Friday, June 30, 2006

In America

At the end of a busy three weeks I take a trip to Boston to advise Big Pharma about the unmet needs in hematological oncology. Since the success of imatinib in CML everyone is into targeted therapy. It sounds good, but when it comes down to it there are just too many targets, and the drugs that are the excitement of the moment, Velcade and Revlimid, seem to block just about every pathway. So despite the brilliance of molecular biologists it is the clinicians who can point to where the effort should be focused. Readers of this blog could probably write their own script for CLL. We need something that doesn't also wipe out the T cells and we need something that kills cells that have lost their p53 genes.

The first thing that struck me about Boston was the new tunnel that moves you out onto the freeway in double quick time. The second thing was the weather. Almost as hot and humid as Singapore. The East Coast has been having tropical rainstorms and flooding, though it didn't rain in Boston while I was there. I flew business class by BA. The flight is less than seven hours so the red-eye doesn't take long enough to get a good night's sleep, even in those clever electric chairs that turn into beds. Instead, BA serves you dinner in the lounge before you fly so can at least get 5 hours shut-eye.

American television is never so good in America as it is in England. The News channels are parochial and everything is constantly interrupted by advertisements. Even on PBS you get thanks to all our sponsors, who are often the same people who advertise on the commercial channels. I enjoy watching House, ER and Gray's Anatomy. I was always a sucker for medical detective stories. I can leave aside the smooching and concentrate on the cases. My daughter is fan of CSI. But these shows take forever in America because of the adverts. At home I VCR them and fast-forward over the ads.

Americans are as friendly as ever and opinionated about their President (and his team/henchmen - strike one for whichever side you are on). I think this is new. It used to be that the President always attracted goodwill because of the office (like our Queen - we may rant about Prince Charles, but when he becomes King [Heaven forfend]we will revere him) but now somepeople haven't a good word for Mr Bush, and those that do haven't a good word for his opponents.

One of my correspondents, a poet with CLL, has written a new poem about the disease and posted it here. I think it captures very well the pathology of CLL and is very clever in relating the life of the tumor cell to the life of the patient.

The verse form is called a villanelle - you can Google it for an explanation - but he has departed from the strict rhyming structure. The best known example is 'Do not go gentle into that good night' by Dylan Thomas. I think that by using this verse structure he is evoking the memory of Dylan Thomas's poem, and expressing what most CLL patients feel - I shan't let this disease beat me without a fight.

There is a strange resistance in America to soccer and the World Cup. This quote from Andrew Sullivan's blog "Soccer is the perfect game for the post-modern world. It's the quintessential expression of the nihilism that prevails in many cultures, which doubtlessly accounts for its wild popularity in Europe,"

I guess this fits in with Gary Lineker's description, " Some guys in shorts and long hair run around in the sun for a couple of hours chasing a ball, then the Gemans win on penalties." It's certainly how the host nation beat the Argeninians this afternoon.

Wednesday, June 21, 2006


Michael Owen has ruptured his anterior cruciate ligament. The cruciate ligaments are the fibrous strands that hold the knee together, joining the femur (the upper bone) to the tibia (the lower bone). They cross over each other, which is why they are called cruciate. It is almost always the anterior one that gets torn. Typically the injury involves a twisting of the knee with the foot anchored and the weight of the body falling in such a way as to lever open the knee joint. It is extremely painful. I tore my left one in 1960 at the age of 17; it was the end of my chance of playing soccer seriously. In those days there was no treatment, though when I tore the right one in 1966 at least the doctors knew what it was and first aid allowed the inflammation to settle down more quickly. Brian Clough had his footballing career ended in 1962 when he ruptured his in a league game against Bury. Clough was the most prolific goalscorer for Middlesborough and Sunderland, and might have been England's greatest center forward had it not been for the injury. He went on to be one of teh greatest soccer managers England has ever seen, If not the greatest, thesn certainly on a short list of one.

Paul Gascoigne famously tore his in the 1991 FA Cup Final when attempting a high tackle on Nottingham Forest's Gary Charles. He was out for 16 months, but it was repaired and cape back to score that wonder goal against Scotland in 1996.

Alan Shearer did his in 1997, but after the repair he was back playing in 4 months and went on to become the greatest goalscorer in English football, though everbody said he had lost a yard of pace.

Prospects for Michael Owen are perhaps more dubious. He is a striker who relies on pace. He doesn't have the immense quadraceps of Alan Shearer and may find it harder to regain his winning ability.

England did enough to top their group and in patches showed how good they can be, but schoolboy defending allowed the Swedes to gain a draw. Their equalising goal in the last minute was remarkable. A throw-in from the left bounced over everybody into the right hand corner of the goal. It seemed to touch either Mellberg or Henrik Larsson on the way in. That touch was important; otherwise it would have gone in dirct from the throw, and been disallowed.

Monday, June 19, 2006

Volunteering for a phase 1 trial.

