here.

Sieze the day

I am indebted to fellow blogger Alan Sullivan for drawing my attention to this site. It is an erudite criticism of the sieze-the-day mentality. It is not the alacrity of the activity that he complains about, but what it is that is siezed.

He discusses the famous Robert Herrick poem, 'To the virgins':

Gather ye Rose-buds while ye may,

Old Time is still a flying:

And this same flower that smiles to day,

To morrow will be dying.

The glorious Lamp of Heaven, the Sun,

The higher he's a getting;

The sooner will his Race be run,

And neerer he's to Setting.

That Age is best, which is the first,

When Youth and Blood are warmer;

But being spent, the worse, and worst

Times, still succeed the former.

Then be not coy, but use your time;

And while ye may, goe marry:

For having lost but once your prime,

You may for ever tarry.

This, if anything, is an injunction to sieze the day. But that interpretaion fails to contextualize the poem. Herrick was an Anglican priest, writing at a time when evryone was a Christian. Note that he does not inveigh the virgins to sleep around, but to marry.

If it were a simple folk song, we would not hold Herrick in such high regard. We must catch the allusions. Where would an Anglican pries go to for his references? Where else but to the King James Bible. We have virgins and a lamp. Obviously we are taken to the parable of wise and foolish virgins. The poem is a parable, and like all parables it is parabolic, its outside meaning cntains a hidden truth.

Jesus spoke in parables for a reason, "Unto you it is given to know the mystery of the kingdom of God: but unto them that are without, all these things are done in parables: that seeing they may see, and not perceive; and hearing they may hear, and not understand" Mark 4:11-12.

The poem advocates early marriage. But marriage to a clergyman of the Church of England meant more than a sanctification of sex. The marriage of a man and a woman is an image of the heavenly Marriage of Christ and His Church.

The parable of the wise and foolish virgins has them waiting for the appearance of the bridegroom; parabolically the second coming of Christ. The spiritual meaning of the poem is therefore to urge us to convert to Christ while we are young since if we wait too long, we "may for ever tarry."


Arthur Koestler had CLL. He also developed Parkinson's disease. In my first 200 patients with CLL nine also had Parkinson's disease. Two of them developed their Parkinson's aftere a particularly severe attack of shingles.

I wonder if any of my rare readers has had a similar experience?

Darkness at noon

Not the Arthur Koestler anti-Stalin novel, but St Matthew's Gospel 27:45 "Now from the sixth hour there was darkness over all the land until the ninth hour".

Attempts have been made to explain how this could be. Suggestions have been made that this was an eclipse of the sun; though this is impossible because the crucifixion took place at Passover, a time of a full moon.

Here in Bournemouth we have been enjoying a hot and sunny July - the rain the other day was but a brief respite. Today at noon the sky went black. We had an eclipse of the sun here a few years ago, the last one in my lifetime. The sky was never so black then as it was today.

The darkness at noon did not herald the graves giving up their dead, but a tremendous thunder storm. The road outside my window is under water. The other night I watched an item on the news where a fireman in California was hosing down a forest fire. Comparing his hose with the one that I had used earlier on the garden, I wished for one of similar force. Today the garden has been watered by what I call a hosepipe.

Wolves Eat Dogs

I have just finished the latest Martin Cruz Smith novel, Wolves Eat Dogs.

We first met the Russian detective, Arkady Renko, in Gorky Park, what must be 20 years ago. Since then the Cold War has ended and the Soviet Union has been dissolved. This story is set in a Russia of the Oligarchs, a Russia where the same KGB thugs thrive as bodyguards or run protection rackets, where the government functionaries still accept bribes (as sinecures in the great companies), where the average Russian lives a life of hopelessness relieved by vodka and where Renko displays his Presbyterian temperament among an orgy of Orthodox extravagance.

Incorruptible, plodding, lacking in imagination, Renko sees everybody as damaged goods.

The story opens with the apparent suicide of one of the oligarchs. Renko's bosses do not want an investigation. There are plenty of motives for murder, but an investigation would affect the share price. Something smells wrong to Renko, but he is ordered off the case. When the number two in the company is found dead in Chernobyl Renko is sent to investigate. As a Russian investigating with no authority in the Ukraine, now a foreign country, Renko is expected to find nothing. He is lied to, obstructed, threatened and seduced by the atmosphere. Although the area around the abandoned power station has been quarantined the older villagers have returned to take up their old life. It is an area rich in agricultural plenty with much to harvest. Only the shellfish and the mushrooms are particularly radioactive.

He we see a Russia of the peasants, making the best of their life, recognizing that everybody is damaged goods, why should the land be any different?

As a metaphor for the opacity of the case, Renko has become involved with a young orphan in the care of the social services. He takes him out at weekends to the sort of places that divorced fathers take their children and he tells him fairy stories. He plays chess with him, but the child always easily defeats him. The child won't speak to him, but when Renko is away in the Ukraine the staff of the orphanage keep ringing him up. When is Renko coming to take him out again? Renko speaks to him on the phone. He relates another episode of the fairy story, a fairy story that seems now to include aspects of the case. As usual the child says nothing.

Like Chernobyl, this is a country that you can't live in too long. Those who work there officially are rotated out every four weeks. Renkoland is too oppressive for me. I shall be back and perhaps before another twenty years, but not soon

What attracts journalists.

Just a thought. More than twice as many people have died in the 'mini-tsuami' in Java last week that have been killed in the Israel-Lebanon 'mini-war'.

Thursday, July 20, 2006

Stem cells

Predictably, there has been much hostile reaction to President Bush's vetoing of federal funds for embryonic stem cells. However, he has some surprising support.

This is a quote from Andrew Sullivan's blog. Andrew is a Sunday Times columnist who has been critical of the President's handing of Iraq since the war. He has been particularly critical of the 'Christianists', his name for the American right-wing evangelicals.

"I feel obliged to come to the president's defense on his embryonic stem cell research veto. I find the absolutism of those who view a blastocyst as a human person to be morally unpersuasive, but I cannot see how it can be seen as anything other than human life. I know also that many of these superfluous blastocysts and embryos will be discarded anyway and so not using them for research does not protect them from extinction. Nevertheless, it is hard not to be troubled by the line this crosses. Human life is created and then experimented on to save other human lives. I think the argument for the benefits of such research is compelling; there's little doubt that this avenue could be extremely fruitful. I live with one of the diseases, HIV, it might help cure or treat. For those reasons, I don't believe such research should be banned - or even that individual states shouldn't, if their citizens support it, directly finance such research from the public purse. I'm a federalist. But when a very significant number of Americans feel deeply that this really is morally unconscionable, and when the research is taking place anyway under other auspices, I see no reason why the feds should actively finance this research as well. I don't think that Bush's compromise is so unreasonable, in other words. This isn't a ban on such research; it's a decision not to throw the weight of federal financing behind it. I respect the case of those who favor it; but, when push comes to shove, I'm with Bush on this. It took political courage to take this stand. And the morality it reflects - a refusal to treat human life as a means rather than as an end - deserves respect even from its opponents."

Andrew is, of course, a Roman Catholic, and even though he is at odds with much of that Church's teaching - he is a practicing gay, for example - he is not apt to dismiss Catholic dogma willy nilly.

