Dandelions

I have just been round the garden and uprooted 17 dandelions. While there I counted 44 different types of flowers blooming. Although I don't know the names of them all, and some were weeds, they included the last of the cherry blossom, the first of the apple blossom, plum and almond blossom, the dregs of the daffodills, narcissi, tulips, hyacinths, grape hyacinths, cyclamen, two different species of periwinkle, several heathers, violets, daisies, buttercups, azalias, a prunus, a species of flowering laurel, bluebells, forsythia, purple and magnolia colored magnolia, hazel catkins, pyrrus, forget-me-nots, polyanthus, primrose, honesty and camelia. In the greenhouse strelitzia and geraniums. There wer near to bursting buds on the lilac and the clematis. Only two birds, though, a blackbird and a robin. And one squirrel. Gray.

Cancer is vulnerable where it is strong

In two of my earlier posts - on micro-RNAs and PARP inhibitors - I forgot to add what is really exciting about these developments.

Why is it that cancers are so dangerous? It is because they have lost a control mechanism that would normally prevent them from proliferating in this way. What these topics tell us is that the point of survival advantage is also their point of vulnerability.

Think of the cancer as the young man on a motor cycle. He abandons the rules of the road and races away at the lights. But his very lack of care is what causes him to have an accident. Thus in CLL with an ATM deletion there is a defect in DNA repair. This gives the CLL clone a survival advantage over other B cells, and allows it to develop further DNA damage, but it is only because it has the ATM deletion that it is vulnerable to PARP inhibitors. If you like it is like Judo - you use the cancer's strength against itself.

John Prescott

What must Deputy Prime Minister, John Prescott, do to get himself fired?

After owning up to a 2-year, Bill-Clinton-like affair with an underling (who is also the mistress of a long distance lorry driver in Bordon, Hants), it now emerges that he took her rather than his wife to a relgious service for Iraq veterans.

This is the man whose green credentials extend to driving 200 yards in one of his two gas-guzzling Jaguars so that his wife's hair wouldn't get mussed up, who punched a heckler on the hustings, whose housing arangements are so 'involved' that he recently had to repay a tax bill of several thousand pounds due to a 'misunderstanding' about his three residences and who when asked a question on the radio so mangles the answer that he out-George Ws George W for incomprehensibilty. When standing in for Tony Blair at Prime Minister's question time recently, he so distorted an answer that William Hague had to call for a translation into English.

It is probably not true, however, that he ate an elephant at Blackpool zoo according to this link. http://www.deadbrain.co.uk/news/article_2005_12_28_1729.php

Consultation document 2

This is the mangled paragraph unmangled.

In the original paper describing Rai staging, stage 0 patients were reported to have an overall survival in excess of 10 years [15]. It should be remembered that at this time the diagnostic criteria for CLL required a lymphocyte count greater than 15 x 109/L. Subsequently, the French Co-operative group [16] recognized a type of smoldering Binet stage A’ CLL with Hb greater than 120 g/L and lymphocyte count less than 30 x 109/L. Of the patients fulfilling these criteria 25% had progressed by 5 years. The Spanish group [17] defined smoldering cases as stage A patients having Hb greater than 130 g/L, lymphocyte count less than 30 x 10 9/L, non-deffuse bone marrow histology and a lymphocyte doubling tgime of greater than 12 months. The actuarial ten year preogression-free survival for these was 78%.

Consultation document

This is a draft of a paper that I am writing. I would appreciate comment from the CLL community. I have corrected some of the errors that crept in during cutting and pasting and have added the references

Is “Leukemia” an appropriate label for all patients who meet the diagnostic criteria of chronic lymphocytic leukemia?


In the new World Health Association (WHO) classification of hematological malignancies chronic lymphocytic leukemia (CLL) is recognized as a disease of neoplastic B cells, only distinguishable from small lymphocytic lymphoma by its presence in the blood [1]. The cells are characteristically small lymphocytes with a dense nucleus, showing partially aggregated chromatin with no obvious nucleolus, and a narrow rim of cytoplasm. The immunophenotype is specific: the cells are CD5, CD19, CD20 and CD23 positive and express surface immunoglobulin with light chain restriction [2]. The levels of CD20, CD79b and surface immunoglobulin are typically low compared with that of other B cells. Although NCI guidelines [3] published in 1996 required the lymphocytosis to be at an arbitrary threshold of 5 x 10 9/L, current custom and practice now merely requires an absolute lymphocytosis (in practice an absolute lymphocyte count greater than 3.5 x 10 9/L) with the characteristic morphologic and immunophenotypic profile [4].

At the same time a new entity of monoclonal B cell lymphocytosis (MBL) has been described [5]. It has been discovered that 3.5% of normal individuals over the age of 40 have monoclonal lymphocytes with the immunophenotypic characteristics of CLL cells at levels below 3.5 x 109/L in their blood [6], and that in first degree relatives of patients with familial CLL the prevalence of MBL is between 13.5% and 18% [7, 8].

On these criteria the only difference between CLL and MBL is the level of the absolute lymphocyte count and this is set at such a low level that minor fluctuations in the number of normal T cells, which comprise the majority of lymphocytes in a normal absolute lymphocyte count, could influence the distinction.

In “Guidelines on the diagnosis and management of chronic lymphocytic leukaemia” by the British Committee for Standards in Haematology [9] the statement is made: “A frequent dilemma is whether to convey the diagnosis of CLL to an elderly asymptomatic patient with low count stage A disease diagnosed on a routine blood count”. For many of these patients it is likely that therapy will never be needed. Many will have a life expectancy no different from that of age and sex matched controls. Nevertheless, the patient, despite the benign nature of the condition, is labeled as having a type of leukemia. Leukemia, whatever the type, is commonly regarded as a malignant disease with a poor outcome. Quite apart from the anxiety conveyed by the word “leukemia” to older people, younger individuals are faced with what may be unnecessary decisions and difficulties about their families, mortgages and life assurance.

The relationship between MBL and CLL is analogous to that between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. MGUS, which has a similar prevalence as MBL [10] is thought to transform to myeloma at a rate of 1% per year [11]. After many years of seeking defining characteristics to separate MGUS from myeloma an international working party has interspersed a third category, asymptomatic myeloma, between them [12]. This has the effect of ensuring that inappropriate treatment of asymptomatic disease is not undertaken.

We propose that a category that we call asymptomatic lymphocytosis should be interspersed between MBL and CLL

Most hematologists are well aware that among those diagnosed as having CLL are symptomless patients in whom the raised lymphocyte count is the only abnormal finding. In these cases, discovered by chance after a routine blood count, the lymphocytes are found to have the characteristic immunophenotype of CLL, but the rest of the blood count is normal; lymph nodes and spleen are not clinically enlarged. Within this “benign” group are a substantial number of patients in whom the clinical findings and white count remain substantially unchanged over many years. Attempts have been made in the past to recognize such patients [13, 14].

In the original paper describing Rai staging, stage 0 patients were reported to have an overall survival in excess of 10 years [15]. It should be remembered that at this time the diagnostic criteria for CLL required a lymphocyte count greater than 15 x 10 9/L. Subsequently, the French Co-operative group [16] recognized a type of smoldering Binet stage A’ CLL with Hb >120 g/L and lymphocyte count <30>130 g/L, lymphocyte count <30>/L, non-diffuse bone marrow histology and a lymphocyte doubling time of >12 months. The actuarial ten year progression-free survival for these was 78%.

We propose that the term asymptomatic lymphocytosis be used for conditions where the absolute lymphocyte count is less than 30 x 10 9/L and the Hb and platelet count are normal, where there are no palpable lymph nodes, spleen or liver, and the patients has no symptoms referable to the lymphoid proliferation.

For MGUS three prognostic factors have been defined which predict progression: a serum paraprotein of at least 15 g/L, a monoclonal immunoglobulin other than IgG, and an abnormal serum free light-chain ratio. If all three risk factors are present there is a 58% risk of progression over 20 years, if two are present the risk is 37%, if one is present the risk is 21% and if none are present the risk is 5% [18].

