Polyphenols: natural products to treat leukemia

I was asked a question today about polyphenols which reminded me of an editorial I wrote about them a year or so ago. I don't think this has ever appeared on the blog so I reprint it here. It was in response to the Mayo Clinics trial on green tea.

Shanafelt et al. have described the beneficial effects of green tea extracts in four patients with low grade B-cell malignancies [1]. It is one more example of the increasing interest in the possible use of natural products for malignant disease. There is a tendency for scientists to back away from the word “natural” for fear of being contaminated by the beards and sandals brigade flogging organic produce, acupuncture meridians, radio-ionic diagnosis and snake oils of various flavors. We tend to forget that plants have proved a rich source of medicines from digoxin, quinine and aspirin to vincristine and taxotere.

Anyone approaching this subject afresh is met with a bewildering range of names that have no reference point, though they hint at some connection with organic chemistry. Plant products with strong anti-oxidant properties are known generally as polyphenols. Polyphenols are categorized as bioflavonoids, phenolic acids, stilbenes and lignans. Bioflavonoids are the most abundant group—over 6000 have been identified and they provide the color and flavor of fruits, vegetables, berries and flowers. Leukemia Research has recently reviewed the multiple effects of bioflavonoids on gene regulation, cell proliferation and apoptosis [2]. These natural plant pigments are essential for the growth, development and survival. Many are biologically active in mammalian cells as well as plant cells. In a typical study Matsui et al. demonstrated that six individual bioflavonoids, flavone, luteolin, apigenin, genistein, quercetin and fistein could induce apoptosis in leukemia and lymphoma cell lines in a dose-dependent manner [3]. The mechanism of action involved disruption of mitochondrial membranes and activation of caspase-3.

Resveratrol is a stilbene rather than a bioflavonoid, a different type of polyphenol. It too induces apoptosis in B-cell lines and fresh chronic lymphocytic leukemia (CLL) cells, apparently by inhibiting nitric oxide synthetase, nitric oxide being a well recognized inhibitor of caspases. However, the semi-synthetic flavonoid, flavoperidol, has similar actions, suggesting that pro-apoptotic properties may be possessed by a wide range of plant products [4].

Resveratrol is a grape phytoalexin. Phytoalexins are part of the defense mechanism of plants against invading fungi and bacteria. The cruciferous phytoalexins including brassinin, 1-methoxybrassinin, and spirobrassin and related compounds are produced by plants of the Cruciferous family such as broccoli, Brussels sprouts, cabbage and cauliflower. They are not chemically related to resveratrol, being indole based, but were also found to be pro-apoptotic in the Jurkat T-cell line [5].

Many of the products offered by health food shops are not so refined, being mixtures of many phyto-active substances. Propolis is a resinous substance used by bees to maintain their hives. It is a mixture of bioflavonoids, phenolic acids and wax. It has been shown to have a pro-apoptotic effect on a cell line derived from T-cell acute lymphoblastic leukemia by inhibiting the expression of telomerase [6]. Pycnogenol is a commercialized supplement extracted form the bark of the European coastal pine that contains a mixture of bioflavonoids and phenolic acids. It has pro-apoptotic and differentiating effects on HL-60 cells [7].

More familiar plant extracts are also being exploited. The cannabis component tetrahydrocannabinol has been suggested as a new treatment modality for tumors of the lymphoid system. It induces apoptosis in Jurkat cells via the intrinsic pathway [8]. Garlic has been suggested as an anti-cancer agent for 3500 years. Several studies have demonstrated an in vitro effect of the garlic extract, ajoene, in stimulating apoptosis and inhibiting proliferation of leukemia cell lines [9].

Ah! There's the rub. Translation of what happens in the test tube to an effective agent in the patient has been the downfall of many a white hope. Perhaps the best example is the semi-synthetic flavonoid, flavoperidol. In the test tube this drug is able to kill CLL cells, even those refractory to other drugs because of p53 deficiency. In the patients they produced only toxicity. Despite not binding to fetal calf serum, flavoperidol is tightly bound to human serum albumin [10]. It therefore comes as a great relief that the polyphenol extracted from green tea, epigallocatechin-3-gallate (EGCG), has been reported to have a clinical effect [1]. Ever since this same group reported on the in vitro ability of EGCG to induce apoptotic cell death in CLL cells, in part mediated through its effects on the VEGF receptor [11], there can hardly be a CLL patient with access to the internet who has not tried it. Sales of green tea, both caffeinated and decaffeinated, or of EGCG capsules have blossomed. Anecdotally, white counts have risen and fallen. Some swear by it; others decry it. Here, at last, is an objective report. Three patients with CLL and one with follicular lymphoma, of their own volition, took EGCG containing products. Before and after measurements of their disease are available. In three there were partial responses as judged by recognized criteria and in the other a sustained reduction in absolute lymphocyte count. There was little if any toxicity.

Of course, this report can be criticised: it was not a formal trial; we do not know how many patients were taking green tea but failed to respond; we do not know how much EGCG each patient took, or even if the preparation really contained EGCG; the responses may have been spontaneous regressions. Two of the three CLL patients were negative for ZAP-70 (the other was not tested) and it may be that natural dietary supplements have some role in controlling cancers that are principally diseases of accumulation owing to a failure of apoptosis, but will appear much less impressive in diseases with a more prominent proliferative component.

Nevertheless, the Mayo Clinic has initiated a phase I/II clinical trial of green tea in patients with asymptomatic early stage CLL. This trial will have merit in more formally evaluating the activity of green tea and in alleviating what the patients call watch and worry.

References

[1] T.D. Shanafelt, Y.K. Lee, T.G. Call, G.S. Nowakowski, D. Dingli and C.S. Zent et al., Clinical effects of oral green tea extracts in four patients with low grade B-cell malignancies, Leuk Res 30 (2006), pp. 707–712.

[2] P.M. Strissel and R. Strick, Multiple effects of bioflavonoids on gene regulation, cell proliferation and apoptosis: natural compounds move into the lime light of cancer research, Leuk Res 29 (2005), pp. 859–861.

[3] J. Matsui, N. Kiyokawa, H. Takenouchi, T. Taguchi, K. Suzuke and Y. Shiozawa et al., Dietary bioflavonoids induce apoptosis in human leukemia cells, Leuk Res 29 (2005), pp. 573–582.

[4] C. Quincey, D. Dauzonne, C. Kern, J.-D. Fourneron, J.-C. Izard and R.M. Mohammad et al., Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B cells, Leuk Res 28 (2004), pp. 851–861.

[5] M. Pilatova, M. Sarissky, P. Kutschy, A. Mirossay, R. Mezencev and Z. Curillova et al., Cruciferous phytoalexins: antiproliferative effects in T-Jurkat leukemic cells, Leuk Res 29 (2005), pp. 415–421.

[6] C. Gunduz, C. Biray, B. Kosova, B. Yilmaz, Z. Eroglu and F. Sahin et al., Evaluation of Manisa propolis effect of leukemia cell line by telomerase activity, Leuk Res 29 (2005), pp. 1343–1346.

[7] W.W. Huang, J.S. Yang, C.F. Lin, W.J. Ho and M.R. Lee, Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL60 cells, Leuk Res 29 (2005), pp. 685–692.

[8] C. Lombard, M. Nagarkatti and P.S. Nagarkatti, Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in delta 9-tetrahydrocannabinol (THC)-induced apoptosis in Jurkat cells, Leuk Res 29 (2005), pp. 915–922.

[9] H.T. Hassan, Ajoene (natural garlic compound): a new anti-leukemia agent for AML therapy, Leuk Res 28 (2004), pp. 667–671.

[10] Y. Lee, N. Bone, A. Strege, T. Shanafelt, D. Jelinek and N. Kay, VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B cell chronic lymphocytic leukemia, Blood 104 (2004), pp. 788–794.

[11] I.W. Flinn, J.C. Byrd, N. Bartlett, T. Kipps, J. Gribben and D. Thomas et al., Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity, Leuk Res 29 (2005), pp. 1253–1257.

Building a relationship with God

We should pray because Jesus did. Sounds convincing doesn't it, but you might as well say we should walk on water or heal lepers or feed 5000 with 5 loaves and 2 fish or still the storm or raise the dead; because Jesus did. He prayed because he was special. He had a relationship with God since the beginning of time. Apart from the desolation of the cross, they had always been together. They had been inseparable. Jesus is up there and we are down here, how can we presume to do what he did?

But we have just seen that we are children of God. Romans 8:17 tells us that we are heirs of God and co-heirs with Christ. Galatians 5:7 tells us we are no longer slaves but sons; and since we are sons, God has also made us heirs. I Peter 3:7 tells us husbands that our wives are heirs with us of the gracious gift of life so that nothing will hinder our prayers.

See how being an heir is linked with prayer. And of course it should be. If we object to praying on the ground that God is so distant that he could not possible listen to me, the fact that He has brought us close by making us heirs should answer that objection.

I think that our reluctance to pray in part comes from our rebellion against being told what to do. If you are anything like me, you like to make your own decisions about things. Instructions to young Christians that they must pray morning and evening and read through their Bibles three times a year are very laudable, but make communion with God a task to be fulfilled rather than a relationship to be established. As if getting to the end were the purpose rather than enjoying the journey. That's why I have entitled this piece, "Building a relationship with God".

OK, but a relationship requires a two-way conversation. Not only have I never heard God speak to me in an audible voice, but I don't know anyone who has - at least no-one outside an asylum for schizophrenics. Oh, how I long for a word from God!

Silly! I have the Bible. God has spoken. Think how many times when troubles have beset me that a verse of Scripture springs to my mind. Think how many times a faithful pastor has brought a word of God to my situation. Think how many times a Christian friend has spoken a word into my circumstances. Think how many times someone has intervened to relieve my troubles. Think how many times my enemies have been thwarted. Dare I say that my conversation is one way?

