Friday, February 29, 2008

Dave Clark Five

Mike Smith of Sixties group The Dave Clark Five has died aged 64. Smith, the band's lead singer and keyboardist, was admitted to the Stoke Mandeville Hospital's intensive care unit on Wednesday with a chest infection. He had been in hospital since September 2003 following a spinal cord injury that left him a tetraplegic and only recently moved in to a specially modified family home.

When I was a student the Dave Clark Five had hits with "Bits and Pieces" and "Feeling Glad all over". We always wondered who Glad was.

Wednesday, February 27, 2008

Grannies for hire.

My mother (aged 88) is staying with us at present while some repairs are being done on her bathroom. She needs a lift to church on Sunday mornings. Although she used to walk the two miles there and two miles back, this is beyond her now. There are no buses and she doesn't drive. Despite this members of the church have been happy to help her. Over the past year two of her drivers have had to give up through illness or emigration, but whenever someone drops out another steps forward to help.

She sees it as the LORD's provision but others are more cynical. Parking is very difficult around the church and she has an invalid parking permit. Could it be that people are keen to deliver her so that they can park their cars illegally on double yellow lines right outside the church?

I suggested to her that she should consider hiring herself out to those whose trips involve particularly difficult parking. She might see the world.

Monday, February 25, 2008

Fundamentalists

In the March edition of Evangelicals Now is an interesting article by Barry Seagren. He asks the question as to whether there is any difference between Evangelical Christians and fundamentalist Muslims.

Both believe that they have the absolute truth - not a relative truth in the post-modern sense of 'if it works for you, fine'.

Both believe that that truth derives from an ancient text

Both place their loyalty to God above national laws.

Both believe that a lived-out faith affects every aspect of their lives, including politics.

Both believe there is a sharp dividing line between believers and unbelievers.

Both are against nominal religion.

Both seek to convince non-believers of the truth of their belief.

So what difference is there? Why should evangelical Christians object to being lumped together with fundamentalist Muslims as one of the dangers of the age?

There are three major differences, says Seagren.

1] The most blatant difference is the Islamic willingness to use force. Muslims certainly dispute whether Islam truly teaches this, but the jihadist support their case with quotations from the Qur'an, and Mohammed himself could hardly be said to have been a man of peace.

Jesus, on the other hand, was archetypically the man of peace and although some of his later followers have besmirched his cause with violence (the crusaders, the Inquisition, abortion home bombers) St Paul preached sacrificial love rather than violence and fundamentalist Christians follow this teaching.

2] The proof of the pudding is in the eating. The liberal humanist New York Times - no lover of evangelical Christianity - wrote in August last year, "For more than a millennium, the West took inspiration from the Christian image of a triune God ruling over a created cosmos and guiding men by means of revelation, inner conviction and the natural order. It was a magnificent picture that allowed a magnificent and powerful civilization to flower".

Today millions of Muslims are fleeing Muslim countries to migrate to the West. They are voting with their feet. By their fruits you shall know them.

3] Whereas Christians claim a relationship with a person, Muslims seem to relate to a religion. Ed Hussain, the fundamentalist Muslim who reneged on his commitment to radical Islam (as detailed in his book The Islamist) describes what led him out. "Despite huge political success I despised myself for appearing pious and upright in Muslim eyes when all the time I knew there was a vacuum in my soul where God should be". In describing his converts he writes, "We drew them to Islam as a force, a power. Today, I doubt very much of they were humble hearts who turned to God."

There is a difference, but those words of Ed Hussain are a warning to Christians.

Sunday, February 24, 2008

GBS

We have started watching the plays of George Bernard Shaw on DVD. Last night we watched 'Man of Destiny' and 'Arms and the Man'. Shaw was once thought second only to Shakespeare as an British playwright. This DVD collection was first broadcast on BBC TV in the eighties. Many well known actors appear as callow youths, among them Simon Callow who plays Napoleon and Helena Bonham-Carter who is a long way from the corpse bride in the farce set in Bulgaria.

These are clearly filmed plays and they are very stagey. Nevertheless the actors do well and the diction comes over so well we turned the subtitles off. I doubt on this evidence that Shaw has weathered well. He is very given to aphorisms but they are not so witty nor so wise as those of Oscar Wilde.

Ensuring freedom with increasing technology

Would a universal DNA database lead to a police state?

Various dystopias such as '1984' and 'Minority Report' have put the case against universal surveillance.

The fact is that CCTV cameras have already been put in place to deter crime, if not universally, at least in a widespread manner. Speed cameras are well established as a means of controlling the speed of cars on our highways. Motorists don't like them because they perceive them as simply revenue-collecting devices. They recognize that it is not speed that causes accidents, but inappropriate speed for the conditions. 70 mph may be too fast in some conditions but too slow in others. Remember (in the UK at least) the 70 mph limit was introduced during the 1970's oil crisis to save gas. If cameras were used to check average speed over a larger distance - say between toll gates - (stopping the widespread practice of speeding up between cameras) they would be even more unpopular. The answer to that is more appropriate speed controls. Finding out the truth is always preferable to living a lie. Other cameras are present on our roads to monitor traffic flow. Although their primary purpose is to avoid traffic snarl-ups by issuing warnings on radio and by sign, they also prove to be very useful for catching fleeing fugitives.

Businesses and public authorities install cameras to protect their property and deter vandalism. The fact is that such cameras also prove useful to the police in establishing the path taken by victims and their attackers.

Telephone tapping and the installation of audio-bugs to detect criminals is under the strict supervision of a judge or parliament. Improper use will be rapidly pounced upon by the press. No minister could withstand such a charge in the public view.

DNA evidence is less intrusive than any of these. It cannot be used as the only evidence that supports a prosecution - there may be other explanations as to why someone's DNA is found at a crime scene, but such a finding is a legitimate reason for questioning someone.

In the US there are already non-criminals who are on such a database - members of the armed services, for example. Despite the comments on my last posting I still can't see a reason for fearing a universal DNA database.

Let’s take the objections one at a time:

Perhaps the police should be able to randomly pluck people from the streets, and try to beat confessions out of them. Only the guilty need be afraid!

Arresting someone implicated by DNA evidence is not a random pick-up. Cops no longer beat up criminals – if they do they are sent to prison. They too are subject to video surveillance when interviewing suspects. Evidence obtained by tortue is of no value. DNA evidence often obviates the nee for a confession.

Perhaps the police could administer drugs to random pick-ups off the street.

Administering drugs to obtain cofessions is also outlawed.

Everyone should be under surviellance at all times. Every move, every action would be analyzed by the State for possible wrong-doing.

I don’t believe that anyone is envisioning anything like that. Why would they want to?

Here is an example of what it might be used for. A 9-yeasr old girl is missing from her home in Dewsbury for 48 hours. CCTV footage shows her leaving her school and heading north, but after that nothing. Was she abducted? Did she run away? More CCTV footage might have given an answer.

Perfect security and safety could exist if 1/4 of the population was engaged in monitoring everyone. (Even the watchers would be watched.)

Common sense dictates that no such police state necessarily follows from more CCTV cameras and a national DNA database.

What guarantees our freedom is not withholding technology from the law enforcement agencies, but a free press, an independent judiciary, a multi-party state and eternal vigilance.

Saturday, February 23, 2008

Is my DNA safe with you?

Just as Britain has more CCTV cameras than anywhere else in the world it also has more DNA records than anywhere else. Perhaps coincidentally there are more people in prison than anywhere else in Europe.