In recent years several prognostic factors have been identified for CLL (Table 1)

Table 1

Prognostic factors associated with progressive disease in CLL

Lack of somatic mutations in the immunoglobulin VH genes [19, 20]

Aberrations of chromosomes 11 and 17 [21]

Expression of surface CD38 [22]

Expression of cytoplasmic ZAP-70 [23-25]

Elevated serum thymidine kinase [26]

Elevated serum CD23 [27, 28]


and some of these are able to predict progression at an early stage of disease. CD38 expression is independent of both VH gene mutations and ZAP-70 expression and provides extra prognostic information when used in combination with either [29, 30]. A recent study [31] examined 150 patients, who satisfied the smoldering criteria of the French Collaborative Group [16] at presentation, for unmutated VH genes, ZAP-70 and CD38 expression, and 11q or 17p deletions. None of the patients who were negative for all these criteria has progressed so as to require treatment after follow up of between one and 35 years (median 6 years). The single most useful measurement was CD38 expression; CD38 negative cases had a progression rate of 11.6% over the period of observation and none had died of CLL.

Currently, prognostic tests need to be standardized and evaluated in prospective trials. However, the natural history of asymptomatic lymphocytosis is so long that guidelines are necessary now for the management of such patients. There is no evidence that such patients should be treated. We believe that such individuals should be offered the full range of prognostic markers and the frequency of follow up should be determined by the results of these. The word “leukemia” should only be used either when there is sign of progression or if there is strong evidence of the likelihood of progressions from the results of prognostic marker studies.


References

1. Jaffe ES, Harris NL, Stein H, Vardiman JW. Eds Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001.
2. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994;8:1640-1645.
3. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87: 4990-4997.
4. Binet J-L, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia Blood 2006;107:859-861.
5. Marti GE, Rawstron AC, Ghia P, Hillmen P, Houlston RS, Kay N et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol, 2005;130:325-332.
6. Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans Pa et al. Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002; 100:635-639.
7. Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002;100:2289-2290.
8. Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom 2003;52:1-12.
9. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Brit J Haematol 2004;25:294-317.
10. Kyle RA, Therneau TM, Rajkumar SV. Larson DR, Plevak MF, Offord JR et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.
11. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569.
12. Durie BG, Kyle RA, Belch, Bensinger W, Blade J, Boccadoro M et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003;4:379-398.
13. Han T, Ozer H, Gavigan M, Gajera R, Minowada J, Bloom ML et al. Benign monoclonal B cell lymphocytosis--a benign variant of CLL: clinical, immunologic, phenotypic, and cytogenetic studies in 20 patients. Blood 1984;64:244-252.
14. Chanarin I, Tidmarsh E, Harrisingh D, Skacel PO. Significance of lymphocytosis in adults. Lancet 1984;2:897-899.
15. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219-234.
16. French Cooperative Group on Chronic Lymphocytic Leukaemia. Natural history of stage A chronic lymphocytic leukaemia untreated patients. Br J Haematol, 1990;76, 45-57.
17. Montserrat E, Vinolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol. 1988;30,359-361.
18. Rajkumar SV, Kyle RA, Therneau TM, Melton LJ 3rd, Bradwell AR, Clark RJ et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812-817.
19. Hamblin TJ, Orchard JA, Gardiner A, Oscier DG, Davis Z, Stevenson FK. Immunoglobulin V genes and CD38 expression in CLL. Blood 2000;95:2455-2457.
20. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94:1840-1847.
21. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
22. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775.
23. Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105-111.
24. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.
25. Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D, et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood. 1999;93: 1732-1737
26. Reinisch W, Willheim M, Hilgarth M, Gasche C, Mader R, Szepfalusi S et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J Clin Oncol 1994;12:2146-2152.
27. Sarfati M, Chevret S, Chastang C, Biron G, Stryckmans P, Delespesse G et al. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 1996;88:4259-4264.
28. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002;99:1023-1029.
29. del Giudice I, Morilla A, Osuji N, Matutes E, Morilla R, Burford A et al. Zeta-chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 2005;104:2124-2132.
30. .Hamblin TJ, Gardiner AC, Mould SJ, Glide S, Best G, Davis ZA et al. Can we predict which patients with early stage CLL will progress and require treatment. Leukemia Lymphoma 2005;46(suppl 1):S46 P24.

Lady Windemere's Fan

I have just watched a delightful DVD. Helen Hunt, Scarlet Johansson and Tom Wikinson in "A Good Woman". It was a "modern" version of Lady Windemere's Fan, set in the 1930s on the Amalfi coast. I don't remember it appearing in the Cinema. No car chase, no CGI, no writhing on beds, no obscenities, no blasphemies, no murders, just good acting and a witty script. No wonder it couldn't find a distributor.

I'm a fan, Oscar.

PARP inhibitors

PARP inhibitors may offer the first really targeted therapy for CLL.

Although monoclonal antibodies are thought of as targeted therapies they are more like carpet bombers than laser guided missiles. Campath targets CD52 which is present on T cells, monocytes and spermatozoa as well as on B cells. It makes me think of those B52s in Afghanistan. The collateral damage is immense. Rituximab targets CD20, an antigen first known as B1. The B1 bomber is more discriminatory, but as I recall it managed to hit the TV station in Serbia and the Chinese embassy (or were these the real targets?) Compared with imatinib in CML you can’t really call it targeted therapy. The problem is that CLL is a much more heterogeneous disease than CML.

Poly-ADP-ribose polymerase (PARP) is an abundant nuclear protein that binds to a DNA single strand break and catalyses the formation of poly ADP-ribose polymers, which protect the breaks and attract DNA repair proteins to the site of damage. The process is extremely complex, but for our purposes we don’t need to know much more about it, except to say that one of the methods of repair is called homologous recombination. The broken ends of the chromosome are repaired using the information on the intact homologous chromosome. This requires searching around in the nucleus for the homolog.

Two of the proteins used in homologous recombination are encoded by the genes BRCA-1 and BRCA-2. Inherited mutations in these genes predispose women to breast and ovarian cancers. Inhibition of PARP triggers homologous recombination which is ineffective when BRCA-1 or BRCA-2 are non functional. Inhibitors of PARP have been used to kill breast cancer cells.

Now a recent paper has appeared in Nucleic Acids Research http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556909&query_hl=48&itool=pubmed_docsum
which is likely to be of great importance for CLL patients. The authors, Helen Bryant and Thomas Heeleday from Sheffield and Stockholm, demonstrate that PARP-induced homologous recombination repair of DNA single strand breaks requires intact ATM gene function.

20% of CLLs have deletions of the ATM gene at 11q23. This variant of CLL tends to occur I younger men and is associated with enlarged lymph nodes in the abdomen. After those with del 17p13, those with del 11q23 have the worst prognosis. Several companies have their own versions of PARP inhibitors. I think it very likely that clinical trials of these agents in this variant of CLL will begin later this year.

Iraq 3. Conspiracy theories.

On the whole I don't believe in conspiracy theories. From the Da Vinci Code to JFK they make good suspense stories, but on the whole they are a load of baloney.

Most people think that “baloney”, meaning nonsense, comes from the name of the sausage. The idea is that the sausage contains all sorts of meat-like substances of dubious origins and is therefore a metaphor for junk. Interestingly, on the same basis the computer generation calls junk-mail “spam”. In the 1930s the catch phrase, “It’s baloney no matter which way you slice it,” was popular.

Another possible origin is as a mispronunciation of blarney, another kind of nonsense, this time of Irish origin. Kissing the Blarney stone, so located on the local castle that you have to bend over backwards to do it, endows the kisser with that verbal dexterity known as “the gift of the gab”.

The term is bears all the hallmarks of coming from New York, where Irish and Italian rivalry and ribaldry enriched both America and English.

