Friday, November 28, 2008

Churchill 1899

At the age of 25 Winston Churchill wrote this:

"How dreadful are the curses which Mohammedanism lays on its votaries! Besides the fanatical frenzy, which is as dangerous in a man as hydrophobia in a dog, there is this fearful fatalistic apathy. The effects are apparent in many countries. Improvident habits, slovenly systems of agriculture, sluggish methods of commerce, and insecurity of property exist wherever the followers of the Prophet rule or live. A degraded sensualism deprives this life of its grace and refinement; the next of its dignity and sanctity. The fact that in Mohammedan law every woman must belong to some man as his absolute property (either as a child, a wife, or a concubine) must delay the final extinction of slavery until the faith of Islam has ceased to be a great power among men. Individual Moslems may show splendid qualities. Thousands become the brave and loyal soldiers of the Queen; all know how to die; but the influence of the religion paralyses the social development of those who follow it. No stronger retrograde force exists in the world. Far from being moribund, Mohammedanism is a militant and proselytizing faith. It has already spread throughout Central Africa, raising fearless warriors at every step; and were it not that Christianity is sheltered in the strong arms of science (the science against which it had vainly struggled)the civilisation of modern Europe might fall, as fell the civilisation of ancient Rome."

Alas, the science is transferable.

Living forever

I see that the world's oldest person has died in Indiana. Edna Parker, died on Wednesday in a nursing home in Shelbyville, Indiana. She was 115 years, 220 days old. Coincidentally it was the same nursing home where the world's tallest woman died last year. Maria de Jesus of Portugal, who was born on September 10, 1893, is now the world's oldest living person.

I noticed that at the Cenotaph memorial service in London on November 11th the oldest survivor of the First World War laid a wreath. He was 114.

People are living longer. I saw in a news item that scientist reckon that they will be able to reverse aging. So I thought to myself, 'Would I want to live for ever?' The answer, of course, was, 'Not if I have to put up with this backache.'

When we see these very old people we pity them. Their bodies have become shrunken and feeble. The man at the Cenotaph wanted to lay the wreath himself, but in the end he was unable to rise from his wheelchair. Our bodies betray us. If we escape disease, the wear and tear of normal living destroys the cartilage in our joints, enfeebles our muscles and dims our senses. We accumulate more and more bits of plastic and stainless steel. Teeth, lenses, joints, heart valves; the replacement industry is one to buy shares in.

The Bible tells us that 'there is a time to be born and a time to die'. Yet Christians expect eternal life. I pose the question, "If scientists really did solve the aging question; if they reversed the wear and tear and left us with the bodies we had when we were 25 and our minds continued to work well and accumulate knowledge, would they still want the eternal life the Bible offers or would they want more of this present world, albeit with new super resilient bodies?"

Paul calls the situation of the dead Christian 'better by far'. Why is that? In the first place, we won't be stuck with these mortal bodies. Here is what Paul writes in I Corinthians Ch 15 "We will all be changed." and "We shall bear the likeness of the man from heaven." and "The perishable must clothe itself with the imperishable."
In Romans 8:29 he writes that we are destined to be 'conformed to the likeness of his Son' and in Philippians 3:21, "we eagerly await a Savior from there, the Lord Jesus Christ, who, by the power that enables him to bring everything under his control, will transform our lowly bodies so that they will be like his glorious body."

Second, we will be with Christ. Paul writes in II Corinthians 5:6 that as long as we are at home in the body we are away from the Lord. He would prefer to be away from the body and at home with the Lord. Whenever I go away to a meeting I miss my wife. I am so pleased that this year at ASH we will be going together. We will be able to share the experience of visiting San Francisco. Normally after just a few days away I am longing to be back home. This feeling of longing is multiplied a hundred times for the Christian. To be at home with Christ must be bliss.

Third, it is all about where we will be with Christ. The disciples knew Jesus face to face and that must have been a wonderful experience, but it was detracted from by the fact that they were living under Roman oppression, in a place of poverty and hardship. People around them were crooks and charlatans, pompous and proud, bombastic and overbearing. They encountered disease and sickness every day. There were beggars and blind men on most street corners. Persecution was the way of the world. When we die we go where there is no sin. No more crying then. He will wipe away all tears from our eyes.

So we have no need to cling to this crippled frame. Anything the scientists come up with will be definitely second best - and were we to live 'forever', the world will end someday. He is coming again.

Tuesday, November 25, 2008

Christmas poem 2

I was asked to write a fourth verse to the Christmas poem, so here it is:

I came to you at Christmas but not just for Christmas Day.
All through the year I’ll hunt you and I will not go away.
Though you think you do not need me, that your staying power’s too strong,
The calamities that crush you will be bound to prove you wrong.
If you think you’re irredeemable; you’ve long since burnt your boats;
The die was cast when years ago you sowed your wild oats,
Oh! Hesitate to think so for I’ve rescued worse than you,
My blood can make the foulest clean; I offer life anew.
I came to you at Calvary; to you and all mankind,
To give you peace from God above; none need be left behind.
Don’t let the world distract you, don’t hanker after things,
However they attract you, they always come with strings.
My Christmas present for you is superb beyond compare;
On that Resurrection Morning won’t you meet me in the air?

Surgery in CLL patients

CLL mpatients have to have operations just like anybody else. Are they at particular risk? The answer is no, not unless they have reduced platelets or reduced neutrophils. The reduced immunoglobulins or T cell deficiency do not come iinto play. Surgeons always take account of the platelet count and set their own safety levels according to the type of surgery. If the neutrophil count is less than 1 then either G-CSF or prophylactic antibiotics may be necessary.

The particular operations that CLL patients are subject to are, bone marrow biopsy, for which no special precautions are necessary, lymph node biopsy, which is usually safe if superficial, though a deep lymph node may require platelet cover, and splenectomy. If possible I recommend laparoscopic splenectomy as teh blood loss is usually less. An open operation does carry greater risk and in this circumastance particular attention must be paid to platelet and neutrophil counts.

Sunday, November 23, 2008

Psalm 62

Last week we were at a family funeral, this morning a visiting preacher told us of one of his elders who was suffering from terminal cancer. On both occasions the sermon was based on Psalm 62. I imagine that at Bible College they tell you that a good topic for sad occasions is Psalm 62. It comes with the instruction pack.

It is supposed that David wrote the psalm when he had been deposed by his son, Absalom, before he regained the throne, but it doesn't really matter; its theme is universal.

Sometimes we find ourselves in a vulnerable condition; a leaning wall, a tottering fence - we are real pushovers for adversity. Where do we turn to for support?