A story in the Times today suggests that the European Court might order the destruction of 13% of those DNA records. Currently, the procedure is that anyone arrested for a criminal offence has his or her fingerprints and DNA taken and these remain on the database, whether or not the person is charged or convicted. Although someone inadvertently caught up in the investigation can petition the local chief constable to have his record eliminated, this is at the Chief's discretion. Obviously, there are cases where the police are convinced that someone is a criminal yet lack the evidence to obtain a conviction, and in these cases the Chief Constable could use his discretion to retain the DNA and fingerprint information.

I think that this raises questions over civil liberties that need to be teased out. The inadvertent loss of laptops and computer discs recently have raise the possibility that DNA data may not be secure. Currently, there is a BBC serial running which takes the Civil Liberties viewpoint and suggests that we are an over-observed and regulated society. In the serial a private sector firm that runs the database is clearly cast as the villain. We will have to see what happens in the long run, but if the BBC runs true to form we will be told that nationalized firms are good; private sector bad, that surveillance is bad and freedom from surveillance is good.

This needs to be set against the fact that this week two serial murderers were convicted by DNA evidence. Both committed sexually related crimes and in both cases the victims' families are calling for the death penalty. (This is a separate but related issue, since the most convincing argument against the death penalty is that you might execute the wrong man; something that is less likely to happen with DNA evidence). One of the killers was on the database because years ago he stole money from the till when he was working as a barman; a rather trivial offence for which he got community service, but his DNA would still have been there had his employer decided not to press charges after his arrest.

It is difficult to know why America isn’t making the running on this. Normally, America leads the world in technological advances. But of course there is a strong strand of individual freedom running through the American democracy. It is commendable that people should mind their own business. It used to be said that an Englishman’s home is his castle, but that applies especially in America, where there are extreme limits on how much the state can intrude on an individual’s space.

In discussions about freedom the question always arises of where freedom becomes license. A car sharing story illustrates this. Though rare in the UK, car-sharing lanes are relatively common in America as an attempt to beat snarl up. To share a car represents some inconvenience to the sharers but benefits the community by reducing the number of cars. To recompense those who make the sacrifice faster moving lanes of traffic have been devised which are barred to cars with single occupants. In an effort to claim the benefit without the sacrifice, drivers have put blow-up dolls, enlarged photographs or even disguised dogs in their passenger seats. Loughborough University has come up with the design of a camera that can see through these ruses. It is hoped that they will make a lot of money exporting these to the States. Respectable, middle-class people have a criminal heart too.

Should we object to this surveillance? There are obviously possible abuses of the power inherent in so much information, but we have a free press and the political process to guard against that. A DNA data base that apparently criminalizes a group of people who have never been convicted of a crime is obviously unfair, but why should there not be a universal DNA database? Only those with something to hide should object to it. There will be some who have paid their debt to society who have changed their name and started a new life who might object to being unmasked, but there would anyway be a data trail that could unmask them, and if only the government held the information in an encrypted form, it should be free from unwarranted prying. A lot of the scare stories owe more to the imagination of a science fiction writer than to real life.

What clinches it for me as a Christian is that we see ourselves as under universal surveillance at all times. And the sanction against us is far worse than a few years in prison.

Monday, February 18, 2008

A complete victory

It had been billed as the match of the season. The FA Cup is the oldest football competition in the world, and Saturday's draw had thrown together the two top teams in the country. Arsenal and Manchester United have been jockeying for position all season, with first one and then the other holding top spot. In fact for the past ten years it has been these two teams that have dominated football in England.

Manchester and London, north and south, working-class and middle-class; this was a match. The two managers, the fiery Scot, Sir Alex Ferguson and the cerebral French professor, Arsene Wenger, provided another contrast. Moreover, whereas most football in England is broadcast on pay-TV, this game was being shown by the BBC. All the nation would be watching.

Manchester United have won the cup 18 times and Arsenal 17. Manchester have a mix of youngsters and more experienced stars, including Giggs and Scholes from the golden generation of British footballers, as well as the brilliant youngsters, Rooney and Ronaldo. Arsenal seem to produce a stream of gifted, black, French stars and their young Spanish midfielder, Ces Fabregas, has dominated all season. But when the teams are announced there is disappointment. Both teams had omitted their chief goalscorer. No place for the mercurial Ronaldo or the huge Adebayor, but captain Giggs, schemer Scholes and stopper Hargreaves were all missing for United and Arsenal lacked both their first choice full backs as well as the emerging mid-fielder Flamini. Still at this time in the season injuries are to expected, and that is why the teams have large squads. No reason not to expect a well fought match.

In the event it was completely one-sided. Arsenal were humiliated. It was as though only one side had turned up. United were first to every ball. They won 4-0 and it could have been ten. In the second half Arsenal showed their nasty side and began to cheat. After the match Wenger blamed the state of the pitch as if it were worse for his side than for United.

In Mark 16:1-8 everybody seemed to have accepted defeat. Jesus, the hoped for Messiah, had died on the cross, defeated by the Roman occupier at the behest of the religious authorities, betrayed by one of his own followers, denied by his most ardent disciple and deserted by the rest.

The women knew where they had buried him, so while it was still dark they went to the tomb expecting to do a woman's duty; wash the body and anoint it with sweet smelling perfumes to disguise the stink of decomposition. They were in disarray. They were at a loss as to who would grant them access to the tomb. There was a huge stone (weighing as much as a ton) sealing it. And they knew nothing about the armed soldiers that Pilate had set to guard it. With a Micawber-like hope that something would turn up they approached the tomb.

When they got there depression turned to alarm. The stone had been rolled away, but instead of the body of Jesus, a young man in a white robe was there. This in itself must have been bewildering. Only priests wore white and priests were not young men - you had to be at least 30 years old to become one.

He is not here. He is risen! No wonder the women were trembling and bewildered. But why? Peter's mother-in-law had been miraculously healed by Jesus, the paralyzed man had taken up his bed and walked, the daughter of Jairus had been raised from the dead, blind Batimaeus had received his sight, Only the previous week Lazarus had been raised after being 4 days in the grave, and Jesus himself had declared to them "After I have risen, I will go ahead of you into Galilee".

They had seen and heard who Jesus was and is, yet they had not believed the evidence of their eyes and ears.

The defeat had seemed so overwhelming, yet it was a victory. The Devil had thrown his worst at Jesus. The military had inflicted extreme violence on him. The civil authorities had vented their spite on him. The religious authorities had spewed their hatred upon him. Yet he walked free. Death could not hold him.

He was the lamb without blemish. He was without sin. No-one could lay a glove on him. No accusation would stick. The wages of sin is death, yet he had no sin to earn such a wage. Instead he was pierced for our transgressions, he was crushed for our iniquities and the punishment that was upon him brought us peace.

Had he a single sin, death could have claimed him and kept him. The daughter of Jairus, the widow of Nain's son and Lazarus all had to die a second time. Not so Jesus. His resurrection was of a different nature. He was raised eternally, It was a complete victory. He was raised to show that the price he paid was enough. Had he remained in the sepulcher we might have suggested that he died for our sins, but we would always wonder, "Was it enough?" His resurrection showed that it was complete. For all past sins and all sins to come, no more duty is due.

Go and tell his disciples and Peter, instructed the Angel (for such he was).

Trembling and bewildered the women fled from the tomb. They said nothing to anyone because they were afraid. And here ends story the according to Mark, what he called "The beginning of the Gospel of Jesus Christ, the son of God".

