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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Stathopoulos, G. & Elliott, E.V. (1974) Formation of mouse or sheep red-blood-cell rosettes by lymphocytes from normal or leukaemic individuals. Lancet, i, 600-601.
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leukaemia. Journal of Experimental Medicine, 169, 255-268.
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Trump, D.L., Mann, R.B., Phelps, R., Roberts, H. & Conley, C.L. (1980) Richter's syndrome: diffuse histiocytic lymphoma in patients with chronic lymphocytic leukemia. A report of five cases and review of the literature. American Journal of Medicine, 68, 539-548.
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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).

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

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.

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.

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.

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.

The Archbishop

The furor over the Archbishop of Canterbury's comments on Sharia law has been astonishing. I don't believe many people have read his lecture or even the transcript of his interview on the BBC

I have read both. I won't even attempt to summarize his lecture. It is an academic paper in an arcane area in which I have no expertise. Had it not been publicized on BBC radio, no one would have been aware of it. Most people who happened upon it would have given up reading it after the first paragraph. It is written in an academic style, full of subordinate clauses and parentheses, which does not make for easy understanding. To my mind it is badly written, since it seeks to obfuscate rather than aid understanding. I firmly believe that among the 1000 lawyers who were listening for hour to his lecture, fully two-thirds would have slumbered for part of the period.

The BBC interview is more accessible though itself not a model of clarity. Here is a quote that gets to the nub of the problem

"What we don't want I think is either a stand-off where the law squares up to religious consciences over something like abortion or indeed by forcing a vote on some aspects of the Human Fertilisation and Embryology Bill in the Commons, as it were, a secular discourse saying 'we have no room for conscientious objections'; we don't want that, we don't either, I think, want a situation where because there's no way of legally monitoring what communities do, making them part of public process, people do what they like in private in such a way that that becomes a way of intensifying oppression within a community and that happens; that happens. So how does the law engage critically and intelligently – the law of the land – with the custom, the imperatives, the principles of distinctive religious communities? It's a large question, much larger than the question about Islam and I think it's a question which the Church can quite reasonably be thinking about."

In other words what he is saying is that it is wrong to impose laws on people that do not take account of people's religious beliefs. I don't think I could live in a community which made it compulsory for doctors practicing in obstetrics to perform abortions. That's why the Abortion Act of 1967 contained a clause that allowed doctors to opt out for religious reasons.

There are also areas where the Law has no interest in what religious communities do. How many times should a priest genuflect before an alter. How exactly should an animal be killed to make meat halal? How many yards of cloth should go into a turban? And so on. The religious communities must be allowed to decide these things for themselves. But, and it's a big but, what they decide must not conflict with the human rights of the people at large. That's what he means by "we don't ... want a situation where because there's no way of legally monitoring what communities do".

There are certain conflicts that have arisen because of the tensions between community rules and the law of the land that show that such problems have not always been addressed. A good example would be in recent legislation defending the rights of gays. Catholic adoption agencies were not granted exemption that would allow them to refuse permission to place children with gay couples. The Bishop of Hereford was recently penalized for failing to give a job to a gay man even though he regarded homosexuality as something forbidden by the Bible. There are many other issues. Animal rights activists might well have a view on how animals are slaughtered for halal meat. There was the whole upset about the veil.

It is clear that religious beliefs can come into conflict with secular beliefs and I think that the Archbishop was trying to draw attention to this problem. By emphasizing the Islamic aspect of this, I suspect he was trying to avoid the charge of special pleading for Christians, but I believe it was a naive and silly decision.

Since 7/7 Britons have been afraid of the Moslems in out midst. Press referrals to Islam have concentrated on the abuses of civilized behavior committed by primitive Islamic societies like Saudi Arabia, Pakistan, Palestine etc. The countries may be rich in oil money or possess nuclear weapons, but they are still culturally primitive.

Sharia law, argues the Archbishop, is a way of looking at law - derived from the Koran. How that is codified is a cultural response. Primitive societies interpret Sharia in a way that is incompatible with modern Britain. But not to realize that the very mention of Sharia would connotate with amputations and beheadings demonstrates that the Archbishop's unworldliness is a serious defect for a man in his position.