I realize that stem cells are one of the most polarizing issues around. People from either side of the argument are calling each other names and seem unable to understand each other's viewpoint. I think this is because they have very different philosophical presumptions. Jeremy Bentham was the founder of utilitarianism. This is the idea of the greatest good for the greatest number. It seems apparent to those who espouse this philosophy that when you weigh up the future of a blastocyst, created as a spare that will be discarded when not needed against the possibility of using these cells to find a cure for diseases like diabetes, Parkinson's disease and dementia.

On the other side of the debate are people who stress that the end does not justify the means. They reach this conclusion because in their view the means involves the destruction of a human life. No-one, for example would countenance conceiving a baby to produce a heart donor for a child a congenital heart defect. It would involve allowing the baby to be born, then removing its heart to give it to its sibling, and allowing the donor then to perish. How about killing the fetus two weeks before birth and harvesting an organ? Or four weeks? Or at 24 weeks gestation, the legal limit for an abortion?

Society in its wisdom has set a limit after which the embryo cannot be destroyed for this purpose. Baroness Warnock's committee set a limit at the formation of the neural streak, the first indication of organized nervous tissue. I have always thought this a sort of committee decision; a limit that gives some scope to researchers, but one that could be defended on quasi-logical grounds against religious people. After all, why should a few nerve cells make a difference? It is not as though a 14 day embryo has any consciousness of personhood.

On scientific grounds I have always believed that the fusion of egg and sperm to form a fertilized ovum was the beginning of a life. I know that it has been argued that at this stage the fertilized egg might give rise to twins or triplets, but i hardly see that this is an argument for destroying it. Indeed it makes the act more wicked, if wicked it be, because it would result in the destruction of two or three lives.

It is of course true that the fertilization of an egg does not guarantee the development of a baby; indeed it has been demonstrated a fairly large proportion of fertilized eggs never make it (I have seen figures suggesting 20% to 50%). There is no way of knowing which embryos are going to make it, however, and any act of destruction might kill not just a potential child, but a future Beethoven. The normal reaction of a physician is to try and save a human life not to destroy it.

It must be conceded that as a society we do not hold a fetus of a few weeks of gestation in the same regard as a young child; nor do we hold a wake for a miscarriage in the same way that we would for an old friend. But I do know that a miscarriage is a time of great sadness for an expectant mother. The loss of a potential life still leads to grieving.

The embryology regulators in the UK, while taking a liberal approach to IVF and the creation of spare embryos, still found it hard to swallow the idea of producing a baby solely or mainly for the purpose of donating its bone marrow to a sibling, even though they were assured that the baby would be a loved and welcome member of the family. They didn’t like the idea of creating another human being to use in this way. It could of course not give consent, and the parents acting for it could not give unbiased consent.

In the past the beginning of life has been taken to be at various levels of gestation by different religions, but these were set out of ignorance. They did not understand about the fertilization of gametes. Government commissions set up to advise on these matters in the UK usually have religious representation among their number, but they usually find a tame priest of liberal persuasion who could be relied upon not to rock the boat. The Bishop of Oxford, Richard Harris, got on a lot of advisory boards.

Christians who tend to follow the Bible have difficulties in taking a low view of the status of the fetus. Both David (in Psalm 139) and Jeremiah (chapter 1 verse 5) give evidence of being known by God while still in the womb, and then there is the remarkable story in Luke Chapter 1 of the fetal John the Baptist leaping with joy within his mother’s womb when his mother encountered Mary carrying the embryological Jesus.

It could be said that these passages refer to people specifically chosen by God and not to all fetuses, or you could interpret it generally.

Similarly, with the only passage in the Bible that specifically mentions a miscarriage, Exodus 21:22, different beliefs determine how the Hebrew is translated. It refers to a fight in which a woman standing nearby is stuck and forced to deliver prematurely and no harm comes, then the perpetrator is forced to pay a fine. Does this mean no harm comes to the mother or no harm to the baby? It is not clear and certainly not convincing enough to build a doctrine on.

Obviously the Catholic Church takes a high view of the status of the embryo as do evangelical churches. An objective scholar would come to the conclusion that the Bible is not absolutely clear about the question – it was a question that was never required to be answered when the Bible was written; it doesn’t say anything about space travel either. Christians then must come to a conclusion based on the whole teaching of Scripture.

For myself I find the whole idea of using spare embryos for experimentation very uncomfortable, particularly since adult stem cells are turning out to be much more plastic than had been suspected so that the utilitarian argument is weakened. On a radio debate this morning I heard a new argument. Suppose, said the researcher, that we were able to dedifferentiate adult stem cells so that they became just as plastic as embryological stem cells. They would then be implantable in a womb and could become fetuses, so that the same ethical questions would apply.

He was quite wrong there. No ethical problems would arise because the adult stem cells would have been donate by a donor with full and informed consent, not taken from an embryo unable to consent, and since he or she would die in the process must be deemed to have been unlikely to give it.

So if you are still with me, you must make up your own mind about this question, but please do so after giving it some thought and considering the evidence, rather than making a knee jerk response based on prejudice or even political persuasion.

Road Traffic Injuries

I have once suffered injury on the road. As a teenager I broke my finger when I trapped it between my brake lever on my moped and an army truck. It was one of those silly crashes that occur at traffic lights when the vehicle following assumes that when the vehicle in front starts to go when the lights turn green, it intends to continue going rather than suddenly stop because the driver has stalled or missed a gear. I never learned my lesson because I have had accidents like that since, but I have been lucky; I have never since injured myself or anyone else.

A leader in last week's BMJ tackles the topic of death and injury on the roads. People like me, professional classes in the first world are least likely to be injured. Those in lower socioeconomic classes and those in low and middle income countries. Although Britain has among the safest roads in the world, there is no room for complacency. Still one in six drivers in London do not wear seatbealts. Legislation forbidding using hand held cellphones while driving is largely ignored. Some well-publicised heavy fines are overdue. It is estimated that in France perhaps 20% of serious motor injuries are caused by drivers falling asleep at the wheel.

I have certainly fallen asleep while driving and now always take action when I feel sleepy. I do not try opening the window, or turning on the radio loudly. I immediately pull off the road, lower the backrest of my seat and take a power nap. Twenty minutes will get me home safely.

Wednesday, July 19, 2006

It's raining in my heart - Rockets on Beirut

Rain at last! Today was the hottest July day in England since 1911. I have met searing heat like this before in Singapore, Texas and Florida and even south of Boston in midsummer, but this is 51 degrees north and on the coast. I remember it very hot in 1957 and 1967 and 1976, but today was something special. Then this evening as we were driving into Bournemouth suddenly the skies opened and lashings of soft summer rain. (Lashings is a good word, isn't it? Remember the famous five and their lashings of ginger beer?)

I feel the need to say something about the rockets raining down in the Middle East. The BBC is careful to call the Hezbollah fighters militants not terrorists, though the Israelis have no such inhibitions. The trigger for the current round of violence was Israel withdrawing from Gaza. This prompted Hamas to invade Israel and kill some soldiers and capture another. Not to be outdone Hezbollah did the same in the north. They proclaim themselves as heroes for driving Israel out of southern Lebanon whereas the Israelis would say that they withdrew of their own accord to encourage the peace process.

Peace process? What peace process? It looks as though Ariel Sharon's policy of land for peace is dead in the water.

Who is in the right here?

