Lord Jim

I have spent the past three weeks reading Lord Jim by Joseph Conrad. About 40 years ago I saw the film that starred Peter O'Toole, James Mason, Jack Hawkins and Eli Wallach, but I couldn't remember the plot. I remember being powerfully struck by the presence of O'Toole - who is now appearing on television adverts as a wizened old man. O'Toole was then in his heyday with performances in Laurence of Arabia, Becket and The Lion in Winter. His piercing blue eyes and blond hair marked out Jim as someone special.

The story is a convoluted one, and Conrad's style, beautiful though it is, does not make the story flow. A page-turner this is not, and many readers get stuck and give up. So if you think of reading it, don't hurry. Take time to savor the prose. Don't worry that you can't work out what is going on - all will be revealed. The first third of the book is taken up by the great disaster that has befallen Jim, but it is some time before we realise what the disaster is. The book uses the literary device of having a narrator tell the story second-hand (and sometimes third-hand). This adds to the confusion since one story becomes nested inside another and sometimes it is difficult to work out who is speaking.

Eventually we discover that Jim had been Mate on a steamer taking 800 pilgrims from Malaya to Arabia. The ship hits an underwater obstruction and taken on water. With bulkheads bulging and too few lifeboats the crew decides to abandon ship, leaving the pilgrims to their fate. Jim, who though described by the narrator as 'one of us' is not at one with the crew, yet he makes no common cause with the pilgrims. Fearing shipwreck yet aware of his duty, he still jumps and gains the lifeboat.

When the crew turns up in port claiming shipwreck, their deceit is exposed by a French frigate appearing with the intact ship in tow and the pilgrims safe. At the subsequent Court of Inquiry the rest of the crew goes AWOL, leaving Jim to face the music. Despite advice to flee, he takes it (he knows he deserves it) and is admonished and loses his seaman's licence.

In the second part of the book Marlowe, the narrator, finds work for Jim in various ports and he performs it well, but always someone arrives who knows about his shame and Jim feels he must move on. Eventually he is found a place as a trading agent on a remote island where nobody goes. He with courage and honesty he begins to redeem himself. Such is his good judgement, kindness and valor that he is held in great esteem by the natives. The call him Tuan (Lord) Jim. He becomes romantically involved with a young girl. He is a close friend of the King's son. He has an ardent and loyal following of native islanders. It seems that he has found peace. There are some who hate him, including Cornelius, the former agent, and some of the bully-boys that he has deposed on the island.

In the final part of the book, comes the testing. A group of pirates led by Captain Brown (James Mason in the film) are looking for sanctuary and see the island as a place where they could displace Jim and exploit the locals. However, Jim has trained the natives well and the pirates are resisted, and end up held at bay on a small river islet. Jim, who has been on an expedition to the interior, returns and the islanders look to him to resolve the impasse. They expect him to defeat the pirates in battle. Instead Jim talks to Brown and realizes that but for a change in his luck, he too could have been a pirate. Out of compassion Jim agrees to let the pirates have free passage down river to leave the island. He pledges to the islanders on his own life that no harm will come of this act of grace. He reckons without the treachery of Cornelius, the former agent.

The king has sent his son to guard the mouth of the river, to ensure that the pirates leave, but Cornelius shows them an inlet to take that allows them to avoid the sentries at the mouth, and then to land behind them and attack them. This they do and kill the king's son.

When Jim hears what has happened, he realises that all is up for him. He goes to see the king. His life is forfeit. The kings shoots him dead.

Jim is a romantic idealist. He is the son of a country vicar, brought up in a Victorian public school to always do the right thing. Having let himself down he seeks to redeem himself. Since his offence has been against the Muslim pilgrims, he seeks to serve them. When one dies as a consequence of his decision he has to pay - a life for a life.

The story seems old fashioned - Kipling-esque - in today's climate. The brown people are very definitely the 'white man's burden'. Jim was 'one of us', not just white but an English 'officer and gentleman', expected to behave better than Germans or Portuguese. He has shamed not only himself, but his family, and race.

Marlowe, the older, more experienced narrator, realises that all men are flawed, and that Jim has set himself a standard that no-one could live up to. He has pity on Jim and gives him another chance - and not just one.

Jim does well, but grows no wiser. When he confronts Brown, he fails to recognise the degree to which Brown has fallen. He thinks that even the most depraved deserves another chance and in giving him this he hazards the lives of his followers. This time there is no further chance for Jim. His final punishment is not because he is flawed, or because he is fated; it is because he is a silly ass. He has not learned to negotiate a path in the world. He remains a romantic idealist. He has not learned that some are beyond redemption.

And that is an interesting topic to debate. I have touched on it before.

Praying to a real person.