One of the interesting questions about the TeGenero trial was why it was conducted in normal volunteers. In fact why are any trials conducted in normal volunteers? Increasingly new medicines are targeted towards specific abnormalities that are often only present in a particular group of patients; it would be folly to use the agent in people who did not have the target lesion.

However, there are some agents that are aimed to be used in everybody - flu vaccines, for example, and normal volunteers could be expected to benefit.

But if there is no possible benefit, why would a normal person vulunteer?

It was a great suprise that after the Northwick Park incident, far from our seeing a reduction in volunteers, there was actually an increase. The reason is very clear; people became aware of how much money there was to be made from volunteering.

If money is the motive, or if there is some coercion (such as PhD students in the lab being asked to 'volunteer') then I think the trial is unethical. Patients who might have some small chance of benefiting from a phase 1 trial might well volunteer and those whose relatives or friends have suffered from the targeted condition might reasonably volunteer. Those who claim to be altruistically motivated should have their expenses reimbursed, but nothing that resembles a bribe must be given. It should be remembered that to impecuneous students a bribe doesn't have to be very great.

In my experience cancer drugs are never given to normal volunteers. Although the TeGenero antibody was possibly targeted at CLL, the company was mainly interested in rheumatoid arthritis, hoping that it would switch on regulatory T cells and so switch off the autoimmune process. Boosting regulatory T cells might not have been a good idea in cancer. On the other hand boosting normal T cells in normals turns out not to have been a good idea either. Had rheumatoid arthritis patients been used the effect might have been worse.

Clearly, testing 6 volunteers together was a mistake, but it is exactly how phase 1 trials of small molecules are usually done. The likelihood of serious toxicity is so small that the lower doses are hurried through. The problem here was unexpectedly the dose was very wrong. Whether this was a Siglec5 effect remains to be determined. I think a general lesson is that the first time a new molecule goes into man it should be into a man (or woman).

When we calculate the dose to be used, we estimate the number of target molecules on the cell and the number of target cells in the body, and calculate a dose necessary to saturate them. This rule of thumb methode can be substantially and unexpectedly awry.

Sunday, June 18, 2006

Body of a girl

My latest reading is a novel by Leah Stewart - Body of a Girl. It is told in the first person by a female crime reporter and tells the story of a promising young daughter of a well known doctor, who is found raped and murdered. The reporter inveigles her way into the dead girl's life by fair means and foul, looking for a suspect among friends and relatives, and uncovering an unsavory background of drug abuse and incest. The punch line is that none of this is true. She was killed by a stranger bent on robbery. The unsavory 'facts' are from false assumptions made by the reporter.

An antidote to investigative reporting.

Northwick Park

Tomorrow I have to give evidence at the enquiry about what went wrong at the Northwick Park Phase 1 study of the TeGenero superagonistic anti-CD28 antibody in March, when 6 normal volunteers suffered a severe systemic reaction that put them into the intensive care unit and almost killed them.

For those who haven’t been following the story, anti-CD28 is a costimulatory molecule on the surface of T cells. It is normally involved in the interaction between T cells and dendritic cells in an immune response. A protein antigen taken up by the dendritic cell is broken down into peptides which are then presented in a groove in the class II major histocompatibility (MHC) molecules on the surface of the dendritic cell. In performing the two functions, antigen capture and peptide presentation, the dendritic cell has to mature, losing its phagocytic function and developing the costimulatory molecules, CD80 and CD86, on its surface.

CD4 positive T cells are committed to react with specific antigens. The commitment lies within the T cell receptor (TCR) on the surface (this is the counterpart of the immunoglobulin molecule on B cells, and like immunoglobulin it is a different shape for every antigen). A CD4 positive T cell recognises the peptide in the MHC groove and moves in to dock with it. As the TCR engages with the MHC, various other surface molecules also link up, chief of which is CD80 with CD28. Stimulation and costimulation of the CD4 positive T cell cause it to proliferate and secrete cytokines like interleukin-2. The CD4 positive T cells is known as a helper cell and it aids other cells like B cells and cytotoxic (CD8+) T cells to attack the invader. The CD4+ reaction is controlled by a similar mechanism. When activated the CD4+ T cells produces a molecule CTLA-4 on its surface. This also reacts with CD80 on the dendritic cell, but this reaction has a suppressive effect. CTLA-4 is also expressed by CD4+, CD25+ T cells known as regulatory T cells, which also suppress an immune response by the same interaction.

Stimulating CD28 by itself does not stimulate T cells, the interaction of the TCR and MHC is also required. Instead of CD80, CD28 can be bound by antibodies to CD28, but most antibodies bind to a single CD28 molecule at a time and this is insufficient to build up a lattice of molecules on the surface of the T cells that causes stimulation. Antibodies against the TCR complex given together with an anti-CD28 can help to build the lattice. What TeGenero were able to do was produce an antibody that crosslinked CD28 and thus stimulate T cells without the need to ligate the TCR. In the event the antibody stimulated T cells too well and the volunteers almost died of an overactive immune system.