It depends on how far back you want to go in history. I may have a totally wrong opinion about the history, but this is how I see it. If I am mistaken, I've no doubt someone will correct me. Undoubtedly, Israel is a land once owned by the Hebrews. They achieved supremacy through conquest at the times of Joshua, Samson, David and Solomon. They, themselves, suffered conquest at the hands of the Assyrians, Babylonians, Medes and Persians, Greeks and Romans, with only short periods of independence under the Maccabees. They were finally expelled by the Romans in AD 70.

As the Roman Empire decayed the area was controlled by an Islamic empire, which spread across the whole of North Africa, southern Spain and north into Europe to the gates of Vienna. The Otterman Empire controlled this area until it fell at the end of the First World War when the great powers (principally France and Britain) divided up the empire between them. France had responsibility for Lebanon and Syria, Britain for Mesopotamia and Palestine. This was not expansion of the British and French Empires, but what would have been called in those days, 'taking up the white man's burden'. No doubt a mistaken viewpoint steeped in paternalism, but a fair description of what was felt at the time.

In World War One, Britain had made the mistake of promising Palestine to both Arab and Jew. After the Holocaust the Jews took them up on the offer and started moving in by the boatload. Britain held a UN mandate at the time to keep order in the country and tried diplomatic means to find an agreement. I believe a home in Uganda was offered. The Jews would have none of this sort of delay and using a series of terrorist atrocities achieved a homeland in Palestine. It would be fair to talk about Jewish terrorists in this context. Throughout 1948 battles with the Arabs raged and during this period there is no doubt that some Jewish atrocities against Arabs occurred. A lasting enmity between the two was laid down then, but even though Jew and Arab had lived in peace together in Palestine for years, there was a history of conflict. Most of those who were displaced in 1948 are dead, but it has become a folk memory, steeped in resentment. It is fueled by poverty and unemployment. It smarts all the more when you see what the Jews have done with the land. The dessert blooms while the refugee camps seethe with the poor whose only relief is religion. Exactly as Marx said, it is the opium of the people; it takes away their pain.

In 1956 Britain, France and Israel together attacked Egypt when Nasser nationalized the Suez Canal. America stepped in and threatened the Europeans with bankruptcy if they did not withdraw. From then on it was apparent that America was top dog, and that Britain would never act on the world stage against America's national interest. (In a rare show of independence Harold Wilson refused to send troops to Viet Nam and Margaret Thatcher sent a task force to the Falklands against American advice). Suez was half way to India. With Suez gone the Empire was dead.

In 1967 and again in 1973 Israel defeated Arab armies seeking to destroy it. The subsequent occupation of the West Bank, Gaza, the Golan Heights and later (in 1980?) southern Lebanon, have all been strategically important as matters of defense. Putting settlements on the West Bank and in Gaza muddied the waters - the land was no longer kept as a military necessity for protection, but as conquered assets for living in.

Can an argument be made for sustaining the settlements? I suppose it is true that everyone lives everywhere because of conquest. Certainly Britain has been settled by a succession of conquerors. America, Canada, Australia, South Africa, New Zealand: sometimes the conquest has been very brutal, resulting in genocide. We can hardly claim to be holier than thou. Nevertheless, in return for peace the settlements might go; without peace they are a bargaining chip.

Who owns the land? Frankly, the answer is whoever has possession of it at the moment, however they obtained it. Whenever did anyone voluntarily give up a land they were living in?

From Israel’s point of view, the occupation of surrounding land is a safeguard against being attacked. Their current policy is to withdraw if peace can be secured. The policy of the Hezbollah and Hamas is that Israel should remain under constant attack. Israel’s response is to reoccupy land that they have withdrawn from. The current destruction of Lebanon appears disproportionate, but in Israel it is deemed necessary to diminish Hezbollah. Generations of international politicians have attempted to find a peaceful solution to the problem. Nobel peace prizes have been won for what in retrospect appear to have been nothing more than temporary truces.

Can Israel destroy Hezbollah bet all this bombing? Of course not. They will inflict a lot of damage to the infrastructure of Lebanon that will make it difficult to replace the rockets. They will give the country a bloody nose as a warning not to harbor a private army. They will kill a small number of terrorists. They will for a while sterilize the borderland.

These are not fundamentalist Jews. They have no time for the Bible’s restriction of an eye for an eye. They seek ten eyes for every single Israeli eye. They have been exposed to that sort of arithmetic and they have learned.

Could the Palestinians drive out the Israelis by force of arms? Whether they use conventional war or what people now call asymmetric war, this is not going to happen, not while America exists.

What is the best they could hope for? They might get the return of most of the West Bank. Jerusalem would be a sticking point, the best that they could hope for there is for it to be declared an international city with access for the three major monotheistic religions.

Could they get rid of the settlers? I doubt that they will get rid of them all, but this is at least something to negotiate about. A separate Palestinian state that is economically viable is in Israel’s interest as much as it is in the Palestinians’.

Is Israel subject to the World’s opinion? Not really. She will respond to pressure from America, but American public opinion is hardly likely to favor Shiite Arabs over Jews.

Are Syria and Iran behind this? Undoubtedly there is some connection. They continue to be strongly anti-Israel and anti-America. With the American army tied up in Iraq and Afghanistan and vulnerable to Shiite groups there, a proxy war in Lebanon suits the Shiite purpose. However, if you blind yourself to the day-to-day horror of the war and the hundreds killed and thousands injured, strategically, this is just a skirmish in a bigger ideological confrontation.

How will it end? I suspect that some time next week the Israelis will discover that at least some of their military objectives will have been achieved, they will agree to an American brokered cease fire. Syria will put pressure on Hezbollah to stop firing rockets. There will be a prisoner exchange, with the Israelis releasing some of their Palestinian prisoners and the Arabs giving up the three Israeli soldiers. Both sides will claim a victory. The Israelis will claim to have damaged Hezbollah significantly. Hezbollah will show the release of prisoners as evidence that their little war was successful. The Lebanese government will make an accommodation with Hezbollah that gives them more power over policy in return for at least some control over the young men who actually fire the rockets. A stronger, though not strong enough, UN force will be placed in Southern Lebanon. It will include contingents from Norway, Yemen and one of the former Soviet Republics.

There will be a boom in the Lebanese construction industry. Money for reconstruction will come from the EU and Saudi Arabia. And America.

Cripples will become a common sight on the streets of Beirut.

Monoclonal antibodies 3: mainly about Campath

As I was saying before I got sidetracked onto the Brambell receptor, Geoff Hale was telling us about the half lives of antibodies. Zenapax, Herceptin and Avastin last for the expected three weeks, and rituximab for almost three weeks, but other antibodies, like Remicade and Simulect last for only a week. This seems mainly to be caused by the antibody being removed from the circulation by binding to its target. Typical therapeutic levels of antibody vary from as little as 0.1 to 10 micro gm/ml, while total IgG levels are 100,000 times this. This is obviously a technical challenge for measurement, but ELISA assays can be designed.

He then went on to talk about Campath. The CD52 antigen is an unusual molecule. It is a glycoprotein (meaning it is made from amino acids and sugars). The peptide element is only 12 amino acids long: from the C terminus it goes ser-pro-ser-ser-thr-gln-ser-thr-asp-asn-gln-gly. The C terminus is linked to a glycosylphosphatidylinositol (GPI) anchor (many CD antigens are linked to the cell surface by GPI anchors). At the asn residue is a large carbohydrate, rich in sialic acid and therefore strongly negatively charged. Campath recognized an epitope containing the 5 amino acids nearest the cell surface. Geoff has developed a flow assay using either a T-cell or B-cell line as substrate to satisfactorily measure blood levels.