When God communed with Abraham it was spectacular. On at least one occasion He appeared in human form and had a conversation just like any other. When He spoke to Moses it was out of a burning bush that was not consumed. Gideon met an Angel. Samuel heard a voice calling him by name in the night. Elijah heard God as a still, small voice after the wind, earthquake and fire. Daniel saw visions, Joseph dreamed dreams. The disciples lived with Jesus for three years and were able to talk to him about the ordinary things of life.

My prayer life is different. I have never had God come to me in a dream. I have never had a vision. No burning bushes in my neck of the woods; no voices from the clouds; no Angels have come calling on me and I've never been in an earthquake.

What would you give for a conversation with Jesus?

Yet this is what Jesus said to the disciples who had that privilege, "It is for your good that I am going away." (John 16:7)

What could be better than the actual living and breathing presence of Jesus? This sounds like a bit of flannel to keep their spirits up; making the best of a bad job. The enemy was closing in. Jesus knew he was going to be captured and executed. He was consoling his followers.

But no. He continues, "Unless I go away, the Counsellor will not come to you, but if I go, I will send him to you."

He means the Holy Spirit. He actually means that we are better off having the Holy Spirit than we would be having the physical presence of Jesus. Think about it.

Sitting next to Princess Margaret: Luke 14:1-24

If you Google “What if they threw a party and nobody came?” you get over a million hits including a Spanish local radio station and a pop song by Tom Flannery. Then there are all the derivatives: what if they threw a war and nobody came, what if they threw an inflation party and nobody game, an election party, a winter solstice party, an Alex Rodriguez party (A-Rod) and Madonna never came, a trial and nobody came, a press conference and nobody came, a caucus, an election, a convention, a culture war, a coup d’etat, a revolution, a crisis and nobody came.

If you throw your search engine the word “Luke” in addition, you get a whole lot of sermons based on this parable including one which assures us that it is a call to putting showers in the church basement for the down and outs.

To know what it really means we must look at the context.

Jesus had been invited to a party by a prominent Pharisee. You might think this was a great privilege. I remember being invited to a party where Princess Margaret was guest of honor. I even got to sit two away from her. Another party I went to was called a ‘trial by sherry’ party – it was part of a candidate selection process. They were assessing your manners. Would you use the right fork? Would you get drunk? Would you reveal your indiscretions? The Pharisee’s party was a bit like that. Luke tells us that Jesus was being carefully watched. This was a Friday night party – the Sabbath had started and they stuck a sick man in front of Jesus. If dropsy meant the same then as it means now, he was a man with terminal heart failure.

Crafty old Pharisees! They were goading him to heal on the Sabbath. Jesus goes straight into the attack. He asks the experts in the law, “Is it lawful to heal on the Sabbath or not?” They refuse to commit themselves. If they said yes, their trap was sprung, if they said no they stood accused of callousness. So he healed him and sent him home and pushed home his point by asking them which of them would leave his son or even his ox trapped down a well for the whole of a Sabbath day.

Having noticed how keen they had all been to sit as close as possible to Princess Margaret (well, you know what I mean), he admonished them not to push themselves forward. Sit at the back and someone may notice you and invite you forward; sit at the front and it is likely that you’ll be shoved out of the way to give up your seat for someone more important. “Whosoever exalteth himself shall be abased and he that humbleth himself shall be exalted.” He was reminding them of the well know Proverb (25:6-7). But having got them on the defensive he rams the point home. “And by the way, I couldn’t help noticing that you’ve only invited the toffs to this dinner. I can see what it is. You scratch my back and I’ll scratch yours. Your idea of love your neighbour is those who live in Canford Cliffs and Talbot Woods (or if you’re very lucky, Sandbanks.).” You’ve had your reward for your ‘kindness’. Instead, he says, invite the poor, the crippled, the lame and the blind –then you will be blessed. Although they cannot repay you, you will be repaid at the resurrection of the righteous.

The phrase ‘resurrection of the righteous’ prompted one of the Pharisees to exclaim, “Blessed is the man who will eat at the feast in the kingdom of God.”

What exactly was the point of this is not clear. Was he trying to change the subject? Was he embarrassed by the way the conversation was going? In any case it is an opportunity for Jesus to tell this story.

A certain man was throwing a great party with many people invited. The tradition there was to send out two invitations – first to see if the invitees wanted to come and second when everything was ready to say “Come now.” There had been no problem about getting people to say that they wanted to come – who’s going to refuse free food? But when they were asked to “come now” they started out with the lame excuses. ‘I’ve just bought a field and I must go and see it’ ‘I’ve bought five yoke of oxen and just on my way to try them out’ and ‘I’ve just got married’.

As excuses go these are of the calibre of ‘The dog ate my car keys. We're going to hitchhike to the vet’ or ‘I can’t come in today, my computer’s caught a virus’. I mean, the field won’t still be there tomorrow? Your life depends on trying out your oxen this moment? Your wife doesn’t like parties?