My contribution to this inquiry stems from experiments that we did in the 1990s. For many years my colleagues in Southampton, George Stevenson and Martin Glennie, have been working with antibody molecules, using chemical reactions to engineer the antibodies into different shapes (George worked in Oxford with Rodney Porter who won the Nobel Prize for discovering the structure of antibodies.) Antibodies have three business ends, 2 for attacking the target (known as Fabs) and one to bind to the various effector mechanisms that antibodies use to kill invaders with (such as killer cells, macrophages or complement). This end is known as Fc. You can think of three double pointed probes sticking out from a central hinge. A fairly simple chemical reaction will make them come apart at the hinge, and then they can be stitched together again, but not necessarily in the combinations that they were in originally. This we have made bispecific antibodies by taking one Fab from an anti-CD20 and one from an anti-CD16, and these can be made with or without an Fc.

The particular molecule that we tested was a trispecific with Fabs from anti-CD3, anti-CD2 and anti-CD28 stitched together. CD3 and CD2 are part of the TCR complex, and the purpose was to activate T cells by forming the lattice that I mentioned earlier. We examined this antibody in the test tube, and sure enough it was excellent at stimulating T cells. Both at making T cells divide and in making them secrete interleukin-2, it was 5 times as good as PHA, which is the standard reagent for stimulating T cells in the test tube.

We intended to use it in patients with melanoma, since we know that this is one of the few cancers in man that are definitely under immune control, and one of the few that responds to large doses of interleukin-2. We had experience of using interleukin-2 and we knew it produces very severe side effects. So we started our first-in-man tests at a very low dose. We decided to treat a patient with advanced melanoma who had no other available treatment and who had an obvious tumor on his skin that we could measure.

You all know the dose of rituximab – around 500 mg. Our starting dose was less than one two thousandth of that – 200 micrograms. Like rituximab, we gave it by slow intravenous infusion. It produced no effect. We gradually raised the dose to 1.2 mg. At this dose he had interleukin-2 type side effects – rash, fever, rigors, hypotension, muscle pain and rising serum creatinine. We stopped the trial. Although there was a marginal improvement in his tumor, it was clear that this treatment was no better than interleukin-2.

In our studies using various engineered antibodies, we have occasionally found other severe side effects. With an anti-CD37 x anti-CD64 bispecific used in advanced CLL we saw a patient with a similar cytokine storm, and with an anti-CD38-saporin immunotoxins used in intractable myeloma we saw transient blindness lasting 36 hours.

Of course none of this explains why the TeGenero antibody was so toxic in the volunteers when it was so harmless in mice and monkeys (which had a 500 times greater dose). I think that the answer to this lies in a paper from Nguyen et al in PNAS (May16 2006, 103:7765-70) They describe a molecule, Siglec-5, which is present on all animal T cells including chimpanzees, gorillas and orang-utans. Siglec-5 is an inhibitor of T-cell activation via the TCR.

From this I have drawn up some principles for the testing of biological agents in man.

1. Good as animal experiments are, there is no animal perfect model.
2. Biological therapy is increasingly targeted. There is no point in applying it in people who lack the target. It follows that trials in normal volunteers are inappropriate.
3. Agents are used first in incurable patients suffering from the target illness
4. Since the trials take place in individuals that have the target, they are designated phase I/II trials and look both at safety and efficacy.
5. One patient at a time is treated with time taken to evaluate the response
6. We give antibodies by slow intravenous infusion
7. We start at very low doses

Saturday, June 17, 2006


We have been having a mini-heat-wave in England with temperatures in the eighties. I had to spend a couple of days in Holland, where it was cold and wet. An interesting event on the plane home. I flew in a turbo-prop with only 27 seats, but the flight attendent calculated that we had 22 passengers instead of 21. She had a roll-call instead and found two passengers with exactly the same name who had been allocated the same seat. Somehow they had been assumed to be the same person when they were booking in.

There was a similar story in one of the medical journals last week. Sitting in an out-patient clinic the doctor asked for the next patient. When he came in he was accompanied by another man who sat silently beside him throughout the whole consultation. The doctor thought this a little strange, but knowing today's society assumed that this was his 'partner' with whom he had had a lover's tiff.

At the end of the consultation the patient left the room, but the other man stayed on. "Did you want to ask me something about the consultation?" asked the doctor.

"Yes," replied the man. "When are we going to talk about my case?"

It transpired that this man and the other patient had the same name and both had entered the clinic room when the name was called.

When I was much younger I had two patients with the same name. Their surname is the commonest in England, and both being children of the Victorian age, they had been named after the Queen's late consort. They had also been both born on the same day, though in different parts of the country. Strange to say, they had both at one time lived at the same address, one had sold the house to the other. Finally, they had both had a prostatectomy from the same surgeon.

There the resemblance ended. One was short and fat and the other tall and gaunt. One had CLL and the other polycythemia. I had been seeing them for several years at staggered three monthly intervals when I realized that they had been given the same hospital number and were sharing the same set of hospital notes.