The difference between "baloney" and "blarney" was explained in 1954 by Bishop Fulton J. Sheen, "Baloney is the unvarnished lie laid on so thick you hate it; blarney is flattery laid on so thin you love it.”

A famous question in medical student examinations asks about the Baloney amptutation.

"Who was Baloney?" asks the examiner.

The too-clever-by-half med student replies,"Not a person, sir, it refers to the Italian city of Bologna, famous for its University and early medical school, and of course the pressed meat concoction that bears its name."

"Idiot!" exclaims the professor, "It's spelt b-e-l-o-w k-n-e-e."

C3PO

If I continue not have a sympathetic hearing this might happen.

RS3PO

Yesterday I was asked to open a champagne bottle. I was unable to comply.

This is not a tract in favor of teetotalism, nor was I making a protest about the event we were asked to celebrate. I physically couldn't get the cork out.

For some months I have been suffering from pains and weakness in my arm muscles. The pains are quite discrete; I can easily point to the very spots. They are related to the use of certain muscles - not muscle groups - distinct and discrete muscles.

I believe it is a manifestation of my personal connective tissue disease that nobody seems to have heard of.

Some years ago I was preparing a talk to be given at the International MDS symposium in Paris on autoimmunity in the myelodysplastic syndrome. I came upon a rare syndrome associated with MDS called RS3CPE. It stands for Recurrent Symetrical Seronegative Synovitis with Peripheral Edema. It is a condition of men over 60 who are HLA-B7 positive.

When I was doing my doctorate many moons ago I found myself to be HLA-B7.

The condition is no-progressive and not lethal, just uncomfortable. It responds to steroid injections into the inflamed synovium.

In England oedema is spelt with an O. So it becomes RS3PO.

This is unfortunate. It makes it sound like a cousin of the Star Wars character.

I get no sympathy.

York Minster

Christians often debate whether natural disasters are signs of the punishment of God. After all, insurance companies often refer to them as "Acts of God". Recently some Christains have suggested that Hurricane Katrina was a punishment on New Orleans, a self promoted City of Sin. Of course that begs the question of why Las Vegas is still standing, but we might examine whether there are Biblical grounds for suspecting this.

There is a history here. The Genesis Flood was apparently punishment on the whole earth for their sinful ways and the destruction of Sodom and Gemorrah was as a result of the Angels failing to find even 10 righteous people.

On the other hand the evils that beset Job were the consequence of God giving permission to Satan to test him to demonstrate that he wasn't what we would nowadays call a rice Christian. In Luke Ch 4 Jesus himself warns us not to assume that those on whom disaster falls are greater sinners than the rest of us - those whose blood Pilate had mixed with their sacrifices (v 2) and those on whom the Tower in Siloam fell (v 4).

However, early in the morning of the 19th July 1984 York Minster was partially destroyed by fire shortly after the installation there of the heretical David Jenkins as Bishop of Durham. It had apparently been struck by a lightning bolt out of a cloudless sky. Some Christians at the time saw this as an Act of God. Jenkins had denied the bodily resurrection of Jesus, saying he wasn't interested in a "conjuring trick with bones". They said that it was just what God would do when mankind had tried His patience just too much; nobody was even injured. The magnificent Rose Window was destroyed - but that could be seen as an example of idolatry. There was more concern over the destruction of a work nof art than about an insult to God, or about an intellectual damaging the simple faith of thousands of ordinary Christains.

This suggestion met with short shrift from the hierarchy of the church. A vengeful God like that was not what Christianity was about.

In response I wrote this poem - not because I necessarily thought that God would rain down lightning vengeful bolts, but because I objected to the complacency that assumed that he would for ever restrain Himself.

York Minster

Would you really
Rain fire down merely
Because of doubting?
Really flame those windows out
Fusing fine and thrilling lines
Of laid up treasure?
Derive pleasure from unmaking?
Want us quaking,
Knees shaking,
Slaking the pride of God the vandal;
Who wreaks havoc and upheaval
On one small, self-seeking scandal?

No, God is love and meekness, kindness:
Shows complete, benevolent blindness
To our foibles.
Long suffering, He forgives, forebears,
Does not notice when we err.
Forty-winks at deviation,
Falling short or reprobation.
Wouldn’t make a fuss
About us. Don’t worry,
Gomorrah will be here tomorrow.
Sodom is safe.

John Updike on Easter

I could not resist this Easter poem by John Updike.

SEVEN STANZAS AT EASTER

Make no mistake: if he rose at all
It was as His body;
If the cell’s dissolution did not reverse, the molecule reknit,
The amino acids rekindle,
The Church will fall.

It was not as the flowers,
Each soft spring recurrent;
It was not as His Spirit in the mouths and fuddled eyes of the
Eleven apostles;
It was as His flesh; ours.

The same hinged thumbs and toes
The same valved heart
That—pierced—died, withered, paused, and then regathered
Out of enduring Might
New strength to enclose.

Let us not mock God with metaphor,
Analogy, sidestepping, transcendence,
Making of the event a parable, a sign painted in the faded
Credulity of earlier ages:
Let us walk through the door.

The stone is rolled back, not papier-mache,
Not a stone in a story,
But the vast rock of materiality that in the slow grinding of
Time will eclipse for each of us
The wide light of day.

And if we have an angel at the tomb,
Make it a real angel,
Weighty with Max Planck’s quanta, vivid with hair, opaque in
The dawn light, robed in real linen
Spun on a definite loom.

Let us not seek to make it less monstrous,
For our own convenience, our own sense of beauty,
Lest, awakened in one unthinkable hour, we are embarrassed
By the miracle,
And crushed by remonstrance.

Climate change 2

One of my correspondents takes me to task for swallowing the Climate Change Deniers Handbook. On climate change I am not an atheist, but an agnostic. I am not an expert on this, but I know enough about experts to take what they say with a pinch of salt. For true believers you might try http://illconsidered.blogspot.com/2006/02/how-to-talk-to-global-warming-sceptic.html as an alternative to the website I posted last time.

What I am sure about is that if there is a problem to be dealt with it will not be solved by self-denial. China and India and eventually Africa are going to want the same sorts of luxuries and mobility that we enjoy in the West. Better technology has to be the answer.

With that in mind I was interested to read the following article in the Washington Post yesterday. http://www.washingtonpost.com/wp-dyn/content/article/2006/04/14/AR2006041401209.html

Patrick Moore, the co-founder of Greenpeace has joined James Lovelock, the inventor of Gaia, in calling for an expansion of nuclear power. He makes the cogent point that deaths from nuclear power are far fewer than from coal mining or drilling for oil. Even what might happen if a highjacked aeroplane flew into a nuclear power station has been greatly exaggerated.

I have been a long-term supporter of nuclear power - even to the extent of losing money by investing in nuclear power stations on ideological, rather than pecuniary, grounds. Of all forms of power generation I have long thought coal was the worst. I have seen chest X-rays from miners and been down a coal mine. One of my great heroes is Lord Shaftesbury, who got the women and children out of the British coal mines. I predict that one day Lord Hesseltine will be thought of in the same way. He was the politician who effectively got the men out of the Brittish coal mines. Just after the second world war there were close to a milion men who worked down the mines. Now that number is just a few thousand.

Working down a coal mine is a dirty and disgusting job that inflicts health problems on the miners but until recently gave them an unhealthy grasp on economic power. In the UK Mrs Thatcher was able to break that economic stranglehold by facinmg down Arthur Skargill. Those same economics have now handed that same power to a few unstable states in the Middle East. I have little doubt that were it not for the oil the West would take as much interest in who rules in Iraq as they do in who rules in Darfur. On the other hand I do not buy in to the conspiracy theories that have Bush and Cheyney personally enriching themselves; rather it is a case of the West being vulnerable to cutting off of oil supplies, and seeking to ensure that their supplies are secure.