We may turn to others. So we should. Being part of a Christian community not only requires us to help those in need, but also to ask for help when we are in need. But though others may help we cannot rely on them. They will let us down. The middle verse in the whole Bible is "Put not your trust in princes." For as we see here, "Lowborn men are but a breath, the highborn are a lie; if weighed on a balance they are nothing; together they are only a breath." From the highest to the lowest, a man is but a puff of wind; he is ephemeral. Be he ever-so trustworthy he has no control over the future. How many have faltered when their sponsor or mentor is carried off by death or by new circumstances. As a young doctor I had hitched my wagon to a rising star (there's a good mixed metaphor), until one day he told me he was off to Chicago and I was left to fend for myself. Be he ever so important or just a journeyman, a man may promise the earth but he cannot guarantee to deliver. Perhaps this night his life will be required of him.

You might put your trust in riches. In today's climate who would dare? I do not have a job to lose so I won't be affected by my firm going bust, though many will. I don't have a loan so I won't be made bankrupt if the loan is called in, though many will. I don't have a mortgage so I won't be forced to sell my house at a loss, though many will. Nevertheless, the pound has declined against the Euro and the dollar so much of my wealth has disappeared. In order to bail out the banks the government has borrowed billions. Those billions must be paid back and the government can only repay by taxing more. It's like putting your money in a pocket full of holes. I have not set my heart on riches.

Who then can be relied upon? Where then can my soul find rest? In God alone. He alone is my rock and my salvation. He is my fortress, I shall not be shaken.

Over and over again this psalm insists that we are secure in God and nowhere else. One thing God has spoken, two things have I heard. That you, O God are strong.

It is a sign of the times that we have this picture of a weak and watery God. I have just finished reading "Seeing Red" the autobiography of Graham Poll the soccer referee. Poll is famous for his action during the 2006 World Cup. Certainly the top referee in the UK and highly regarded throughout the world, in many quarters he was expected to be chosen to referee the World Cup Final. As it happened it was to be an Italy v Germany Final so he would have been strongly tipped to get the match as the culmination of a long career.

Those who don't know soccer should recognise it as a violent game. In America is is often seen as a game for children and women, but in Europe and South America it is a game for real men who don't wear body armor. In Columbia and Iraq you are likely to be shot if you lose. In certain countries racism is rife. Twenty years ago crowd trouble was very common with pitched battles in the stadia and streets. Supporters were killed. Although some measure of control has been achieved, the fans are still aggressive. They are known for their singing. The songs are often funny, but more usually sexually explicit and abusive. The referee is often the butt of the humor.

The players are frequently foul-mouthed, deceitful and aggressive. They seek to intimidate the referee into favoring their side. The only defence that the referee has is the card system - a yellow for a warning, but a second yellow means a red card and dismissal from the field of play. At least it did until Graham Poll came along. In the Croatia versus Australia match he managed to give a Croatian defender three yellow cards. It was a tragedy for Poll and ensured that he was sent home in disgrace, his lifetime ambition unfulfilled.

A lot of people see God like that - a lot of warnings but no red card. They imagine a God who talks big but doesn't deliver. They mistake patience for tolerance. They think he winks at sin. So many people seem to 'get away with it' that there seems no point in obeying the rules. "They take delight in lies; with their mouths they bless but in their hearts they curse."

At football matches a company called Pro-zone films every incident. Thirty-six video cameras watch the action from every angle. The referee may miss a shirt tug or a sly push, but the cameras collect it. Things missed by the referee may still result in a retrospective red card. Pro-zone may be new to the Premier League, but God has had it for years. He never misses a trick.

What a referee to have on your side! Nothing the opposition can throw at you goes unnoticed. He is a strong supporter.

But why doesn't he act? The thing is, He is concerned about the result. In any game of football there may be setbacks. In the European Cup final a couple of years ago Liverpool were 3-0 down to AC Milan at half time. It would have been easy to give up in the face of such adversity. Liverpool refused to surrender despite the set-back and eventually won on penalties. God is not primarily concerned about our comfort. He is not looking out for our bank balances. He cares about the result. It is our salvation that matters, ours and every one else's. He is strong enough to protect those He loves.

That was the second thing the psalmist heard. God is not only strong, He is loving. That's why he is so patient. It is not His purpose that any should perish, He wants everyone to repent and reform. You may say it's not going to happen, but how do you know? The most unlikely have turned from their wicked ways. Look at the Nixon henchman, Chuck Colsen. Look at that privileged crook Jonathan Aitken. What about you? You changed didn't you? Do you imagine that others like you won't?

Saturday, November 22, 2008

Shingles vaccine

It has been standard advice that CLL patients should not receive vaccines containing live attenuated viruses. Thus MMR, oral polio, yellow fever and a few others are forbidden to patients with CLL, even those with mild disease.

The reasons for this are that patients with CLL have a profound immunodeficiency that is hard to measure. The most obvious manifestation is the low level of serum immunoglobulins, but there is also an ill-defined T-cell defect and a difficulty in antigen presentation by antigen presenting cells (APC).

Now all cancers are associated with poor immunity and all tumors of lymphocytes (lymphomas) have particularly poor immunity even among cancers, but CLL is worse than all the other lymphomas, with the possible exception of Hodgkin’s disease. I think it is the APCs that are the main problem. These are necessary for foreign antigens to be processed into a form recognized by T-cells, and T-cells are necessary for B-cells to make antibody. Normally, dendritic cells are the APCs but in CLL the CLL cell can act as an APC – but a very poor one. I think that what is going on is that the CLL cells – being present to a numerically greater extent than dendritic cells – grab the available antigen and hide it from dendritic cells. Like dogs in the manger they can’t do the job very well themselves but they don’t allow the professionals to do the job properly.

The result is that response to vaccines in CLL is very poor. I demonstrated this along time ago (1974) using the bacteriophage phi-X-174. This is a virus that lives in the bacterium e. coli. It is a new antigen for humans, but very immunogenic. Patients with CLL are completely unable to make antibody to it when they see it for the first time, although if you keep injecting it about half will eventually make a smidgeon of a response. The interesting thing was that even stage 0 patients with very low white counts suffered from the same defect. Among our normal controls there was one individual who had a much better response than anyone else. Two years later he developed Hodgkin’s disease – suggesting that even early Hodgkin’s disease does not have the profound immunodeficiency that early CLL does.

Immunity to Herpes viruses is a special case. Most of us are exposed to most of the herpes viruses when we are children and we never get rid of them. The commonest example of this is a cold sore. If you’ve ever had one you’re bound to have another. You know the things that bring them on: another virus infection like a cold, exposure to the sunlight, being run-down by any of life’s troubles, chemotherapy – anything in fact that diminishes our immunity. This is because the herpes simplex virus, once it inside us stays there and is kept under control by the body’s immune system. Herpes simplex II, which causes genital herpes, varicella/zoster, which causes chicken pox and shingles, EB virus, which causes glandular fever and CMV, which causes a variety of illnesses, are all herpes viruses that continue to live within us after an infection. CMV is especially interesting since about 15% of individuals over the age of 60 have never met it. It is a well known fact that untreated patients with CLL have increased numbers of T cells – but this is only true for those who have previously been infected with CMV. It turns out that the excess T cells are programmed to keep the CMV under control. Similarly with EBV; a lot of T cells are keeping the EBV under control.