In CLL, as you might expect, highest blood levels were achieved in those patients with lowest blood counts and response was related to levels achieved. Although iv Campath gave the highest blood levels quickest, the same levels could be achieved by subQ Campath, eventually. In patients with negative tests for minimal residual disease, the half life of Campath was about 3 weeks.

Geoff presented similar results for rituximab blood levels. What he is saying is that we ought to adopt a more scientific approach than giving everybody the same dose. With antibodies being so expensive, it would make sense to tailor the dose to individuals according to the blood levels achieved.

Peter Sonderman from Glycart gave a talk on the importance of glycosolation in monoclonal antibodies. As you remember, the sugar molecules on Campath were mentioned by Geoff Hale in his talk. It is important to remember that the monoclonal antibodies that we use to treat patients are artificial creations. In order to produce them in the quantities that are needed for treatment the pharmaceutical companies have genetically engineered them so that they will grow in cell lines like Chinese Hamster Ovary (CHO) cells. Unfortunately, CHO cells lack the enzymes that put the right sugars on the antibody. Some years ago, Martin Dyer made the observation that the current Campath wasn’t as good as the Campath1H that he got from Geoff Hale and Herman Waldmann. The difference was that the original Campath was made (as antibodies should be) in plasma cells, but Alemtuzumab is made in CHO cells. He began to suspect that it was all down to the glycosolation.

The Glycart technology involves transfecting the gene for an enzyme, GNTIII into the CHO cells. This catalyzes the addition of N-acetylglucosamine (GLcNAc) to the string of sugars (in the diagram it bisects the two mannoses), and this reaction prevents the addition of fucose to a different GLcNAc. I don’t pretend to understand this, but the effect is to make the antibody bind 50 times more efficiently to the human FC gamma IIIa receptor (this is the important receptor on NK cells that works in ADCC). Sure enough, Campath that has been treated in this way is far more effective in an ADCC assay, but does this matter clinically?

The evidence that it does comes from some clinical experiments with Rituximab. There is known to be a polymorphism in the FC gamma III receptor. At position 158 there may be either a valine or a phenylalanine. Only 10-15% of the population are homozygous for valine at this site, but these are specially favored if they get follicular lymphoma, because their response to rituximab is 100% as opposed to 67% for those with phenylalanine. Unfortunately this does not seem to be the case for CLL, which is why we believe that ADCC may not be an important mechanism for CLL and rituximab.

Nevertheless, applying the Glycart technology to both anti-CD20 and anti CD52 makes them much more effective in the test tube, and a trial has just begun with a glycarted anti-CD52 in CLL. Preliminary results are encouraging.

Tuesday, July 18, 2006

Monoclonal antibodies part 2: Rogers Brambell

It is some time since I first reported on the Spring meeting of the UKCLL Forum on monoclonal antibodies in CLL. Here at last is the second half of the meeting.

Geoff Hale invented Campath. He reported on the difficulties in estimating what happens to monoclonal antibodies once they have been injected. In comparison with small molecules, like standard chemotherapy drugs, antibodies often have non-linear pharmaco-dynamics; they have a much more restricted distribution space, often being confined to the vasculature and extra-vascular fluid with poor tissue penetration. They are broken down, not be metabolic activity, but by proteolysis; they are not cleared by the kidneys, but they are often immunogenic and cleared by an antibody response. They have a high affinity binding to their target, so that binding usually leads to clearance. The half-clearance time of IgG1, IgG2 and IgG4 is 3 weeks, while for IgM, IgA and IgG3 it is one week. However, high levels of antibodies are cleared more quickly. Clearance rates can be prolonged by altering glycosolation, by linking polyethylene glycol to the molecule or by making changes to the FcRB binding site.

The FcRB or Brambell receptor (which is present on the cells that line blood vessels and other tissues) is the means by which the long half life of antibodies is achieved (in this function it is known as FcRp – for protection). It also is responsible for the transference of antibodies across the placenta to the growing baby (here it is known as FcRN – for neonate. In some animals (but not in humans) it is also responsible for the transfer of antibodies from mother to child in the colostrum, the first few secretions of the breast after birth (FcRT for transport). The Brambell receptor is thus very important.

FW Rogers Brambell was Professor of Zoology at Bangor University in North Wales until 1968. As it happens he was the mentor of one of my colleagues at Southampton, Arthur Wild, and the PhD examiner of one-time Professor of Immunology at Southampton, Leslie Brent. (Leslie was famous as part of the team that discovered the mechanism of skin graft rejection – Medewar, Billingham and Brent). To complete the circle, Leslie Brent was the PhD supervisor of Lee Rayfield while he was in Southampton, and Lee is now Bishop of Swindon, and a colleague of mine on GTAC.

Arthur was able to give me some information about Rogers Brambell. He was born in Ireland in 1901. At the time of his birth, Ireland was part of the United Kingdom, but Brambell was born in the south, in fact in Dublin. His accent betrayed his southern origin; he couldn’t say his ‘th’. He’d say tree tousand trushes in te trees. At Aravon School he was thought rather dim; there was some question that he might be mentally retarded. He was good at nature study and things biological, however, and although there was some worry that he might never be able to make a living, he was advised to try farming ‘in the colonies’.

Despite his apparent unteachableness he went to university at Trinity College where he also did a PhD. Research in University College, London led to a DSc and he became in 1930 the Lloyd Roberts Professor of Zoology at one of the smallest universities in Britain, Bangor in North Wales where he established a well-regarded department of marine biology at Menai Bridge.

During the war, because of the Atlantic blockade by U-boats the Government was worried about feeding the people. Rabbits became an important study, but were becoming scarce. Of all the most unbelievable assignments, Brambell was given the task of increasing the fecundity of rabbits.

He began to examine the cause of rabbit miscarriages. He found the presence of fibrinogen in the blastocyst. How did it get there? It must have come from the rabbit mother’s blood. What other proteins managed to get there? Surprisingly immunoglobulins were found. So began the research which culminated in the discovery of the Brambell receptor with its threefold function.

Arthur remembers Brambell as an aloof, academic, aristocratic sort of man. He ran an efficient department that was focussed on research and was good to work for, but he was a bit detached from this present world. He used to go home at 4 o’clock in order to go fishing in lake on the Isle of Anglesey. His wife used to run him. A story is told of his wandering around Bangor with no money in his pockets. He went into his bank to withdraw some. They sent for the manager who explained, “Professor Brambell, you do not have an account here. The money is all in your wife’s name.” An innocent abroad.

For his research on the FcRn receptor Rogers Brambell was awarded the Gold Medal of the Royal Society. During his later academic life he was Dean of Faculty, twice vice-principal of the University, a member of the Agricultural Research Council, on the council of the Royal Society, a member of the University Grants Committee and the Chairman of a Royal Commission on factory farming. His commission’s report established that farm animals feel pain, and led to the banning of the debeaking of battery chickens. He bacme CBE in 1966.