When people ask why if regime change was the real reason for the invasion of Iraq, does not the Western Alliance march into Zimbabwe or North Korea, the answer is that those countries do not control our oil supply.

So you admit it is about oil?

Only in the sense that currently the world's economy depends on oil which thrusts it into an undeserved importance. The real solution is to divest ourselves of our dependence then we could allow Shias and Sunnis to squabble over the desert to their hearts' content.

Easter

In her despair Mary was comforted.

In his doubt Thomas was assured.

In his shame Peter was restored.

Christ is risen!

He is risen indeed!

Hallelujah!

You're nearer to God in a garden

Today was spent painting. My super-strong, guaranteed-ten-years, black paint was applied to the window frames. And not a moment to soon - the drizzle started shortly afterwards. This is the making of England's green and pleasant land. Warm April showers are marvellous for the garden where buds are on every bush and tree. Row upon row of grape hyacinths are standing like light blue soldiers in their green foliage. The heathers are brightly garbed in purple and white. In the greenhouse the geraniums have successfully over-wintered. The strelitzia is about to burst orange and the bougainvillea is showing signs of life. On the top branch of the cherry tree a lone robin is whistling.

I think we'll leave those anonymouses (or should it be anonymice) arguing among themselves and change the subject.

This is a story about the pointlessness of wealth. A very rich man was told by his doctor that he was going to die. This caused him dismay as he had often been told that he couldn't take it with him. He was a believer and because he had made a commitment to Christ at a Presbyterian church early in his life and he had been told, "Once saved; always saved," and therefore he was certain that he was going to heaven, but the thought of leaving all that he had worked for behind him was unimaginable.

That night he prayed vehemently to God, "I can't leave all this behind; please let me bring something with me."

As he was sleeping an angel appeared to him in a dream. "There are no pockets in a shroud, " he said, "You must leave it all behind."

Even more dismayed, the next night he prayed even more vehemently, "Lord, you have prospered me all my life, surely you don't want me to abandon all these blessings you have given me."

In his dream that night the angel came and this time said, "God has relented; you may bring one suitcase."

The next morning he rang his broker and told hime to liquidise everything and turn it into gold so that that night, as he went to sleep, he had beneath his bed a suitcase full of gold ingots.

In the night he died and he began dragging this heavy suitcase up to heaven. It was an arduous journey, but he finally arrived at the pearly gates. St Peter stopped him. "I'm afraid you can't come in here with a suitcase. You must enter heaven with empty hands."

"But God has given me a special dispensation. He said I could bring one suitcase."

St Peter sent an angel to ask God if this was true and when he returned the angel said, "God did give him this dispensation, but he says that you must check for contraband."

St Peter opens the case and stares at the gold with astonishment.

"Paving stones?" he says, "You've brought paving stones?"

Iraq - influences of the Thirty Years War

My last post uncovered how polarized is American public opinion. I suppose that such invective and vigorous argument is a symptom of a healthy democracy. However, I am reminded of one of my favorite books which is entitled "The Great Virtues". The author states that the first and fundamental virtue is politeness, for without politeness there can be no discussion. I would also remind readers of my plea not to post anonymous comments unless there is a real reason to do so. Since so many of my readers are patients, it is quite reasonable for them to keep their personal details confidential, but political opinions ought to be owned by their authors, and if not they assume the status of the anonymous letter written in green ink, which I have always, whether they praised or abused me, crumpled up and filed in the round filing cabinet beneath my desk.

My purpose in writing about Iraq was not to stir up a hornet's nest nor to apportion blame, but to explore the basis of what some have called a 21st Century conflict played by 20th Century rules. The following link leads to an important contibution to this debate made by the British Defence Secretary, John Reid.
http://www.mod.uk/DefenceInternet/DefenceNews/DefencePolicyAndBusiness/
ReidAddressesRusiOn20thcenturyRules21stcenturyConflict.htm

If we think that the current war is unpleasant a return to the time of the Thirty Year War in Europe is terrifying. This was one of the few wars in history that England managed to keep out of. It was within this period, 1618-1648, that we had our own civil war, which had similar origins - the conflict betwen Catholics and Protestants.

My knowledge of this period of European history it is very minimal, and mainly garnered from a fascinating book called "Q" written under the pseudonym of "Luther Blisset" by four Italian anarchists, Fredrico Guglielmi, Lucia Di Meo, Giovanni Cattabriga and Fabrizio Belletati. http://mostlyfiction.com/history/blissett.htm Luther Blisset was one of the first black footballers to have a successful career in England. He played for Watford, the football team owned by singer Elton John, but was transferred to AC Milan where he was certainly a character, though not an outstanding success. He finished his playing career here in Bournemouth, where under their successful manager, Harry Redknapp, his career had a late flowering. He owned a sports equipment shop just round the corner from my house. Harry's children were at school with my oldest boy.

The book is about the Peasants War (one hundred years earlier than the Thirty Years War) written from the point of view of the anabaptists (anarchists like the authors). However, the reasons behind the Thirty Years War were similar, revolving around the relationship between religion and statehood, and the conditions of the protagonists were similar. It is a good read to reveal the brutality of war in the 16th and 17th centuries.

The Thirty Years War was in part a religious war. Although in Germany the various Principalities had achieved self rule and established Lutherism for 75 years, and had reached a Truce with Rome at the Peace of Ausberg in 1555, the consequences of the Reformation were certainly not settled. The Protestants had split between Lutherans and Calvinists, and Calvinists were not included in the truce. Anabaptists were as much enemies of Luther as they were of Rome. The Jesuit counter-reformation had taken hold, so that there was a powder keg in Germany waiting for a match to set it alight.

The Spanish Netherlands had become Protestant and thrown off the Spanish yoke and were allied with France. Although France was Catholic, its long standing rivalry with Spain had meant that my enemy's enemy is my friend. Spain in seeking to re-establish its authority over the Netherlands could not sail there (since the defeat of the Armada in 1588, England held the Channel), but must take an overland route via Northern Italy, the Alps and Southern Germany. The Holy Roman Empire and Spain were both ruled by Hapsburgs. France felt at risk from a Hapsburg encirclement. Only the assasination of Henry IV in 1610 averted war then.

Denmark and Sweden were also at odds. Scandinavia had once all been ruled by the King of Denmark, but Sweden had broken away. In an attempt to restore its authority Denmark unsuccessfully attacked Sweden in 1611. There was a dynastic struggle in Sweden as the King of Poland had a better claim to the throne than Gustavus Adolphus. But Sweden was Protestant and Poland Catholic - the Spain of the North. To put pressure on Poland, Sweden allied herself with the Russian Tsar, Boris Gudunov. Boris was overthrown and Sweden then allied herself with both Holland and the Evangelical Union in Germany.

Bohemia (the modern Czech Republic) provided the spark for war. The region was a mixture of Calvinists, Catholics, Lutherans and Anabaptists who lived in harmony. In 1617 Archduke Ferdinand of Styria became Holy Roman Emperor and determined to reimpose Catholicism on Bohemia. In protest two Catholic deputies (Martiniz and Slavata) were defenestrated in Prague. This was a classical Czech habit of chucking people out of windows. They were not hurt; they landed in a dung heap (unlike Jan Masaryk who was murdered this way by the Communists in 1948). This was an insult to Ferdinand (who was to become Holy Roman Emperor) and following a dispute over the succession to the Kingdom of Bohemia he defeated the army of Frederick, Elector of Palantine at the Battle of White Mountain, and expelled the Protestants from Bohemia. This laid down the gauntlet and the Protestant countries picked it up. War raged for 30 years.