Monday, June 12, 2006

World Cup

Good to see Australia beating Japan in the World Cup. I am glad that Tim Cahill scored a couple; he has been playing very well for Everton. No disgrace for the USA to be beaten by the Czech Republic, probably the best team in Europe; Eddie Johnson was the best American player. The biggest surprise so far has been Trinidad holding Sweden to a 0-0 draw.

England looked very good in the first half against Paraguay, but tailed off in the second when the 80 degree heat got to them. Hot weather doesn't suit the English style which relies on high energy, closing down the man on the ball amd much running off the ball. This is all much easier to do in a cold climate. England's only success in 1966 was played in England. Playing the game in June doesn't really suit the British players. In fact about the only venue that would really provide the weather they prefer would be New Zealand, preferably South Island. Pategonia would probably suit. Still, I'd like to see these South American Fancy Dans on a November evening in Newcastle. In two pairs of leggings and woolly gloves their delicate touches would be ever so slightly less likely to come off. They's be also put off by the Newcastle supporters who prefer to go bare chested throughout the winter.

Freaky Deaky

Elmore Leonard is over 80 and I've just got around to reading my first novel by him. Get Shorty and Jackie Brown were both based on his work, so it was about time I read him. Freaky Deaky is a cops and robbers novel that is amazingly well written. It moves so fast that you need to take time to appreciate the craft. There is no message and the characters are all various shades of pond scum, but they are well drawn and rounded. The plot is preposterous, but it hangs together and you could really believe it happening in such an exotic place as Detroit.

Detroit exotic? Hey, to a resident of sleepy old Bournemouth Detroit is exotic.

The characters are all left-overs from the sixties; still doing grass and acid. Even those with straight jobs have been left with a hanker after devilment. In a way, the characters all get what they deserve, so there is a pleasant sense of completeness when you finish it. What's nice about it is to enter the thinking of one character after another and watch each of them develop of strategy that trumps the last one.

Will I read another? Probably not, at least for a while. AW Tozer was once asked his reading strategy. "Don't read good books," he said. "There's not enough time." Read only great books."

Freaky Deaky was a good book.

Sunday, June 11, 2006

Cheaper by the dozen

I've just watched a DVD of "Cheaper by the dozen". This was a popular movie that got sniffy reviews by the critics.

I rather enjoyed it. Of course, it was a farce and a lot of people think farce is beneath them. It had the full panoply of slapstick and a lot of people don't like slapstick. But I think the real reason the critics didn't like it was that it portrayed an unpopular message. It said that you can't have it all. You can't have a family and a big career. No matter how hard you work, something has to go. Or you have to be married to a saint.

A successful marriage has to be built on compromises as well as promises. It is about putting other people in the family first. A successful career depends on putting the business first. That is too big a price for a happy family to bear.

Apparently 27% of evangelical pastors a suffering from burn out. The symptoms are failure to pray, failure to read the Bible, failure to fully prepare sermons. The consequences are yielding to sexual temptations. And if pastors suffer from burn out, what about the lay-leadership, who have a career to maintain as well as church responsibilities?

Burn out comes from over-commitment; taking on too much and never learning to say, "NO". I once took a time management course which instructed me to never commit more than 40% of my work time. The rest must be for thinking. I never knew a doctor who could comply with these instructions.

In the feeding of the 5000, Jesus had compassion on the multitude who had chased after them. He had first shown compassion for the emotional well-being of his disciples by taking them to a secluded. When the crowds turned up he had compasiion for the intellectual well-being of the crowd and taught them, then he had compassion for their physical well-being and fed them. A Christian doctor must follow this example, but guard against burn out.


Three inmates commit suicide at Guantanamo: how should we regard that? If one had killed himself, we might have put it down to being held in oppressive conditions, or cruelty by the guards. If three had killed themselves at intervals of a month or so, this point of view would have been endorsed. But three killing themselves at the same time sounds like a conspiracy. Remember these are people who regularly kill themselves as terrorist acts. Suicide bombers don't kill themselves to damage property or to kill a few American troops, they do it to push home a propaganda message, to attack allied morale, to sap the will of the American people. The suicides at Guantanamo have the same motive.

I was beginning to think that Guantanamo would have to be closed, but I have changed my mind. It may be that some of those locked up there were innocent by-standers, but these suicides make clear that among those imprisoned are some of the right people. If they are willing to engage in a suicide conspiracy to make a propaganda point, these are seriously dangerous people; the kind that become suicide bombers if they are let out.

Viet Nam became a media war in which the Americans were defeated because their public opinion was more tender-hearted. Iraq could go the same way. Whatever the reasons for toppling Saddam, Iraq has turned into a surrogate war between the forces of oppression and those of democracy. It may surprise some readers to learn that the oppressors are not the Americans but the Islamists who oppress people in the following ways: they do not allow women to dress the way they want to or to have an independent existence apart from that of their fathers or husbands; they do not allow the practice of any religion except their own and in particular do not allow those whose background was Muslim to choose a religion for themselves; they do not allow freedom of expression; they do not allow freedom of sexual orientation; they commend murderers; they dop not respect the human rights of their prisoners.