Varicella/zoster lives in nerve cells and if immunity drops it crawls out along the nerve the area of skin (a dermatome) supplied by that nerve and causes a very painful rash (shingles). This occurs in about a quarter of old people, but it is rather commoner than this in patients with CLL, and in CLL patients who are treated, especially with fludarabine of Campath, or who have a transplant, it is much more common, unless they have aciclovir prophylaxis. In those with the most severe immunodeficiency, the zoster rash will disseminate and become a florid chicken pox. What doesn’t happen is patients with CLL catching shingles (or chicken pox for that matter) from a child with chicken pox. It seems that you can’t get a superinfection with varicella/zoster, even if you are immunodeficient.

What has brought this up is some correspondence that doctor and CLL-sufferer, Brian Koffman, has been having with Dr Rafael Harpaz of the Herpes Virus Team, Division of Viral Diseases, NCIRD/CDC over the advice given by the Advisory Committee on Immunization Practices (ACIP) on vaccination against shingles in patients with CLL.

The statement that he and I both take exception to is “Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines.”

As far as live viruses generally are concerned, this may well be true for solid tumors and for AML, CML and ALL, and perhaps for diffuse large B-cell lymphoma, but CLL is a special case among secondary immunodeficiencies since treatment makes the immunodeficiency worse, not better. The only treatments that induce complete remissions in any quantity are combinations containing purine analogues like fludarabine or the monoclonal antibody alemtuzumab. Both types of drug suppress CD4+ T-cells to AIDS-like levels and the suppression continues for at least six months in the case of alemtuzumab and in excess of two years in the case of fludarabine. We in the CLL community recommend that prophylaxis against pneumocystis continue for at least a year or until the CD4 count is greater than 200. It would be perverse to allow vaccination with live vaccines at three months into a remission. The blood transfusion authorities insist on irradiated blood transfusions for patients who have received fludarabine or alemtuzumab, because of the risk of transfusion-induced graft versus host disease. I am sure that we should not allow treated CLL patients to receive live-virus vaccines.

In 30 years experience of treating CLL I have never known patients to recover their immunity, no matter what treatment has been given. Complete remissions in CLL are unsatisfactory, allowing the marrow to retain 30% lymphocytes. Newer standards of response involving elimination of minimal residual disease (MRD) have not been evaluated for any return of immunity, but suppression of B-lymphocytes to this degree usually involves equivalent suppression of T-cells.

However, perhaps the zoster vaccine is a special case. This is how the ACIP argument runs:

“*Virtually all adults aged 60 and over are at risk of HZ (i.e., are infected with latent varicella zoster virus, or VZV). In contrast to other live vaccines, HZV does not protect by preventing infection but by preventing reactivation of this latent infection, which is much more likely in immunocompromised persons. A strategy of vaccinating household contacts would not protect a person with CLL (in contrast, say, to vaccinating household contacts with varicella vaccine to protect a child with leukemia).

* People receiving HZV have pre-existing immunity to VZV. While second episodes of chickenpox occasionally occur, second VZV infections remain uncommon even among the most profoundly immunocompromised persons and those rare episodes that do occur are not severe. Immunity to VZV in such patients appears to be adequate to protect against disseminated infection from the wild-type, natural VZV virus, and the risk of adverse effects from live-attenuated VZV contained in HZV should be correspondingly lower.

* In fact, there is empiric evidence to support the safety of HZV in immunocompromised persons. In early trials, the live-attenuated VZV used in varicella vaccine as well as HZV was administered to hundreds of profoundly immunocompromised children with leukemia in remission and *without* preexisting immunity to VZV, and the vaccine was well tolerated. These children tolerated subsequent second doses of the vaccine even better. Live attenuated VZV has since been safely and effectively used in many more children with other immunocompromising conditions such as transplant recipients and HIV infection. Live attenuated VZV is now recommended in HIV-infected persons without prior immunity to VZV. Finally, live attenuated VZV has also been used in HIV-infected children with prior varicella infection and immunity. As would be expected, the children tolerated the vaccination very well.

* General guidance on use of live attenuated vaccines by persons with leukemia has been evaluated by ACIP and published in their General Recommendations on Immunization published Dec. 2006. The document states that "Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines."

Given the potential severe, life threatening HZ in persons with CLL in remission, and the considerations regarding the safety of this vaccine, the ACIP recommends that the vaccine should be used in such circumstances.”

Their argument is not without merit. It could well be that the presence of the HZV virus under control signifies that there is sufficient protection against reinfection with new HZV and that an attenuated HZV virus vaccine would be without danger. I certainly hope so. But it would be foolhardy to accept this without an appropriate clinical trial. Experience in ALL in remission and among children with HIV infection before they become profoundly CD4+ T-lymphocytopenic is not relevant to what would happen in CLL.

A clinical trial is feasible, since it would be possible to vaccinate patients with antivirals standing by in case a serious infection ensues. I think that such a trial should be conducted, but it won’t be as long as Merck is bolstered by the advice from ACIP.

Sunday, November 16, 2008

Idiotype vaccines - an update

The idea that the B cell receptor might be used as a target for immunotherapy belongs to George and Freda Stevenson who published a paper in Nature in 1975. They called this target idiotype because it was the same for every tumor cell but different for every other normal B lymphocyte. The following year they made an antibody which I used to treat a patient with CLL. Subsequently Ron Levy at Stanford made monoclonal antibodies against idiotype and successfully treated patients with non-Hodgkin's lymphoma with them. In 1981 Ron Levy and George Stevenson were jointly awarded the first Armand Hammer Prize for Cancer Research for this work.

It soon became apparent that the labor involved in making made to measure anti-idiotypic monoclonal antibodies for lymphoma patients was so great, that it was never seriously feasible - even in America, and certainly not in the NHS. The focus turned from monoclonal antibodies to idiotype vaccines. Work in mice showed that it was possible to produce immune responses against idiotype that were therapeutically active. Ron Levy managed to produce vaccines from the patients' tumors and carried out a trial in lymphoma patients. In a paper published in 1997 in Blood he showed that if an antibody response was generated by a patient against the idiotype vaccine, then such patients lived for significantly longer than patients who were unable to generate an antibody response. This looked like good news, but an alternative explanation, other than that the vaccination was doing the patients good, was that this was a way of separating good risk patients from bad risk patients - if you were capable of mounting an immune response you were in a better risk bucket than if you couldn't

Nevertheless, this result was so encouraging that no fewer than three randomized clinical trials were undertaken to see if vaccinated patients lived for longer than non-vaccinated patients. AT least two of these trials have now reported (though not yet published). The bottom line is that it is certainly true that if you make antibody against idiotype you live longer than those who can't make antibody, but overall there was no difference in survival between the two arms.