After early victories by the Catholic generals Tilly and Wallenstein, Gustavus Adolphus entered the conflict and took control of Germany. A restored Wallenstein hindered Gustavus and though defeated at Lutzen so that he had to retreat to Bohemia, Wallenstein inflicted important damage on the Protestants; Gustavus was killed. Swedish power was now at its zenith. Wallenstein exceeded his authority and began making peace treaties. He was murdered by his own officers. In 1634 a major battle at Nordlingen saw the Protestant army defeated and the Peace of Prague ensued. This provoked France into re-entering the war and allied herself with Sweden, the low countries and some Northern Italian states. Cardinal Richelieu (yes we're in Three Musketeers' territory) had several setbacks at first, but managed to repel the Spanish invsion. Spain suffered naval defeats by the Dutch and the French and even at home there were embarrassed by a Catalan rebellion. Defeats for the Empire at Nordilgen (again) by the French and at Jankau by the Swedes meant that it could no longer carry on, but neither France nor Sweden could push home their advantage. By 1645 military exhaustion had set in throughout Europe. Millions had been killed, plague had ravaged populations, agriculture had failed and nations were bankrupt. It was estimated that urban areas in Europe had suffered a 33% population loss and rural areas a 40% loss.

The Peace of Westphalia in 1648 ended the Thirty Years War. It is considered by historians to mark the beginning of the modern era. As a result of the Peace Accord the Netherlands finally gained independance from Spain, ending 80 years of conflict. Sweden gained some teritory in Northern Germany. The power of the Holy Roman Emperor was finally broken, but Germany remained a group of 360 independent and seperate principalities. Calvinists were given legal recognition. France was the overall victor; it acquired Alsace and Lorraine and a vote in the German Reichstag. Switzerland was recognised as a fully independent nation.

The most important consequence was that it ended for all time the idea that the Holy Roman Empire having secular dominion over the entire Christian world. The nation-state would be the highest level of government subservient to no other. No state had any right to determine how another state undertook its business.

In Mein Kampf Hitler states that the Treaty of Westphalia cemented Germany's internal divisions for over 200 years and prevented Germany acquiring an Empire like Britain's or France's. Communism predicted the demise of the Westphalian system seeing it replaced by an International Workers' Union. In 2004 in the aftermath of the Madrid attacks, Lewis 'Atiyyatullah, an al-Qaeda spokesman, predicted that the Westphalian system would collapse and be replaced by a system under the leadership of a mighty Islamic state. In 2000 Joshka Fischer, the German Foreign Minister, predicted that the Westphalian system of nation states would be replaced by a supranational European Institution.

What can we learn from the Thirty Years War? First, that to assume that a decisive battle imposes your will on another nation state by force is to deceive yourself. War must either be prosecuted to ultimate and complete victory or else it sows the seeds for the next conflict. Second, in the end you have to negotiate a settlement that satisfies all parties. Third, you cannot change men's minds on religion by force. Fourth, people of different religions can live in harmony with one another when they accept conclusion 3.

We need to reconsider whether the sovereign nation-state is subservient to no other. Is it right for a national leader to attack a section of his own people because of the color of thei skin, their religion, their politics or what they write or say? Who is to defend their human rights?

Iraq: where did it all go wrong? Part 1

Civil war in Iraq? Bush's popularity at an all time low? Where did it all go wrong?

It has been a long term United Nations maxim that the internal affairs of a country are its own business and not to be interfered with by other countries. The fact that both the USSR and China had nuclear weapons probably had something to do with the fact that neither the US nor the UK sent an army to those countries to correct their despised forms of government.

It was not always so. Palmerston's means of conducting foreign policy was to send a gunboat, and until 1945 most nations saw war as a more active branch of diplomacy. The formation of the United Nations established a natural stalemate, with the Soviet Union unwilling to agree to any American-led war. Modern air travel would have prevented the Korean War since it was only approved by the Security Council because the Soviet representative arrived too late to say no.

War thereafter was largely a by-proxy practice. When Britain and France were made to back down over Suez by America's economic threats there seemed little chance of any nation starting a war of acquisition, or even to retain what they had bought and paid for.

The second half of the 20th century was marked by a series of small wars of independence as new nations threw off their erstwhile colonial powers. It was strange to see America, a nation formed by a revolution against the colonial power, again and again taking the side of the bosses against the little man. This had the effect of throwing the revolutionaries into the hands of the Soviets, who imposed their brutal form of totalitarianism on them. Was it necessary for Cuba to become hardline Marxist? Heaven knows the Batista regime was evil enough to need overthrowing. The unsavory picture of Kennedy, the Massachusetts liberal, in bed with casino-owning Mafiosi is unedifying enough, but the sort of foul governments supported by the US in South America during this period in the name of stopping communism is shameful.

The culmination came in Viet Nam. What started as a war of independence in French Indo-China became a surrogate hot-spot in the cold war. In retrospect the wisdom of the British in leaving India and Burma in 1947 is apparent. The capitalist societies in Viet Nam and even China demonstrate that Soviet style uniformity and oppression holds no attraction for ordinary people.

In the fifteen years after World War II communism became a colossal boogie-man to America. Several strands contributed to this. The stealing of the nuclear secrets by Klaus Fuchs, the outcome of the Potsdam conference, allowing Stalin to run Eastern Europe as vassal states, the McCarthy hearings, Churchill's iron-curtain speech, the Korean War, and the launching of the first Sputnik in 1957 all contributed. I suspect that America's isolation was a major factor. Such a vast country, so self-sufficient, so ignorant of the outside world; Americans were unable to assimilate communism into their political spectrum, in the way that France or Italy did, and unable to ridicule it in gentle way that Britain did.

So, the Domino Theory demanded that Viet Nam was defended and became America's nemesis. Defeat in Viet Nam did not happen on the battlefield, but on the University Campus. Young Americans became disgusted by what the military was doing. This defeat lodged in the American psyche and emasculated the country for a generation. It was reinforced by Carter's abortive attempt to rescue the Iranian hostages and by the Black Hawk Down defeat in Somalia.

Meanwhile, Britain had discovered a new virility. After a failed experiment with socialism which left the dead unburied and rats in the street nibbling at uncollected garbage, Mrs. Thatcher put backbone back in the nation by defeating the Argentineans in the Falklands.

This was a clean war. It was in response to a call for help from the indigenous people who were of British extraction and willing colonials. It was fought against a regime widely recognized as evil, a dictatorship kept in power by brutal police action against its own people who had modern weapons sufficient to destroy several British warships. It was won by the heroism of tough soldiers who marched across rough terrain in filthy weather to defeat the occupiers in hand to hand combat when the helicopters that were meant to allow them to fight like Americans were sunk with the Atlantic Conveyer, a container ship that the Argentinean pilots mistook for an aircraft carrier. Not only were the Falklands secured, but the Argentinean tyranny was overthrown at home.

In some ways the first Iraq war was similar. The invading power had long claimed the invaded land as its own. It was ruled by a sinister dictatorship. In the circumstances it was not difficult to put together a huge coalition that even included Syria. This war was different from the Falklands, though. It was won not by individual heroism but by overwhelming fire power and military superiority. It was won by the Americans; her allies were make-weights, there to give the semblance of world unity. The invaded country was not populated by poor farmers but by oil-rich Arabs and contract workers who had no say in how the country was run.

Colin Powell stopped on the road to Baghdad when it got too much like shooting fish in a barrel. Saddam survived. To have removed him would have had the Arabs deserting the coalition. In retrospect I think this was a mistake and one that would not have happened if Mrs. Thatcher had not been deposed during the build up to the war. She was adept at pulling the strings.

Just as Thatcher had restored Britain's self confidence, so Reagan restored America's. The defeat of the Soviets in the cold war was done by bravado. It was a poker game in which America kept upping the ante until the Soviets folded.

In the nineties small nations started behaving badly. Perhaps the Russians had been restraining their client states during the cold war. A free hand was given for ethnic cleansing. In Yugoslavia, Indonesia and Africa atrocities abounded. The West was shamed into intervening. In East Timor the Australians went in to protect the Christians from the Moslems, in Kosovo Clinton and the EU went in to protect the Moslems from the Christians, but nobody had protected the Catholic Tutsis from the Catholic Hutus and nobody had protected the Bosnian Moslems from the Serbian Orthodox and no-one had intervened between the Catholic Croatians and the Orthodox Serbs, and still nobody intervenes between the Shona and the Matebele in Zimbabwe or between the Moslems and the Christians in Sudan.