The new chairman of the East London Mosque, Dr Muhammad Abdul Bari, has given an interview to the Daily Telegraph. In it he praises Britain's tolerance, education system, innovation and hard work, but criticises drunkenness, gambling and divorce. Such critisism would not come amiss from the Archbishop of Cantebury, but not Dr Bari's proposed remedy - arranged marriages. Nevertheless, I applaud Dr Bari's approach to evangelism; he tries to convert people by reasoned arguement, not with bombs and bullets. It goes to show that Muslims should not all be tarred with the same brush. I think their religion is wrong and misleads millions, but in matters of religion people must be allowed to make their own mistakes. A coerced conversion is no conversion at all.

There is a natural tendency for the Press to stand up for the underdog. Enemies of America receive an oversympathetic treatment by the media because of this. People should realize that Amrica can be defeated only by propaganda. The enemy realizes this and all his fire is directed in this way. Journalists should apply the same scrutiny to allegations against the US government that they rightly apply to statements by the US government. Scientific journals now insist that authors declare their interests before publishing their papers. Newspapers should ask their informants to do the same. They are quick to declare when the Army is the source. Of course, there is no journalistic advancement in regurgitating government handouts, but a native source gains kudos. The native source recognizes how useful gullible idiots can be to its cause.

Just think for a moment what Guantanamo would be like if it were run by the Islamists. Hooded men would gloatingly behead the prisoners in front of the television cameras.

Saturday, June 10, 2006

Summer rambles.

Summer has undoubtedly arrived. Most of England is sweltering under cloudless skies with temperatures in the eighties. A drought order is being applied for in London. Here in Bournemouth we benefit from sea breezes that make the heat bearable. The garden is lit up by a haze of purple geraniums, all buzzing with visiting bees. Our plum tree bears fruit for the first time, though several leaves are speckled with tiny green bumps like ants eggs. I suspect an insect attck.

The small fountain is running, endlessly recycling the same few liters of water over pebbles and porcelain frogs. Once a pond was there, rich with water lillies in pink, red and white. Alas we had to drain it lest our grandchildren became pond life.

Clock golf was difficult. We secretly cut the grass without the gardener's permission, but our lawn lacks the smoothness of a putting green. When asked how the Wimbledon courts were kept so perfect the greens-keeper replied, "It's a simple process, sir, you plant the seed, then water, roll and cut for about three hundred years."

Our lawn has only been down for thirty years so it lacks the smoothness required.

It has been an eventful week. My daughter has been away in Budapest for a few days on holiday. I don't think she was very impressed. It was expensive and run down. Also cold and wet. My other daughter returned from her honeymoon in Mauritius. The weather was wonderful, but she was concious of the poverty of the locals who were providing her with luxury.

The disparity between rich and poor in the world seems an insoluble problem. I remember during the 1950s - a time of grim grime and hardship in England - watching the output of Hollywood with considerable envy. Watching smartly clad, beautiful people driving large cars, living in well-appointed, well-furnished apartments, going to night clubs clad in white tuxedos, drinking martinis with gorgeous women dressed in low-backed, sequined dresses emphasized how poor we were.

Men in England seemed always to wear grey shapeless jackets that were too short in the sleeve, uncreased trousers and down-at-heel, skuffed shoes. They couldn't even afford ready-made cigarettes, but smoked roll-ups constructed from the remnants of other people's smokes.

Of course, that picture of America was just as false as that in the mind of today's would-be Indian immigrant who regards Paddington, Edgeware Road, Tooting Bec and Streatham as magical places.

The English Flag of St George has been rehabilitated. Once it was only flown by far-right, anti-immigration political parties, but it has been redeemed by football supporters. It flies from every flagpole, every gas-station, almost every automobile. The World Cup began yesterday with Germany showing attacking flair but a leaky offside trap and Ecuador unexpectedly defeating the Poles. Perhaps the temperature had something to do with it. Isn't ecuador Spanish for equator? England play today against Paraguay. The form book says England should walk it, but I remember when Bournemouth beat Manchester United.

I guess the big news of the week has been the killing of Al-Zarqawi. Hard to think of anyone who deserved it more. The only dissenting voice seems to come from a Mr Berg, whose son was murdered in Iraq and who is running for office somewhere in America on an anti-war ticket. I guess that grief makes some men less objective than would otherwise be the case. In many ways I favor the death-penalty, but I have become convinced that enough mistakes have been made as to render it an impractical solution to the problem of murder. I do not consider it an immoral response by a community to the most heinous crimes, and I have no sympathy for those who are clearly guilty. Its great flaw is that it cannot be undone if a mistake is made, and it is a human inevitability that mistakes will be made.

What has changed from those grim days of the fifties is an enormous lessening of the fear of punishment. I used to have dreams - nightmares - about being hanged. I imagined that something that I might do might lead me to kill somebody. No doubt we are less deterred by the fear of punishment today. The number of homicides in Britain before the end of the death-penalty was about 160 a year: now it is about 1000; still rather few by American standards but continuing to increase. Can it be reversed?