Philip Yancy tells a story from a time early in his marriage. He was staying at a four-bedroom guest house with no other occupants. Over dinner he and his wife had had cross words and though they sat up late trying to resolve the problem the anger escalated and eventually he stomped off to bed. A few minutes later the door opened and his wife appeared with a new set of arguments. He wouldn't listen and fled to another bedroom. A few minutes later the same thing happened and off he went to yet another bedroom. It had all the trappings of a Whitehall farce and of course in the morning they saw the comical side. But the message is (and don't all we married couples know it) not communicating is worse than fighting.

This illustration is particularly apposite because the Bible calls us the bride of Christ. If we are not speaking, is it because we have had a marital spat? For some of us the sulks have been going on for a long time.

Death and multiplication

You may well ask why I have posted so many technical articles recently. Anyone who attempted to come to terms with yesterday's offering may well have given up half way (if they got that far) with the question, "Why do I need to know this?" I must confess that that has been exactly my reaction over the last few years, but the extra time that retirement brings has meant that I can read more widely.

When I was at University there was no such subject as molecular biology. DNA was never mentioned and even biochemistry was no more complicated than the measurement of urea and glucose. When I was a postgraduate student genetics meant learning about inborn errors of metabolism such as sickle cell disease and G-6PD deficiency, and although the thalassemias opened our eyes to the complexity of genetic disease, we had our hands full with extracellular biochemical pathways, and the inner workings of the cell were a black box.

Later, I began to hear about processes that perplexed me. Words like apoptosis and caspase were opaque to me, as were promoters and enhancers, introns and extrons, and especially words like myristoylation. Then there were the acronyms. Unless you know their origin (which are usually hard to find) you are like a juggler with too many balls in the air. When you read a difficult passage of prose and you come upon a word you have never seen before you can often guess its meaning from the context. I had this problem when I read the Patrick O'Brien books of the Master and Commander series. Technical terms from eighteenth century sailing ships kept cropping up. If you can't guess them then you have to hold them in the air in the hope that all will be explained. Eventually you have so many balls in the air that you start dropping them.

(As an aside let me tell you the story of the Jnk gene - pronounced junk. You'd think it was something to do with junk DNA, which couldn't be further from the truth. It stands for Jun kinase. And Jun is nothing to do with either the month or the girl, it comes from ju-nana, the Japanese for the number 17 because it was isolated from avian sarcoma virus 17. Jun is often associated with Fos which itself is nothing to do with the Fosse Way, but comes from the FJB murine osteosarcoma virus. FJB? These were the people who isolated the virus in 1966, Finkel, Biskis and Jinkins.)

So without going back to the previous article, can I explain src family kinases for those who can't manage the technology?

All cells in the body have things to do. For many their chief function is to manufacture something. For example the chief function of a plasma cell is to make antibody. But most cells have two common functions : to reproduce themselves and to die. Of course, some cells have reached the end of their reproductive life and death is all they have to look forward to. Reproduction and death are very specific and non-random procedures, and they are done properly and in order according to protocol. In the growing embryo, death and multiplication are pre-programmed and take place in a specific order, but in the adult death and multiplication result from external stimuli in the context of the tissue that they live in.

Cells have receptors on their surface to receive these external stimuli. For example, breast cells have estrogen receptors, thyroid cells have receptors for thyroid stimulating hormone etc. White blood cells have very many receptors and alongside the receptors they have co-receptors that modify the way the receptor responds to a stimulus. For T-lymphocytes the T-cell receptor (TCR) only responds to a particular foreign stimulation - it will respond to measles but not to mumps, for example. It is therefore called a cognate response because it seems to know when it should respond and when it should not. For B-cells it is the same, only we know that the B-cell receptor (BCR) is actually the antibody that it has been pre-programmed to make.

The decision on death or multiplication is made in the nucleus of the cell. It involves switching on certain genes and switching off others. The mechanism is in the hands of proteins called Transcription Factors. So how does a message get from the cell surface receptor to the nucleus? Obviously there has to be a system of relays which pass the message along. These signaling molecules pass their signal to the next relay in the form of a parcel of phosphate - often attached to an amino acid called tyrosine, which is part of their protein structure.

Of course, it is much more complex than that with stimulatory and inhibitory processes kept in balance so that all changes are smoothly modulated. The relay pathways are not straight lines, but have branch lines that affect the final outcome. But I am sure you get the gist.

In cancer, these pathways are disorganized. Death and multiplication are both affected. Programmed cell death (that's what apoptosis means) is usually inhibited and multiplication is exaggerated. It is quite obvious that cells must sometimes multiply more quickly than normal - during an infection more white cells must be produced to fight it, but when the emergency is over the number of white cells must return to former levels. Therefore these things must come with an 'on' and 'off' switch. Very often in cancer the switch is jammed in the 'on' position.

If we are to develop truly targeted treatment for cancers we must understand what the molecular mistake was. Glivec (Gleevec) has been successful because the disease, CML, has a relatively simple molecular mistake. The multiplication enzyme known as ABL (short for Ableson) is jammed in the 'on' position. All such enzymes need a power supply to keep running and what Glivec does is to cover up the socket where the energy supply plugs in. This puts ABL out of action and the result is remission.

src family kinases

In 1966, Francis Peyton Rous received the Nobel prize for Physiology or Medicine. He proposed that viruses can cause cancer and proved it in 1911. It was only because he lived almost forever that he lived to win the prize some 55 years after his scientific discovery. The delay can perhaps be attributed to the Nobel Committee awarding the 1926 prize to Johannes Andreas Grib Fibiger who had discovered the fungus Spiroptera carcinoma which he mistakenly believed was the cause of cancer. They didn’t want to make a second mistake and for a generation the idea that infection could cause cancer was thought to be heretical. It is said that people don’t change their minds, its just that the people who hold the old ideas die off.

Rous, who died in 1970 at the age of 91, worked on chickens. Some chickens grow a tumor called a fibrosarcoma. Rous minced up these sarcomas, centrifuged them down to remove the solidsl, and injected the liquid that remained into chicks. The chicks also developed sarcomas. The liquid contained a virus, now called the Rous sarcoma virus (RSV – note this is nothing to do with Respiratory Syncitial Virus, which causes chest infections in children).

Later work by others showed that RSV was a retrovirus like HIV. Retroviruses that don’t cause cancer contain three genes, called gag, pol, and env, but cancer causing retroviruses may also contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of the Rous Sarcoma and that the other genes do not take part in causing the cancer.

Src codes for a tyrosine kinase which is required to transmit signals from cell surface to the nucleus where functions like movement and proliferation are controlled. The v-src protein lacks the C-terminal inhibitory phosphorylation site (tyrosine-527) that most tyrosine kinases have, and is therefore always switched on and can’t be switched off.

In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely-related to v-src. The normal cellular gene was called c-src (cellular-src). This discovery led to their being awarded the Nobel prize in 1989. c-src which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an example of an oncogene whereas c-src is a proto-oncogene.

This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer.

The Src family includes nine members: Src, Lck, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk.

Lck or leukocyte-specific protein tyrosine kinase is found in lymphocytes, most commonly in T cells. It associates with the bits the CD4 and CD8 co-receptors on repectively T helper cells and cytotoxic T cells that poke through the cell membrane into the cell so as to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck acts to phosphorylate the intracellular chains of the CD3 and zeta-chains of the TCR complex, allowing another cytoplasmic tyrosine kinase called ZAP-70 to bind to them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT (short for Linker of Activated T cells). The tyrosine phosphorylation cascade started up by Lck produces a flow of calcium (Ca2+) ions and activation of important signaling cascades within the lymphocyte.

Hck or Hemopoietic cell kinase is a protein-tyrosine kinase expressed in hemopoietic cell types. It may help couple the Fc receptor to the activation of the respiratory burst. In addition, it may play a role in neutrophil migration and in the degranulation of neutrophils.

Fyn (Feline yes-related protein) was previous known as slk (src-like kinase) but there was confusion with another Slk (Ste20-like kinase). It was also previously known as syn (src and yes related protein). It is a membrane-associated non-receptor protein tyrosine kinase of approximately 59kDa, Fyn is expressed predominately in tissues of neuronal and hematopoietic origin. Neuronal Fyn and hematopoietic Fyn differ at the junction of the SH2 and kinase domains due to tissue specific alternative splicing. Fyn has been shown to be involved in B-cell and T-cell activation as well as keratinocyte differentiation. In T-cells, Fyn associates with the T-cell antigen receptor and Thy-1. Fyn activation in response to integrin ligation occurs through association of Fyn and integrins with caveolin-1. Activated Fyn binds directly to Shc and phosphorylates it resulting in recruitment of Grb2 and Sos culminating in ERK/MAPK activation. (Sorry about all those acronyms – I will get around to explaining them later.)

Blk or B-lymphoid kinase Blk is a Src family protein tyrosine kinase expressed in all stages of B cell development. Activation of B cells by various ligands is accompanied by activation of Blk. It has been suggested that Blk is involved in the control of B cell differentiation and proliferation. Blk transcripts have also been detected in human thymocytes, but not in mature T cells, implicating that Blk may play an important role in thymopoiesis. Blk function may be redundant, however, as mice that do not express Blk are not impaired with respect to B cell development and immune response.

Yes is nothing to do with Meg Ryan. The cellular oncogene c-Yes and its viral homologue v-Yes (the transforming gene of Yamaguchi 73 and Esh avian sarcoma viruses) encode a 60 kilodalton, cytoplasmic, membrane-associated, protein-tyrosine kinase. Yes is ubiquitously expressed in many tissues and cells. Like other Src family members, Yes contains several conserved functional domains such as an N-terminal myristoylation (look it up in Wikipedia) sequence for membrane targeting, SH2 and SH3 domains, a kinase domain and a C-terminal, non-catalytic domain. There is also a growing body of evidence to indicate specificity in Yes signaling. Yes is activated downstream of a multitude of cell surface receptors, including receptor tyrosine kinases, G-protein-coupled receptors and cytokine receptors. Additionally, both Yes and Src kinases are activated during the cell cycle transition from G2 to M phase. Dysfunction of Yes is associated with the development of various cancers.