Last week at the Annual LRF lecture, I heard Ron Levy give an update on these trials. The idiotype protein is strapped to a carrier protein called Keyhole Limpet Hemacyanin (KLH) Rather than go to the expense of measuring anti-idiotype (a separate assay for each patient), you can pick out your good responders by measuring the response to KLH. Sure enough the vaccinated patients who made an antibody response to KLH did better than those who did not - so if you want to use it as a screening test choose immune response to KLH rather than immune response to idiotype.

Of course the control patients were given KLH and some made a response to it. The important question is, "Do they get an improved survival over control patients without an immune response to KLH?"

The answer is, they do not. Therefore, if you are capable of generating an immune response, then vaccination against idiotype does improve survival - at least that is the new hypothesis. Because this was a subset analysis, and the original trial was not designed in this way, the statistics are not valid. The results can only be used for hypothesis generating. A new randomized trial restricting the entrants to those capable of making an immune response is about to start.

I emphasize that this is in follicular lymphoma. Although a trial in CLL has been under way, CLL patients have a poor ability to generate an immune response and are therefore not good candidates for such a trial.

Another trial mentioned by Ron Levy concerned the use of CpG - an immune stimulant that stimulates antigen presentation via the Toll-Like Receptor 9 on dendritic cells. It appears that this process can be stimulated by a mixture of monoclonal antibodies - an agonistic anti OX40 antibody and an antagonistic anti-CTLA4 antibody.

Wednesday, November 12, 2008

Christmas poem

I came to you at Christmas when the frost had fixed the grass,
When they decorate department stores with balls of coloured glass,
When the Square is lit with silver shapes and sparkles green and red
And the trees are decked with fairy lights that flicker overhead,
When the shopper-laden buses hustle down Westover Road
And you wonder if that tea set will suffice for Mrs Spode;
When the speakers blare out ‘Jingles Bells’ off-key and very loud
And the bargain hunters muscle through the shoulder-crushing crowd;
When a lady limps and lurches under purchases too large
From a bright and shiny toyshop never known to undercharge,
When you fight for bulbs and batteries and each last-minute task,
For an electronic Christmas that is all that they could ask;
And I caught your eye and thought, for a moment, you might stop;
But the fever was upon you and your only thought was,”Shop!”

I came to you at Christmas down at number thirty-four
Where the reindeer and fat Santa quite irradiate the door,
Where the presents are piled high underneath the plastic tree
And the herald angels hark from a plasma screen TV,
Where there’s whisky overflowing and a Quality Street tin
And heaps of chocolate biscuits and buckets full of gin,
Where the parsnips and potatoes are roasting in the pan
And the turkey has been cooking since before the day began,
Where the cake from Marks and Spencers will be passed off as your own,
Just like the Christmas pudding – last year’s gift from Auntie Joan;
And it’s time to do the vegetables, the peas and beans and sprouts
And the microwavable mince pies at four or thereabouts.
And I caught your eye and thought, for a moment, you might look;
But the fever was upon you and your only thought was, “Cook!”

I came to you at Christmas; but not as a masquerade,
All safely wrapped in swaddling clothes and in a manger laid.
I was not at the rehearsals; I was sorting goats from sheep
For my gaze is universal and you know I never sleep.
In Zimbabwe I was hungry; in Romania I was cold,
In Malawi I was orphaned and in Darfur I was sold;
In other lands imprisoned; in other countries stoned;
The plain facts skated over or by other means condoned.
I was there in Boscombe Crescent sleeping on that slatted seat
I was scrabbling in the rubbish bin for something fresh to eat
I was with the young offenders down at Portland on the coast
Kept away from home and family at a time that matters most.
I was sick in the Macmillan and I almost caught your eye
But the fever was upon me and, of course, I came to die.

Sunday, November 09, 2008

Answered prayer.

Most people get better from most things most of the time. You break a leg? Mostly it heals up after a while and you can walk again. You get the 'flu? Generally you're better again after a few days in bed. Measles? Mumps? Chicken pox? Even before vaccines, most people caught them as children and most survived. Even with heart attacks and strokes, although more likely to be lethal, many people make an uneventful recovery.

Do doctors help? Well, they might make sure your leg sets straight, and relieve your suffering with some aspirin, but for most things doctors do as they have done for centuries - comforting words and placebos; a good bedside manner.

That is not the end of it, of course. Over the past 50 years we have got pretty good at treating bacterial infection. Pneumonia was the most important of these. Viral respiratory infection (for which we can do nothing) opens a gate for the common bacteria to get in, and as in most situations where the drainage of fluid is impaired an serious infection ensues. Penicillin and its many successors have saved many lives. Safe surgery has been another boon. Anesthetics that allow it and antiseptic techniques that prevent the germs getting into open wounds have ensured enormous advances that have made fatal cancers curable, and many otherwise dangerous condition like appendicitis trivial.

Many of the other medical advances have been to do with public health. Sir Richard Doll's epidemiological observation that demonstrated that smokers got lung cancer mush more commonly than non-smokers was the beginning of a realization that the way we live inflicts upon us various ailments. There are all sorts of drugs like anti hypertensives and statins that don't make us feel any better, yet they prevent us being struck down by a potentially fatal illness (we hope). Even with some cancers, we detect them when they cause us no problems and apply treatments in the hope that they never will.

It comes as no surprise therefore that people who take precautions about their health - eating well, not smoking, taking plenty of exercise, drinking little alcohol - live longer than those who live a life of riotous hedonism. Not should surprise us that such people are found more commonly in churches than outside of them. We could also say that the sense of community provided by church membership settles the mind and spirit, making mental and psychosomatic illness less likely.

It was Francis Galton, I think, who believed that he had a proof that prayer did not work. 'God save the King' was, he said, the most commonly prayed prayer, yet on average kings lived shorter lives than the rest of the population, and therefore prayer did not work. It is, of course, a facile argument with so many flaws that it is not worth contradicting. However, of recent years a number of other studies have been published suggesting that when Christians pray for, say, patients in coronary care units, those prayed for survive better. In one famous study volunteers prayed for half of the 393 heart attack patients in a San Francisco hospital. Among the group prayed for significantly fewer died, most had a faster recovery, requiring the use of fewer potent drugs and none had to be put on life support. The study was blinded; the patients did not know they were being prayed for. There are some similar studies that show contradictory results. and some observers find methodological flaws in such approaches. I make no comment.