Who should police the world? From Pax Romana to Pax Britannica it has been the role of the strongest nation to act the magistrate. America had been reluctant to do so. After 9/11 things changed.

Attacking Afghanistan had near universal support. Bin Laden had sought sanctuary there and he was behind the Twin Towers disaster. The Taliban would not give him up and in any case they were a repressive, intolerant regime that cut off the hands of thieves and destroyed ancient statues of the Buddha. The success in Afghanistan must have encouraged Bush to go on down his list. Saddam was unfinished business. In those days everybody believed in WMD even if they were only believed to be a battlefield threat.

Regime change was the real motive behind the Iraq war. Saddam was indeed an evil tyrant. The destruction of the Marsh Arabs after Gulf War I was something that America felt guilty about. Encouraged to rebel they had been abandoned by the coalition. Saddam's retribution was harsh. The UN had instituted sanctions, but they were being evaded. Saddam was building palaces while children starved and the UN, not Saddam, was getting the blame. There was a movement to lift the sanctions.

Saddam was in a cleft stick. He had no WMD, but his hold on power depended on the pretence that he did. He stalled the weapons inspectors so as to keep up the pretence as long as possible. The UN passed resolution 1441 threatening worse than sanctions if the weapons inspectors could not do their job. But if he let them do their job and they found nothing then for him it would be worse than sanctions. Besides he did not believe that the Security Council would vote for war. Too many permanent members were benefiting financially from sanctions busting. He stalled and stymied and bluffed it out.

Oliver Twist

I watched another DVD over the weekend, Polanski's Oliver Twist. Apart from Ben Kingsley as Fagin and Edward Hardwicke as Mr Brownlow, most of the actors were not well known.

I guess the best known version of the book is Lionel Bart's Oliver!, the musical version and an altogether sunnier approach than this. The classic David Lean/Alec Guiness version is the best reviewed. Then there was a TV version written by Alan Bleasdale(co-production between Carlton and WGBH/Boston) in which he wrote a back-story based on some hints in the last chapter of the novel. That version had some well known TV actors in Robert Lindsay, Lindsay Duncan, Julie Walters and Michael Kitchen. Alan Armstrong turned up in both this version and Polanski's though playing different parts.

The Alec Guinness Fagin is such an immense characterization that it must intimidate anyone trying to perform a new version. They tend to go for gimmicks - music, a new back-story - in order to breathe some freshness into such a well known story.

Does Polanski succeed? Not really. Kingsley follows the Guinness path and even has a bit of Ron Moody about him, but nothing original. Nancy is less sympathetic than Shani Wallis makes her in Oliver! Jamie Foreman does not seem as evil as Oliver Reed. One interesting fact - the actor who played Sykes in the TV version was Andy Serkis. Yes Gollum! and King Cong!

I was under 10 when I first saw the black and white version in the cinema. I doubt I will ever find a better one.

Forgiveness again

Azalias are out and so are the tulips. Blue periwinkle flowers are creeping over the flower beds and buttercups on the compost heap. Spring is really here.

I spent the afternoon repairing window frames. Nasty blisters had begun appearing in the paintwork. Sanding down the paint I found that those expensive decorators who did the job last time had not prepared the wood properly. It needed paring down to bare wood, cutting out areas of wet rot, treating with hardener, filling with a special filler and sanding down. I did about half the job in 6 hours. Interruptions came in the form of a dish cloth jamming the waste disposal unit and the boiler blowing out. Such are the joys of being a house owner.

But I had a reply from Ben Witherington on forgiveness. Readers interested in religion might try his site at http://benwitherington.blogspot.com/ . He says that we are commanded to forgive in the Lord's Prayer - forgive us our trespasses as we forgive those who trespass against us. Although forgiveness has to be accepted for the deal to be done, that is beside the point. It is our job to offer it. I think he is right.

So, decorators everywhere: I forgive you.

Pride and Prejudice

Two films in a day! This evening I watched Pride and Prejudice in DVD. I did not think that the Colin Firth BBC version could have been bettered, but the recent Keira Knightley version equals it. It is much faster paced and it does suffer from the modern blight of music that is too loud for the voice track, but the design was excellent and there were many strong performances.

I preferred Barbara Leigh-Hunt's Lady Catherine to Judy Dench's and Bernard Hepton's Mr Bennett to Donald Sutherland's, but Keira Knightley and Rosamund Pike were quite stunning as the older Bennett girls. I was surprised how well Matthew MacFadyen did as D'arcy; quite as good as Colin Firth.

When I saw that Knightley had been nominated for an Oscar, I was sceptical. She was dreadful as Lara in the TV version of Dr Zhivago, and simply eye candy in Bend it like Beckham, Pirates of the Caribbean and King Arthur, but in this she shows that she can really act.

Nixon

When I first started as a hematologist I had so little to do that I used to got to the movies in the afternoon. Business soon built up and for most of my career I have too much work. Now in semi-retirement I occasionally have time to put on a video in the afternoon, so while my wife was watching a wartime drama by Noel Coward starring John Mills, I sneaked off into teh other room to watch Oliver Stone's Nixon.

I can understand why Anthony Hopkins was nominated for an Oscar for this performance. He is seldom of the screen, and gives a tremendous exhibition of acting. This is not mimickry; he does not look at all like Nixon, but he captures the man behind the face. To do the part justice demands an actor reared on the Shakespearean stage. He makes Nixon into a figure not too distant from Macbeth. I would have thought it were impossible to make Nixon at all sympathetic, but Hopkins turns him into a figure of tragedy by revealing the greatness in the man that was hidden by compromises with integrity that he made while climbing the greasy pole. History will judge hime more kindly than his contempories, says one character. It depends on who writes the history, quips back Nixon.

The movie, alas was not as good as the performance. It needed a better writer.

micro RNAs

Now this is not for the faint-hearted. If it's too technical read the one about Irish politics instead.

In my lab we have been working on 13q14 longer than anybody else. My colleague David Oscier gets the credit for this. He published a paper detailing the first report of deletions at this site in hematological malignancies. It is not only important in CLL, but it also the most important chromosomal abnormality in multiple myeloma as well. He also found the deletion in some cases of myelofibrosis. (Fitchett et al Cancer Genet Cytogenet. 1987 24:143-50).

The chromosome lab that he set up was the first to regularly get good results with conventional karyotyping in CLL so that the original paper demonstrating that del 13q was a good prognostic feature in CLL and that there was a hierarchy of prognoses depending on the karyotype was largely composed of his patients (Juliusson et al N Engl J Med. 1990 323:720-4).

He isolated the bit of chromosome 13 that was always missing and sequenced the length of DNA that was missing. He also identified the genes that are represented on this missing piece of DNA. (Hawthorn et al Oncogene. 1993 8:1415-9. Chapman et al. Oncogene. 1994 9:1289-93. Liu et al Oncogene. 1997 15:2463-73) .Now here's the rub. Everybody expected the mechanism to be that of the classic tumor suppressor gene.

Retinoblastoma (which is also located at 13q14) is the classical example. This is a tumor of the eye in children that is caused by the loss of the Rb1 gene from both chromosome 13s. Usually the child inherits one mssing or damaged Rb1 gene from one parent and loses the other in childhood. Loss of both tumor suppressor genes allows the tumor to grow, but while there is one still intact, there is no tumor.

It was expected that there would be another gene at 13q14 that acted in a similar way to cause CLL. Although some CLLs do indeed have a deletion on both chromosome 13s, this is not the common finding. Never mind, we thought, although the other gene is there, when we sequence the area we will find a crippling mutation on the other chromosome. There are not many genes in this area. Depending on how you count them there are no more than 5, and possibly as few as two, so it was not going to be difficult to find a mutation. To cut a long story short there were no mutations, nor were there any epigenetic mechanisms like aberrant methylation that would account for both chromosomes not working (Corcoran et al Blood. 1998 91:1382-90. Kapanadze et al FEBS Lett. 1998 426:266-70. Grand et al Genes Chromosomes Cancer. 2004 40:78-83).