Yrk of course stands for Yes related kinase. While screening a chicken kidney cDNA library for the normal homolog of the yes oncogene, a clone that encoded a novel non-receptor type protein tyrosine kinase of the Src family was isolated. This gene product was named Yrk (York), as an acronym for Yes-related kinase. As predicted from the cDNA sequence, the Yrk protein consists of 536 amino acids and has all the canonical features of a Src kinase. At the amino terminus it contains a myristylation signal, followed by a unique domain, SH3 and SH2 motifs, an ATP binding site, a kinase region and a carboxy-terminal sequence with a potential regulatory tyrosine at position 530. The sequence of the Yrk protein showed 79% identity with human Fyn and 72% identity with chicken Yes. The sequence data together with Southern and Northern blot analyses showed that the chicken yrk gene is distinct from the chicken fyn gene. Antibodies generated against the unique domain of the yrk protein expressed in bacteria precipitated a 60-kDa protein that was active in an immune complex kinase assay and was phosphorylated on tyrosine. Expression of the Yrk protein in adult chicken tissues was elevated in cerebellum and spleen. Relatively high levels of Yrk were also found in lung and skin.

Lyn is a V-yes-1 Yamaguchi sarcoma viral related oncogene homolog. It is mainly expressed in hematopoietic cells and in neural tissues. In various hematopoietic cells, Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of Lyn is associated with cell surface receptor proteins, including the BCR, CD40 and CD19. Following engagement of the receptors, Lyn undergoes rapid phosphorylation and activation. Lyn activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase. These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation.

Intriguingly, Lyn also plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1, which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. By acting as a key regulator of both positive and negative signals, Lyn plays an important role in B cells. In these, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.

FGR comes from the Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog. The encoded protein contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified.

CLL papers without nice pictures

At a recent CLL meeting in Copenhagen Daniel Catovsky, one of the greatest hematologists of his generation, was heard to applaud a paper that actually showed pictures of CLL cells while he muttered something derogatory about pictures of gels. There were murmurs of approval throughout the hall. As hematologists our primary skill was to be able to recognize blood cells down the microscope. Increasingly hematology papers are not about that, but show pictures of bands on gels that are unfamiliar to most of us. In order to understand these papers some basic understanding is required.

So a visit to Wikipedia is in order.

Phosphorylation is the addition of a phosphate (PO4) group to a protein molecule or a small molecule. Reversible phosphorylation of proteins is an important regulatory mechanism that occurs in cells. Enzymes called kinases (phosphorylation) and phosphatases (dephosphorylation) are involved in this process. Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Reversible phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated. Phosphorylation usually occurs on serine, threonine, and tyrosine residues.

One such example of the regulatory role that phosphorylation plays is the p53 tumor suppressor protein. The p53 protein is heavily regulated and contains more than 18 different phosphorylation sites. Activation of p53 can lead to cell cycle arrest, which can be reversed under some circumstances, or apoptotic cell death. This activity occurs only in situations wherein the cell is damaged or physiology is disturbed in normal healthy individuals.

Upon the deactivating signal, the protein becomes dephosphorylated again and stops working. This is the mechanism in many forms of signal transduction, for example the way in which antigen stimulates a B lymphocytes.

Elucidating complex signaling pathway phosphorylation events can be difficult. In a cellular signaling pathways, a protein A phosphorylates protein B, and B phosphorylates C. However, in another signaling pathway, protein D phosphorylates A, or phosphorylates protein C. Global approaches such as phosphoproteomics, the study of phosphorylated proteins, which is a sub-branch of proteomics combined with mass spectrometry-based proteomics, have been utilised to identify and quantify dynamic changes in phosphorylated proteins over time. These techniques are becoming increasingly important for the systematic analysis of complex phosphorylation networks.

There are thousands of distinct phosphorylation sites in a given cell since: 1) There are thousands of different kinds of proteins in a lymphocyte. 2) It is estimated that 1/10th to 1/2 of proteins are phosphorylated. 3) Phosphorylation often occurs on multiple distinct sites on a given protein.

Since phosphorylation of any site on a given protein can change the function or localization of that protein, understanding the "state" of a cell requires knowing the phosphorylation state of its proteins. For example, if amino acid Serine-473 ("S473") in the protein AKT is phosphorylated, AKT is, in general, functionally active as a kinase. If not, it is an inactive kinase. (For explanation of Akt - see previous entry).
Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is the most common, followed by threonine. Tyrosine phosphorylation is relatively rare. However, since tyrosine phosphorylated proteins are relatively easy to purify using antibodies, tyrosine phosphorylation sites are relatively well understood.

Antibodies can be used as powerful tools to detect whether a protein is phosphorylated at a particular site. Antibodies bind to and detect phosphorylation-induced conformational changes in the protein. Such antibodies are called phospho-specific antibodies; hundreds of such antibodies are now available. They are becoming critical reagents both for basic research and for clinical diagnosis. Phosphorylation replaces neutral hydroxyl groups on serines, threonines, or tyrosines with negatively-charged phosphates. Thus, below pH 5.5, phosphates add a single negative charge; near pH 6.5, they add 1.5 negative charges; above pH 7.5, they add 2 negative charges. The relative amount of each isoform can also easily and rapidly be determined from staining intensity on 2D gels.

Having got that out of the way, let’s turn to a paper in this month’s Blood from Marta Muzio and colleagues from Federico Caligaris Cappio’s laboratory in Turin, entitled Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy.

There seems to be very good evidence that stimulation of the lymphocyte via the B-cell receptor (BCR) is very important in the pathogenesis of CLL. That stimulation triggers the phosphorylation of syk which then passes the phosphate parcel down a number of possible pathways. One of the difficulties in understanding all this is the stange names given to these enzymes. Syk stands for spleen tyrosine kinase, Y being the single letter symbol for the amino acid Tyrosine that is used by biochemists. When you come across these acronyms it is worth Googling them to find out what they stand for.

Five or six years ago we showed that only about 50% of CLLs would respond to BCR stimulation by phosphorylating syk. We expected that these would be the ones with unmutated VH genes, but although there was an association it was by no means precise. Fecerico Caligaris Cappio has always had the idea that CLL cells were anergic cells, unable to react to normal stimuli beause their signaling mechanism has been dulled by constant low grade stimulation by autoantigens – it is one of the mechanisms that stops us from continually attacking our own tissue.

In mice anergic B cells have a characteristic molecular signature, showing constitutive expression (ie switched on all the time) of tyrosine phosphorylation with activation of the MAPK ERK that cannot be further induced after BCR stimulation.

(Explanation: MAPK, mitogen activated protein kinase. First named MAP kinase in 1988, but from one of its specific substrates: microtubule associated protein (MAP-2). By 1989, it was realized that this was the same as the 42 kDa protein, phosphorylated by mitogen stimulation, known since 1981, and so it was retro-acronymically renamed mitogen activated protein kinase. When the protein was cloned in 1990 it was named, not MAPK, but ERK1 for extracellular-signal regulated kinase, a somewhat uninspired choice. MAPK is now more commonly used for the superfamily of related kinases of which the ERK family is one.)

Muzio et al in this paper show that the cells from CLL patients who are unable to respond to BCR stimulation also have constitutive phosphorylation of ERK without evidence of Akt phosphorylation. The only anomaly in this paper is that there seems to be no correlation with prognostic factors.

Thus this paper is added evidence to support Federico’s long held hypothesis.

What does AKT mean?

In a previous entry about CD30 I mentioned the enzyme Akt without defining what it meant. To tell the truth I didn’t know and I have spent some time searching for it. Finding out what these abbreviations stand for is quite a task, since everybody assumes that everybody knows, and nobody dares ask for fear of feeling foolish.

Most of these enzymes with a ‘k’ in then are kinases, so that seems to be a start, especially since it appears that Akt is the same as Protein kinase B (or PKB). But actually that seems to be a dead end. I got back as far as 1993 when it was still known as Akt/PKB but no indication as to what it stood for. I thought perhaps it might be A Kinase for Tyrosine, but Tyrosine is usually represented by a ‘Y’ in biochemistry-speak.

Then I thought about the AKR mouse, a white mouse much used in laboratories because of the ease with which it develops leukemia. Looking up the mouse gave me the answer.

The site I found is well worth preserving because the author clearly has a fascination for sorting out these enzyme names. Here is an abridgement of what he says:

The K was not a kinase, but arrived in 1928 from a strain of mouse, the mouse A came from a Pennsylvania pet shop, and the T arrived 50 years later from the Thymus.

AKT was isolated from the AKR/J mouse, the Jackson Laboratory strain bred for a high degree of leukemia by Jacob Furth at the Cornell Medical School. The Jackson Laboratory says, “AKR Albino. Origin: a dealer named Detwiler in Norristown, PA. Carried by Firth as a high leukemia strain from 1928-36, then random bred at Rockefeller Inst. For several generations b x s by Mrs Rhoades to F9 then C. Lynch to F21.

Furth’s own account goes like this: …began interbreeding three stocks of mice; two obtained from a commercial breeder were ‘A’ and ‘S’. ‘A’ mice were purchased from a dealer in Pennsylvania who was the supplier to the long defunct cancer research laboratory (supported by the DuPont family) where I learned that leukemia did occur in the ‘A’ stock, albeit infrequently. … ‘A’ eventually yielded the AKR strain.