There are, of course, good reasons for turning down invitations. Perhaps, some of us need to say ‘No’ more often. But these aren’t reasons, they are trivial excuses. The truth is they didn’t want to go.

Have you ever put on a dinner and nobody wanted to come? It’s a pretty devastating experience. It’s not just the waste of money and all the hard work of preparation. You’re on the end of a pretty humiliating insult. It says, I don’t consider you as important as taking a stroll over my new property. You’re not worth as much to me as my job. Rather than come to your party I would rather stay a home and do nothing.

You can imagine that the party- thrower was pretty cross. He tell his servant to go through the city, scouring the streets and alleys for the poor, the crippled, the lame and the blind and when these have come in and there is still room for more, he sends them out again, this time outside the city to roads and country lanes to bring in the alien and the outcast.

Notice that the first group that he sends for are the same four categories, the poor the crippled the lame and the blind, that Jesus criticizes the Pharisees for, for not inviting to their dinners.

So what it is all about? Of course, the first lot who refuse to come to the party are the Pharisees themselves. In many ways the Pharisees were exemplary. They were Biblical scholars. They took their religion seriously. They obeyed religious law. They worked out that there were 613 commandments, 248 positive and 365 negative. They were Sabbath keepers. They determined that there were 39 prohibited acts on the Sabbath. They were exclusive. Josephus worked out that at the time of King Herod there were just 6000 of them.

In modern parlance they were box-tickers. They thought that simply by ticking all the boxes, keeping their noses clean and obeying the rules, their passage to heaven was assured. They claimed to fulfill the letter of the law, but when it came to keeping to the spirit of the law, they weren’t at the party at all. They thought that they were special, better than the ordinary Jew. They looked down on ‘tax collectors and sinners’. And as for the woman who washed Jesus’ his feet with her tears and dried them with her hair, and then anointed them with perfume - well if Jesus was really a prophet he’d know what sort of woman she was and have nothing to do with her. Jesus gives us a picture of a Pharisee at prayer, “God, I thank you that I am not like other men – robbers, evil doers, adulterers – or even like this tax collector I fast twice a week and give a tenth of all my income.” And he uses this same proverb again: Everyone who exalts himself will be humbled and he who humbles himself will be exalted.

The Pharisees were nit-pickers, always ready to criticize others. Jesus said of them, “They tie up heavy loads and put them on men’s shoulders, but they themselves are not willing to lift a finger to move them.” Jesus quotes Isaiah at them, “These people honor me with their lips, but their hearts are far from me. They worship me in vain; their teachings are but rules made up by men.”

Those whom the party-giver drags in from the streets and alleys of the city are the very people the Pharisees despised. Although depicted as the poor, blind, crippled and lame, these are spiritual descriptions. We would call them the average Jewish man-in-the-street. This is an invitation to sinners to come in. The Pharisees despised them because they were sinners; Jesus loved them because they were sinners. Only the sick need a physician, he says. I have not come to righteous, but sinners to repentance.

But what of the third group - those from outside the city? The aliens and the outcasts. This was a group even more shocking to the Pharisees. They weren’t even Jews at all! The Jews prided themselves on being the Chosen people. Gentiles were called ‘Dogs’. Yet from Old Testament Times God had declared himself God of the whole world – not just of Israel. In Luke chapter 4 Jesus tells his followers, “There were many widows in Israel in Elijah’s time yet Elijah was not sent to one of these, but to a widow in Zaraphath in the region of Sidon and there were many lepers in the time of Elisha, yet not one of these were cleansed except Naaman the Syrian.” Just saying this was enough to make the Jews attempt to murder him. But in Luke chapter 7 it was not a Jew, but a Roman Centurion who understood what it meant to be a man under authority who had the faith to ask Jesus to heal his servant at a distance. And in Luke chapter 10 he told the story of a man who fell among thieves is was not a Jew, but a native of the hated Samaria who turned out to be the hero of the tale. And when he witnessed to the woman at the well it was not a Jewish woman, but a woman of Samaria. The mission of Jesus was primarily to the Jews. When a Greek woman from a place near to Tyre asked him to cleanse her daughter from an evil spirit he replied, “First let the children eat all they want, for it would not be right to take the children’s bread and toss it to their dogs.” But in response to her witty answer that even dogs can eat the crumbs that fall from the table, he healed the girl. And when he cleansed the Temple of dove sellers and swindlers in Luke 19 he cried out, “My house will be a house of prayer, but you have made it a den of thieves.” He was quoting from Isaiah 56:7 – the full text is ‘My house will be house of prayer for all nations’. The area that they were despoiling was the Court of the Gentiles.