Isaiah 44:22

I have swept away your offenses like a cloud, your sins like the morning mist. Return to me, for I have redeemed you.

God does not bear grudges, why do we? When we were forgiven our sins they are no longer remembered. God doesn't say, "OK, I'll forgive you this time, but I'll be watching you very carefully from now on, and the next time you show the merest smidgeon of rebellion, you're out." Instead he says when the Devil accuses us of past sins, "What sins? I laid them all on my son Jesus and he paid the full price for them. They are extinguished."

Not to say we don't keep on sinning. Of course we do. This side of glory we will never be sinless, but if we confess our sins he is faithful and just to forgive us our sins and to cleanse us from all iniquity. That's why we keep short accounts with God.

It is not a license to go on sinning. If we saw it as such we would not have repented of our sins. Our sins offend us and we want them dealt with. Daily He deals with them.

So if we are dealt with with such love why do we continue to hold other people's sins against them?

You know the sort of thing. He's OK, but once he cheated on his wife. It wouldn't be safe to leave him alone with yours. She's got a bit of a reputation for stealing. Didn't she once get arrested for shop lifting? Well, we'll know where to go if any of the spoons go missing. He could never be a deacon - his first marriage ended in divorce. Thirty years ago he was caught kissing the baby-sitter. That would debar him from ever becoming an elder. I'm not happy with him leading the singing. Once upon a time he jilted my daughter. Her daughter had an illegitimate baby; we couldn't allow her to teach Sunday school.

God be merciful to me, a sinner.

David Mason, RIP.

I am sorry to report that Professor David Mason of Oxford University has died following complications of routine surgery. David who was in his early sixties was the fifth most cited author in Oncology. He was responsible for many innovations in the immunological definition of lymphoid tumors and involved in formulating both the REAL and WHO classifications. I served with him on an LRF committee.

Boscombe

From 1974 to 1992 I worked at the old Victorian hospital at Boscombe. Today the site is given over to social housing. The other main employer in the area, the Danish Bacon Company, had closed a few years before the hospital. One of the results was that the Boscombe shopping center became increasingly run down. Some of the larger stores like Marks and Spencer and Safeway moved out and the Charity shops moved in. A small park became the home of drunks and drug addicts.

Now the council has decided to spend some money on the area. The seafront is being upgraded with the first artificial surfing reef in Europe. This should make Boscombe an attraction for surfers. A large amount of building is taking place with luxury apartments close to the beach and refurbishment of the pier.

This morning we went for a walk on the beach (it is 5 minutes from here by car). It was a completely cloudless day with the temperature in the sixties. The beach was deserted and we had a clear view of the Isle of Wight as well as the Isle of Purbeck. We walked back through a delightful garden to Shelley Park, which is being developed also. These are the grounds of Shelley House, once the home of Sir Percy Shelley, son of Percy Bysshe and Mary Shelley.

Whatever hapened to Yogic Flying?

The Maharishi has died aged 91. The old charlatan deceived the Beatles, who may have known a thing or two about pop music, but were hopelessly naive about living life. George Harrison funded the Natural Law Party which contested the 1992 General Election fielding a candidate in nearly every constituency and garnering 0.4% of the vote. Not enough to have kept John Major in power. That was accomplished by the Welsh Windbag falling over his feet on Bournemouth beach and tumbling face first in the surf.

The picture illustrates Yogic Flying, the NLP's answer to all human ills. After the demise of the NLP, its leader was interviewed by the BBC in his hotel room in the Bahamas.

Page 2

I phoned the ward and asked my houseman to arrange for his admission. There would be things to do; a bone marrow with samples sent for chromosomes, a chest X-ray, and swabs to check for infection. The houseman knew what to do. We follow a protocol these days; we don’t have to think.