He goes on to point out that it was really an Akr mouse because the ‘k’ and the ‘r’ were sublines. So we can imagine that ‘k’ is just the twelfth subline that he produced and ‘r’ the nineteenth. The T seems to have arrived in 1977 when AKT was isolated from a thymoma cell line AKT-8 from a spontaneously lymphomatous AKR/J mouse.

Elections

David Davis was heading to be the next Minister for Home Affairs when the Tories get back into power next year, yet he threw it all up to fight an unnecessary by-election last week. He was protesting against the Government's desire to hold terror suspects for 42 days without charge. The civil libertarians all supported him. That he romped home with an increased majority was no surprise, especially since the Liberal Democrats (who agree with him) did not field a candidate and the Labor party (who knew they would lose heavily) didn't either. There were 25 other candidates of whom only two received more than 5% of the vote, those from the Green Party, and the English Democrats (a new party that is opposed to their being too many Scots in the Cabinet). You have to put up a cash deposit in order to stand, and the other 23 candidates lost theirs. What amazed me was how few friends people have. Two of the candidates only garnered 8 votes each. Since most people have that number of family members eligible to vote, it suggests that they need to get out there and do some networking.

Making the best of it

Forty-six years ago this October I watched my parents and my girl-friend drive away in their black Ford Consul leaving me alone on the steps of my new lodgings in Bristol. I was afraid, lonely, friendless and abandoned. I wanted to be back home with my family, sleeping in my own bed with familiar things around me. In this new place everyone spoke with a strange accent and I wasn’t sure that I understood them. I was offered food that I had never had before and I didn’t like it. In my lodgings people lived differently; they had customs and traditions that I was a stranger to and I was apprehensive, afraid of making a mistake. No-one in my family had ever been to university before, and I had no idea how I was supposed to behave, how I was to study, whom I should look out for and whom I should be wary of. The weather was something I was unaccustomed to; it seemed never to stop raining. At least I was sure of one thing: I could go home at Christmas.

In 598 BC the Jews who were exiled to Babylon had no such reassurance. They had been taken to a strange land; they didn’t speak the language; they didn’t like the food; the Babylonians were boorish; the schools were no good; they couldn’t find a church to worship in; the weather was too hot; their complaints kept coming.

It’s strange how every calamity is a business opportunity. Even with the current economic slowdown some people are coining it: bankruptcy lawyers, for example. In the sixth century BC, three chaps, Ahab, Zedikiah and Shemiah, found they could make a good living selling nostalgia. Don’t worry, they said, God hasn’t abandoned us. He will soon take us home. This is only going to last a short while. Don’t build houses; live in tents, there is no point in putting down roots. Don’t bother with marriage and having children, you’ll be back home before they are grown and babies will be a burden on the journey. Have a few ‘temporary liaisons’.

In response to this Jeremiah, back in Jerusalem, wrote a letter to the exiles in 594BC. He tells them, “Build houses and live in them; plant gardens and eat their produce. Take wives and have sons and daughters. Seek the welfare of the city. Pray to the LORD on its behalf. Don’t listen to these false prophets.”

In other words you are in it for the duration, better get used to it. Don’t sit and pine for Jerusalem. If you do you will live lives of squalid failure. Instead make the best of your situation. In fact, the exile became the ‘crucible of Israel’s faith’ as JA Sanders in the Interpreter’s Dictionary of the Bible puts it. Not only did they renew their relationship with God there, but they were exposed to all the amazing knowledge of the Babylonian Empire. The Library of Babylon was even larger than the Library at Alexandria. Jewish men like Daniel, Mordecai and Nehemiah rose to positions of influence in the Empire and King Nebuchadnezzar himself was converted to believing in the Living God.

Jeremiah’s letter promises that God will restore them to Jerusalem but not yet. They had to spend 70 years in exile and they had better get used to it. God had plans for them, plans to prosper them and not to harm them, plans to give them hope and a future.

How was this to be achieved? You will call upon me and come and pray to me, and I will listen to you. You will seek me and find me when you seek me with all your heart. I will be found by you, declares the LORD.

The first time I heard David Pawson preach, this was his text. Note that it does not say “When you seek me with all your heart you will find me.” The initiative is God’s not ours. “I will be found by you,” he says. He is in control.

We are often nostalgia freaks ourselves. We remember when things were better. ‘If only we could go back to the old hymn book.’ ‘We don’t hear preaching like we used to.’ ‘They don’t seem to do things decently and in order like they used to.’ As a result we find ourselves well prepared to face the problems of the nineteen fifties. We must live in the here and now. We don’t have to become Babylonians, but we must be in the world to win the world. ‘I have plans for you, plans to prosper you and not to harm you.’ The promise is still true.

Not only that, it is at times of adversity when people are likely to turn to God. The privations of the Exile brought the Jews into a renewed relationship with God. Nebuchadnezzar was saved out of madness. The credit crunch is exposing the shallowness of the things people rely on. You money was in your beautiful house with its panelled walls? Real estate is plummeting; it is a pocket full of holes. I have my investments? The market is plunging. You feel safe because at least you have a job? I’m sorry, but we’re letting you go. At least I have my health. I have seen too many suddenly struck down to rely on that. They are always coming up with new treatments. But they are so expensive that the NHS won’t pay, Medicare won’t pay and your insurance company won’t pay.

When you seek him with all your heart, He will be found by you.

The love of God

The love of God is greater far
Than tongue or pen can ever tell;
It goes beyond the highest star,
And reaches to the lowest hell;
The guilty pair, bowed down with care,
God gave His Son to win;
His erring child He reconciled,
And pardoned from his sin.

Refrain
O love of God, how rich and pure!
How measureless and strong!
It shall forevermore endure
The saints’ and angels’ song.

When years of time shall pass away,
And earthly thrones and kingdoms fall,
When men, who here refuse to pray,
On rocks and hills and mountains call,
God’s love so sure, shall still endure,
All measureless and strong;
Redeeming grace to Adam’s race—
The saints’ and angels’ song.

Refrain

Could we with ink the ocean fill,
And were the skies of parchment made,
Were every stalk on earth a quill,
And every man a scribe by trade,
To write the love of God above,
Would drain the ocean dry.
Nor could the scroll contain the whole,
Though stretched from sky to sky.

Refrain

My late mother-in-law was a fine singer in her youth and this was her favorite song. There are many songs about the love of God, most notably the one sung at President Reagan’s funeral or perhaps the Stuart Townend hymn, “How great the Father’s love for us”, but this one always comes to my mind.

The third verse of this song is based on the Jewish poem “Haddamut”. It was written in 1050 AD by a Jewish Cantor from Worms named Meir Ben Isaac Nehorai, and translated into English by Frederick Lehman, who was born in Germany in 1868, and died in 1953, in Pasadena, California. Lehman moved to America with his family at the age of four and settled in Iowa, where he lived most of his childhood. He attended Northwestern College in Naperville, Illinois while preparing to enter the ministry. He pastored Nazarene churches in Kingsley and Audubon, Iowa; New London, Indiana; and Kansas City, Missouri. He devoted most of his life to writing sacred songs; the first being written in 1898. He compiled five hymnals, authored and published numerous sacred songs, and established Nazarene Publishing House in Kansas City, Missouri.

He wrote The Love of God in 1917. It was published in Songs That Are Different, Volume 2, in 1919. In 1948 Lehman described how he came to write this hymn: One day, during short intervals of inattention to our work, I picked up a scrap of paper and wrote the first two stanzas and chorus of the song. This was written with a stub pencil while I was seated on an empty lemon box pushed against the wall. I adopted the third stanza from a Jewish poem, Haddamut, which was found on the wall of a patient's room in an insane asylum after he had been carried to his grave. The general opinion was that this inmate had written the epic in moments of sanity.

The words were quoted during our church holiday which took the benediction of 2 Corinthians 13:14 as its theme. The session on grace I have already alluded to. On Saturday evening we considered the love of God. Paul’s prayer in Ephesians chapter 3 expresses the incomprehensible nature of God’s love for us.

I pray that out of his glorious riches he may strengthen you with power through his Spirit in your inner being, so that Christ may dwell in your hearts through faith. And I pray that you, being rooted and established in love, may have power, together with all the saints, to grasp how wide and long and high and deep is the love of Christ, and to know this love that surpasses knowledge—that you may be filled to the measure of all the fullness of God.

‘So high you can’t get over it, so deep you can’t get under it, so wide you can’t get round it’ sing the children, but we somehow start thinking that my sins make me unreachable. I remember speaking to a dying man about the only hope he had; the hope of salvation in Jesus. “I have made my bed. I will have to lie on it,” he replied.

It isn't true. God's love is overwhelming. No sin is irredeemable be it ever so despicable. His love is the remedy for every ill save a stiff neck. His will can overcome everything but, "I won't!"

Consider the case of Max Moseley, the President of FIA, the motor racing organization. This old man was recently exposed by a Sunday Newspaper for taking part in sado-masochistic orgies. He admitted in court that he had been doing so for decades. Is this man beyond the reach of the love of God? How about Pete Doherty, boyfriend of Kate Moss, now more famous for his drug addiction than his career as a pop singer? Think about Robert Mugabe, rigger of elections, torturer of his own people. Could Adolf Hitler have repented? Or Pol Pot or Joseph Stalin? Are we sure that they did not? Are child pornographers beyond the reach of the love of God? Are pedophiles?

It disgusts us to think that our father God could look at one of these and see only the beauty of His son, Jesus, but that is what the Bible teaches us. Because we have an inflated view of our own virtue with think that God loves us and not them. As Paul says in Romans Ch 3: “What shall we conclude then? Are we any better? Not at all! As it is written ‘There is no-one righteous, not even one; there is no-one who understands, no-one who seeks God. All have turned away; they have together become worthless; there is no-one who does good, not even one.’”