I guess people began to think that a small lab like ours had made a mistake, but the really big labs like Carlo Croce's and Ricardo Dalla-favera's confirmed David's findings.

Then Croce reported on microRNAs (miR). miRs are small lengths of single stranded RNA that are able to bind to messenger RNA to prevent its being translated into protein. They are part of the normal control system which allows cells to express or not express particular genes. In CLL Croce found that two miRs, miR-15a and miR-16-1, which are normally located at chromosome 13q14.3, are down-regulated in about 65% of patients (Cimmino et al PNAS 2005 102:13944-9).

The messenger RNA that these miRs target is the one that codes for bcl-2. They normally help to switch off bcl-2 production.

Bcl-2 is one of the complex series of proteins that controls apoptosis or programmed cell death. It happens to be one of the most important inhibitors of apoptosis. It is very important in the functioning of B cells. During an immune response against a foreign germ it is necessary to make a lot of antibody, and the right antibody at that. A process of rapid somatic mutation takes place in lymph nodes and spleen, as genes are shuffled and mixed, altered and corrected so that the appropriate antibody is made. This is a random process and a lot of nonsensical or even harmful antibodies are made. It is very important that the cells makeing these antibodies are killed. They don't need any bcl-2 around preventing that; hence the miRs to switch it off. However, the good antibody producing cells need to survive, and in them bcl-2 needs to be upregulated - but only for a while; when the germs have been dealt with we need the cells used in the immune response to die back, so the bcl-2 has to be switched off. Transgenic mice have been made in which the bcl-2 gene is always switched on. These mice grow huge lymph nodes and spleens - not because they have tumors, but because their lymphocytes are immortal and they bkeep accumulating.

Of course in CLL the lack of these specific miRs to switch off bcl-2 means that the CLL cells don't die properly either.

I am writing about miRs because of a paper that appeared recently in Cell. This concerns miR223 (yes there are a lot of them). Acute promyelocytic leukemia (APL) is quite a rare leukemia (sometimes called M3) where the leukemic blasts begin to mature but get stuck at the promyelocyte level. It is important because most patients get disseminated intravascular coagulation, and used to bleed to death. These patients almost always have a chromosomal transocation between chromosome 15 and 17 (t15;17) which puts the APL gene next to the RAR gene. It was a Chinese discovery that these patients respond well to a form of vitamin A known as all trans retinoic acid (ATRA). Treatment with ATRA has revolutionized the outlook for APL patients, and now it is one of the best types of acute leukemia to have, if you have to have leukemia.

In the Cell paper (2005; 123:819-31), Farzi and colleagues from Rome describe a series of experiments that help to sort out how ATRA works and what the function of vitamin A is in the normal development ofwhite cells. There are two transcription factors that compete to bind the promoter of miR223, NFI-A and C/EBPalpha. These two factors have long been known to regulate the growth and differentiation of many cell types.

This is how they interact. NFI-A keeps miR223 at low levels, but when ATRA is added the NFI-A is replaced by C/EBPalpha. miR223 the suppresses NFI-A. In APL, introduction of the gene for miR223 so that the miR is expressed cause the cells to overcome the block in diferentiation, while knocking out the miR223 blocks their ability to differentiate in response to ATRA. Some cases of APL become resistant to ATRA, and an understanding of this mechanism offers a way forward.

These microRNAs have allowed us a greater understanding of the regulation of genes and it would not be difficult to think of how small molecules could be adapted as drugs for more precise management of leukemias.

Irish politics

The British and Irish governments have given the Northern Ireland politicians a deadline of November 28th this year to form a government of national unity or else they will draw a line under the Good Friday agreement. Hard to believe that the parties will do so. The Good Friday agreement was negotiated by the moderate Ulster Unionists and SDLP parties. Despite being endorsed by a majority of the Norther Irish electorate, that same electorate has turfed out the moderates and voted for the hardline Democratic Unionists and Sinn Fein, who won't even sit down in the same room as each other, let alone form a government together. The DUP say the republicans' claim to have give up the war is bogus. They point to the huge bank robbery last year, the murder of Robert McCartney and now the execution of the English spy, Dennis Donaldson as evidence that the republican movement is one huge criminal conspiracy

It doesn't bode well for a united government in Iraq.

Chucking out memories

How hard it is to throw things away!

Today we have been in the garage clearing up all those things that were carefully stowed away just in case we might need them again.

First it was necessary to get up in the garage loft to dispense with the things we had put up there last time we cleared out the garage. So out went some decorative glass shelving, a broom handle, an old snooker cue with a chip in it, an underwater pump from when we had a pond, my waders with perished rubber from when we had a pond, baskets for planting water lilies (from when we had a pond), hundreds of old flower pots, the remnants of hanging baskets, a pair of dumb-bells, a game of Scrabble with pieces missing, a net for chipping golf balls into, various bicycle pieces including a tire and inner tube, some gears and brakes and a pedal or two, a half-used box of pre-seed lawn fertilizer and seven plastic imitation Grecian urns that were used as plant holders.

Elevated from the garage to the loft went a host of children's garden toys. Pedal cars, see-saws, tricycles, bicycles, wheelbarrows, space-hoppers, paddling pools, sand trays, scooters - throwing those away will be a lot harder. Perhaps the grandchildren will use them when they come to stay.

When I last threw away a few hundred paperbacks I took down the shelving that they were stacked on. Today I removed the wooden shelves from the metal struts, but stored the wood on the perhaps mistaken ambition of floor-boarding the house loft someday.

Then all the discarded rubbish, together with cardboard and polystyrene packing was bagged up, put in the back of the station wagon and taken to the recycling center.

A good day's work and much tidier, but only half the job done. Nostalgia and memories have halted the process.

Outcomes in clinical trials

A recent paper in the New England Journal of Medicine has given us all something to think about. It did not concern CLL; rather it was about a similar disease, multiple myeloma.

Myeloma, like CLL, is an incurable disease of B cells. It has a rather worse prognosis than CLL, but like CLL it has a forme fruste Monoclonal Gammopathy of Undetermined Significance (MGUS) that fits alongside Monoclonal B cell Lymphocytosis.

For those who can take it, standard treatment is an autologous stem cell transplant. This treatment has been pioneered at Little Rock, and where one is good two may be better. Little Rock now propounds the virtue of two successive autografts. There is evidence that, if you can stand it, two are better than one, although some of the evidence is conflicting.

When the patient relapses what is there to do? It turns out that thalidomide will rescue more than a third of patients. If thalidomide is so useful why not add it in at the beginning and continue as long as possible? This was the trial reported in NEJM. A comparison between thalidomide all the way through or only later. Sure enough, patients receiving thalidomide had a greater number of complete remisions and longer lasting remissions, but unfortunately the overall survival was no better. The only difference was that they had to suffer the side effects of thalidomide throughout their illness: tiredness, peripheral neuropathy, constipation and venous thrombosis.

In chronic diseases like myeloma and CLL, trialists have been reluctant to look at overall survival as the end point of trials because it takes so long to get an answer. Instead, surrogate endpoints like remission rate and progression free survival are chosen. It suits pharmaceutical companies because if they wait 15 years for overall survival their patent will have run out before they are allowed to sell the drug.

In the recent CLL4 trial in the UK comparing Fludarabine with Fludarabine + cyclophosphamide (FC) with chlorambucil, FC gave the highest response rate and the longest progression free survival; but the overall survival for the three arms is so far not different. The same is true of the German F v FC trial.