I let my mind slip back to how it used to be when I first got into this game. The average survival time for children with leukaemia was ten weeks and for adults it was six weeks. We had no really effective drugs, blood transfusion services were rudimentary and the only antibiotics that we had were either ineffective against the germs that infect leukaemia patients or so toxic that you risked killing the patient if you used them. The first patient I treated had died from a brain haemorrhage after five days and the second had got septicaemia and died after two weeks.

Things were better now. We could all but guarantee Ronnie a remission of sorts if he decided to go for it, though how long it would last for might deter him from even trying for one. Of course, some patients could be cured with a bone marrow transplant, but at his age…

I snapped out of it. This was a long clinic and I had to get on.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

It had been quite a surprise to see June with Ronnie. She had recognised me, of course – I wasn’t the one who had a different name – but she made no comment. Perhaps she thought that I would not have recognised her, it had been more than twenty years since we had last had contact. We had met first at a party when I was a medical student and she was training to be a teacher. I’ve no idea whose party it was. We were both gatecrashers.

Students today would hardly have recognised it. For one thing we had short hair and no gel. It was before drugs became generally available; no pot, no ‘E’, not even speed. We took caffeine tablets to stay awake before exams. There was a lot of booze, but it was pretty foul stuff. I seem to remember drinking pints of British sherry; sweet, sickly and red.

They were playing “If I fell in love with you” by the Beatles; it was that era. She wore a black dress made of some sort macramé network that was more holes than substance. Skirts were very short that year. It’s hard to remember what a shock that was. Several accidents were caused by motorists taking a surprised second look at an abbreviated dress walking by. Tights had replaced stockings and this technical advance had enabled designers to be even more daring. Agony aunts debated whether knickers should be worn above or beneath the tights.

“Who is your favourite poet?” she asked.

“Bob Dylan.” I replied.

She scoffed at the idea that a singer could be a poet. She was studying Shelley, Keats and Wordsworth, about whom I knew next to nothing. I tried Wilfred Owen, which was met a bit more sympathetically and then Gerard Manley Hopkins, which impressed her. I think I passed out shortly after that and it was some weeks before I saw her again.

We had an on and off romance. I liked her a lot. We laughed at similar things. She introduced me to Rhythm and Blues and French film. I amused her with stories from the accident department and operating theatre. You have to understand that in those days young people didn’t just move in together. The pill was available but few were taking it. Having a girlfriend was more about frustration than sex.

June had been a Catholic, but had lapsed before coming up to University. You never lose the memory of that first communion, though. We didn’t agree about religion and I never met her parents. She wasn’t the only girl I was seeing either.

On one occasion we broke up after an argument. I had been telling her about an incident in the accident and emergency department. In those days they used to employ medical students to stitch up wounds. We weren’t paid, but we got our board and lodging. I was penniless so that free food was incentive enough and besides it was hands-on experience that was a clear improvement on poorly attended lectures from reluctant teachers.

O’Brien was an Irish drunk well known to the Casualty Officers. This time he had been brought to the hospital with a scalp injury. The story was that he had heaved a half house-brick through the window of an Indian restaurant provoking three waiters to come out and beat him about the head with hockey sticks. He was rude, violent and incoherent and the Casualty Officer, a guy called Jeremy Stevens, didn’t fancy him at all. After a peremptory examination he detailed me to stitch up his head wound.

It was a bloody mess. I poked about a bit, but O’Brien was so uncooperative that eventually I just squirted some local in and started stitching up his scalp. It was a difficult wound, the tear going in three different directions. As I struggled to get the edges straight I pulled out a square inch of skull, exposing the mushroom coloured brain beneath. “What shall I do with this?” I asked Dr Stevens (who had been qualified for nearly two years).

“Just stick it back in and keep on stitching.”

And so I did. By the time I had finished, Corky had stopped his cussing and struggling and was sleeping peacefully.

Relieved that he had finally succumbed to the booze, I started to examine him properly. I asked Jeremy Stevens “Should he have different sized pupils?”

The cry of desolation.

And at the ninth hour Jesus cried out in a loud voice, "Eloi, Eloi, lama sabachthani?"—which means, "My God, my God, why have you forsaken me?"