This passage comes immediately after what most Christians believe is Paul's diatribe against homosexuals. It is true that Paul describes homosexual acts as the punishment that men and women receive in their bodies for their wilful failure to recognize God as their Creator and Lord, but he goes on to say, "Furthermore...he gave them over to a depraved mind to do what ought not to be done. They (that is the idolaters who worship the creature rather than the creator - not they = homosexuals) have become filled with every kind of wickedness, evil, greed and depravity. They are full of envy, murder, strife, deceit and malice. They are gossips, slanderers, God-haters, insolent, arrogant and boastful; they invent ways of doing evil; they disobey their parents; they are senseless, faithless, heartless, ruthless." While we are gloating over this strong condemnation of homosexuals he comes straight back at us, "You, therefore, have no excuse, you who pass judgment on someone else, for at whatever point you judge the other, you are condemning yourself, because you who pass judgment do the same things."

When we realize our own filthy rags, it amazes us that anyone should love us, let alone a God so majestic, so holy and so perfect. Why would he sully his hands with us let alone give up his one and only son to torture and death? You can perhaps imagine someone so in love with a woman that he sacrifices his home, his career and his family to possess her; but our God does not wish to possess us, he wishes that we possess Him. I will write another time of the bonds that bind Father to Son, but here I will say just imagine the Godhead torn apart. They, who were together from all eternity, were wrenched asunder so that the Son should literally suffer Hell; the absence of God. But God demonstrates his own love for us in this: while we were still sinners, Christ died for us.

How deep the Father's love for us,
How vast beyond all measure
That He should give His only Son
To make a wretch His treasure

How great the pain of searing loss,
The Father turns His face away
As wounds which mar the chosen One,
Bring many sons to glory

Behold the Man upon a cross,
My sin upon His shoulders
Ashamed I hear my mocking voice,
Call out among the scoffers

It was my sin that held Him there
Until it was accomplished
His dying breath has brought me life
I know that it is finished

I will not boast in anything
No gifts, no power, no wisdom
But I will boast in Jesus Christ
His death and resurrection

Why should I gain from His reward?
I cannot give an answer
But this I know with all my heart
His wounds have paid my ransom

Anglicans and homosexuality

The Most Revd AET Harper, OBE, Anglican Archbishop of Armagh and Primate of All Ireland has delivered an address to the USPG Conference, Swanwick on the topic of "HOLY SCRIPTURE AND THE LAW OF GOD IN CONTEMPORARY ANGLICANISM IN THE LIGHT OF RICHARD HOOKER’S LAWES”. It can be accessed here.

This may seem a strange thing for me to write about, but his talk addresses one of the issues of contemporary Christianity.

Hooker was appointed Master of the Temple in 1585, supplanting his cousin by marriage Walter Travers, who had exercised a very influential “readership” or “lectureship” there, obtained for him by his patron Lord Burghley in 1581. Travers was ousted on the advice of Archbishop Whitgift who considered him too much of a Calvinist for his taste and saw that he threatened Anglican Episcopy with his radical views. Harper considers that Hooker's “The Lawes of Ecclesiastical Polity” to provide the intellectual basis of Anglicanism; far more so than Cranmer's Book of Common Prayer. Hooker makes crucial distinctions between the whole body of scripture and what he identified as "the Law of God".

Hooker was engaged on issues to do with the form and governance of the Church and the sources of authority for that form and governance. Those who advocated a Presbyterian system claimed, in essence, that such a system was the only one consonant with scripture and church government in primitive Christianity. They also pleaded that the only authority that might be referred to or relied upon was Holy Scripture. Hooker’s defence of the polity of the Church of England, as it had emerged under Elizabeth I, was that it could be entirely reconciled with the evidence of scripture as we have it, taking account of legitimate developments of tradition and the appropriate application of human reason. It is this three-fold cord of Scripture, Tradition and Reason that provided the essential components of the Anglican method.

Here is how Hooker puts it:

Two opinions therefore there are concerning sufficiency of holy Scripture, each extremely opposite unto the other, and both repugnant unto truth. The Schools of Rome teach scripture to be so insufficient, as if, except traditions were added, it did not contain all revealed and supernatural truth, which absolutely is necessary for the children of men in this life to know that they may in the next be saved. Others justly condemning this opinion grow likewise unto a dangerous extremity, as if scripture did not only contain all things in that kind necessary, but all things simply, and in such sort that to do anything according to any other law were not only unnecessary, but even opposite unto salvation, unlawful and sinful. Whatsoever is spoken of God otherwise than as the truth is; though it seem an honour, it is an injury. And as incredible praises given unto men do often abate and impair the credit of their deserved commendation; so we must likewise take great heed, lest in attributing to Scripture more than it can have, the incredibility of that do cause even those things which indeed it has most abundantly to be less reverently esteemed .

I'm sorry for the Elizabethan phraseology which does make what he says indistinct to the modern ear, but his plain message is this: parts of the Bible are the Law of God other parts are simply narrative, descriptions tied to time and place, without the authority of law. Now apart from the difficulty of distinguishing one from the other, I wonder from where he derives his authority to say so, for does not Paul writing to Timothy say, "All Scripture is God-breathed and is useful for teaching, rebuking, correcting and training in righteousness." (2 Timothy 3:16) and does not Peter in his second letter say, "just as our dear brother Paul also wrote you with the wisdom that God gave him. He writes the same way in all his letters, speaking in them of these matters. His letters contain some things that are hard to understand, which ignorant and unstable people distort, as they do the other Scriptures, to their own destruction." (2 Peter 3:16), insisting that Paul's letter should be treated as Scripture?

Archbishop Harper draws this conclusion from Hooker's writings: Hooker makes an important distinction between material in Holy Scripture that can be determined as being the direct oracles of God and that which may be, or may have been, derived from what he calls “by-speeches in some historical narration or other.” Hooker specifically criticizes the use of such “by-speeches” by those who “urge them as if they were written in the most exact form of law.” He goes on, “What is to add to the Law of God if this is not?” Therefore, in seeking to identify those scriptural elements that possess universal application as the Law of God it is necessary to exclude all that may be accounted “by-speeches” associated with some form of mere narration and to refrain from interpreting them in any sense as “the most exact form of law.”

He continues: Self evidently, to distinguish between direct oracles and “by-speeches” requires the application of reason to the study of scripture. Reason cannot be excluded from the appropriation of the word of God in scripture. Indeed, Paul himself, as well as the Fathers, applied reason to the interpretation of scripture. In Paul’s case it was the interpretation of Old Testament scripture. In the case of the Fathers it was both Old Testament and the New. This being the case, it is inappropriate to exclude the application of reason to the writings of Paul, especially in respect of those sections in which Paul specifically exercises his own faculty of reason.

Of course, those who insist that Paul wrote his letters under the inspiration of the Holy Spirit, and that the Holy Spirit miraculously preserved only those letters which would become part of Scripture and that the Councils that decided which documents would be included within the Canon of Scripture and which would be excluded were guided by the Holy Spirit; all those who insist on these things are to be dismissed as what? Fantasists?

Harper continues: To what extent, then, may it be possible to say that the Patriarchs, the Prophets and witnesses such as St Paul may from time to time be mistaken? Not, surely, when they are declaring the oracles of God conformable with the Gospel of Christ; but, perhaps, where it may be said that they are defective in fact or in reasoned extrapolation, deduction or assertion based upon false premises. Such are tests we need to apply in all cases of scriptural interpretation as it may be applied to faith, truth, morality, and the Law of God.

He goes on to apply this reasoning to the current debate on homosexual acts. He draws attention to Romans 1:18-27, a crucial passage. I won't take space by writing it down here; I take it that any reader who has reached this far will own a Bible, or be able to find the text on the Internet.

His first and correct observation is that the passage deals with the denial or suppression of truth. It is clear from looking at nature that there must be a creator and rather than worship this creator men worship the creature - "images made to look like mortal man and birds and animals and reptiles."

As a consequence "The wrath of God is being revealed." Punishment, therefore is visited by God on those who are complicit in the suppression of the truth and that punishment is that they are given over by God “in the sinful desires of their hearts to sexual impurity for the degrading of their bodies with one another.”(v24) “Shameful lusts” (v26), therefore, are the punishment of God visited upon those who “exchanged the truth about God for a lie.”(v25)

Those shameful lusts are identified as acts of homosexual intercourse. "Even their women exchanged natural relations for unnatural ones. In the same way the men also abandoned natural relations with women and were inflamed with lust for one another. Men committed indecent acts with other men, and received in themselves the due penalty for their perversion." (vv26-27)

So far so orthodox, but after this Harper follows a more shadowy path. According to him we are wrong to think that such acts were degrading in themselves it is because they are 'unnatural'. He lays emphasis on the fact that these women's natural sexual orientation was towards men, and it is the reorientation towards other women that is the shameful lust or degrading passion. Similarly, the men abandoned natural relations with women and were inflamed with lust for other men. The obvious and astonishing conclusion being that if the natural orientation of these individuals was homosexual then their punishment would be to be inflamed with heterosexual desires, and therefore those who were once homosexual and have become heterosexual are just playing out their shameful lusts.

In Harper's opinion, Paul’s assumptions about what is “natural” and what “unnatural” are based upon the knowledge and understandings of the time, relying to a degree on the presuppositions of the Old Testament. If, on the basis of additional knowledge and the application of human reason, such assumptions and presuppositions are shown to be inadequate it will become an absolute requirement to re-visit the definition of what in this area may be described as “natural” and “unnatural”.

Harper concludes: Thus, in the case of the passage under discussion, the essentially narrative character of the account rendered by Paul, dealing with a particular situation involving what Paul interprets as the deliberate punishment of God on persons who defy and renounce the truth about Him, and featuring the application of reason and the contemporary knowledge of the time to the activities of persons who appear radically and wilfully to have changed their normal sexual orientation to embrace an orientation that was not originally normal for them, it cannot be held that what is unquestionably Holy Scripture is also a declaration of the Law of God. The only aspect that can be placed in the category of “Law” is the requirement to recognize the truth about God and not to exchange such acknowledgment of truth and the worship that goes with it, for the lie that anything other than the God revealed in scripture and through the created order is worthy of recognition and worship.