Most Christian doctors I know have never seen an unequivocal authentic miracle. Dr Paul Brand, the famous leprosy surgeon/missionary, spent many decades in practice and never saw one. When people mentioned the success of tele-evangelists, he commented that he must have spent his life in the wrong profession. Why had he spent so much time doing painstaking surgery, when he could have achieved the same or better results in the twinkling of an eye? I remember a patient of mine with chronic myeloid leukemia who had a blastic transformation. In the days before imatanib that was a lethal development. He was a keen Christian and the elders of his church prayed over him and laid hands on him. He went into remission. I was shocked. All I had given him was prednisolone. When I shared this with a CML expert he referred me to a few similar cases that had responded to prednisolone. I remember also a mix up where an old lady with acute lymphoblastic leukemia was inadvertently given chlorambucil. She went into remission, even though that drug is supposed to have no effect. There was no suggestion of any supernatural intervention in this case.

The body has remarkable natural healing powers and although we presume to understand the pathology of leukemia, what we don't know is greater than what we do. Do miracles occur? Of course they do - our whole faith is based on the fact that a dead man came back to life. As Paul said - 'if Christ be not risen we are of all men most miserable'. But at least in Western Civilization where these things can be subjected to scientific scrutiny, I am pretty sure that the sort of miracle that happened in Jesus's time no longer happens now. We don't see blind men made to see when mud is placed on their eyes, or the paralyzed take up their beds and walk, or water turned into wine or 5000 fed with five loaves and two fish or men who have been dead and rotting in the grave for four days brought back to life. Perhaps these things still happen in non-scientific communities where the only proof is what a witness says and there is still scope for disbelief, but it seems to me that God is concerned to ensure to us that the laws of physics and chemistry are a constant and reliable circumstance. Perhaps He also wants to ensure that we don't lapse into a 'benefits' culture. If everything were available by miracle service, why would we ever work for a living.

Imagine a particular faith healer who had a reliable record of curing people. The scientists would be swarming all over him to investigate exactly how he worked the 'trick'. It would be Simon Magus all over again.

There will always be stories of miracles, but they will never be truly testable. A God who could be proved would require no faith. Sceptics will always be able to say 'there was insufficient evidence'. New Testament miracles were signs authenticating Jesus, just as Moses was given a shape-changing staff to prove his representative authority before Pharaoh. We have the Scripture; we have the Holy Spirit; we don't have authenticating miracles.

In the eighteenth century millions died from smallpox. Christians prayed to be free of this terrible scourge. God answered that prayer. He sent them Edward Jenner. He has also sent them thousands of scientists, physicians, nurses, radiographers, physiotherapists and pharmacists. The rate of cot-death has reduced remarkably by the simple expedient of lying the child on its back. Thousands of parents cried out in bafflement, "Why did God take my child?" It wasn't God to blame. We simply did not know better. At the time of the black death in London long-haired prophets saw it as a sign of the coming Apocalypse; yet the remedy was rat poison. Pious Dutch Calvinists saw smoking as a sign of a spiritual Christian; only the rebellious refused to smoke. They accepted their lung cancer and emphysema as God's will for them. God sent them Sir Richard Doll.

Even though I have never seen a healing miracle, I continue to pray for them. I never presume on one. I believe God is sovereign and He will have His way. Even in the years after Jesus' death Paul was well aware that prayer could not command relief from illness; Epaphroditus, Trophemus, Timothy and Paul himself were not miraculously healed despite their proximity to the resurrection. Paul's prayers were for the salvation of souls and their growth in grace. As for illness he was content with, "My grace is sufficient for you."

Saturday, November 08, 2008

Do Statins make Rituximab ineffective?

A few years ago a revolution took place in medical publishing with the introduction of open access journals freely available on line. Of course, someone has to pay for all the work that goes into publishing a journal and if there are no subscribers, it has to be the author who pays. This might seem like vanity publishing – like those slim volumes of dreadful poems, but clearly the journals hope that scientists will include provision for paying for publication in their grant applications. To some extent this already happens since page charges are slapped on everything that is published by journals like Blood. Indeed publishing in Blood is costly and the referees who do the work of assessing the article and making constructive criticisms receive no reimbursement. The American Society for Hematology makes a fine profit from the enterprise.

This is by way of introducing the fact that until now I had not read any of these open access articles, but I have just read an important paper in PLoS Medicine (I think that stands for public library of science. The article by Magdelena Winiarska from Warsaw, Poland tells us that “Statins impair antitumor effects of rituximab by introducing conformational changes of CD20”.

The title alone strikes fear into the heart of patients receiving statins who are also receiving rituximab. So before we jump to any conclusions we ought to read the paper and see if it says what the title implies.

First they demonstrated that incubating Raji cells (an EBV stimulated B-cell line often used for B cell experiments) with a statin for 48 hours reduced rituximab-induced complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC) in a dose dependent manner. Incubation with statins reduces the binding of anti-CD20 antibody to the surface of Raji cells, but it does not reduce the amount of CD20 produced by the cells. It appears that it is the reduction of cholesterol in the cell membrane that is responsible for this effect, which is common to all statins and works for other lymphoblastoid cell lines like Daudi and Ramos and with other anti-CD20 antibodies of both type I and type II. Incubation with cholesterol after the statin treatment restores the CDC and ADCC to normal. Although, binding of rituximab to CD20 translates the antigen into cholesterol-rich lipid rafts, this mechanism is not involved in the reduction of CDC or ADCC. Using something called an “atomic force microscope” and also limited proteolysis with trypsin and chymotrypsin they were able to establish that incubation with statins induces conformational changes in the CD20 antigen that affects the binding of type I and type II anti-CD20 antibodies.

Experiments with lymphoblastoid cell lines are all very well, but does this have any meaning in clinical practice? To address this question they incubated freshly isolated tumor cells from patients with mantle cell lymphomas with MbetaCD (which like statins extracts cholesterol from the cells membrane) and attempted to kill them with rituximab in a CDC assay. Killing was significantly reduced.

They also demonstrated that inpatients who were receiving statins for hypercholesterolemia, the binding of anti-CD20 to normal B cells decreased by 15-20%.

So does this have any meaning for CLL patients who are treated with rituximab?

First, I must draw attention to the fact that the clinical experiment has not been done. No-one has shown a lesser effect for rituximab in patients on statins.

Second, the reduction in killing of fresh lymphoma cells (as opposed to cells from a lymphoblastoid cell line) was after incubation with MbetaCD rather than a statin. I am sure they did the experiments with a statin but did not report it probably because there was no effect.

Third, as well as the incubation experiment with cells from three mantle cell lymphomas they also used cells from a patient with small B cell lymphoma (probably CLL but one can’t be sure). This patient started off with less surface CD20 on his or her cells and although incubation it was lessened significantly, but not by very much.

Fourth, if statins really did make such a difference as is implied, I would expect to see this paper in Blood or JCO or Haematologica or B J Haem – not in PLoS Medicine.