This is among the most profound passages in the whole of Scripture. Jesus was quoting Psalm 22, but he was also expressing his own anguish. What was going on here?

It seems, at first sight, a mystery. How could the God/Man be perplexed about what was happening? Was He not all knowing?

Jesus was fully man and fully God. John's gospel tells us 'He was with God in the beginning'. We cannot understand the Trinity. How can God be both three and one? Still less can we imagine the Trinity ripped apart. But that seems to be what was happening.

The pictures of Hell in the Bible are either of a inextinguishable fire or of outer darkness. Some have described Hell as the total absence of God. We are familiar with the idea of common grace. God makes it to rain upon the just and unjust. Imagine that grace withdrawn. In The Great Divorce, CS Lewis imagines a place of outer darkness peopled with great villains like Napoleon who are completely separated not only from contact with God, but even with human contact. Jesus had already been deserted by his friends not be was abandoned by God. We have all felt abandoned by God, but none of has been. We were just unable to discern His presence, because of fault in us, not in Him. He has always been there. But Jesus had never been separated from the Father. Even from eternity past they had always been together.

In an inexplicable way God was incarnate in His second person, yet retained that special intimacy with the other persons of the Trinity. Now suddenly the Godhead was wrenched apart. How that occurred I do not know. Was the Son of Man separated from the Son of God? I do not know.

The Apostles creed tells is that, "He descended into Hell." Some have linked this to the text in Ephesians chapter 4 about descending to the lower, earthly regions and leading captivity captive, and that other text in I Peter Ch3 about Jesus preaching to the 'spirits in prison', but what it is really describing is this time on the cross when Jesus experienced for the first time in all eternity the absence of God.

We do not know we cannot tell what pain he suffered there
But we believe it was for us he hung and suffered there.

William Cowper was a great poet. His mother was a Donne and he is perhaps a descendant of the poet John Donne. He is the author of several of out best loved hymns including "There is a fountain filled with blood", "God moves in a mysterious way" and "Oh for a close walk with God". For mush of his life he suffered from severe depression and lacked assurance. Elizabeth Barrett Browning was moved that such a poet should be so depressed and wrote a poem entitled 'Cowper's Grave' these are the last two stanzas:

Deserted! God could separate from His own essence rather;
And Adam’s sins have swept between the righteous Son and Father;
Yea, once, Immanuel’s orphaned cry His universe hath shaken --
It went up single, echoless, “My God, I am forsaken!”
It went up from the Holy’s lips amid His lost creation,
That, of the lost, no son should use those words of desolation!
That earth’s worst frenzies, marring hope, should mar not hope’s fruition,
And I, on Cowper’s grave, should see his rapture in a vision.

How right she was. Because of Jesus' desolation, none should share it. How perverse that some should choose to do so.

Gender imbalances

Five years ago I retired from the NHS. My three days a week at Bournemouth were replaced by two consultants working between them ten and half days a week. I would like to think that this meant that I was practically irreplaceable, but in fact the hospital took the opportunity to expand and improve the service. I refrain from making the sexist point that it took two women to replace me, especially since back in the 1980s I got into trouble by raising alarm bells over the fact that the number of women going to medical school had massively increased. My point then was that the average woman worked for seven years after qualifying whereas the average man worked for 35 years after qualifying. No doubt the truth was that women would in future not work for a few years before marrying and retreating into a life of domesticity and the occasional family planning clinic.

So I was interested to see a new paper in the Journal of the Royal Society of Medicine (101:27-33) entitled 'Gender and variation in activity rates of hospital consultants'. The authors have surveyed the number of 'Finished Consultant Episodes' (FCE) attributed to various doctors in the NHS. The surprising finding was that male consultants were responsible for at least 20% more FCEs than female consultants in equivalent posts with equivalent case mixes. Other variables like age, specialty and hospital were taken into consideration. Indeed male doctors tend to have the more complicated casemix, and when workload is adjusted for this, the excess activity for males approaches 100%.