Romans 1, therefore, provides no declaration of the Law of God in respect of homosexuality and homosexual acts. Reference to such acts is what Hooker might call “by-speeches” in the context of an historical narrative and, as such, not a declaration of God’s Law. Furthermore, Paul, in his treatment of the issues, employs reason based upon the knowledge and presuppositions accessible to him in his day. These may be challenged if the knowledge base changes definitively. It is therefore inappropriate on the basis of Romans 1.18-17 and following to judge or anathematize persons on the basis of sexual orientation. It will be necessary to scrutinize other sections of scripture in a similar way to discover whether elsewhere there may be established evidence of the Law of God in this matter and I have not attempted to do that in this essay. I remain committed to the view, however, that the tools of analysis which Hooker articulated are essential to our contemporary purpose and are especially relevant for the purpose of distilling the Law of God from the total corpus of Holy Scripture.

Finally, let us be clear on this: it has not yet been conclusively shown that for some males and some females homosexuality and homosexual acts are natural rather than unnatural. If such comes to be shown, it will be necessary to acknowledge the full implications of that new aspect of the truth, and that insight applied to establish and acknowledge what may be a new status for homosexual relationships within the life of the Church.

Appealing to 'nature' carries no weight with me. Can Harper be unaware of the extent to which Paul was familiar with the natural world? Anyone who has been in the close proximity of animals is aware that some cows attempt to mount other cows and male animals are remarkably undiscerning over what they attempt to have sex with. Nature is no judge of morality. What if some future scientist decided that there was a gay gene? I have discovered that my nature is to lie, to cheat, to be promiscuous, to steal, seek vengeance, to throw my weight about, to bully, to gossip, to boast, in fact to do all manner of evil. Our natural selves are what we need saving from. The Bible tells us about Jesus; it is our primary source. You can't get there by either reason or tradition.

CD38 polymorphisms

Why are we all so different? The plain answer is genetic polymorphisms. Perhaps the best known example is sickle cell anemia. Most people have hemoglobin A, but an unlucky few have a polymorphism at position 6 of the beta chain of hemoglobin so that what would normally be a glutamic acid is replaced by a different amino acid, valine. The effect of this is that under certain stressful conditions, the hemoglobin molecules line up as needle like crystals that distort the shape of the red cells so that they can't get through the narrow holes in the blood vessels and therefore cause ischemia in organs supplied by those blood vessels.

But sickle cell anemia is just the most severe of hundreds of polymorphisms of the hemoglobin molecule. Some cause anemia but many are entirely asymptomatic and people have no idea that they have them. So it is for just about every molecule in the body, but together they determine our every physical characteristic.

I have written about CD38 several times before. CD38 also has a polymorphism characterised by a C>G variation in the regulatory region of intron 1. A study from the excellent group in Turin, Italy has studies 248 patients with CLL, but find that this polymorphism is no commoner in patients than in controls. However, those with the polymorphism were more likely to have bad prognostic markers, more likely to have enlarged lymph nodes and spleen, and in particular, more likely to develop Richter's syndrome.

Prayer - grace makes the difference.

Atheists believe that everything came from nothing, that there is no plan or formulation, no intelligence behind the universe; no creator and no God. Deists are practical atheists. There must have been a first cause, they say, but that creator 'God' just wound up the world and let it go like a clockwork toy that keeps on running until the spring winds down. This 'God' takes no concern with how things work out and obviously there is no point in praying to him.

Christians believe that not only is there a God who made the universe, but this God is concerned with the day to day happenings of our world. Moreover, his concern is not just about the great issues of the day - the outcome of the Iraq war or whether or not the hungry of Africa are fed - but also with the minutest detail of our lives. A God who counts our hairs and watches over sparrows is a God who cares.

But... You see it all sounds so illogical, so unbelievable; when you see the detail involved and the huge canvas on which it is painted, how could anyone care what happens in every particular corner?

It's more incredible than that. This weekend I have been at our Church house party and illustration from Chris Kelly brought it home to me just how unreasonable it all is.

Imagine this: in 1999 Tony Blair was the first serving British Prime Minister to father a child for more than 150 years (Lord John Russell had been the last). 10 Downing Street has a pleasingly central location but has never been thought of a nice place to live. The house had been built on fetid, swampy ground, and where there's a swamp there are rats.

There is this saying that wherever you are in Britain you are never more than 20 feet away from a rat - and this is absolutely nothing to do with the occupant of number 11 Downing Street who at the time was Gordon Brown. (In fact at the time because of the relative sizes of their families and the relative size of the apartments, the Blair family lived at number 11 and Brown at number 10. In fact, the saying about how close we live to rats is an urban legend, completely untrue and based on the estimate from 1900 that there were 40 million rats in Britain and 40 million people.

Nevertheless, imagine that one of these rats from the Downing Street sewers managed to climb up the waste pipe and emerge from the toilet bowl in the Blairs' bathroom. This filthy brown rat, smelling of excrement and covered in fleas, makes its way furtively across the Blairs' carpet. Lurking in the shadows as it invades the bedroom, it espies newborn baby Leo's cot. Sniffing the air, it creeps menacingly across the room to the cradle where the baby is sleeping peacefully. There is no-one to disturb it as it jumps up on the crib.

The rat has long, narrow teeth housed in strong jaws which enable it to devour carrion rotting in the sewers. Its dank, malodorous breath stems from its saliva which is a breeding ground for bacteria. The rat's urine, which is continually shed to mark its territory, contains the bacterium Leptospira ictero-haemorrhagiae which is lethal to humans if it not treated soon enough, causing jaundice and internal bleeding.

The fingers and toes of the newborn human are soft and pliable. The bones are cartilaginous and have not yet calcified and will easily come apart. As the rat bites into the baby's toes it is no great feat for him to take them whole. The fingers too provide a small meal for the dirty creature. The baby cries, but Cherie, the experienced mother, knows that you mustn't respond to the baby's first whimper - that way lie endless disturbed nights. But the crying is persistent and becomes screaming and the infant yelps with pain and the blood streams from his gnawed hands and feet. Cherie feels she must go and comfort the child. As she approaches the cot she sees this black, hairy, foul-smelling creature clasped to the neck of he baby. She screams and in rushes a security guard who snatches the animal from the child's neck. Cherie picks up the child and holds him to her breast, but the blood is flowing and won't stop. An ambulance is called; St Thomas' Hospital is the closest. The infant human contains about the same volume of blood as a rabbit; that is to say about 200 cc, less than half a pint. When the ambulance arrives at the emergency room they set up a drip - no easy task on an infant. A tiny tube is inserted into his trachea. Oxygen is started. But he does not move. His eyes have glazed over; his pupils are dilated. The doctors gently compress his chest. The paddles are applied, the electric pulse administered. All to no avail; the child is dead.

Back in 10 Downing Street the security guard holds the distressed animal at arms length with thick, blue rubber gloves awaiting Tony Blair's decision as to what should become of the beast. Will it receive two shots from a soldier's machine gun? Just as we are used to seeing on our televisions as the SAS dispose of a terrorist. Surely that would be too quick and too easy for such a villain. Perhaps it would be beaten with staves until it was a pulp. Perhaps it would be thrown on the fire to be burnt alive. Perhaps the Blairs' other children would be invited to stab it repeatedly while it was pinned down until life was forced out of it. But when Tony Blair returns from the hospital, a cage is produced and the animal is dispatched to the veterinarian.

To be painlessly put down? Well, no, the vet has instructions to clean the animal up, to de-flea it, to treat it with antibiotics and then to groom it and pamper it. For, you see, the Blairs intend to take it into their family. They intend to adopt it, not as a family pet, but to look after it as if it were the son they had lost. It will sleep in the baby's crib, be fed on the baby's food, be pampered as if it were a son.

Fantastic, you say? Of course, it is just a fantasy, but it illustrates what God has done for us. You see, at just the right time, when we were powerless, Christ died for the ungodly. Very rarely will anyone die for a righteous man, though for a good man someone might possibly risk death. But God demonstrates his own love for us in this: while we were still sinners Christ died for us.

There was no goodness in us that would attract him. He did not die for us because we were better than the others or even because we were the best of a bad bunch. All our righteousness was as filthy rags. We had made no movement towards him; we were rebels, we were enemies of God. It is all, all of grace and nothing of ourselves.

We pray because we have been adopted as sons; rats though we were. He loves to listen to our prayers because He regards us as sons. We pray because we would be unnatural children if we refused to speak to our father.

More from EHA on CLL

At the recent EHA meeting at Copenhagen, Michael Hallek reported on current therapeutic options for CLL. He emphasised that most patients entering clinical trials are younger than 65, and therefore the treatments recommended following these trials may not be valid for older patients. Of particular interest was the German CLL5 trial which is unpublished, but which he reported in preliminary form. It compared fludarabine and chlorambucil. As expected there were more complete remissions with fludarabine and longer remissions, though this was not statistically significant, but when it came to overall survival the chlorambucil arm seemed to do better. However, there were 7 chances in a hundred that this result could have occurred by chance and normally we do not consider this to be statistically significant, requiring there to be fewer than 5 chances in 100. Nevertheless, this was sufficiently counter-intuitive to make the Germans look at the question more carefully. I would be interested in a meta-analysis on this point because the the British CLL4 trial was rather similar, and the Polish trial comparing chlorambucil and Cladribine apparently gives the same answer.