Finally, I should draw attention to a paper in Leukemia from 2003 by Polyak et al from Canada. They demonstrated that the monoclonal antibody FMC7 reacts with an epitope of CD20. As most CLL students know, FMC7 is usually absent from CLL cells. Why is that? It appears that the CD20 molecule undergoes a conformational change that hides the FMC7 epitope under certain circumstances. What circumstance? When the membrane is depleted of cholesterol. It appears that in CLL the cholesterol has already been depleted, which may explain why rituximab is such a poor drug in CLL compared to its activity in other kinds of lymphoma

Phrases that upset.

Today's Telegraph has a list of phrases that upset that has been compiled by researchers at Oxford University. The top ten are:
1 - At the end of the day
2 - Fairly unique
3 - I personally
4 - At this moment in time
5 - With all due respect
6 - Absolutely
7 - It's a nightmare
8 - Shouldn't of (instead of shouldn't have)
9 - 24/7
10 - It's not rocket science

What is interesting is that the article to date has attracted 1477 comments. A lot of people are upset.

My own personal hate is 'fulsome praise'. Most people seem to think that it means extravagant praise when it means quite the opposite. 'fulsome' derives not from 'full' but from 'foul'. 'Fulsome praise' means praise contaminated by a sneer. If you like, it is a snide remark that seems at first to be praising but when you think about it has a rotten core.

Better than a Zimmer

Walking aids just got better. This new device produced by Honda supports those who have difficulty walking any distance or in working in a crouched position. If you have dodgy knees this is for you!

Tuesday, November 04, 2008


The weather forecaster yesterday predicted a low cloud cover for the south coast today. He was absolutely right. It is dull and overcast. Quite a grey day in fact. It was a grade A weather forecast.

Sunday, November 02, 2008


No, I am not about to come out for either Obama or McCain. I am tackling the knotty problem at the start of I Peter.

The doctrine of election is anathema to many Christians. They can't bear to think of God choosing some for damnation. But there it is in Scripture, "Peter, an apostle of Jesus Christ to God's elect." This is not an isolated instance. Paul writes to the Ephesians "For he chose us in him before the creation of the world," and John writes "to the chosen lady" and Jude "to those who have been called."

The thing is that not only is it plainly present in Scripture, but it is also absolutely necessary. Jesus died on the cross to purchase everything needed for salvation. Whether you are a little old lady in Bognor Regis or a Napoleon of crime there is nothing you have done to is too dirty to be washed away. Dishonesty, lying, theft, extortion, adultery or any sexual sin, bullying, betrayal, greed, lust, laziness, gluttony, selfishness, brutality, even murder; none of them is so large or so heinous that they cannot be washed clean by Jesus. But here's the rub, whether you are a Napoleon of crime or a little old lady in Bognor Regis, there is no-one so clean as not to need washing. White lies, speeding, failing to declare something small on your tax return or not declaring a foreign purchase to the Customs Officer, lascivious thoughts enjoyed even if left unacted upon, a bus fare unpaid as a child, an apple stolen from a stall, a secret passed on as gossip, perhaps disguised as a prayer, an angry word, rudeness to a call center, cowardly backing down when you should have stood up for what is right, acquiescence at evil, neglect of those in need, a joke told against the helpless or weak or undefended minority; there is nothing so trivial that it doesn't need paying for. The Bible tells us that all have sinned and fallen short of the glory of God.

Sin in English is a technical word from archery. It is used when an arrow falls short of the target. Unless you hit the bullseye every time you are a sinner in need of a savior. Does Tiger Woods get a hole in one every time on every par 3? Does David Beckham score every time with every free-kick from just outside the penalty area? Did every Beatles record go straight to number 1? Is every hit a homer from Alex Rodriguez? Did Mohammad Ali win every fight by a knockout? Even the best professionals aren't perfect; do you expect to be?

So you'd better repent. Isn't that what all Christian preachers demand?

And just how do you think you are going to do that? The Bible says that we were all dead in trespasses and sins. Paul's letter to the Ephesians chapter 2 begins: As for you, you were dead in your transgressions and sins, in which you used to live when you followed the ways of this world and of the ruler of the kingdom of the air, the spirit who is now at work in those who are disobedient. All of us also lived among them at one time, gratifying the cravings of our sinful nature and following its desires and thoughts. Like the rest, we were by nature objects of wrath. But because of his great love for us, God, who is rich in mercy, made us alive with Christ even when we were dead in transgressions—it is by grace you have been saved.

We had no capacity to save ourselves. Even though Jesus had done everything that was necessary to spare us from the consequence of our rebellion against God, we could do nothing to grasp hold of it. Can the dead live? In Christ, God has demonstrated that they can, but only if God makes it so. God, who is rich in mercy made us alive with Christ when we were dead in transgressions. We are alive in Christ because God has chosen to make us alive in Christ; of our own strength we could not have done it.

Certain theologians want to make salvation a joint activity. Christ paid the price on the cross and we did our bit by choosing Christ. How did we do that when we were dead? For it is by grace you have been saved, through faith—and this not from yourselves, it is the gift of God — not by works, so that no one can boast (Ephesians 2:8-9)

How does that square with human responsibility? If we are only saved on God's whim and we can do nothing about it, how can we be blamed for not believing?

Human responsibility is also taught in Scripture. Imagine a ward full of drunks all in liver failure. Who is responsible for their being there? It's my ward, but I never made them drink. Indeed, I and doctors like me have been telling anyone who listens that alcohol is dangerous and can cause cirrhosis. I have been warning that younger and younger people are coming into hospital with damage to their livers. I have been trying to make them stop.

Is the fault of the shops who lower the price of alcohol as a loss leader and thus make it easier for them to drink? I think the shops who do that are irresponsible, but I, like millions of others walk straight by the stack of gin bottles in the supermarket and don't give them a second thought.

Is it the fault of their parents who set them a bad example or ill-treated them when they were young? There are thousands of children who come from bad homes yet turn into model citizens.

Is it the fault of the kind people who give money to beggars and don't consider that the money will go straight into the next bottle of spirits? I think giving money to panhandlers is silly - far better to buy them a sandwich, but even so the donors were only being kind.

Is it the fault of their genes? Some people can drink with impunity. Yes, but many alcoholics are rescued by AA and don't end up on the liver ward.

No, when it comes down to it the person who ends up with alcoholic liver disease, despite all the excuses, can only accept that he or she is personally responsible.

Suppose, now I come along and offer one of the patients a liver transplant. He doesn't have to pay, all he has to do is accept. Will you blame me that I don't offer a transplant to every patient? Will you tell me I am being unfair? Will you say that I have chosen to condemn all the others to a terrible death?

I would be being unfair. If fairness came into it I would leave them all to take the consequences of their drinking. Just as if God chose to save none he would be being fair to all. God's offer of salvation is not about fairness, it is not about justice, it is not even because some deserve mercy. It is all about grace - undeserved mercy. No-one should demand their rights from God -if they got what was due to them they would be excluded from His presence for ever.