Of course, we know what happened next from the other gospels. How Jesus appeared to Mary Magdalene and she reported to Peter and John, how he appeared to the two on the road to Emmaus, on two occasions in the upper room, to the disciples by the lake, on the Mount of Olives and on one occasion to 500 at a time. But Mark leaves us there. The final verses in our modern Bibles are a later addition, not necessarily untrue, but not Mark.

Why did he stop there? Because the victory is Christ's alone, achieved despite our failures. We continually let him down. We desert him, deny him, betray him and even when we have seen a miracle are afraid to speak out. What is our excuse? The pitch was too muddy? We didn't have our best players out? The opposition was too strong?

We all like sheep have gone astray, each of us has turned to his own way; and the LORD has laid on him the iniquity of us all.

Sunday, February 17, 2008

Bobi's girl.

Despite the internet, we get more and more paper delivered by post each day. Our post box, which was an original fitting built into our front porch 80 years ago, has become too small. So Diane and I decided to purchase a new one. We bought a Bobi, which is a steel box with a proper lock. Of course, it is too large to fit in the porch. We decided to fix it to the side of the house.

Here was our first difficulty. Our house is covered with a rendering with lots of bobbles in it, making a bobbly surface not flat enough to fix the Bobi to. Our first solution was to put felt washers in between the box and the wall. Finding felt washers that were thick enough to make a difference was hard, but eventually I found some that were designed to protect a hardwood floor from furniture feet, which seemed to fit the bill.

The second difficulty was in drilling through the steel box. I had to go out and find appropriately sized titanium drill bits. Our local hardware man was sure he had some somewhere and eventually we dug them out. Only £1 each, but the time it took finding them!

The third problem was in holding up the heavy box for long enough to mark the holes in the wall to match those we had drilled in the box. We solved this problem by building a plinth of bricks to rest the box on while we marked up.

We marked and drilled the holes in the wall, but then came the fourth problem. When we tried to screw through the box, the holes didn't match up and the felt washers weren't thick enough. We had to abandon this plan and think again.

The solution was obviously to attache some battens to the wall and then attach the Bobi to the battens. I looked in the garage loft, but here was the fifth problem: no wood of the right size. Off I go again to the hardware shop to buy a piece of wood. Again, easily solved at less than £1 though by now my petrol is probably running at nearer £5.

This time I fix the battens and the box and all seems well.

That was yesterday and today we have our first delivery. Not the postman, today is Sunday, but someone delivering leaflets by hand. I see the young woman go to the porch, pause, then walk round to the side of the house. As soon as she is gone I nip out with my key to see what she has delivered.

Can you believe it? It is a leaflet offering alternative health products. Full body holistic massage £30, hot stone massage £45, Indian head massage £25 and the one that really fascinates me, Hopi ear candles! 45 minutes for £25. I would want more than £25 to sit with a candle in my ear for 45 minutes.

Saturday, February 16, 2008

History of CLL (Part 5)

To the end of the Millennium

Today, we think of diseases in terms of molecules. Our molecular understanding of CLL is incomplete. It had a poor start. It was not until 1979 that the first consistent chromosomal abnormality (trisomy 12) was reported (Gahrton et al, 1979). We still do not know what it means. The translocations t(11;14)(q13;q32) and t(14;18)(q32;q21) involving the supposed B-cell leukaemia oncogenes BCL-1 and BCL-2 proved to relate mainly to what the ancients called lymphosarcoma cell leukaemia. Translocations at t(14;19)(q32;q13) involving BCL-3 (Ueshima et al, 1985)do occur in CLL, but are vanishingly rare. The commonest abnormality involves deletions at 13q14 (Fitchett et al, 1987) and its unravelling has thrown up candidate genes
that might be responsible for most cases (Liu et al, 1997). An important subset of more malignant cases and bulky lymphadenopathy has deletions at 11q23 (Dohner et al,
1997). As with most tumours, p53 is involved somewhere (Lens et al, 1997) and not to the advantage of the patient.

A new and important cell marker, CD79b, is surprisingly absent, although probably present as a short splice variant (Alfarano et al, 1999). This has been included in a cell marker definition of the disease that is remarkably helpful (Moreau et al, 1997).

We no longer consider CLL to be a disease of accumulation of long-lived functionally incompetent lymphocytes. We prefer to describe the cells as anergic, activated and
antiapoptotic (Caligaris-Cappio, 1996; Caligaris-Cappio & Hamblin, 1999), which comes to much the same thing. But in another respect, David Galton was right. He described two types of CLL, one progressive and one stable. This can also
be translated into molecular parlance. By studying the immunoglobulin variable (V) region genes, we can discern the same two distinct types. One type, derived from a naive cell (recognized by having unmutated V genes), is progressive with a median survival of 8 years. The other type, derived from a memory cell (recognized by having mutated V genes), is stable with a median survival of 25 years (Damle et al, 1999; Hamblin et al, 1999).

What is remarkable about the study of CLL is how often the great doctors of the past have been scintillatingly right. What is comforting is how often they have been
spectacularly wrong.

This review was written in the last year of the last century and is published in the British Journal of Hematology 2000, 111, 1023-1034. It probably needs updating, but almost all of what has happened subsequently is published wlsewhere on this blog.

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History of CLL (part 4)

Complications

Patients with CLL seldom die because of a high white cell count, but there are plenty of other fatal characteristics of the disease. Immunodeficiency. Before the Second World War, Wintrobe recognized that patients were particularly sensitive to
infection (Wintrobe & Hasenbush, 1939) and we now know that most patients will develop low levels of immunoglobulin if cases are followed for long enough. Hypogammaglobulinaemia was first recognized as a clinical entity by Bruton (1952), when electrophoresis of serum revealed the surprising absence of the gamma fraction in an otherwise normal pattern. Immunological studies showed a complete absence of antibodies and isohaemagglutinins. Odd case reports of agammaglobulinaemia in CLL began appearing shortly afterwards (Brem & Morton, 1955; Jim & Reinhard, 1956). Jim (1957) found that 17 out of 50 patients had hypogammaglobulinaemia. In a more comprehensive study, Cone & Uhr (1964) found deficiencies in all classes of serum immunoglobulins and failure to produce an antibody response to phi x 174, a primary antigen, or diphtheria toxoid, a secondary antigen. There was also a failure to sensitize to dinitrofluorobenzene, although most patients did produce a delayed hypersensitivity response to recall antigens. Later studies correlated the more severe falls in serum immunoglobulins with more advanced disease (Fiddes et al, 1972) and demonstrated that it was possible to generate an immune response to a new antigen (phi x 174) in early stage patients if sufficient inoculations were given (Hamblin et al, 1975). Really profound immunodeficiency had to await the arrival of the purine analogues as a popular treatment (O'Brien et al, 1993). Why the mmunodeficiency of CLL is so much worse than that of other lymphoid tumours is one of the unsolved mysteries of the disease.

Autoimmunity.

Winifred Ashby (1879-1975) moved from London to Chicago at the age of 14. She carried out her pioneering work into the life span of red cells at the Mayo Clinic between 1917 and 1921. Her technique (Ashby, 1919) involved the transfusion of red cells that were compatible with, but serologically distinct from, those of the recipient and then tracking their survival by differential agglutination. Berlin (1951) used this technique in nine patients with CLL. All had a shortened red cell survival, even though only one had a reticulocytosis. This was probably the first demonstration that the anaemia of CLL might be haemolytic in nature.