Similar results have been found in both the USA and Canada, but in these systems more work brings more pay, so that there is an element of choice in how much activity is undertaken. In the UK everyone is paid the same. Well, not quite. There is a system of discretionary points and merit awards which are supposed to reward those who work especially hard or are in other ways meritorious. And sure enough, doctors in receipt of those awards do work harder. However, protests have been made that fewer women than expected get these rewards and instructions have come from government to remedy this imbalance. It seems from this survey that the distribution of these awards is indeed fair.

Another finding of this survey is that doctors who have a private practice in addition to their NHS practice, actually work harder for the NHS than those doctors who don't have a private practice. This again contrasts with what the government has been telling us, that doctors who sneak off to Harley Street are neglecting their NHS patients.

Entry into Medical School in the UK is 60% female. Is this wise?

Darkness at the sixth hour Mark 15:33

I have written before about darkness at noon but now we come to this verse in the exposition of Mark's gospel. For those who are new to this series may I say that I have been listening to the sermons of Pastor Chris Kelly at Lansdowne Baptist Church, Bournemouth and then meditating on what I have learnt. As this series nears its end I do recommend that readers order the series on tape, CD or DVD from this site. I value this series of sermons particularly be cause Chris has devised a structure to Mark's gospel that I have never seen before and one that explains why there is an apparent lack of consistency between the various synoptic gospels.

Skeptics regard this miraculous happening as fiction. If such an extensive period of darkness occurred over such a large area, why was it not mentioned by contemporary writers?

Actually, it was. In AD 52 Thallus wrote a history of the eastern Mediterranean world since the Trojan War. Although his original writings have been lost, he is specifically quoted by Julius Africanus, a renowned third century Christian historian. Africanus states, ‘Thallus, in the third book of his histories, explains away the darkness as an eclipse of the sun—unreasonably as it seems to me.’

As Africanus recognized it is indeed an unreasonable explanation. Eclipses of the sun last for only a few minutes; certainly not for three hours. Even more significantly, it is physically impossible to have an eclipse of the sun at the time of full moon, and as everyone knows, the Jewish Passover, when Jesus was crucifies, takes place at the time of a new moon.

Phlegon was a Greek historian who wrote an extensive chronology around AD 137 writes:
"In the fourth year of the 202nd Olympiad (i.e., AD 33) there was ‘the greatest eclipse of the sun’ and that ‘it became night in the sixth hour of the day [i.e., noon] so that stars even appeared in the heavens. There was a great earthquake in Bithynia, and many things were overturned in Nicaea.’

Phlegon provides powerful confirmation of the gospel accounts. He identifies the year and the exact time of day. In addition, he writes of an earthquake accompanying the darkness, which is specifically recorded in Matthew’s Gospel (Matthew 27:51). However, like Thallus, he attempts to interpret the darkness as a direct effect of a solar eclipse.

Africanus composed a five volume History of the World around AD 221. He was a pagan convert to Christianity. His historical scholarship so impressed Roman Emperor Alexander Severus that Africanus was entrusted with the official responsibility of building the Emperor’s library at the Pantheon in Rome. This is what Africanus wrote: "On the whole world there pressed a most fearful darkness; and the rocks were rent by an earthquake, and many places in Judea and other districts were thrown down. This darkness Thallus, in the third book of his History, calls, as appears to me without reason, an eclipse of the sun. For the Hebrews celebrate the Passover on the 14th day according to the moon, and the passion of our Savior falls on the day before the Passover; but an eclipse of the sun takes place only when the moon comes under the sun. And it cannot happen at any other time but in the interval between the first day of the new moon and the last of the old, that is, at their junction: how then should an eclipse be supposed to happen when the moon is almost diametrically opposite the sun? Let opinion pass however; let it carry the majority with it; and let this portent of the world be deemed an eclipse of the sun, like others a portent only to the eye. Phlegon records that, in the time of Tiberius Caesar, at full moon, there was a full eclipse of the sun from the sixth hour to the ninth—manifestly that one of which we speak. But what has an eclipse in common with an earthquake, the rending rocks, and the resurrection of the dead, and so great a perturbation throughout the universe? Surely no such event as this is recorded for a long period."