Others hold back at the presumption of predestination. Verse 2 of 1 Peter 1 says that the elect are chosen according to the foreknowledge of God the Father. Does that mean that He zipped round to see the ending and then came back in time and chose those who would eventually choose Him? By no means. The word translated 'according to' does not mean 'depending on' but 'in harmony with'. God certainly knows the end from the beginning; from His point of view the future is fixed - but not from ours. There is no future is relying on destiny. We live our lives in the hope of every possibility. Yesterday, Liverpool (top of the league) played Spurs (bottom of the league) Within 3 minutes Liverpool were ahead and thereafter peppered the Spurs goal with monotonous regularity. They seemed destined to win easily. Then, the Liverpool central defender inadvertently scored for the opposition and in the last minute of overtime Spurs scored an improbable goal to win the match. It's never over 'til it's over. Charles Haddon Spurgeon, the great preacher of the nineteenth century was once admonished for spreading pearls before swine. "There is no point in preaching to those who are not elect, sir."

"I agree, " said Spurgeon, "Perhaps you would be so good as to put a chalk mark on the shoulders of those who are elect. Then I will be certain only to preach to them."

Why God chose whom he chose is a mystery. Jesus said, "I praise you, Father, Lord of heaven and earth, because you have hidden these things from the wise and learned, and revealed them to little children. Yes, Father, for this was your good pleasure. (Matthew 25:11,12) All we can say is they are chosen for the Father's good pleasure.

How is it done? How do the dead live? Through the sanctifying work of the Spirit. This is the work of the Holy Spirit

Why was it done? For obedience to Jesus Christ and sprinkling by his blood.

Here is the answer to those who say, "Once saved always saved; therefore I can rest on my laurels." We are saved for obedience and when we stumble as we all do there is still the sprinkling by his blood to cleanse us anew.

The grace of God is a wonderful doctrine. Spurgeon again, "He must have chosen me because, knowing my heart, I should never have chosen Him. And He must have chosen me before I was born, because he certainly would not have chosen me after I was born and started sinning."

"I'm forever grateful" goes the chorus, and from that gratitude comes every good work of the Christian. We don't strive for good works to earn our salvation - how would we ever know if we had done enough. We strive for good works because of our salvation - not to repay the cost, but out of gratitude and praise.

Unanswered prayer

We all have to wrestle with unanswered prayer. I remember at the age of 13 learning about my grandfather having bowel cancer. I went to my bedroom, got down on my knees and prayed vehemently that he be healed. Of course, he died from secondaries about eight months later.

The truth is that most prayers for healing go unanswered and that in this world one out of one die.

In Niango in Nigeria, there is a missionary graveyard. Of the 56 graves, 33 are those of small children. It is hard to imagine people with more faith than those who gave up everything for God and ventured out into the heart of Africa to witness to pagan tribes. Can you imagine that they did not pray for their children? Yet God saw fit to take them rather than answer their prayers. Don’t let anybody tell you that your prayers are not answered because you have too little faith.

Of course, some prayers cannot be answered. In the American Civil War both sides prayed for victory. The Confederate General, Robert E Lee, was a much more devout man that his counterpart in the North, Ulysses S Grant. Yet the North triumphed. Not only was it impossible for God to answer all the prayers affirmatively, but it would hardly have been in God’s character to a side fighting to preserve slavery.

The athlete prays for fine weather while the farmer prays for rain. They can’t both be answered, yes.

John Betjeman captured the irony of prayer for victory with:

Gracious Lord, oh bomb the Germans.
Spare their women for thy sake,
And if that is not too easy
We will pardon Thy Mistake.
But, gracious Lord, whate’re shall be,
Don’t let anyone bomb me.

The Law of Unintended Consequences confounds most government action and inaction. It is humane to give aid to the needy, but when does it become a perverse incentive leading the recipients to depend on aid rather than on the work of their hands? Many an aid programme has ended up polluting the water or destroying trees or putting power in the hands of tyrants. Are governments right to bail out banks in the credit crunch? Some economists think that it would have been preferable to let these institutions sink or swim according to market forces. Who am I to say who is right?

The film ‘Bruce Almighty’ took a light-hearted look at what would happen if a mere mortal had God’s powers. Jim Carrey lassoed the moon to bring it closer for a romantic evening with his girlfriend and caused a tsunami in Japan. He answers ‘yes’ to every plea about the lottery so that the prize is worth less than the stake. Every answer he gives to prayer has unintended consequences.

Yet we presume to advise God on how to run His universe.

We hear about answered prayer: how a couple each working in a different tower of the World Trade Center managed to ‘miraculously’ escape the carnage. What does that say to the relatives of the 3000 who were killed? Did they not pray hard enough for their husband or son? When we read about the ‘Heroes of Faith in Hebrews chapter 11 there were those who died for the sake of preaching the Word. Sawn in half, put to the sword, flogged, stoned, destitute, ill-treated, imprisoned – all were commended for their faith, yet none of them received what had been promised. God had planned something better for us so that only together with us would they be made perfect.

Throughout Scripture we read of unanswered prayer. Despite leading the Israelites in the wilderness for 40 years, Moses’ request to enter the Promised Land was turned down. David prayed for a week for the child of his and Bathsheba’s adultery, but the child died.
Moses, Job, Jonah and Elijah all prayed to be allowed to die, but God ignored their requests. Often Israel prayed for victory only to be defeated – each event led to soul searching.

Habbakuk prayed for deliverance form the Babylonians; Jeremiah prayed that Jerusalem not be destroyed; Paul’s prayers for the churches seem to have fallen on deaf ears, for when we look at what happened to them we are dismayed – there is hardly a Christian Church left in Turkey, Paul’s old stomping ground. And Paul’s ‘thorn in the flesh’ was not removed. When he wrote to Timothy about his weak stomach, he advised that he took a little wine rather than expecting a miraculous cure. Shadows and handkerchiefs seemed to have lost their effect.

If God had said to us, “I am giving you the gift of prayer. You have to realise, of course, that you don’t have perfect wisdom, so there are limits as to how exactly your prayers will be answered, but I promise to listen and consider your suggestions, and where you ask appropriately, I will do my best to answer your requests,” then I could live with that.

But what Jesus actually said was:

I tell you the truth, if you have faith and do not doubt, not only can you do what was done to the fig tree, but also you can say to this mountain, 'Go, throw yourself into the sea,' and it will be done. If you believe, you will receive whatever you ask for in prayer."

Again, I tell you that if two of you on earth agree about anything you ask for, it will be done for you by my Father in heaven.

Therefore I tell you, whatever you ask for in prayer, believe that you have received it, and it will be yours.

You may ask me for anything in my name, and I will do it.

These extravagant promises seem too much. Jesus seems to be over claiming. Our difficulty comes from the fact that we do not see mountains throwing themselves into the sea and happily everything we ask for is not granted. How can we explain it? Were the promises just for the disciples? Or are we missing the qualifiers? “Whatever you ask in my name.” “If you remain in me and my words remain in you.”