There were some other interesting observations from the German trials. Although fludarabine/cyclophosphamide generally seems to be better than fludarabine alone, especially for patients with del 11q and del 13q, this does not hold for patients with trisomy 12, where the reverse is true.

The other regimen that the Germans are interested in is FC+Campath for patients with del 17p or p53 abnormalities.

Finally just to make the point, in the recent American epidemiological study 72% of CLL patients were over-65.

Why this is the most unpopular Labor Government.

In 1997 Tony Blair won a landslide victory for 'New' Labor in the general election. His victory over John Major was built on accusations of dishonesty. Instances of Tory MPs taking cash from lobbyists for asking questions in Parliament and stays at luxury hotels paid for by foreign businessmen created an impression of Tory 'sleaze' while 28 'stealth' taxes were identified. In an attempt to raise money without raising the basic rate of income tax, alternative forms of taxation had been introduced, some of which were hidden from cursory examination.

Within weeks of his election Tony Blair accepted a gift of £1 million for party funds from Bernie Ecclestone, head of Formula One motor racing, apparently in order to absolve the adverts on racing cars in the anti-smoking legislation. At that time nothing stuck to Teflon Tony. As the years rolled by instances of bribery and corruption multiplied, the chief example being the 'cash for honors' scandal in which it appeared that Michael Levy, Tony Blair's tennis partner, Middle Eastern representative and chief fundraiser, was obtaining donations to the Labor party on the promise of knighthoods and peerages, an echo of Lloyd George's activities of an earlier era. It was this that finally got to an Iraq-wounded Tony and convinced his party that he had to go. They were confident in this because they thought that they had the perfect deputy waiting in the wings in Gordon Brown.

Brown has the reputation of not being around when scandal is about to break and appeared to be free of the tarnish of both Iraq and the cash for honors. So much so that he gained the nickname 'Macavity' from the TS Eliot poem. When you read the poem you find out just how appropriate it is. Here are a few lines...

You would know him if you saw him, for his eyes are sunken in.
His brow is deeply lined with thought, his head is highly doomed;
His coat is dusty from neglect, his whiskers are uncombed.
He sways his head from side to side, with movements like a snake;
And when you think he's half asleep, he's always wide awake.

He's outwardly respectable. (They say he cheats at cards.)

And when the Foreign Office finds a Treaty's gone astray,
Or the Admiralty lose some plans and drawings by the way,
There may be a scrap of paper in the hall or on the stair--
But it's useless of investigate--Macavity's not there!

Macavity, Macavity, there's no one like Mavavity,
There never was a Cat of such deceitfulness and suavity.
He always has an alibi, or one or two to spare:
And whatever time the deed took place--MACAVITY WASN'T THERE!

He built up a reputation of prudence and financial reliability while he was Finance Minister for 10 years, but having left the job his reputation is crumbling. It turns out that he has introduced 70 stealth taxes during that time and although inflation has been low during the past 10 years, it has become apparent that this was common to all the Western economies because of imported deflation from China. Apart from the silly decision to sell our gold reserves at the bottom of the market and the decision to free the Bank of England from government control, it is hard to think of anything he has done that has influenced the economy during that ten years.

His last act as Finance Minister, was a political one. In an attempt to rival the Tories by appearing as a tax cutting Chancellor, he cut the basic tax rate to 20%, paying for it by abolishing the intermediate 10% rate for the lowest paid. His successor was left with the awkward responsibility of explaining why 5.3 million people were worse off. His attempt to remedy this cost £2.7 billion and still left the 0.9 million poorest worse off.

The wheels are coming off Brown's reputation for competence. Lots of documents have gone missing, not because spies have stolen them, but because of slackness in the administration. Of course, he has been hit by the credit crunch but that wasn't responsible for a 12% growth in the money supply in the past 12 months. His presentational skills are non-existent and his habit of 'not being there' has rebounded on him, most notably when he failed to appear for the signing of the Lisbon treaty. He didn't have the face to show up when he had promised a referendum and failed to deliver. His non-appearance did not fool the electorate and annoyed the Europeans.

Meanwhile more instances of sleaze began appearing. Several ministers have had to resign over either sexual or financial irregularities and several of his MPs have had bad publicity including 'Gorbals Mick', the Speaker of the House of Commons who accumulated £4000 in taxi fares for shopping trips by his wife paid for by the state. This was apparently acceptable because she was accompanied by an official. It turned out that the official was her cleaner who coincidentally received an 'honor' in the Queen's Birthday Honors List. (The Speaker is supposed to be neutral, but many have felt that this particular Speaker has difficulty in sheding his Old Labor upbringing.)

The latest scandal concerns MPs expenses. Because they have to have a residence both in London and their constituency, quite reasonably the state pays for a second home. However, this lends itself to abuse, especially as the expenses are either not audited or audited very generously. Many MPs have made a lot of money while staying within the letter but contravening the spirit of the law. This is not just a Labor issue, but while the few Tories who have had their snouts in the trough have been severely disciplined by David Cameron, the Labor MPs are blatant about preserving their perks. Last night given a free vote, they defeated a motion that would have curtailed these opportunities for fraud. The Times reports that 146 of the 172 who voted against the measure were Labor MPs. And Macavity? The Times reports that "The Prime Minister did not turn up to vote".

CLL latest news from EHA

I have just listened to a podcast by Jesper Jurlander from the recent EHA meeting from Copenhagen. Remember that he was the man who introduced ranitidine for enhancing the effect of vaccination. He also has discovered the CLLU1 gene as a prognostic factor. This talk looked at prognostic factors in a new and interesting way. He first quotes from our 2002 paper drawing attention to the influence of age on prognosis. We looked at a large number of stage A patients who had a median survival of 15 years. However, if you ignored those patients who died from 'natural causes' the median survival was 24 years. At the age that most patients with CLL present, death from natural causes is increasingly common. Indeed in our study 40% of those who died, died from causes completely unrelated to their CLL.

The other interesting facts that he drew out were that CLLU1, despite being a very useful prognostic factor, didn't work at all for patients over 70. And he had an early report of the German fludarabine versus chlorambucil trial for over 65 year-olds. (Incidentally this report is misrepresented on the commercial report from ASH as showing an advantage for fludarabine). Interestingly there was no difference in progression-free survival and in terms of overall survival although there was no significant difference, there was a suggestion that the chlorambucil arm was doing rather better early on in the follow-up.

His final slide was to suggest a management strategy dependent on age. For older patients with good prognostic markers, 'watch and wait' is the strategy, with the likelihood that no treatment will be necessary, but if it is chlorambucil should suffice. Younger patients with good markers get 'watch and worry', and if they need treatment, probably FCR is first line. Younger patients with bad risk markers should be in trials looking at early treatment aiming at disease eradication with FCR followed by Campath or transplant. For older patients with bad markers the outlook is grim.

This approach is not encouraged by the recent CALGB 10101 trial of Campath consolidation following FR induction. Consolidation therapy with SC alemtuzumab (30 mg 3 times per week for 6 weeks) was started 3 months following induction treatment in patients with stable/responsive disease following induction. Six deaths were seen in patients most of whom were in CR. Five fatal infections were reported as follows: viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus (CMV) infection and Pneumocystis jiroveci pneumonia (PCP), all in patients who achieved a complete response (CR) after induction therapy. In addition, a case of fatal EBV associated lymphoproliferative disorder was reported in a patient who achieved a partial response (PR) after induction therapy. Bayer Schering Pharma AG and Genzyme have subsequently been informed of an additional non-infection related fatality believed to be related to Transfusion Associated Graft Versus Host Disease (TAGVHD) in a patient who had received non-irradiated blood products. This was very different from the British experience of alemtuzumab and has reduced prospects for further studies of this type of consolidation.

The alternative approach - allograft - won't have been enhanced by the sad death of Harvey reported on the CLL Topics website.

Is CLL a lymphoma?

This is one of the most frequently asked questions by patients, and the answer is yes and no. It depends on what you understand by the word 'lymphoma'. At its simplest a lymphoma is simply a cancer of the lymph nodes. Lymphomas were among the most easily treated of all cancers; they respond well to radiotherapy or chemotherapy compared to other types of cancer. Therefore the specialty of medical oncology grew up treating mainly lymphomas. It has to be recognised, of course, that not all cancers in the lymph nodes are cancers of the lymph nodes. The lymph nodes act as filters for cancer cells being shed from other types of cancer and so are a common site for secondary cancers. Enlarged lymph nodes full of secondary cancer are commonly seen in breast cancer, melanoma, lung cancer, bowel cancer and many other types. Oncologists began by treating lymphomas, but now treat lots of other types of tumors. An oncologist may spend most of his time now treating breast cancer, bowel cancer and lung cancer with chemotherapy.

At the same time that oncologists were learning to treat lymphomas, hematologists were learning to treat leukemias. The strategy adopted by hematologists was twofold. For acute leukemias the idea was to bash the patient as hard as possible with chemotherapy so that the bone marrow was destroyed, and then strive to keep the patient alive until the normal bone marrow recovered. This worked quite well, producing longish remissions. For chronic leukemias, the idea was to give enough of a drug continuously to keep the white count under control while not damaging the bone marrow too much. Rather arbitrarily two drugs derived from mustard gas were chosen to do this: chlorambucil (or Leukeran) for CLL and busulphan (or Myleran)for CML. Busulphan is not much used for this purpose any more though it is used in bone marrow transplantation, but some doctors still use chlorambucil in this old fashioned way though modern clinical trials have shown us better ways of using it.

CLL has been claimed by both hematologists and oncologists as both a leukemia and a lymphoma and, of course, it is both, though this is just semantics, and it doesn't help to draw conclusions as to who should treat it by which category you put it in.