If you look at the chlorambucil arm pf CLL4, which has remained the same in UK trials since the 1970s, there has been a progressive improvement in 5-year survivals over that time, from 46% to 62%. Part of this might be ascribed to better supportive care, antibiotics, growth factors, platelet transfusiohns and the like, but the most important factor has been the availability of a different drug to use when the patient relapses, namely fludarabine. It has been suggested that there will never be a difference in overall survival in CLL4 because it will be possible for the chlorambucil patients to crossover to FC or even FCR.

The immediate answer is why not? We are not playing a game that has to be fair for both sides. We are seeking the best treatment strategy for patients. There will be some patients who will be fine on chlorambucil, who may never need to be put at the risk of fludarabine immunosuppression. For the rest, if the risk of relapse is allayed by certainty of a response from FC or FCR why not have two bites of the cherry. Of course , the best trials would compare treatment sequences.

Global warming

It certainly hasn't reached Bournemouth yet. Although bright and breezy you need a coat to go out today. But it got me thinking about how much humans can do to alter the climate. I am well aware that the vast majority of scientists believe that greenhouse gasses are to blame for changes in temperature and that natural disasters like Hurricane Katrina are laid at the door of gas guzzling SUVs. But is the evidence convincing? (For a different view of global warming go to http://www.co2science.org)

The scientist in me is wary of stuff that makes headlines in newspapers. Publicity equals money for scientists and scare stories sell newspapers. Hardly anything that is reported in the press about science is accurate. It is oversimplified, sexed-up, exagerated and always I hear someone cranking the handle of self interest.

Two things make me wary. First is the short obervation period. We know that climate does fluctuate. In Roman times there were vinyards in Britain. In the 17th century the River Thames froze over. Although a graph of the rates of fluctuation could be constructed and a varying rate of change could be measured, I suspect that it is too soon to work out whether the change is a temporary blip or a permanent one.

Second is buffering. All systems seem to have a built in homeostatic control. In the human body, for example if the blood gets too acid we start breathing heavily to blow off carbon dioxide which raise our pH. If carbon dioxide levels in the atmosphere rise then plants are encouraged to lay down carbohydrates by photosynthesis. There is a huge reservoir of blue green algae in the Pacific Ocean that is blooming becuase of raised carbon dioxide. Now whether this sort of buffering is or will exert a corrective effect I do not know, nor do I know of anybody working on it.

I can see that there is a case for reducing polution in the atmosphere. Since burning of coal was abolished in Britain it is a much cleaner place and chest infections are fewer. It is clearly technically possible to obtain energy in a less polluting way, and it is technically possible to stop being so profligate in our waste of energy. At the moment our reason to do so is to respond to the propaganda that governments and NGOs pepper us with. It won't work. We won't believe that governments are serious unless they make it economically advantageous for us to conserve fuel. A massive hike in the tax on gas would do it. A concerted effort to raise the tax on air travel would do it. Tax breaks for nuclear power or clean coal technology would do it.

The current fashion is for hybrid vehicles. These cars that run on petrol on long runs but swich to electricity in towns are encourages by tax rebates, low road fund licenses, and freedom from the London congestion charge. However, we should ask ourselves rather whether we really need a new car. The environmental cost of building one is greater than teh environmental savings from running one. The world would benefit more from having one fewer car factory than from a slightly greater mpg. A far better buy would be a second hand diesel BMW. They will match the mileage of a Toyota or Honda hybrid, last for 200,000 miles and run on old cooking fat when the oil wells run dry.

Spring at last

Sunshine, balmy breezes, flowers everywhere, wagtails and blue tits, men in shirtsleeves, buds, blossom; it's here.

A full house with three of the children home for dinner with their respective boy friend or girl friend, and only last weekend we saw the fourth with his family. All is well with the world.

No April fools!

Steroids 2

Steroids and the immune response.

If you get put off by technical language you should skip the next three paragraphs.

Corticosteroids acts through intracellular receptors, which are present in almost every cell in the body. The receptors are present in the cytoplasm of the cell often bound to the chaperoning protein HSP-90 (remember that from ZAP-70?). On binding the steroid the receptor is freed from the HSP-90 and this exposes its DNA-binding region. The steroid-receptor complex then crosses the nuclear membrane into the nucleus and binds to DNA. It has been estimated that the expression of as many as 1% of all genes is regulated by the steroid receptor, which accounts for the multiple effects of the hormone.

In general pharmacological doses of steroids are anti-inflammatory. They suppress the production of a number of inflammatory cytokines such as IL-1, TNF-a, GM-CSF, IL-3, IL-4, IL-5, IL-8, as well as prostaglandins, leukotrienes and adhesion molecules, but the production of other proteins such as endonucleases and lipocortin-1 is increased.

Of all the cells in the immune system, macrophages are the most affected. Normally they
home to sites of inflammation and take part in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Corticosteroids down-regulate the expression of Fc and C3b receptors on macrophages and reduce the secretion of pro-inflammatory cytokines and eicosanoids. Expression of class II histocompatibility molecules is reduced, which in turn inhibits antigen presentation. Expression of adhesion molecules is inhibited, which reduces cell-cell interactions.

So what does all this mean? Steroids are used first and foremost to quieten down inflammation. In diseases like rheumatoid arthritis the pain and swelling heat and redness of the joint are all calmed down by the use of steroids, but there are lots of other diseases where a similar process is going on with macrophages acting in concert with antibody. Patients with CLL will know all about autoimmune hemolytic anemia and immune thrombocytopenia. In both of these an antibody kills the affected cell with the help of a macrophage. Steroids work in these conditions, not by getting rid of the antibody, but by paralyzing the macrophages. But there is a corollary for CLL patients. Antibodies like rituximab rely on macrophages to help them kill the CLL cells. If steroids are given with the antibody, they are likely to lessen their effect.

Another major effect of steroids is to quieten down allergic reactions. This is where those difficult words leukotrienes and eicosanoids come in. The eicosanoids are a family of locally active hormones derived from the twenty carbon fatty acid arachidonic acid. Most members of this family have roles in inflammation, including regulation of vasodilatation, vascular permeability, pain and the recruitment of white cells. The eicosanoid family includes prostaglandins, thromboxanes, leukotrienes and prostacyclins. Leukotrienes cause smooth muscle to contract, increase the permeability of blood vessels and stimulate the secretion of mucus. You can see how this would be involved in asthma, and, of course, steroids are the most useful drugs in treating asthma.

The thromboxanes and prostacyclins as well as being involved in inflammation are important in clotting via the platelets and the blood vessel walls. The synthesis of the prostaglandins involves enzymes known as cycloxygenases often abbreviated to Cox. The recent anxiety over Vioxx related to its role as an inhibitor of Cox. There are very many inhibitors of cycloxygenases – they include drugs like ibuprofen and diclofenac. These drugs have unwanted side effects, particularly bleeding from the stomach. Because of this pharmaceutical firms have tried to inhibit different forms of the enzymes separately. Inhibiting Cox-2 rather than Cox-1 should avoid the bleeding problems. Unfortunately it looks as though this increases the risk of thrombosis.

As well as their effects in quelling inflammation, steroids also have effects on lymphocytes. In T cells, particularly early in their life span, steroids induce apoptosis, although this can be stopped by certain hormones like prolactin, or by signaling trough the T cell receptor or by 17-AAG. B lymphocytes also can be sent into apoptosis by steroids, though again they are more resistant later in their development.

All in all treatment with steroids suppresses inflammation in many and varied ways and also has a rather unpredictable effect on specific immunity. This means that patients on steroids may have their primary disease quelled, but at the same time they become susceptible to infections. The most likely infections are fungal, some bacteria such as TB and viral. More than this, the normal response to infection – fever and feeling unwell – may be absent so a patient may get very sick without the tell-tale signs being noticed.

So the side effects of steroids begin to add up. Diabetes, high blood pressure, thinning of the bones, shape changes of the face and body, fluid retention, acne, striae, muscle wasting, psychological changes and now infections; powerful drugs they may be, but most doctors are reluctant to use them except in short courses.