Almost every day the TV News carries and item about one young person killing another with a knife - this is in a country where hand-guns are banned. You can't ban knives, people need them to cut their food with. At the moment the Police are running a knife amnesty. Among the items handed in was a Klingon Batalith (is that the right spelling? One of those double-handed battle axes from Star Trek). However, the dangerous weapon is the hand that wields it, not the sharp implement. To remedy that requires a change of heart.

In the BMJ there is an obituary of Jean Bernard, the French Hematologist who has died in his 99th year. Apart from describing a rare platelet disorder (the Bernard Soulier syndrome), he also introduced the anthracyclines (daunorubicin, adriamycin) for the treatment of leukemia. The BMJ credits him with diagnosing CLL in the Shah of Iran. It claims it was the admission of the Shah to America for medical treatment by President Carter, that prompted the Iranians to storm the American emabassy and take the hostages. If this is the case then it provides a stark contrast between the motives of the Christian Mr Carter and the Islamists in Iran.

By the way, Bernard got the diagnosis wrong. It was almost certainly splenic lymphoma with villous lymphocytes - or splenic marginal zone lymphoma as it is now called. It is said that the Shah failed to take the chlorambucil he was prescribed for fear of showing weakness. It would probably have made no diference.

Tuesday, June 06, 2006

Mercury fillings

Have you heard about all those people who've had their mercury fillings removed? Have you ever thought of doing the same? Can't decide?

Well, you'll be glad that the latest news will help you decide. I'm sure you've seen it splashed all over the newspapers. It wasn't in your paper? That's funny, it wasn't in mine either. Here's a summary:

The first large scale randomised control trials on the safety of mercury fillings were published just two weeks ago. They studied more than 1,000 children, some were given mercury fillings and some mercury-free fillings. Then they measured kidney function and various neurodevelopmental outcomes such as memory, coordination, nerve conduction, IQ, and so on, over several years. There were no significant differences between the two groups.

Not good news for dentists, I'm afraid. A lady I saw this afternoon told me that she's just seen a private dentist. On her first visit he offered to remove all her mercury fillings and relace them with 'safe' ones. That's strange, she thought, he didn't offer to do that when he was my NHS dentist. So she sacked him.

This is such important news that I'm surprised it wasn't in the newspapers. But then good news is no news, as the saying almost goes.

Monday, June 05, 2006


An important meta-analysis has appeared in the BMJ.

When COX-2 inhibitors appeared they were seen as an answer to one of the real problems of pain relief. For years gastroenterologists have been plagued by hospital admissions for haematemasis (bleeding from the stomach) following treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Drugs like Vioxx and Celebrex seemed to reduce the risk of bleeding. Alas, they also increased the risk of clotting. Vioxx, in particular has been blamed for causing heart attacks.

The meta-analysis looks at the thrombotic risk of COX-2 inhibitors compared to placebos and also old fashioned NSAIDs.

Sure enough there is a risk for all COX-2 inhibitors. Compared to placebos the risk of myocardial infarction went from 0.3% per year to 0.6% per year - an increased risk of 86% (confidence interval 33% to 159%). However, the striking thing was that compared to old fashioned NSAIDs there was no statistically significant increased risk.

This should not be too surprising. We know that the old fashioned NSAIDs inhibit both COX1 and COX2 to varying degrees. In fact, diclofenac (volterol or diclomax or motifene or arthrotec) is a very good COX-2 inhibitor. Even ibuprofen, widely available over-the-counter in various guises, carries the same risk. What stands out is that one particular NSAID seems to carry no increased risk of thrombosis. Naproxen (naprosyn or synflex or napratec) is an excellent COX1 inhibitor. Unfortunately, it seems to be the NSAID with the worst reputation for bleeding from the stomach.

What should we learn from this?

First, that the media hype and the compensation culture, directed at Vioxx was an over-reaction. For a start half the myocardial infarctions that occurred on Vioxx would have occurred if a placebo had been given, and as many would have happened if a standard over-the-counter pain killer had been used. It is also hard to blame a drug company for Vioxx if similar problems have been going unnoticed with the old fashioned NSAIDs for more than 20 years.

Second, we may ask why there has not been a similar outcry against the use of NSAIDs causing stomach hemorrhage.

Third, we are going to have to be more circumspect in our use of these drugs in future. I take ibuprofen in 800mg doses for my arthritis, but only once or twice a week. An editorial in the BMJ is entitled "Life without COX2 inhibitors" spells out the risk.

Sunday, June 04, 2006


The latest possible date for Pentecost is June 13th, so June 4th is a relatively late date for it, though three years ago it was on June 8th. Pentecost is 50 days (hence the “pent”) after Easter and occurs at the same time as the Jewish Shavuot, variously known as the Feast of Weeks (Deuteronomy 16:10), the Feast of Harvest (Exodus 23:16) or First Fruits (Numbers 28:26). For Christians it celebrates the coming of the Holy Spirit (Acts Chapter 2), seen as a fulfilment of the prophecy of Joel (2:28-32).