It was shortly after Ehrlich (Ehrlich & Morgenroth, 1901) published the concept of `horror autotoxicus', the idea that the body would not make an antibody that destroyed its own tissues, that Donath & Landsteiner (1904) described an antibody that did just that. Shortly afterwards, Fernand Widal (of typhoid fame) was probably the first to recognize acquired haemolytic anaemia with red cell agglutination (Widal et al, 1908). Thirty years later, in Boston, Dameshek & Schwartz (1938) stressed the importance of `haemolysins' in the commonest type of acquired haemolytic anaemia. It was not quite clear what these `haemolysins' were until the development of the indirect anti-globulin test by Robin Coombs (Coombs et al, 1945) and its application in haemolytic anaemia (Boorman et al, 1946). Wasserman (not of syphilis fame) found haemolytic anaemia to be present in nine out 58 consecutive patients with CLL; five out of seven patients tested had a positive Coombs' test (Wasserman et al, 1955). A series of studies suggested that autoimmune haemolytic anaemia (AIHA) occurs at some time in the course of CLL in between 10% and 26% of cases (Wasserman et al, 1955; Pisciotta & Hirschboeck, 1957; Beickert, 1959; Dameshek & Schwartz, 1959; Troup et al, 1960; Videbak, 1962).

It is often forgotten that the `I' in ITP (immune thrombocytopenic purpura) originally stood for `idiopathic' and not `immune'. William Dameshek, although a giant of haematology almost without equal, was clearly wrong in his championing of `hypersplenism' as the cause of thrombocytopenia. The spleen was supposed to produce a sort of miasma that inhibited the bone marrow. Harrington et al (1951) first demonstrated that the plasma of patients with chronic ITP transfused into a normal recipient (himself) would produce thrombocytopenia. (Oh what experiments you could do in the world before viruses!) Later, Shulman et al (1965) showed that this plasma factor was present in the 7S gamma globulin fraction and was absorbed by human platelets.

Thrombocytopenia is quite common in CLL. Minot and Buckman (1925) found it in half their patients at presentation and in virtually all those patients whose white cell count rose above 175k. Harrington & Arimura (1961) reported seven cases of autoimmune thrombocytopenia occurring in CLL. Dameshek reported five more (Ebbe et al, 1962), but because of the unsatisfactory nature of platelet antibody tests the true prevalence of ITP in CLL is unknown. An increase in bone marrow megakaryocytes remains the surest touchstone.

Reporting autoimmunity in CLL was then a popular sport. Immune neutropenia (Killman, 1959), pure red cell aplasia (Abeloff & Waterbury, 1974), Sjogren's syndrome (Lehner-
Netsch et al, 1969), nephrotic syndrome (Dathan et al, 1974), bullous pemphigoid (Cuni et al, 1974), Graves's disease (Haubenstock & Zalusky, 1985), systemic lupus
erythematosus, rheumatoid arthritis, ulcerative colitis, allergic vasculitis and pernicious anaemia (Miller, 1962; Dameshek, 1967) have all been associated with CLL. The fact that CD5-positive B cells secrete antibodies that can be made to react with DNA and IgG (Sthoeger et al, 1989) has encouraged speculation concerning the origin of autoimmune disease in CLL. In fact, the clinically important autoantibodies are produced by the residual normal immune system, not by the tumour cells. Most of the associations between CLL and autoimmune diseases occur by chance. Only AIHA and ITP are more common than in an age-matched control population (Hamblin et al, 1986).

The high incidence of AIHA in fludarabine-treated patients (Myint et al, 1995) suggests that autoimmunity is a consequence of the severe immunodeficiency that occurs in CLL and especially the AIDS/like syndrome that may follow treatment with fludarabine.

Transformation.

Richter (1928) described an aggressive lymphoma occurring in a patient with CLL and gave his name to a phenomenon that occurs in up to 3% of patients. Histologically, the tumour is a diffuse large-cell lymphoma (Trump et al, 1980). Modern techniques have demonstrated that in roughly half the cases the second lymphoid tumour is clonally unrelated to the first (Miyamura et al, 1990; Kruger et al, 1993). In prolymphocytic transformation of CLL (Enno et al, 1979), the cell markers remain CLL like. Although of grave consequence to the patient, he does not develop PLL. Transformation to acute lymphoblastic leukaemia has been reported (Brouet et al, 1973). Such was the confusion at the time over what CLL was, I doubt whether this or any of the subsequent cases were correctly assigned.

History of CLL (part 3)

Clinical staging

At the same time as the immunophenotype was being defined, two clinical staging systems for CLL were being developed. In New York, Kanti Rai defined five groups and gave them Roman numerals (Rai et al, 1975), while in Paris Jacques-Louis Binet designated three groups alphabetically (Binet et al, 1977). In reality, both systems were saying the same thing, namely that the more disease you had the worse the prognosis and if the bone marrow started to fail then the outlook was dire. It was no surprise to see the International Workshop on CLL (IWCLL) recommend that the two systems be amalgamated (IWCLL, 1981, 1989), although in reality the Americans continue to use Rai and the Europeans use Binet. A number of other prognostic indicators have since been recognized, including lymphocyte doubling time (Montserrat et al, 1986), bone marrow histology (Rozman et al, 1984) and chromosomes (Juliusson et al, 1990).

Differential diagnosis

Most of the large series of patients with CLL published before 1990 were contaminated with diseases that we would now recognize as not being CLL. Lymphosarcoma cell leukaemia was recognized early as something rather different (Isaacs, 1937), but criteria for its diagnosis varied between different institutions (Zacharski & Linman, 1960; Schwartz et al, 1965). Aisenberg &Wilkes (1976) recognized a type of spillover lymphosarcoma with sparse surface immunoglobulin, similar to CLL (well-differentiated lymphocytic lymphoma), that, by the revised European American classification of lymphoid neoplasms (REAL), we would probably recognize as the same disease as CLL. Those tumours with denser surface immunoglobulin were clearly different, but lymphoma classification was so uncertain that we can only speculate on how different. Many will have been follicular lymphomas (Spiro et al, 1975) or what we may perhaps refer to in the future as t(14;18) disease (Cleary et al, 1986).

Prolymphocytic leukaemia (PLL) was recognized as a separate entity by Galton et al (1974). Because prolymphocytes may accumulate in CLL, there has been confusion, but it should now be clear that CLL does not transform into PLL.

Hairy cell leukaemia was recognized in 1958, albeit under a different name (Bouroncle et al, 1958). It is difficult to believe it could be confused with CLL, although perhaps more excuse could be made for confusing the hairy cell variant (Cawley et al, 1980).

Splenic lymphoma with villous lymphocytes (SLVL) was first recognized in 1979 (Neiman et al, 1979), although again under a different alias. Since the REAL classification gained popularity, this is being recognized as a form of splenic marginal zone lymphoma. Other cases of this disease may not have very obvious villi and may constitute what has become known as CD5-negative CLL (Salomon-Nguyeu et al, 1995).

Because it is CD5 positive, mantle cell lymphoma is the last of the lymphosarcoma cell leukaemias to be separated from CLL. It has emerged as a distinct entity via many different name changes, although its existence in a leukaemic phase was only lately recognized (De Oliveira et al, 1989). It has dense surface immunoglobulin and lacks CD23, but most distinctive is the t(11;14) translocation (Raffeld & Jaffe, 1991). It is a matter of faith in our laboratory that no case of CLL has this translocation.

T-cell CLL was first described by Brouet et al (1975). Several subtypes have now been recognized and the term is no longer used. Although T-PLL had been recognized in a number of prior publications, including some by the Royal Marsden team, the defining description was by Matutes et al (1986). It is usually a very malignant disease with a characteristic karyotype. Despite its distinctive cellular morphology, it is still confused with CLL (Hoyer et al, 1995).