It seems to me contrary to the thrust of the whole of Scripture that we should use prayer as a form of magic spell. Indeed Simon Magus saw it as that and tried to buy the secret from Peter and John. “You have no part in this ministry because your heart is not right before God,” they replied.

And that is the crux of it. Is your heart right before God? Part of prayer is about getting our hearts right before God. When it is we will ask for what is according to God’s will. Prayer is part of the means of grace. We pray, we listen to his word, we wait upon the Lord. Just as for the heroes of Hebrews 11 the answer is often “Not yet”.

Saturday, November 01, 2008

Ross and Brand

Russell Brand, 33, and Jonathon Ross, 47, are two well known radio presenters who were paid huge amounts of money by the BBC to present music and chat shows on radio and television. One night the Brand show, with Ross as a guest, broadcast a telephone call made to the answering machine of Andrew Sachs, 78, an actor best known for his performance as Manuel in Fawlty Towers. The content of the call was a boast by Brand that he had slept with Sachs’s young granddaughter, a singer in a girl-band. The boast was couched in obscene terms and contravenes a British law about sending obscene messages over the telephone. The broadcast received only two complaints, but an alert reporter on the Daily Mail picked up on it and published a piece criticizing the broadcast.

The newspaper article unleashed a frenzied attack on the BBC and the two disc-jockeys. There have now been over 35,000 complaints against the BBC. As a result Brand has resigned and so has the chief executive of the Radio 2, the channel which hosted the broadcast. Ross, the highest paid performer on the BBC has been suspended without pay for 12 weeks while his future employment is considered.

Further information has emerged. It turns out that the broadcast item had been pre-recorded, and must therefore have been approved by an editor and also that the Brand boast was not an idle one; he and the girl had been in a ‘relationship’ for a while last year. It was, nevertheless and ungentlemanly thing to do as well as being illegal. In the meantime another broadcasting offence has been uncovered. ‘Mock the Week’ made lewdly offensive remarks about the Queen and the ‘Disgusted’ of Tunbridge Wells tendency has redirected its attack there.

What has been astonishing is how an after-midnight broadcast, listen to by very few, has caused such a national furore. It is symptomatic of a general unease among middle class, middle-aged Britain.

It has to be remembered that 1947 was the year when Britain’s birth rate was at its greatest. Those born in that year are now 61. They comprise a large slice of the population and, moreover, many are relatively well-off, many are retired and those who are not often hold down jobs of great influence. This is not a constituency to be trifled with. Although, many of these ‘baby-boomers’ were young at the time of the loosening of moral standards in the sixties and seventies and may be thought complicit in the sex, drugs and rock’n’roll revolution, by and large this generation heartily disapproves of Ross, Brand and their ilk.

There are several reasons for this. Many were always opposed to what went on in the sixties and seventies. There was a vanguard of revolutionaries clustered in the capital and infiltrating the media. The Beatles may have come from Liverpool, but they soon made their way to London. The ‘Swinging Sixties’ were centred on Carnaby Street not Coronation Street. I was at a provincial university at this time and never encountered a single spliff. My friends were not sexually promiscuous and nice girls still waited until they were married. We may have approved of David Frost and ‘That Was The Week, That Was’, but their targets were the rich and powerful, not defenceless old men.

The lifestyle ‘enjoyed’ by those in the vanguard was hardly conducive to longevity. Many of those who persisted with it are by now the victims of drug overdose, liver failure, AIDS, cocaine-induced heart attacks, or lung cancer. The hard-core of revolutionaries has been diluted by the conservative majority.

Then, again, there is the natural tendency for people to become more conservative as they get older. You plead harder for the have-nots when you are poor than when you become one of the ‘haves’. This is not the whole story. With age comes experience and the more perceptive have seen what the social changes have brought us in the past forty years. It is hard to applaud the fact that we now need many more prisons, that homicides have risen from about 160 to nearer 1000, that divorces have reached an all-time high, that parents are afraid to allow their children to walk to school for fear of abduction, and that gangs of young people walk around our cities at weekends armed with knives and too drunk to know what they are doing. Who would have thought that a campaign against young women dying from back-street abortions to escape the shame of illegitimacy would have led to newly formed embryos being regarded as disposable and babies only a few weeks away from an independent existence being killed because they were inconvenient? Who would have thought that a campaign to free women trapped in a loveless and abusive marriage would have led to an automatic assumption that sex was available on a first date and such sexual promiscuity that small-print diseases like syphilis have become a such plague that venereology has changed from a Cinderella specialty to one that attracts big brains and high salaries?

Although heard by only a few, this broadcast has awakened a sleeping giant. Middle class, middle-aged people across the country have found a voice and are surprised to find that many people share their view. Of course, there is a backlash. Thousands of young people have signed up on Facebook to the opinion that Brand and Ross are funny and should be defended. A generation war is in the offing.

At the heart of the matter is the BBC. To my generation the BBC was at the center of the Establishment. It was the voice of Authority. Affectionately known as Auntie, you could rely on it for honesty, impartiality, truth, and how to make a space-suit from two washing-up liquid containers and a few sheets of sticky-backed plastic. It may have seemed staid and a little behind fashion, but all the better for it. Others could push back boundaries; we could enjoy the Black and White Minstrels on the BBC.

The BBC has changed. Many regard it as the HQ of the Politically Correct. "Although only 7% of the British have dark-colored skin," they say, "BBC presenters on television represent the London norm which is nearer 40%. However, they all speak with an Oxford accent, except on radio where regional accents are mandatory in order to demonstrate ethnic diversity. Irish and Scottish accents are prominent."

They complain that the BBC favors homosexuality over heterosexuality, Islam over Christianity or Judaism, the European Union over America, Global Warming enthusiasts over sceptics, Palestine over Israel and Nu-Labor over the Conservatives.

There are whole websites given over to attacking the BBC. One constant complaint is that the TV license fee amounts to a tax that funds all this unpleasantness It is impossible to own a television without funding the BBC’s output. I’m not sure that I go along with this. Among license fee payers are people who enjoy Ross and Brand, people who enjoy ‘Eastenders’ or ‘The Antiques Roadshow’ or endless cookery and house redecorating or gardening or mindless breakfast shows. Others only watch football or dramatized Charles Dickens or News shows or Detective Dramas. We all have to pay for what we don’t like in order to watch what we do. If you don’t like TV you don’t have to watch anything or own a set. I think it is not that, that offends; it is the sense that offensive programming is going out ‘in my name’ that upsets people, just as the invasion of Iraq offended them. More than a million people marched in protest against the Iraq war. It was a minority, to be sure, and the minority must accept the will of the majority, but they can still feel offended that there support is assumed.

It will be interesting to see whether the Ross-Brand affair is just a storm in a teacup, or whether the protesters, now having wind in their sails, will affect a change in broadcasting policy.