He was a high-church Anglican and therefore almost certainly one of those English-Irish – not one of the hard-nosed Scots Presbyterians from the North; certainly not a Fenian and not one of the absentee-landlord English that exacerbated the potato famine. One of the English that stayed, lived and melded with the people, and adopted their soft southern ways.

Dead for 36 years, who remembers him now? After a long and academically successful career, could he not face the life outside University? When an influential man is himself debeaked, does it hurt? Is it beyond bearing? He died young. There is an entry in the Concise Dictionary of National Biography, but nothing in the Hutchinson Dictionary of Scientific Biography and nothing in the Oxford Companion to Medicine. On Google only his publications. And his receptor.

It still comes in pints

For the second day running I have had to phone up my bank to complain. On this occasion they made a dollar to pound miscalculation then realizing their mistake put the money back into my account and took out the larger amount. I only found out about it by meticulously going through my statement (which they had forgotten to send out - that's what yesterday's phone call was about). In the meantime I had reclaimed the smaller amount, and I shall now have to go back and reclaim the difference from the Society, explaining why the mistake occurred.

Anyone can make a mistake, but I think the bank should have contacted me to tell me what was happening, rather than simply taking more money from my account without explanation.

I say anyone can make a mistake, but you don't look to a bank to make mathematical errors. After all what are banks for, except to do sums? I blame the education system, and especially Harold Wilson and Tony Benn who forced us into going metric.

When I learned sums, we started on hundreds, tens and units, but soon progressed to pounds, shillings and pence; yards, feet and inches and stones, pounds and ounces. This way we learned to calculate, not only in base 10, but in bases 3, 12, 14, 16 and 20. every time we changed columns we changed bases. The advantage of this is we didn't get sloppy about decimal points. We also learned to estimate size. We never, because of misplaced decimal points, cooked a cake the size of a house or built a bridge the size of a cornflakes packet.

I tested my bright daughter this morning at breakfast. How many ants could you get in this house? After a minute's thought she came back with a billion. American billion or British billion, I asked. British billion.

Show me your workings, I asked.

An ant is about 2 millimeters long; say it has a volume of 2x2x2 = 8 cubic millimeters. The house is about 20x20x20 meters, say 8000 cubic meters. There are a thousand millimeters in a meter, so 1000 x 1000 x 1000 cubic millimeters in a cubic meter. The eights cancel so there are 1000 x 1000 x 1000 x 1000 ants in the house. That's 12 zeros, so ten to the power of 12 ants which is an English billion or a thousand American billions. I think they call it a trillion over there, because nobody does Latin any more.

At least in America, it still comes in pints, I said.

Monday, July 17, 2006

The Sunday Philosophy Club

Those who ony know Alexander McCall Smith for the Botswanan Ladies Detective Agency should try his Edinburgh novels featuring Isobel Dalhousie. They have a gentle pace about them that keeps the story moving along, yet still finds time to digress into abstruse ethical points and take the reader on a tour of Scottish modern painting and a Scotch whisky tasting. It is a whodunnit of sorts, with the usuall red herrings and surprise ending, but it is such fun! I suppose it might be counted as criticism to say that he writes like a woman, but he does just that. He is more concerned with character than plot and the characters he constructs are real people, some of whom I'm sure I've met. Bravo!

Sunday, July 16, 2006

Family farewell

Yesterday the whole family gathered in Royal Tunbridge Wells to bid farewell to Richard and his girls before they depart for Seattle. We had a leisurely pub lunch that went on until 4-30. Of course, they aren't leaving until the end of August, but that is only 6 weeks away and it is a very busy time for them. They have rented a house by Green Lake for a year and have got the older two into schools. Richard has a three mile cycle ride to his work in the center of Seattle. There is a pre-school nursery at the Adventists hall close to where they will live. We are planning to visit them for the first time in October, but we have yet to fix a date.

I am not really a Royalist, but it is a strange coincidence that my other son, David, also lives in a Royal borough, Royal Leamington Spa. He was there with his girlfriend, Charlotte - they are known to their friends as Chas and Dave. He is fitting everybody up with Skype (I think that's how it is spelt) so that we can all keep in touch.

Newly married Karen and Tim were there from Hayling Island. Dr Angela, who lives at home, was also there. She followed up behind us in convoy. The drive from Bournemouth to Tunbridge Wells is an unpleasant one involving A31, M3, M25 and A21. I don't mind the A roads, but the M roads are so crowded, with traffic bunching up and then accelerating away. Nobody attends to the speed limit, so you have cars flashing by at over 100 mph on both inside and outside, changing lanes to gain a few seconds advantage. It requires constant intense concentration, and I had a headache after 5 hours driving, there and back.

We ate at a pub/restaurant called the Beacon. It was a gloriously hot summer's day and we had a large table under a grape vine outside. Five grandchildren were there; wedding photographs were passed around; news was exchanged. An altogether happy occasion.

Speaking of Royals, lots of Americans have a misapprehension of the Royal family in Britain. They hark back to George III and 1776 and imagine royalty as what the Americans rebelled against. Even in 1776 the monarchy had little influence of public life and of course, today it has none.

I notice that Andrew Sullivan in his blog has been calling George Bush, King George; a reference to his assuming to himself executive powers without congressional endorsement. In the UK parliament has been supreme over monarchy since 1688 and the Glorious Revolution. Today, the Queen is the symbolic head of state, deliberately outside and barred from party politics. She has the right to be consulted by the Prime Minister of the day, but although he (or she) must listen he may or may not take any notice of what she says, depending on his own policies. She has to give assent to acts passed by parliament, and although theoretically she has the right of veto (like the American president), were she to execute it without the will of the people she would face a constitutional crisis and the monarchy would go. One could envisage a scenario where a deeply unpopular government undertook an unpopular course of action based on an old electoral mandate. For example if Tony Blair were to commit the country to invade Canada, which he would be able to do because he has a parliamentary majority, she would likely veto it (and not just because she is also queen of Canada) because it would not be the will of the British people. (Actually, George Bush is more likely to invade Canada).

She also has the right to dissolve parliament and order fresh elections. It is possible to imagine scenarios where this might occur. Something similar happened in Australia a couple of decades ago, when the Governor General dismissed the government of Gough Whitlam. Although she is also Queen of Australia, she delegates this role to an Australian who acts with the same power.

The purpose of this safeguard is to prevent an elected tyranny.

All democracies have slight differences in methodology. An anonymous contributor several blogs back, claimed that America is the world's oldest democracy. This is hardly likely to be true as America is just 230 years old and only had true universal suffrage since 1968, when Jim Crowism was legislatively put to rest. Even now there are barriers to some people voting. But, such barriers have been commonplace in all democracies. In the UK suffrage was once the privilege of landowners, then women were denied the vote, finally the voting age was lowered to 18. It is only recently that women have been allowed the vote in Switzerland.

Another question has been raised about democracy following the victory of Hamas in the Palestinian elections. Is democracy the best form of government? Winston Churchill thought that democracy was the worst form of government apart from all the others. Hamas's victory was achieved by campaigning against the corruption of Fattah and promising social improvements. But these social improvements were to be financed by the continuing aid from the US and EU. But another plank of their manifesto was a war with Israel (not explicitly stated, but implicit in their unwillingness to recognize Israel's right to exist). It is plain that US and EU aid would not continue if war with Israel was an objective. So it proved. Hamas won the election by fooling the electorate.