Lymphoma is not just one disease. For more than a century it has been divided into Hodgkin's disease and non-Hodgkin's lymphoma, though in truth this is a bit of a false distinction. However, there are lots of ways of sub-classifying it. At one time oncologists preferred the 'Working Formulation' which made things very easy. This described three types of non-Hodgkin's lymphoma: high grade (which was rare and included conditions like acute lymphoblastic leukemia and Burkitt's Lymphoma), intermediate grade (which included about half the rest) and low grade (which included the other half, and notably CLL).

Because this was very simple it became very popular, and among some oncologists still is. However, the pathologists rather than lumping the lymphomas together insisted on splitting them apart. Chief among them was Karl Lennert from Kiel University in Germany. His classification was very complicated but criticised on the grounds that the distinctions that he made were clinically unimportant. Also he had to contend with the Rappaport classification which talked about lymphocytic lymphoma and histiocytic lymphoma (previously lymphosarcoma and reticulosarcoma). This seemed to suggest that the intermediate grade lymphomas were really tumors of macrophages not lymphocytes. This was so clearly wrong in Lennert's eyes (and mine, for what its worth - I was a mere junior during all this) that there emerged not only a dispute between pathologists and oncologists, but also between Europeans and Americans.

It wasn't until the REAL classification (Revised European and American Lymphoma) Classification emerged that agreement was possible, and soon afterwards a new comprehensive WHO classification was approved. It was the recognition of specific immunological and chromosomal abnormalities that allowed this to happen. In the WHO classification there are 40 different types of Non-Hodgkin's lymphoma, and one of the types of Hodgkin's disease is also now recognised as a non-Hodgkin's lymphoma.

CLL is known as CLL/SLL according to this classification, the SLL standing for small lymphocytic lymphoma. This recognises that rarely SLL can be a totally lymph node-based disease without a leukemia, and that when CLL lymph nodes are examined they have exactly the same histological picture (and indeed immunology and chromosomes) as SLL.

The importance of this comes from how lymphomas are managed by oncologists. So as to know how to treat a lymphoma, an oncologist will stage a patient according to Ann Arbor staging. Stage I is when the lymphoma is confined to a single group of glands; stage 2 can have more glands involved, but they are confined to one side of the diaphragm (either above or below); stage III can be both sides of the diaphragm, but is confined to lymph nodes and stage 4 means the disease has spread outside the lymph nodes into other tissue such as liver or bone marrow. (For this sort of staging the spleen is regarded as a big lymph node below the diaphragm).

CLL therefore presents a problem. Stage 4 lymphoma requires immediate treatment, but since CLL virtually always involves the bone marrow even in the most benign cases, it would seem that nearly all CLLs need treating as soon as they are seen, because they are Ann Arbor stage 4. We know from clinical trials that this is not so and therefore Ann Arbor staging must not be used in CLL. Instead either Rai or Binet staging must be used.

Knowing more precisely about individual lymphomas has become necessary, and will be more so in the future as treatment are targeted to specific molecular mistakes. No oncologist would now make the mistake of treating mantle cell lymphoma in the same way as diffuse large B cell lymphoma, even though they are both intermediate grade lymphomas. Similarly follicular lymphoma and CLL are different tumors and must be managed differently. Alas, we still see CLL patients getting CVP-R even though it has never been tested in CLL and CVP has been shown decades ago to hold no advantage over chlorambucil except that it causes numb feet and fingers (if you call that an advantage - it does allow you to pick op hot plates without feeling pain.)

Interesting fact

The front of a violin is made of spruce and the back is made of maple. However did they arrive at that combination?

Splits and schisms

The decision of Senior Evangelical Anglicans to set up a 'church within a church' has been met with dire warnings from the Archbishop of Canterbury, but these are hardly likely to deter them. The FOCA grouping represents at least half of Anglicans worldwide, and in terms of what they believe, probably 80% of those who actually attend church.

More than 60 years ago Dr Martyn Lloyd Jones, the great Congregational leader appealed to evangelical Anglicans like John Stott to come out from among them and join evangelical non-conformists in a new grouping. Alas, they did not, and while at times the Church of England has had evangelical leaders like Donald Coggan and George Carey, and even today has real Bible believing scholars like Tom Wright among its bishops, too often we have had to suffer the leadership of liberal politicians like Runcie or the unworldly liberals like Ramsay and unworldly intellectuals like Rowan Williams.

Anglicanism has always been a broad church incorporating three groupings, evangelicals, liberals and catholics. The church hierarchy is dominated by liberal catholics, since they are appointed largely by politicians with little faith or none, who are influenced by academic distinction. There have been some very clever Archbishops, but not many wise ones. At present 1300 catholic priests are threatening to leave the Church of England over the possibility of women bishops which demonstrates that the liberals are beset on either side.

The evangelical dispute is portrayed as anti-gay, but that is not a true characterization. The appointment of a practising gay bishop in America is only the trigger of a long running dispute between conservatives and liberals over the basis of faith. Conservatives hold to the supremacy of Scripture. They are not fundamentalists who refuse to see that the Bible is written in various literary forms which need to be interpreted accordingly, but they will not depart from the plain meaning of Scripture as liberals do when it does not coincide with modern mores.

Gay people tend to justify themselves by saying that this is a hard-wired state that they have no control over. That may or may not be true, but what the Bible teaches about sex is that it is designed for marriage. I consider myself to be hard-wired to be attracted to pretty women. I do have control over whom I sleep with, however.

Just as we would not choose a serial adulterer to be our pastor neither would we choose anyone else who misuses sex. This is not a sex thing, it is a sin thing. We would not choose as our pastor a gossip, a thief, a wife-beater, a tax-cheat, or anyone else who fits the description in Romans chapter 1. There is always room for repentance, of course, and all sinners are welcome to our churches. We just don't ask unrepentant sinners to lead us.

I use the word 'pastor' rather than 'bishop' because the words are used interchangeably in the New Testament, which sees no hierarchy of church office. 'Bishop' (episcopos = overseer) is used interchangeably with 'presbyter' (which some say is where we get the world 'priest', but actually means elder) and with pastor (or shepherd). The New Testament does not recognise 'priest' in the Old Testament sense of someone who makes representations on behalf of the people to God. The Protestant reformers spoke about the 'priesthood of all believers'.

This is what Martin Luther said about it: That the pope or bishop anoints, makes tonsures, ordains, consecrates, or dresses differently from the laity, may make a hypocrite or an idolatrous oil-painted icon, but it in no way makes a Christian or spiritual human being. In fact, we are all consecrated priests through Baptism, as St. Peter in 1 Peter 2:9 says, "You are a royal priesthood and a priestly kingdom," and Revelation 5:10, "Through your blood you have made us into priests and kings." For an extensive discussion see this link.
Neither am I much impressed with the other priestly function of being able to conduct the Eucharist in a way that a lay-person could not. This derives from a supposed 'apostolic succession', that Roman Catholics deny belongs to Anglicans anyway. When St. Paul gives instructions for the taking of communion in 1 Corinthians ch 11, there is no mention of a special officer with magical powers to turn bread into flesh and wine into blood. This is a memorial meal (v24 'do this in remembrance of me'). He does, however, emphasise unity and the body life of the church.

One of the difficulties conservative Anglicans find in breaking away from their liberal colleagues is the ownership of church buildings. Although a recent decision of a court in Virginia has suggested that the resident church owns the building, not the distant diocese, this may not hold on appeal and in any case mistakes the church for the building. The church is the people. The building is just a convenience. My daughter visited a church based in a rented school hall last week. they were happy not to have the responsibility of a building to maintain. My own church is facing a large financial outgoing to repair or replace its building. The Church of England owns a huge number of old buildings that the nation sees at its own. They have the responsibility of repairs and upkeep of structures that are increasingly a burden rather than a blessing.

There are some fine buildings among them and no doubt they are peaceful places that aid meditation, but they are a mess of potage when it comes to our (new-)birthright. We worship a God who owns the cattle on a thousand hills and the gold in every mine. Let the heathens have their fine buildings, their colorful vestments, their delightful music, their pomp and show. We would rather have the truth.

1000 transplants

I spent yesterday at the celebration in London of the Kings College Hospital's one thousandth stem cell transplant. Although not rivalling Seattle, it is an stupendous achievement - remember that the population of America is 5 times greater than that of Britain. Such is the increasing popularity or transplantation that about half of those transplants have taken place in the past 5 years.

It was an interesting day during which we not only learned about the growing edge science with lectures and cancer stem cells, regulatory T cells, the GVL effect, and post-transplant immunotherapy, but also about the logistical problems of finding donors, and the organization of funding, commissioning services and monitoring outcomes. There were also two patients who detailed their experiences of transplants. One of them, a man without arms or legs because of a congenital abnormality, was a real comedian.

What interested me most was the talk on cord-blood transplants, by Vanderson Rocha from Paris, who did the first cord blood transplant. It is people from ethnic minorities who are likely to seek a cord transplant, since it is so difficult to find a match from donor panels. Those of mixed race make things particularly difficult. Although there are immense opportunities in cord blood, principally because you don't need a complete match for the graft to be successful, cord blood has its own specific difficulties. First there is the volume required - most cords don't have enough stem cells for an adult transplant. Interestingly the highest yields come from the longest labors; usually first births. Cesarean sections cut down on the yield. Because of this double cords have been used, but only one cord grows, the other provides accessory cells that help expand the other one. There is a high rate of graft failure - about 10%. Also the T cells that derive from the cord are naive - they have no immunity against common viruses such as CMV or adenovirus. A cord blood recipient could die from the common cold.

Although many units are keen to jump on the cord blood bandwagon, it remains an experimental treatment. A lot more work needs to be done before it can be regarded as routine.

For CLL patients transplantation remains a major risk. Such patients are already susceptible to the sorts of infections that cause the early transplant related mortality and become doubly vulnerable following a transplant. With reduced intensity commissioning, some tumors have a TRM of less than 10%; for CLL it remains stubbornly over 20% even in the best centers.