McKenna et al (1977) first described large granular lymphocytic leukaemia. This condition usually has CD8-positive lymphocytes. It exists in CD3-positive and CD3-negative forms (Loughran, 1993). Non-clonal proliferations are also seen. There remain the CD4-positive leukaemias that are either the disease associated with HTLV-1 or part of the mycosis fungoides/Sezary syndrome complex (Matutes et al, 1988). The term T-cell CLL should no longer be used and therefore it is no longer necessary to call CLL `B-cell CLL.

History of CLL (part 2)

The Twentieth Century

Minot and Isaacs produced the first detailed description of the clinical features and natural history of a large series (80 cases) of patients with CLL, and pointed out that radiation therapy shrank the lymph node masses but did nothing for the course of the disease (Minot & Isaacs, 1924). Over the next few decades, many doctors studied CLL, but there were very few insights into its nature. Richard Doll established that it was a disease of late middle age, twice as common in men (Court Brown & Doll, 1959) The usefulness of chlorambucil (Galton et al, 1955) and corticosteroids (Shaw et al, 1961) in treatment was recognized. By the late 1960s, three great haematologists knew all there was to know about the clinical features of CLL and its natural history. The large series of patients from Maxwell Wintrobe's department at Salt Lake City confirmed the very variable survival times in this disease and suggested a means of stratifying the disease according to its clinical features (Boggs et al, 1966). David Galton described a proliferative variant that did poorly and a stable variant that did well (Galton, 1966). He also described CLL as a disease of accumulation of long-lived functionally incompetent lymphocytes, a conclusion arrived at independently by William Dameshek (Dameshek, 1967). In 1973, Mùrk Hansen published a series of 189 cases of CLL that had been followed for a long period of time (Hansen, 1973). This volume, which describes CLL in great detail, is one of my treasured possessions and has been of great value to me in preparing this review. However, because no one had a clear idea of what a lymphocyte did, further progress was inhibited.

What is a lymphocyte?

A major textbook of immunology published in the mid-1950s contains only one reference to the lymphocyte and that was to dismiss it as a serious contender as an antibody producing cell (Boyd, 1956). Although immunology had made great strides after Jenner's rather pragmatic approach to vaccination through the work of Pasteur, Ehrlich, Landsteiner and Metchnikov, it was still all about macrophages and antibodies. As a young medical student in Bristol in the 1960s, I was taught by Professor Yoffey that the lymphocyte was the precursor of the red cell (Yoffey,
1966).

Cell-mediated immunity.

The idea that the lymphocyte was in some way involved in the immune response kept surfacing. James B. Murphy, working mainly alone at the Rockefeller Institute in New York on what he thought was tumour immunity but in fact was probably transplantation immunity, assembled an impressive array of evidence (Murphy, 1926). He found that exposure of rodents to X-rays killed their lymphocytes and lowered resistance to cancer grafts. Murphy also discovered that tumours can be grafted into embryos, but are rejected if a graft of spleen or marrow from an adult is included. Finally, he found that rejection of a tumour graft is accompanied by a proliferation of lymphocytes in spleen and bone marrow and that these invade the tumour.

In the 1940s and 1950s, Peter Medawar and colleagues (Billingham et al, 1954), inspired by the horrific burns suffered by wartime fliers, worked on skin grafts. They demonstrated that the accelerated rejection of second grafts could be transferred by lymphocytes and not by antibody. Even Landsteiner, shortly before his death, had demonstrated that contact sensitivity could be transferred between animals by lymphocytes (Landsteiner & Chase, 1942). Thus, it was fairly easy to accept that the lymphocyte might beresponsible for what became known as cell-mediated immunity.

Antibody.

Antibody was a different proposition. Although McMaster & Hudduck (1935) had shown that most of the antibody produced in response to injection of antigen into the ear of an animal was produced in draining lymph nodes, it was clear that the antigen was picked up there by macrophages. The simplest explanation was that they also made the antibody. However, several workers noticed that such an immune response made no alteration to the macrophage, yet caused the proliferation of the lymphocytes, which became big and blastic. Ehrich and Harris (Harris et al, 1945) in Philadelphia cannulated the efferent lymphatic of a responding lymph node and demonstrated that the antibody contained in the lymphocytes that they collected was six times the concentration of that in the fluid.

The plasma cell.

Better evidence that the plasma cell was the main antibody-producing cell was emerging from Scandinavia. First, the observation that myeloma, a tumour of plasma cells, was associated with an excess of antibody globulin (Bing & Plum, 1937), then the observation that repeated immunization of rabbits led to marked increases of plasma cells in lymph nodes and bone marrow (Bjùrneboe & Gormson, 1943) and, finally, the convincing evidence of the binding of fluorescence-labelled antigen to plasma cells and not lymphocytes by the Harvard workers (Coons et al, 1955). Ehrich and Harris were forced to concede the primacy of the plasma cell, but few scientists are willing to let go of their ideas (and research grants) so easily. In a series of brilliant experiments, Harris and his wife explored the immune response in the rabbit to Shigella bacilli. They demonstrated that lymphocytes taken from a responding lymph node, washed free of antigen and macrophages, would induce the production of antibody when injected into a different animal, presumably by transmogrifying into plasma cells (Harris & Harris, 1960). They were right, but
the sceptics still needed convincing.

Lymphocyte life span.

The final obstacle to proving that the lymphocyte had anything to do with immunity was its fast disappearance time. At the beginning of the century, Davis & Carlson (1909) in Chicago demonstrated that the blood lymphocytes were replaced four times every 24 h. Of their four possible explanations, their first hypothesis (that they were rapidly destroyed) was more easily believed than their last explanation (that they escaped through capillary endothelium and then recirculated via the lymphatics), which happened to be the correct answer. The essence of immunity is memory. For the lymphocyte to play a part in immunity it must live long enough to hold a memory. James Learmonth Gowans, in the Dunn School of Pathology at Oxford, solved the conundrum. He injected radiolabelled lymphocytes into the bloodstream and collected them a few hours later from the thoracic duct (Gowans, 1959). When it became possible to examine the chromosomes of lymphocytes after stimulation by phytohaemagglutinin, it became apparent that treatment of men with ankylosing spondylitis by radiotherapy induced unstable chromosome aberrations. By studying these, cytogeneticists in Edinburgh were able to conclude that the average small lymphocyte went several years between cell divisions (Buckton et al, 1967). The lymphocyte clearly lives long enough to carry memory.

Thymus and bursa.

Beard (1900) in Edinburgh believed that the thymus was the source of all white blood cells, but that this function ceased early in life after the whole body had been seeded. After this the thymus could be removed with impunity. The obvious test of this hypothesis, to remove the thymus immediately after birth, was delayed for 60 years. Jacques Miller, working at the Chester Beatty Institute, discovered that neonatally thymectomized mice had impaired immune responses (Miller, 1961). Workers at Yale demonstrated that this deficiency involved delayed hypersensitivity and graft rejection, rather than antibody production (Arnason et al, 1962).