Anyone can win an election by offering wealth, health and happiness. What's to object to? A sophisticated electorate wants to know how it is to be paid for. Those voting for the first time in a free election may not see that.

The British constitution has arisen over hundreds of years. There are built in checks and balances to keep the government honest. One of those checks is the law against buying power with money. The selling of peerages to rich businessmen in return for contributions was outlawed at the time of Lloyd George. It seems to have been part of Tony Blair's strategy to free the Labor party from the subjugation to the Unions, a worthy aim, no doubt, but against the law. Now that it has come to light, it seems to me that it presages his downfall. He not only has the Tory newspapers against him, he is also at odds with the left wing of his own party, since they see why the peerages were sold.

You can have some sympathy with him since most Tory peers acquired their honor for favors to kings in the past, and New Labor legislation was hindered by the House of Lords which was packed with Tories. In a way he has unblocked that jam by not allowing the hereditary peers a vote in the Upper House (apart from 92 of them who were elected by their peers).

He was unwilling to go the whole hog and have a completely elected Upper House, since that would rival the Commons as the prime legislative chamber. Currently the House of Lords is an appointed House, comprising the great and the good; people are appointed because they have excelled in some aspect of public life - there are doctors, lawyers, businessmen, church dignitaries, soldiers, civil servants and scientists. But there are also failed politicians who are there as lobby fodder and many who are more interested in the honor than the legislative power. So you would in the past have seen such people as Laurence Olivier, Sebastian Coe, Melvyn Bragg, and many others who would hardly ever take part in debates or vote.

In America favors are paid off with ambassadorships, so it is probably little different, and the objections are so much humbug, but it is against the law.

Happily, the Queen is above all this. For the past 54 years she has conducted herself with dignity and patience in the face of great challenge and temptation.

Arthur and George

Let me recommend 'Arthur and George' by Julian Barnes, one of the great reads this summer. Arthur is Sir Arthur Conan Doyle, creator of Sherlock Holmes, famous throughout the world, not only as a man of letters, but as a sportsman: alpine skier, fisherman, cricketer, tennis player - name your sport, he excelled. George is George Edalji, an obscure Birmingham solicitor interested in railway law, the son of a Parsee vicar and Scottish mother, who is accused of sending himself and his parents a series of unpleasant and times disgusting anonymous letters and then running a gang of horse mutilators in the country village where he lodges with his parents. George is found guilty and sentenced to eight years penal servitude.

Arthur takes up his case, acting out the role of the Great Detective.

This is faction. The story is true, but all the interaction between the characters is imagined. It is an important case because it led to the establishment of the Courts of Appeal; before this any one who believed himself falsely convicted could only petition the Home Secretary for a pardon, which was seldom given.

But this is not only a famous legal case; the book opens up the complex character of Conan Doyle. Here is a secret Victorian love story. Here is prejudice, but is it racial or class prejudice? Here is blind ignorance in high places. Here is nepotism.

This is a super book, beautifully written. The best book I have read this year.

Thursday, July 13, 2006

Cord blood doubles

At Kings today we contemplated our first double cord transplant. The patient, a 66 year old woman suffering from AML which had transformed from MDS, had teh bad risk features of absent chromosomes 5 and 7. Although she is in remission she has a less than 10% chance of living for a year. She has no sibling and there is no volunteer donor.

Cord blood transplants are mainly an option for children and small adults, like the Japanese. They have several advantages, the most important being that they are less immunoreactive so that you can allow for a mismatch at a single locus and have no greater risk of GVHD. But how to get round the volume problem?

The baby's umbilical cord and the placenta contain about 200 cc of blood, but it is rich in stem cells. If it is not frozen down it is thrown away. here is a donation that is easy to take and harms no-one. If you have a facility near you, you should offer your baby's cord for freezing. This alone would bean argument against home births.

The Minnesota protocol allows for two cords to be used. Only one will grow and repopulate the marrow, but the other supports and strengthens its growth. They don't have to be a match. It's better if they are a mismatch for the recipient and a mismatch for teh other cord, but in a different way.

So for our patient we have found a 5/6 match from Australia and a 4/6 match from Belgium. Just imagine the organization. A couple in Oz and a couple in Belgium, quite separately decide that they will allow their babies' cord bloods to be frozen down. Some months later those bloods will mingle to save the life of a woman in England they will never meet. Isn't technology wonderful!

Of course it is not completely safe. There is a 15% chance of treatment related mortality. This will be a reduced intensity conditioning (or mini-) transplant. Graft versus host disease of some degree is likely, but face with the likelihood of 85% chance of disease related mortality in the first year, it is a no-brainer.

The other highlight today was a case presentation called "Stroke, stroke, stroke."

A 63 year old woman had been having recurrent strokes since the age of 12. She always recovered after a day or so, but she had suffered progressive deterioration of her balance and control of fine movement. The obvious cause would be emboli coming off an abnormal heart valve, but no, the 'strokes' were preceded by the smell of bacon and eggs. This is hemiplegic migraine. And since her two younger brothers have it, it is familial hemiplegic migraine. The genetic abnormalities have been identified and involve calcium channels. The cerebellar ataxia is part of the syndrome. Treatment with acetazolamide prevents the attacks of migraine.

Learning new things is wonderful.

Tuesday, July 11, 2006


Quite a storm has been raised by a paper in Blood from Alan Rickinson's unit in Birmingham. I have known Alan for about 30 years. He runs the premier Herpes virus lab in the UK. Herpes viruses include Herpes Simplex, Zoster, CMV and Epstein-Barr virus. Epstein was Professor of Pathology in Bristol when I was a medical student and a junior doctor.

Herpes viruses have this in common: once you have them, you never lose them. CLL patients will know that they are prone to shingles attacks. Most people have chicken-pox as children - it's caused by the same virus. After recovery from chicken-pox the virus lodges in the spinal cord and at times of immunodeficiency (or other 'stress') it migrates down a peripheral nerve to infect the skin covered by that nerve. Likewise, as those who suffer from cold sores can testify, being 'run-down', getting a cold or exposure to sunlight can awaken the sleeping virus around the mouth.

I have been interested in EBV for many years and have written a few papers about it. In one of them I postulated that patients reacted to the infection in different ways, some made a rapid recovery, some a slow recovery and some kept getting recurrent symptoms. We were able to show a difference between T cell receptors in the different groups. Of course, in 1983 the methods were unbelievably crude compared with what can be done today, but I was interested to read the paper by Sauce et al in Blood . They studied the IL-7 and IL-15 receptors on CD8+ T cells in patients who had EBV infections.

Interleukin-7 and interleukin-15 are both pro-inflammatory cytokines, both having many targets and functions, but united in their ability to support and activate CD8+ cytotoxic T lymphocytes (CTL), the cells believed to be responsible for killing both tumor cells and virus infected cells. CD8+ T cells have receptors for both cytokines on their surface. These receptors are complicated affairs. In common with IL-2 and IL-12 they both use the common gamma chain as part of the receptor. This is what is missing in those 'boys in the bubble' who suffer from severe immunodeficiency syndrome (SIDS), and who have recently been treated by gene therapy (three of who have subsequently developed a T-cell leukemia). In the case of the IL-15 receptor it also shares the beta subunit with the IL-2 receptor, but also has a private alpha chain that is wholly its own. IL-7 on the other hand has only one other chain, an alpha chain that at least has a number, CD127.