In England we no longer celebrate Whit Monday, which since 1967 has been replaced by the Spring Bank Holiday, which occurs on the last Monday in May. I guess that it was seen as more vulnerable than Easter, but with the introduction of the Communist May Day as a public holiday it now means that we have a cluster of Spring Holidays and then a long summer without one until the last Monday in August. Whit Monday was vulnerable because the Church had forgotten about Pentecost. One of the reasons for this was that the Church of England wished to distance itself from Pentecostal denominations that majored on Pentecost.

Pentecostal Churches associate the Holy Spirit with the spectacular gifts poured out on the Church: speaking unlearnt foreign languages, miracles of healing, visions and prophecies. I think that these churches made the error of not appreciating the significance of Shavuot. It is the Feast of First Fruits. The first fruits are a particularly Mediterranean phenomenon. Harvest does not normally occur in May – this is the early harvest, an earnest, (if you like a deposit) of what is to come later. It is clear that the miraculous gifts of the book of Acts were short lived. In Acts 91:12 we read of Paul’s handkerchiefs touching the sick and healing them, but later on he writes to Timothy to take a little wine for his stomach’s sake and his many ailments. Why didn’t he send a handkerchief?

The miraculous gifts were the first fruits. To pretend that they are still present is technically known as realized eschatology; the idea that the ‘last things’ are already here. Concentrating on the gift of tongues misses out on what it was there for. The point about Acts chapter 2 is that everybody present heard them speaking in his own language. It was the message that was important not the medium.

The Jews of the Gospels were notoriously insular. There had long been strictures about marrying out for fear of foreign gods. In the conquest of Canaan no prisoners were taken. But as God’s chosen people they were chosen for a purpose – to let the world know about Him. So the Deuteronomy passage about Shavuot specifically mentions foreigners among the blessed. Jesus’ first sermon (Luke Ch 4:14-28) raised the anger of his listeners because he spoke of God helping the Gentiles giving examples of Elijah helping a widow from the region of Sidon and Elisha curing the leprosy of a Syrian rather than an Israelite.

When modern Biblical critics consider the two feeding miracles in the Gospels (of the 5000 in Mark 6 and 4000 in Mark 8) they assume that this is the same event somehow confused, but they fail to notice the differences between them. The 5000 took place on Jewish territory in Galilee and the 4000 in Gentile territory in the Decapolis. In explaining their meaning in Mark 8 Jesus harks on about the numbers of baskets. “Do you still not understand?” he asks.
The numbers give the clue. Many people are sceptical about numerology, but without doubt numbers had an important significance in Biblical times. The Jewish feeding is full of Jewish symbolism. 5000 refers to the Pentateuch, the 5 books of Moses; note also there were 5 loaves. Arranging the people in groups of 50 and 100 harks back to Moses in the Wilderness. The 12 baskets refer to the 12 tribes of Israel. The Greek word for basket used here is a specific term for a small lunchbox sized basket used by the Hebrews. On the other hand the word for basket used for the feeding of the 4000 refers to a hamper sized receptacle used by Jews and Gentiles alike. The 4000 is symbolic of everyone – the 4 points of the compass. The 7 baskets refers to the ‘perfect number’ representing all nations; note also there were 7 loaves.

All through the Old Testament there are signs that the Jews were to share ‘their’ God with the rest of the world. Abram is renamed Abraham, the father of many nations. Isaiah talks of his servant being a light for the Gentiles (44:6, 49:6), and Zechariah 8:22 has “many peoples and powerful nations will come to Jerusalem to seek the Lord Almighty.”

Finally Jesus gives the Great Commission, “Go and make disciples of all nations…”

Pentecost is about evangelism … and it worked. Three thousand converted in a single day; evangelists spilled out all over the Roman Empire and beyond,.all preaching a message of a suffering saviour who died to save us and rose to free us and will return to take us home.

My Lord what love is this
That pays so dearly,
That I, the guilty one,
May go free?
Amazing love,
O what sacrifice!
The Son of God given for me.
My debt he paid
And my death he dies
That I might live

Graham Kendrick

Friday, June 02, 2006

This is a true story.

This is a true story. My memory was prompted by Jenny Lou's posting that a watery discharge from the eye turned into white pus after steroids.

It happened about 20 years ago, before we had acyclovir. In those days I had a patient with a very high white count, well over 400K, with massive lymphadenopathy - glands in the armpits about 15cm in diameter - but a normal haemoglobin and platelet count. His serum immunoglobulins were just about undetectable; this was also before iv Ig. Every time we tried to give him chemotherapy he developed widespread herpes simplex lesions all over his body.

In desparation we turned to leucocytapheresis to control his disease. This was quite an ordeal for him as he was 87 years old, but he bore it patiently and even developed an interest in teh creamy solution we were extracting from his blood.

After several session he approached me after the nurse had gone home for the afternoon. "Doctor, I think I have discovered why I have this CLL."

I'm always interested in new theories, so I played along with him, "What do you think it's caused by then?"