The bursa of Fabricius is a lymphoid organ located at the dorsal aspect of the cloaca in birds. Like the thymus, it involutes rapidly after hatching. The obvious experiment of removing it shortly afterwards occurred to immunologists rather earlier than it did for the thymus. Chicks bursectomized shortly after hatching grew up to be chickens, but when (because of a shortage of birds for teaching) they were used in a class exercise they unexpectedly failed to produce antibody against Salmonella (Glick et al, 1956). This theme of two types of lymphocyte being processed by different neonatal organs to constitute the two arms of the immune response had great power and symmetry. Encouragingly, the experimental work in rodents and poultry was mirrored by the clinical studies of Bob Good in Minneapolis on immunodeficient children (Good & Varco, 1955). Thus, we had B cells and T cells. Much time and effort has been expended looking for a non-existent `bursa equivalent' in mammals. Eventually, it was decided that the bone marrow itself fulfilled the function, but it is a mistake to think of B cells as `bone marrow derived' as both types of lymphocytes have their genesis in the bone marrow.

Recognizing B and T cells.

It is difficult to convey the excitement of the period of the early 1970s when it became possible to recognize B and T cells in the peripheral blood. Listening to Martin Raff speaking with that extraordinarily attractive accent at the British Society for Immunology meetings describing anti-theta antibodies reacting with T cells and anti-mu antibodies reacting with B cells fired me with enthusiasm for that fusion of haematology and immunology that I have practised ever since.

Paul Ehrlich had postulated the existence of preformed receptors on the outer surface of cells that could interact specifically with foreign substances (Ehrlich, 1900). He suggested that when these were bound to the receptor the cell would be switched to producing more of the receptor that would be shed into the surrounding medium as antibody. McFarlane Burnet postulated that each lymphocyte was different, genetically predetermined to synthesize only one type of antibody molecule (Burnet, 1959). Thus, after contact with antigen, only those cells preprogrammed to produce an antibody with a complementary structure would be stimulated to proliferate and produce antibody-producing progeny, in effect a clone of the antigen-recognizing cell. Sell & Gell (1965) in Birmingham had first shown that antibodies against immunoglobulin could induce blast transformation in some lymphocytes, implying that immunoglobulin was located on the surface of some lymphocytes, presumably as a receptor for antigen. In Ave Mitchison's laboratory at Mill Hill, Martin Raff and Roger Taylor demonstrated by immunofluorescent staining that this was indeed the case (Raff et al, 1970). It was the common belief at the time that immunoglobulin, or perhaps a portion of the molecule, was also the antigen receptor in T cells. A simple experiment by Raff demonstrated the error. The theta antigen (later renamed Thy-1) is present in the brain, thymus cells and thymus-derived cells in the spleen and lymph nodes of mice (Reif & Allen, 1964; Raff, 1969). Raff (1970) showed that all lymphocytes expressed either theta or immunoglobulin, but never both.

This was all in mice, of course. Then, towards the end of 1971, a flurry of papers appeared. In successive weeks of October The Lancet published first a paper from Gus Nossal from Melbourne using iodine 125 labelled antibody (Wilson & Nossal, 1971) and then one from John Holborrow from the Canadian Red Cross Memorial Hospital at Taplow in Middlesex using direct immunofluorescence (Papamichael et al, 1971) Both studies reported that B cells could be detected in human peripheral blood. Both series included patients with CLL among their subjects. In contrast with normals in whom only approximately 7% of lymphocytes expressed surface IgM, in CLL an average 89% of lymphocytes carried surface immunoglobulin. These studies were marred by non-specific binding of IgG and by the assumption that the T-cell receptor must also be immunoglobulin, but, nevertheless, it had at last been established that the CLL cell was a B cell. The Australian paper also showed that CLL cells had far less surface immunoglobulin than normal B cells.

Who got there first? Was this to be 1845 all over again? There were other contenders. Grey et al (1971a) demonstrated surface immunoglobulin on the cells of 20 CLL patients only a month later in a paper published in the Journal of Clinical Investigation, and this paper was certainly submitted before either of the Lancet papers. Moreover, it had been published in abstract form five months earlier (Grey et al, 1971b). Both Seligmann's (Preud'homme et al, 1971) and Pernis's (Pernis et al, 1971) papers were published in December and a more comprehensive study from Paris (Preud'homme & Seligmann, 1972) appeared 12 months later. It was probably Eva Klein who should be given the priority, as her single case report appeared the previous year (Johansson & Klein, 1970). What this shows is how pointless such squabbles are. This was an idea whose time had come. As the subject of much gossip and speculation on the conference circuit, any one of a dozen laboratories could have found it first.

For humans there was no theta antigen. But the remarkable property of human T cells forming rosettes with sheep red blood cells (Lay et al, 1971) formed a surrogate assay until monoclonal antibodies were developed. There then developed a fashion for rosetting that has now passed. The most useful discovery was the property of CLL cells of forming rosettes with mouse red blood cells (Stathopoulos & Elliott, 1974). The immunophenotype of CLL was quickly defined. As well as IgM, most cells also carried IgD (Fu et al, 1974; Preud'homme et al, 1974). Surface immunoglobulin density was much lower than for normal B cells (Chen & Heller, 1978). Paradoxically, an antigen initially regarded as T-cell specific and later designated CD5 was recognized on the surface of CLL cells by the monoclonal antibodies RFT-1, Leu-1 and OKT-1 (Caligaris-Cappio et al, 1982).

Friday, February 15, 2008

History of CLL (part 1)

HISTORICAL ASPECTS OF CHRONIC LYMPHOCYTIC LEUKAEMIA

In the beginning

As far as we know, leukaemia has always existed. Probably the first patient noticed by a doctor as exhibiting the symptoms was a Monsieur Vernis, a 63-year-old Parisian lemonade salesman (Velpeau, 1827). We know that in this profession and in his former job as a florist he had been a happy, carefree individual with an eye for the ladies; yet he had managed to avoid the ravages of syphilis. Alas, despite Dr Velpeau's eminence, nobody else seemed interested in the disease. It took a controversy over precedence for leukaemia to reach the medical agenda in earnest. In the same issue of the Edinburgh Medical and Surgical Journal in October 1845, two case reports (Bennett, 1845; Craigie,1845) described patients who probably had leukaemia. Craigie's patient, a 30-year-old man whose illness began in 1841, had a spleen that weighed seven pounds three and a half ounces and `pink, wine-lee-coloured, groumous blood mixed with whitish-coloured masses of purulent lymph'. ‘Groumous' means viscous or jelly like. The patient survived for 1 year with deteriorating fatigue, weakness and increasing abdominal girth and pain. It is quite likely that this was the first reported case of chronic myeloid leukaemia.

We do not know for sure what type of leukaemia John Hughes Bennett, the Englishman later to become Professor of Medicine in Edinburgh, reported. His patient, John Menteith, a 28-year-old slater from Edinburgh, had been aware of a mass in the left side of his abdomen for 8 months before he died. At post-mortem examination, he had massive enlargement of his liver, spleen and lymph nodes. Examination of his blood revealed `the existence of true pus, formed universally within the vascular system, independent of any local purulent collection from which it could be derived'. Although the involvement of the lymph nodes suggests chronic lymphocytic leukaemia (CLL), it is more likely that a patient of this age would have had a spill-over lymphoma.

We cannot fully diagnose the case of Marie Straide, reported only 6 weeks later by Rudolph Virchow in Berlin (Virchow, 1845), either. Marie was a 50-year-old cook, who ied with a huge spleen 6 months after presentation. In her blood, the ratio of pigmented to colourless corpuscles was reversed. As she developed furuncles and suppurations of the skin and had several nosebleeds during her short illness, she may well have had acute leukaemia.