Signaling through these receptors makes use of the JAK-STAT pathway. (Some may be familiar with this from all the publicity about JAK2 mutations in patients with polycythemia; in this case JAK1 or JAK3 are involved rather than JAK2). In mice both the IL-7 and IL-15 receptors are altered in response to a viral infection, IL-15R being upregulated and IL-7R being downregulated. The Birmingham study looked at these receptors in patients who had glandular fever.

Strictly speaking glandular fever and infections mononucleosis may not be quite the same thing, but the terms are used interchangeably. Glandular fever refers to the enlarged lymph nodes in the neck together with the fever; infectious mononucleosis refers to the presence in the blood of large numbers of mononuclear cells, which are now known to be CD8+ CTLs reacting to virally infected B cells. Although EBV is the commonest cause of this syndrome other viruses like CMV can produce a similar disease, as can the protozoan toxoplasma gondii.

They followed patients who developed glandular fever over a two year period. At first the T cells had no IL-7R alpha, but as time past this receptor appeared and after 2 years the level was back to normal. In contrast, the IL-15R alpha chain not only disappeared with the infection, but remained absent 2 years later. They were also able to study individuals in whom there was serological evidence of an EBV infection, but no history of any clinical disease - people who had had a silent infection. These individuals had normal levels of both IL-7R and IL-15R.

Thus the suggestion is that people who have glandular fever damage their CTLs for at least 2 years after the event, whereas those who have a subclinical infection with EBV recover normal CTLs. Is this defect permanent? It may be, though the evidence for this is not clear. One individual who had had glandular fever 14 years previously still had the IL-15R alpha defect, and there may be others in whom the effect was long lasting, but we are not given details in the paper. Is it specific for EBV? It would seem so because patients whose infectious mononucleosis was caused by CMV recover their IL-15R in a parallel way to the recovery of the IL-7R. Was there a defect in IL-15R in the first place that caused the patient to have a clinical rather than sub-clinical infection? That's a possibility because they were not able to study any of the patients' T cells from before their infection, but they did look at 30 individuals who had never been exposed to EBV and all of these had normal expression of IL-15R alpha. It would be very unlikely that there is a population of IL-15R alpha deficient individuals waiting to get a severe attack of glandular fever that would not be detected among 30 normal individuals.

Does the loss of the receptor matter? They did experiments to show that loss of receptor correlates with loss of function. Cells that lacked IL-15R alpha were 20 times less responsive to IL-15 than normal cells.

What does it all mean? It looks as though transient down regulation of IL-7 and IL-15 alpha receptors is a normal physiological response to viral infection and there for a purpose. The idea is that it regulates the response to that particular virus, so that the whole T cell repertoire isn't subverted by the immune response by non-specific cytokine stimulation, only those T cells designed to react with the particular virus. But in infectious mononucleosis the IL-15R alpha fails to recover even after many years. Does this matter? In mice this defect can be by-passed by monocytes capturing the IL-15 on their surface and presenting it to CD8+ T cells via the IL-15 beta and gamma receptor sub-units which are not affected by the virus infection. There is evidence that this does not happen in humans.

We do know, however, that post-IM patients maintain high levels of EBV-specific CD8+ T cells in their circulation and that these cells lack IL-15R alpha. Often patients continue to shed virus long after the attack and sometimes there are clinical recurrences. It seems that there is a precarious balance between virus and host after an attack.

We also know that in instances of immunosuppression EBV-related lymphomas may occur (after stem cell transplant or indeed any type of transplant, or after fludarabine or Campath). In Richter's syndrome EBV is often implicated. However, without such immunosuppression EBV-related lymphomas are not known to occur.

CLL Forum has wondered whether CLL might occur more frequently in people who have had a clinical rather than subclinical attack of EBV infection. They are conducting a survey. However, these sorts of data are very difficult to determine and interpret. Patients often believe that they have had glandular fever but never had a blood test to confirm it. Doctors sometimes tell patients that they have had glandular fever to fob them off. Patients with CLL need an explanation and their memories may deceive them. The comparator is difficult to assess. Normal individuals forget particular infections. I can't remember whether I have had mumps or not. Sore throats often go uninvestigated.

Although this story is stimulating and interesting, it is premature to draw conclusions just yet.

Sunday, July 09, 2006

A busy weekend

This has been a busy weekend. First my younger daughter has decided that the daily commute through the New Forest is too much for her and that she wants to buy an apartment in Southampton. She has put in an offer for one here . We went to visit yeaterday, and it certainly is a pleasant flat.

As soon as we got back I spent a couple of hours going through old casenotes. There is a project in England looking for prognostic factors in Multple Myeloma. Unlike CLL, deletion 13q is a poor prognostic factor. However when it is detected by FISH the significance disappears. It has to be detected by conventional cytogenetics. The samples are being tested by our local cytogenetics laboratory at Salisbury. The MRC Myeloma 9 trial provides for the clinical details of most of the patients, but there are still hundreds of tests that were completed before the trial started, and the study would benefit from details about these patients. So, I was despatched to the bowels of the hospital to examine old casenotes.

When I returned my eldest son had turned up with a large white van, into which were packed many boxes of books, CDs, DVDs, kitchen implements, clothes, Hi-Fis, ornaments, pictures etc. He will be moving to Seattle for a year at the end of August. He has rented a house in the Green Lake area of the city, he has got his three girls into schools, he thinks he will be able to manage with a pool car and a bike. He has sytill to rent out his house in Kent and to find a church, but he is well on the way to being ready. Yesterday, he sold his car. It was quite a feat of manual exertion to transfer his freight into our loft for a year. Unfortunately, I haven't lost any weight.

We had our usual discussions about the state of the NHS (certainly getting worse), teh state of the Labor Government (even he, a longstanding Tony Blair supporter expects the Conservatives to win the next eletion) and the state of the English football team (we are both agreed that it was nonsense to take Walcott, that Sven should have played Crouch and Rooney together up front, that Lampard has been awful since his baby was born earlier in the year, that he should have played Carrick and Lampard in midfield, that Beckham should make way for Lennon, and that the Portugal-France game had exposed the reliance on gamesmanship and cheating of the Portuguese.

He advanced his theory, that the nature of a nation was dependent on the type of alcohol that they drank. In the far north it is all grain spirits, which leads to silent introspection, depression and suicide - examples Russia, Sweden, Finland; in middle Europe beer drinking is associated with the Protestant work ethic, industriousness and efficiency - examples northern Germany, Denmark, Holland, England; while the south is the wine drinking area, associated with Catholic langour (or even laziness), dishonesty, organized crime and passion.

Far too general for my liking, and where do you place Ireland?

Wednesday, July 05, 2006

Town and Country

The hot weather finally broke today with a torrential downpour lasting three hours. I spent the day in London at a GTAC meeting. Yesterday, Diane and I took the day off and went for a walk around Kingston Lacey. This is a large house owned by the National Trust, but previously in teh hands of the Bankes family. Joseph Bankes was the most famous of these; a naturalist and collector of the nineteenth century who got into trouble for doing something disgusting with a guardsman. Rather than face the death penalty, he fled the country.

He was the MP for the area in the days when being MP was a sort of hereditary position. There were several generations of Henry, Joseph or Ralph Bankes MP. In the other half of Dorset the Weld family had a similar grasp of office.