What about other early historians such as Josephus, Tacitus, Suetonius, and Pliny the Younger, who all fail to mention the darkness? Arguing from silence is a hazardous profession. It is unreasonable to expect every contemporary writer to include every event that happened—and there are good reasons not to expect these specific authors to mention the darkness.

This objection (the argument from silence)was first raised by Edward Gibbon and has been parroted ever since by skeptics who have never read Pliny or Seneca (neither have I, though I have read Josephus)

Pliny's work is entitled Natural History, and it is a multi-volume work covering a wide variety of subjects - geography, meteorology, mineralogy, zoology, and botany. Volume 2 of this work is concerned with cosmology and astronomy, and is the place we might expect Pliny to have recorded this event - if he indeed did intend to record all such events. He offers examples; he makes descriptions, but frequently from his own observations. There is no indication that his work is intended to be an exhaustive catalog of all possible relevant data. But he was a skeptic and a rationalist of the highest order. He wrote: "I deem it a mark of human weakness to seek to discover the shape and form of God. That that supreme being, whatever it be, pays heed to man's affairs is a ridiculous notion." Temperamentally he would not seek to confirm an event that supported a religious idea.

Seneca's work, Naturales Questiones is even less likely to mention the darkness. His book mostly comprises theoretical surveys of natural phenomena - by no means an attempt at an exhaustive catalogue of events - and he is far more concerned with drawing morals from what he records that with listing events, of which he does very little.

As for Josephus, he was writing for the favor of his patron Vespasian, whom he had credited with fulfillment of Messianic prophecy. He might be safe in mentioning that Jesus did miracles, but to ascribe to Jesus some sign that would have signified special status with God would likely offend his patron.

The phrase 'Darkess at Noon' was, of course, used by Arthur Koestler, the British writer of Hungarian origin, for his famous novel dealing with failings of communism. Koestler suffered from CLL and so may be of interest to some of my readership. But the idea of darkness as a prelude to a terrible event is much older.

In Exodus ch 10 the ninth of the Egyptian plagues is darkess that covered the land. It preceded the death of the first born and the Passover. In Amos 8:10 the LORD says, "I will make the sun go down at noon and darken the earth in broad daylight" as part of his wrath against his people. Darkness is a symbol of the absence of God. "The light shines in the darkness," says John, "the true light that gives light to every man was coming into the world."

Isaiah Ch 60 begins "Arise, shine, for your light has come, and the glory of the LORD rises upon you. See, darkness covers the earth and thick darkness is over the peoples, but the LORD rises upon you and his glory appears over you. Nations will come to your light, and kings to the brightness of your dawn." He sees in the darkness only the opportunity for God to enlighten it, and so it has proved. But before he does so we must visit Hell itself.

Snowdrops

After storms that caused a couple of shipwrecks and snow in the north, today was a still and clear day with bright sunshine. It was fairly cold but we wrapped up well and took a trip to see the Kingston Lacy snowdrops. There are six million snowdrops in the grounds of this Dorset stately home. The grassy banks are covered with them at a time when little else is flowering.

This was the first time that we had seen them and they are certainly spectacular, but when you have seen one flowery knoll you've seen them all and we got rather bored with snowdrops, looking instead for the occasional early daffodil, the odd clump of camellias or even the errant rhododendron, pink on the pale day. We examined the different types of trees; the enormous beeches, spectacular without their leaves, the gnarled oaks and the scruffy hollies.

Then we started looking at the people. I have never seen so many visitors at Kingston Lacy; there must have been three thousand there. What was remarkable was how similar they all were. There were some young ones in their fifties, the majority were in their sixties, quite a few were in their seventies, but the over eighties were also well represented. The local conurbation has over 450,000 people and one in three is over sixty years of age.

Everywhere we looked were grey haired couples in anoraks. This is apparently an annual pilgrimage. Thousand of people nearing the end of their lives troop to Kingston Lacy in the middle of winter to pay homage to the little snowdrop, the first sign that there will indeed be another year.