The word `leukaemia' (leukaemie) was coined by Virchow (1847a), and by that time he had already published a further nine cases (Virchow, 1846, 1847b). Meanwhile, Bennett preferred the term `leucocythaemia' and collected a further 35 cases that he salami-sliced into four papers and a monograph (Bennett et al, 1851a,b,c,d, 1852). Most of the early cases had splenomegaly as a major feature, although at least one of Virchow's cases had generalized lymphadenopathy without splenomegaly (Virchow, 1846), perhaps the first true case of CLL. Thereafter, Virchow classified leukaemia into `splenic' and `lymphatic' forms, recognizing that splenic leukaemias had granular leucocytes with trefoil-like nuclei in contrast to the agranular leucocytes with smooth round nuclei of the lymphatic leukaemias (Virchow, 1851). It is important to grasp the atmosphere as the two competing doctors strove for pre-eminence in the field of leukaemia. Even the name of the condition was acrimoniously disputed.

Bennett was 33 years old in 1845. He had graduated from Edinburgh after a brilliant student career. He was apprenticed to a surgeon in Maidstone and he then spent 2 years in Paris under the great microscopist Donné, who himself has some claim to have described the pathological features of leukaemia before either Virchow or Bennett (Donne, 1844). This case had presented clinically in 1839, and it is easy to believe it had been much talked about by the doctors there. After Paris, where he founded and was first President of the Parisian Medical Society, Bennett spent a further 2 years in Germany and then returned to Edinburgh. Here, he gathered a reputation as an outstanding teacher. By 1845, he was already a Fellow of the Royal Society of Edinburgh, and in 1848 was elected to the Chair at the Institutes of Medicine. That he never achieved the much more prestigious Chair of Physic at Edinburgh University has been attributed to his short temper, pugnacious attitude and certainty of his own virtues. Even the writer of his obituary had to admit that `his tendency to indulge freely in critical and sarcastic remarks upon the works of others did not make him a general favourite with some of his professional brethren' (McKendrick, 1875).

Virchow was only 24 in 1845 and just 2 years out of medical school. The Berlin Army Medical School (Friedrich-Wilhelms Institut) must have been a very much more disciplined establishment than Edinburgh, but Virchow was just as opinionated as Bennett. Part of the requirements for his entry to medical school was an undertaking to serve in the army on qualifying. When sent to report on an epidemic of typhus in 1847, his experiences led him to become a politically active radical and his part in the uprising in 1848 caused his expulsion from the Charité where he held his academic position. He was elected to the Berlin City Council in 1859, where he instituted many public health improvements. Later, as a member of the Prussian Lower House, he opposed Bismarck and became famous for his radical views and polemical speeches. In the Franco-Prussian war, he organized the ambulance service of the German army. Incontrovertibly the greatest pathologist of his generation, perhaps of all time, Virchow became assistant to Professor Froriep at the Charité in Berlin and was given the task of investigating the inflammation of veins. Froriep had been in Paris at the same time as Bennett, so might well have known of Donné’s case.

The first ante-mortem diagnosis of leukaemia was made by Fuller (1846). Both Virchow and Bennett made their discoveries at the autopsy table. How sad it is that so few young doctors are to be found there these days. Despite their dispute, both Bennett and Virchow agreed that the main trouble lay in the enormous number of colourless corpuscles in the blood. Without the ability to stain blood cells, their ideas on pathogenesis were exotic. Bennett believed that the red cells were the extruded nuclei of white cells and that a failure of this process led to the reversal of the ratio of the two types of cell. Virchow believed that the leukaemic cells came from the lymph, although he conceded that the spleen was an alternative source.

The bone marrow.

Ernst Neumann first recognized the central role of the bone marrow in leukaemia (Neumann, 1870). Neumann, like Immanuel Kant a century before, was a lifelong citizen of Konigsberg. He gave us our conception of the marrow as the source of the blood cells, eventually achieving fame as a visionary man of science and a writer of impeccable German. Meanwhile, he had to endure 20 years of ridicule by the medical establishment, who clung to the outmoded ideas of the previous generation. Nothing changes. Neumann recognized two patterns of bone marrow involvement in leukaemia: pyoid hyperplasia, dominated by highly granular cells, and lymphadenoid hyperplasia, where the cells had pale homogeneous nuclei and were almost devoid of cytoplasm (Neumann, 1878).

Stained cells.

Paul Ehrlich (Fig 4) developed a tri-acid stain that allowed the clear definition of nucleus, cytoplasm and other cytoplasmic detail (Ehrlich, 1891). His cousin, Carl Weigert, already a master at staining tissues, guided him. The German chemical industry had recently discovered the aniline dyes ± a prime example of technology driving science. Ehrlich was a man obsessed with his studies. His skin and clothing were stained from his experiments, as was his billiard table where he regularly conducted them. He frequently moved his base; from Leipzig to the Charité in Berlin, to Koch's Institute, to Steglitz and to Frankfurt. Although he was showered with honours, including the Nobel Prize in 1908, his last years were unhappy as he was involved in controversy over his introduction of the arsenicals for the treatment of syphilis. Nevertheless, Erhlich's stains allowed the leukaemias to be more clearly separated, and by the turn of the century Turk (1903) published criteria for the diagnosis of CLL.

Overlap with lymphoma.

In this same publication, Turk stressed the resemblance between CLL and lymphoma. Thomas Hodgkin had first described fatal tumours of the lymph nodes, although in retrospect we now know that only three of his seven patients actually had Hodgkin's disease (Hodgkin, 1832). Virchow (1863) described lymphosarcoma as a malignant tumour of the lymphoid tissue distinct from leukaemia and tuberculosis. Kundrat (1893) used the same term, recognizing that the disease spread between different groups of lymph nodes but spared the blood and bone marrow, thus distinguishing it from leukaemia. However, Turk (1903) pointed out that transitions between lymphosarcoma and CLL did occur and he regarded them as part of a family of diseases. A lively debate between these two extreme positions continued well into the twentieth century and even today there remains some difficulty in distinguishing CLL from some forms of lymphoma

Thursday, February 14, 2008

Pacificism

I have been reading (on the advice of one of my correspondents) Robert W Brimelow's book, "What about Hitler".

The author attempts to answer the question that is a stumbling block for pacifists - is it right to stand by and let evil triumph?

Although I have not quite finished it, I can say that the author does present some cogent arguments about what constitutes a 'just war' and about the end not justifying the means, but so far I am not convinced by them. It may be OK to stand by and allow Hitler to march over you, but I still think that we have a duty to protect the weak from the strong.

Gandhi was asked towards the end of the war, "What about the Jews? Are you prepared to see them exterminated? If not, how do you propose to save them without reverting to war?"

Gandhi's response was that German Jews ought to commit collective suicide, which "would have aroused the world and the people of Germany to Hitler's violence." After the war he justified himself: the Jews had been killed anyway, and might as well have died significantly.

In the opinion of his contemporary, George Orwell, Gandhi did not understand the nature of totalitarian regimes and considered all struggles to be similar to his struggles with the British colonial government. While they might have encouraged Gandhi for fear of getting something worse - like car bombers or armed insurrection - they were essentially decent men with consciences. Not so the like of Heydrich, Himmler and Eichmann.

I also think that pacifist fail to realize that all order in society springs from the threat of violence. We may obey the law because we think it's right, but many obey the law for fear of getting caught. If caught they may be fined. Why pay the fine? For fear of imprisonment. Why submit to imprisonment? Because it is enforced by the threat of violence. In fact, even in states without the death penalty, resistance to the force of imprisonment is eventually met by lethal force. If you resist the arresting officer with firearms you are likely to be shot.

We may try to reduce the force used to control rebels against the authority of the state, but people have been killed by rubber bullets and by tasers, or even by being sat upon by three fat bobbies.