I visited the last Ralph Bankes (not an MP) in the late 1970s. He was someone else's private patient and I had been requested to take blood for a CBC. It's an hour's drive, there and back. I remember I charged him £8. He was a tall, thin man with enormous hands and very large veins. The house was in poor order; he was land rich but income poor. He died in 1981, and being a homosexual, he left no issue. Instead of inheritance tax, his sister gave the house and grounds to the nation, together with Studland, a huge area of coastland between Poole and Swanage.

Anyway, the National Trust has renovated the house and laid out the gardens, and on a day when Bournemouth beach was crowded with bodies smelling of suntan oil, we walked round the country estate admiring the wild flowers and butterflies for about 4 hours in perfect solitude.

I didn't see much of London. We met at Wellington House, just a couple of minutes from Waterloo station, next door to the Old Vic, where Kevin Spacey is the actor/manager. Some of these gene therapy protocols are extremely difficult to understand. Today we had several new members of the committee and they were all a bit reticent in giving their opinions. There was also a division between scientists and doctors, with the scientists wanting more pre-clinical models and the doctors realising that eventually it has to go into man, and that more animal experiments won't change the human experiments. The TeGenero experience also weighs heavily on us, as two of the protocols involved going into normal volunteers. These volunteers are paid $4000 for a week's submission to the experiment. You can understand how young men would be attracted. Especially with that "It couldn't happen to me" attitude.

There are many clinical trials units springing up as commercial concerns now. The question is how they are regulated. All national health service hospitals, all private hospitals, all ambulance services, all general practioner services are regulated by the Health Commission (the organisation that my son works for). It ensures that appropriate standards are met, that patients' rights are upheld, that pharmacy standards are appropriate, that properly qualified staff are employed etc, etc. As far as we can discover, these clinical trials units are not regulated at all. Perhaps that is the lesson of TeGenero.

Tuesday, July 04, 2006


Having so many books to read makes deciding what to read next a diffcult choice. After three weeks of many away days with a lot of strenuous preparation, traveling, and speaking, I relaxed with a PG Wodehouse, 'Right Ho! Jeeves'. Entertaining enough with many a chortle, but I wanted something more substantial so I am now getting into 'Arthur and George' by Julian Barnes. It is the story of Sir Arthur Conan Doyle and his fight for justice for an Anglo-Indian solicitor who was falsely accused of a disgusting crime. It is about injustice and celebrity. It resulted in the establishment of the Court of Appeal. I've only read about 50 pages, so more about Conan Doyle later.

The newspapers are full of stories of injustice at the moment. The broadsheets are rumbling on about the Supreme Court's decision to rule the Military Tribunals at Guantanamo invalid, the red-tops are complaining about Rooney's sending-off at the World Cup.

Both these issues are complex and admit to no easy answer. Read Mark Steyne's essay here , or for more considered conservative response try this . The extreme liberal view is that Guantanamo should be closed down, President Bush leads a nest of criminals who seek to impose authoritarian rule, and the troops should come home now. Perhaps in between the extremes there will be a decision that suits all, or perhaps inflames everybody equally.

On Rooney's sending off the views are just as polarized. Anybody with a computer can re-run the incident. Rooney was sent off by the Argentinian referee for violent conduct. Watch the video and you will see that Rooney receives the ball, but is immediately tackled by three opponents. Remarkably, he does not fall over as most forwards are prone to do (prone being a good adjective for World Cup footballers) but fights for the ball. In the turmoil he clearly steps back on Carvalho's balls as he lies on the ground behind him. The referee is immediately surrounded by Portuguese players who encourage hime to give Rooney a card. Rooney is seen to push away Cristano Ronaldo, the ringleader of this group. The referee then fourishes a red card at Rooney who is thus dismissed the field. As he walks away, Ronaldo is seen to wink at the bench.

There is a subtext here. All three of the principals play for English clubs. Rooney and Ronaldo for Manchester United, Carvalho for their bitter rivals and the current champions, Chelsea. Rooney is well known to have a short temper and opponents use this to rile him in the hope that he will disgrace himself. Ronaldo has a reputation as a sly player who falls over to easily in the hope of fooling the referee.

As for Argentinian referee - there is a long record of rancour between England and Argentina. In 1966 the England manager called the Argentinian players animals because of their brutal fouls. Then there was the Falklands. Last time out Argentina was knocked out by England in the group stages and this time in the quarter finals by Germany. And who could forget the 'hand of God'; Maradonna'a handball that scored an illegal goal in a previous tournament

The crux of the matter is whether Rooney stamped on Carvalho's balls deliberately or trod on them accidentally as he sought to regain his balance. Rooney says it was the latter, the referee the former. Viewers of the video must judge for themselves. For what it's worth I think it is impossible to be sure, but I think it was an accident. The point is that it is impossible to give an unbiased opinion. That's why we have the rule of law and an independent court of appeal.

In English law a person is innocent until proved guilty, and the level of proof is 'beyond reasonable doubt'. There is a tendency for officialdom to believe its officials. In the Conan Doyle case the injustice was perpetrated by a policeman and endorsed by the Chief Constable. We have the principle that no body should investigate itself. On past form Rooney might banned by FIFA and be unavailable for England for their next several matches. With Beckham and Owen both injured this would place them under a handicap. FIFA are unlikely to overrule the referee since thgis would place the validity of their competition in jeopardy. It has been sugested that were Rooney to apologise he would receive leniency. That is the Shawshank Redemption catch - you never get parole until you admit your guilt, even if you are innocent. There is so much money in the game that someone might decide to sue FIFA. The decision then would be on the balance of probabilities.

Children everywhere utter the refrain,"It's not fair."

Have you ever thought why we think it should be?

Saturday, July 01, 2006

Summer Saturday

It's been a beautiful day in Bournemouth. The temperature is in the mid-eighties, but it's not humid and there is a gentle breeze to stop us scorching. As I sit on the lawn in the shade of the apple trees I can smell the jasmine and the lavender, unadulterated by the whiff of singed goat. The barbecuers are not out tonight.

I know where they are though; I can here the strains of Elton John coming through the trees. He is playing tonight at the local football ground and both my daughters have gone.

Talking of football; England are out of the World Cup. As usual they have lost on penalties. Just as two years ago in the European Championships, they lost to Portugal. Just as 8 years ago their golden boy has been given a red card; then it was Beckham, today it was Rooney. England raise their game as they played the last half of the match with 10 against 11, but they couldn't score. Once again they go out in the quarter finals. For England that is par for the course. It is what they expected; no better, no worse. More shocking for Brazil to go out. The last four are France, Germany, Portugal and Italy. Four European sides and no South Americans; the balance of power has changed.

It's the second pop concert my daughter has been to this week. Earlier she was listening to the Pet Shop Boys at the Tower of London. It's something I've never done - been to a pop concert. Can't say I'd really want to.

Andy Murray beat Andy Roddick at Wimbledon. The young Scot gives the Glaswegians a double celebration: England defeated and a Scotsman making the second week in the tennis.

Freddie Trueman dies from lung cancer at the age of 75. England's fiery fast bowler from the fifties has bowled his last over. I guess he couldn't stand the England one day team being whitewahed by Sri Lanka.

All is quiet, now. I have been studying that remarkable poem. It keeps coming back.

The cells divide. The cells that will not die
divide too well and so they multiply.
They kill the host to keep themselves alive