"I haven't had sexual intercourse with my wife for 37 years," he said, "it's back pressure."


We have all heard of p53, usually in a negative way. We know that cancer patients whose p53 has gone missing have bad news disease. It is the gene that is most commonly disrupted in cancer. In CLL deletion of 17p13, where the p53 gene is located, or mutation of the gene so as to make it non-functional, leads to poor prognosis, drug-resistant disease. So what does p53 do?

It is often called the Guardian of the Genome, meaning that it's role is to guard against copying errors in the DNA. The idea is that it recognizes when a mistake is made, puts the cell into stasis to see if it can be repaired, and if it can't, orders the cell to kill itself. It's a dangerous molecule to have around; kept on a leash doing what it's told it serves an essential function; let loose, like the dogs of war, it could cause untold damage.

One of the ways of controlling p53 is through the molecule MDM2 (it stands for Murine Double Minute - a reference to the mouse chromosome it is found on). In humans mdm2 is on the short arm of chromosome12. MDM2 is the master regulator of p53. (By the way, if you are getting confused by the use of italics, the covention is that the gene is in italics and small letters whereas the protein is not italicized and often capital letters are used. p stands for protein and the 53 refers to the molecular weight in kiloDaltons. there are other important molecules called p21 and p16 etc.)

MDM2 controls p53 in several ways, including blocking its transactivation domain so that it blocks its ability to activate transcription, also by aiding the nuclear export of p53 and by acting as a ubiquitin ligase to promote p53 degradation by proteosomes. Normally a cell has very low levels of both p53 and MDM2. It has been well demonstrated that disruption of p53-MDM2 interaction leads to activation of p53 and tumor suppression, but until recently disrupting this interaction has been very difficult. The breakthrough came from examining the crystal structure of MDM2 which showed that there is a relatively deep hydrophobic (= water repelling) pocket in the molecule which raised the possibility that small molecular weight molecules might be able to block the interaction with p53. Scientists at Roche have been screening molecules that might do this. They hit upon a series of molecules called cis-imidazolines (Chaya will understand precisely what this means) which they named Nutlins. The name puzzled me for a while until I realized that the Roche Research Institute is based at Nutley, New Jersey. Thus Nutley inhibitors.

The nutlins have been shown to activate the p53 pathway and to have anti-tumor effects in tumor cell lines, especially in those that over-express MDM2. and including some cell lines derived from acute myeloid leukemia and myeloma. In fresh CLL cells the nutlins activate the p53 pathway and induce apoptosis. They synergize with fludarabine and chlorambucil and they are much less toxic to noemal T cells.

They seem to have great promise in CLL; they are orally available and they penetrate cell membranes. Of course they have yet to be tried out in patients, but it can't be long before they are in clinical trials. In order to act they require an intact p53 pathway, so they will of no use in drug resistant CLL, but nevertheless to have a non-toxic agent in CLL that works will be a great boon.

Thursday, June 01, 2006

Trading estate shopping

We have blue tits nesting in the bird box in the garden, which means no more football on the lawn. With eldest grandson coming on Monday this presents a problem - how to entertain him all day with no soccer. The solution we hit upon is clock golf. But where to buy a clock gold set? None of the local stores can help, so we resort to the internet. We find that they are made by the ancient firm of Jacques - who made John Prescott's croquet set. We find a site who will sell us a set, but they suggest delivery will take 5-7 days. That will not guarantee that we will get it in time, but the site also suggests "If you are local, drop in and see us."

They are based in Downton, a small village between here and Salisbury. It's a nice drive that takes half an hour or so along country lanes. We arrive at a rather forbidding and deserted trading estate amd enter what seems to be a block of offices. Yes, they'd be happy to sell us a clock golf set and immediately produce one. They have a staff of five very pleasant people who do most of their business over the web, but have about seven customers a week who call in, so it is an event when someone does. Their main business is kitchenware so I ask them if they have a carving dish with rubber feet that won't slide all over the working surface in the kitchen. Not only do they have one, but it doubles as a chopping board and has a heat retaining block to stop the meat cooling while cutting. They have another sale. We are very popular when we leave.

We proceed to another trading estate in Poole, looking for an art gallery. We have been through the yellow pages looking for art galleries because we want to give out daughter a present reminding her of home when she returns from her honeymoon in Mauritius. All the galleries in Bournemouth have large tasteless paintings that are massively overpriced. At the Poole trading estate he has thousand of pictures - prints and originals - and hundreds of choices of frame. He shows us a set of watercolors of Christchurch harbour by Christopher Hollick, a local artist who has now moved to Norfolk and won't be painting any more Dorset views. We purchase three.

I don't like shopping as a rule. I mainly visit the internet when I want to buy something, but trading estate shopping seems tolerable. The man at the art gallery gave us a book about the Dorset Art Fair. Local artists are exhibiting in their own homes for the next month. It is an opportunity to see what they have to offer. The first one we must visit lives 5 doors away from us. After 30 years at this address it is a wonderful excuse to meet out neighbours.