I will have more to say on this subject when I finish the book.

Tuesday, February 12, 2008

Learn2Lead

I occasionally speak on the Learn2Lead course at church and yesterday led the session on the Prophets. 17 books by 16 authors is a large task for 90 minutes. In fact we only touch on Elijah, Amos, Isaiah and a bit of Jeremiah. I was struck by how contemporary Amos is. He preached at the time of King Jereboam the second, a time of great prosperity for Israel. The borders were extending, they were wealthier than at any time since Solomon, they took neighboring tribes captive and sold them into slavery. Even their beds were inlaid with ivory. Yet they had neglected God. Their sacrifices, instead of being a propitiation for the times they lapsed into sin, had become an alternative to sinlessness. They were just a ritual to be enacted as an alternative to living a righteous life. There was huge gap between the rich and the poor.

Amos heaps curses on the surrounding nations. They have many sins but each is condemned for a particular sin. For Judah and Israel, though, he reserves a double curse; they have the Law, and know how they ought to behave. Even without the Law, the surrounding nations have no excuse; they have their consciences. Bur Israel has conscience and the Law and is doubly condemned.

Amos appears the epitome of the Old Testament prophet. He is not all doom and gloom though. Like Moses of old, he pleads with God for his sinful nation.

I wonder if the situation sounds familiar? What strictures would Amos bring on our nations were he preaching now? Then he faced opposition from the school of prophets at Bethel (remember Elisha?) Those who preach the truth now face opposition from the formal church. We have had the gospel for so long yet we continue to sin grievously in our paneled houses. We may not sleep on beds of inlaid ivory, but what would Amos have made of out new SUVs and flat screen TVs? Are there still poor among you? What about your religion? Has it become formulaic? We, perhaps justifiably, heap scorn and damnation of Moslem suicide bombers, but we have the Word of God and know how we should live. As Christians we believe that they do not. We are worthy of double condemnation.

How delightful then to come to Isaiah chapter 40 v 2. "Speak tenderly to Jerusalem,
and proclaim to her that her hard service has been completed, that her sin has been paid for, that she has received from the LORD's hand double for all her sins."
and chapter 43:"Fear not, for I have redeemed you; I have summoned you by name; you are mine. When you pass through the waters, I will be with you; and when you pass through the rivers, they will not sweep over you. When you walk through the fire, you will not be burned; the flames will not set you ablaze. For I am the LORD, your God, the Holy One of Israel, your Savior"

There's a way back to God from the dark paths of sin, there's a door that is open and you may go in. At Calvary’s cross is where you begin, when you come as a sinner to Jesus.

Monday, February 11, 2008

Isaiah 45:13

I will raise up Cyrus in my righteousness: I will make all his ways straight. He will rebuild my city and set my exiles free, but not for a price or reward, says the LORD Almighty.

Cyrus remains a great hero to modern Iranians as the father of Persia. Yet Cyrus is also a hero to Jews, because he liberated them and was famously tolerant of Judaism. So, you have Iran, a nation led by anti-Semites, sharing a hero with Jews.

Cyrus conquered Babylon or in today's terms, modern day Iraq.

Two and a half thousand years later the same teams are playing.

And we complain that it's always Manchester United, Arsenal, Chelsea and Liverpool that contest the Premiership.

Sunday, February 10, 2008

Whose life is it anyway?

My friend, CLL sufferer and poet, Alan Sullivan has posted a poem on his blog which poses a question for every sick person.

Remission

A brief reprieve—I could have bought a yacht
for what it cost—a Hallberg-Rassy ketch—
not new but prime—her heading mine to plot,
her mizzen set while I kept midnight watch.

I read a legend once—a Sitkine clan
canoed downstream after the fish-run failed.
A glacier blocked their way; the river ran
a cold blue slot. The strongest paddlers quailed.

Their eldest volunteered to shoot the length:
“What use am I? My legs are giving way.”
What use am I?—no tribe to save—no strength
to seek epiphany, only to say

like Scott’s companion, Oates, his beard all rime,
“I am just going outside, and may be some time.”

In response his friend, Tim Murphy, posted this poem by Derek Mahon on the same theme:

Antarctica

‘I am just going outside and may be some time.’
The others nod, pretending not to know.
At the heart of the ridiculous, the sublime.

He leaves them reading and begins to climb,
Goading his ghost into the howling snow;
He is just going outside and may be some time.

The tent recedes beneath its crust of rime
And frostbite is replaced by vertigo:
At the heart of the ridiculous, the sublime.

Need we consider it some sort of crime,
This numb self-sacrifice of the weakest? No,
He is just going outside and may be some time—

In fact, forever. Solitary enzyme,
Though the night yield no glimmer there will glow
At the heart of the ridiculous, the sublime.

He takes leave of the earthly pantomime
Quietly, knowing it is time to go.
‘I am just going outside and may be some time.’
At the heart of the ridiculous, the sublime.

As it happens in my musings on the gospel of Mark I had just come to the death of Jesus and the question of why Jesus died so quickly on the cross. Those who saw "The Passion of the Christ" will, perhaps, conclude that Jesus died not from hanging on the cross, but from the damage inflicted by the flagellation. Indeed many years ago I wrote a piece for World Medicine which suggested just that. (I will post it in the next few days for comparison)

However, I have since learnt to interpret Scripture with Scripture, and John 10:17-18 has Jesus saying, "I lay down my life—only to take it up again. No one takes it from me, but I lay it down of my own accord."

In other words, it sounds as though Jesus, perhaps by some act of will, ended his own life; if not an act of suicide, an act of surrender. Hence the connection with Captain Laurence Oates whose words are referred to in both poems.

So, is suicide justified? I remember a classic movie called Soylent Green. Set in 2022 it is in the format of a thriller in which Charlton Heston plays a cop investigating the murder of the Chairman of the Soylent company that manufactures food concentrates in an overcrowded world. The concentrates, supposedly made from plankton, come in various colors, but Soylent green is tastier and more nutritious and is only distributed on Tuesdays. There are riots when there is not enough for everybody.

Because of the shortages there is much subtle pressure on the old to opt for euthanasia and Heston's friend, Roth, (played by Edward G Robinson) eventually acquiesces to this. Heston subsequently discovers that Soylent green is made from the recycled cadavers from the euthanasia factories.

This is the ultimate in Utilitarianism. But why should Christians object when their own leader seems to have surrendered his life deliberately when His task was completed? Again the answer comes from John's gospel. John 10:18 continues, "I have authority to lay it down and authority to take it up again. This command I received from my Father."

Today many might claim the authority (and the power as it is in the KJV) to lay down their lives, but no-one seems to have the authority (or power) to take it up again.

Scripture certainly tells us that "Greater love hath no man than this that he lays down his life for his friends." but I am sure that does not mean committing suicide so as not to be a financial burden on the young and virile. You might dare to hold the bridge while your comrades escape or throw yourself on a grenade in the trenches or even take the hit of a wayward truck on a street to save your baby, but deliberately depriving your brothers and sisters of the opportunity to care for you is not in the same league.

Captain Laurence Oates lived not far from me at Selborne, in Hampshire, coincidentally in the same house as Gilbert White, the famous naturalist. One room of the Gilbert White museum is given over as a memorial to Oates.

Whether he really was the heroic figure that history has made him is questionable. Five years ago an article in the Guardian suggested that he had fathered a child on an 11 year old girl. He apparently despised Scott whom he thought a glory hunter. It has been suggested that his suicide had nothing altruistic about it, but merely an exit from intolerable pain. He died on his thirty-second birthday.