So that’s all right then. This is a parable told against the Pharisees, foretelling God’s casting aside of the Jews and replacing them with the Gentiles. We have nothing to worry about.

By no means. In Romans chapter 11 the Apostle Paul describes the cutting off of the Jews and the grafting in of the Gentiles in a rather elaborate gardening metaphor about olive trees. He tells us not to get cocky. Verse 19: You will say then, “Branches were broken off so that I could be grafted in.” Granted. But they were broken off because of unbelief, and you stand by faith. Do not be arrogant, but be afraid. For if God did not spare the natural branches, he will not spare you either.

We Reformed Evangelicals are most prone to the sins of the Pharisees. We are Bible students like them. We take our religion seriously. We obey the law. We may well be Sabbatarians. We tithe. We are exclusive. We call ourselves the elect. We find it easy to be proud of ourselves and to look down on sinners. We often gather in middle class churches and we are not the friends of sinners but the friends of other Reformed Evangelicals.

Jesus warns his followers in Luke 12, “Be on your guard against the yeast of the Pharisees, which is hypocrisy. There is nothing concealed that will not be disclosed, or hidden that will not be made known. What you have said in the dark will be heard in the daylight, and what you have whispered in the ear behind closed doors will be proclaimed form the housetops.”

American doctor says NHS is best.

Donald M. Berwick, MD, MPP, FRCP is President and CEO of the Institute for Healthcare Improvement (IHI) and, is one of the America’s leading authorities on health care quality and improvement issues. He is also clinical professor of pediatrics and health care policy at the Harvard Medical School. Dr. Berwick has served as vice chair of the U.S. Preventive Services Task Force, the first "Independent Member" of the Board of Trustees of the American Hospital Association, and as chair on the National Advisory Council of the Agency for Healthcare Research and Quality. An elected member of the Institute of Medicine (IOM), Dr. Berwick now serves on the IOM’s governing Council. He served on President Clinton's Advisory Commission on Consumer Protection and Quality in the Healthcare Industry. Co-chaired by the secretaries of health and human services and labor, the Commission was charged with developing a broader understanding of issues facing the rapidly evolving health care delivery system and building consensus on ways to assure and improve the quality of health care.

Dr Berwick has written a piece in today’s BMJ that praises the British NHS far more than I would praise it. He calls it one of the outstanding human endeavors of modern time. At a time when successive government in the UK have sought to distance themselves from taking the blame for the deficiencies of the NHS, he claims that it is just because of its national scale and indebtedness to general taxation and consequently its subjection to political debate that gives it its strength and appeal.

It operates, he says, from the premise that health care is a human right. He contrasts this with the attitude in America where people ask, “How can health care be a human right? We can’t afford it.” As a result one American in seven does not have health insurance. Common humanity will not allow people to go completely without, so in America there is the safety net of Medicare and Medicaid, the VA, County Hospital ER rooms and measures for children etc, which are such an inefficient means of delivering health care that the US government ends up spending a greater proportion of the GDP on their bit of health care than the UK government spends on the whole of the NHS.

How is it that the US spends 17% of GDP while making healthcare unaffordable as a human right while the UK spends less than 9% and insists that it is a human right? You might go for the obvious answer that the 17% buys better quality, but in terms of outcome measurements that is simply not true. In almost every outcome measurement, whether it be longevity or infant mortality, the UK outperforms the US.

The UK and the US operate completely different models of healthcare. In the US it is supply driven. Someone makes a better mousetrap and everyone flocks to buy it. Someone else makes one on the same principle but makes it cheaper and purchasers switch to that. Suddenly there are a thousand mousetraps and they compete in the marketplace on the basis of cost and efficiency. Advertisers extol their color, shape, cost and kill rate. The consumer has choice.

In the UK it is needs driven. Money is allocated by government of the basis of how many people there are and how much sickness they have. Choice is limited, but experts decide not only what possible treatments there are, but also which is the most cost-effective. There is threshold beyond which the purchaser will not go; if it costs more, you can’t have it. The process of choice is transparent and challengeable in open court, but there is no mechanism to drive prices down.

The UK model sounds bureaucratic and therefore expensive, but in fact it is not. Administrative costs comprise 20% of the American healthcare bill, but only 6% of the UK bill.

You’d think that we British would be delighted with the bargain that we are getting, but we complain. In a restaurant we consume overcooked vegetables and tough steak without demur because complaining is not a very ‘British’ thing to do; but we moan about the NHS. Those who have been treated by it usually have nothing but praise for their experience, but somewhere in the British psyche is the thought that anything the government runs is bound to be hopeless.

Within the NHS we are sick to death of reorganization. One of the consequences of the complaints is that government reorganizes the service. I was appointed to be head of my department in February 1974. When I needed more facilities I went to the head of the local authority’s health committee and made my case. Two months later that had all gone and we were employees, not of the local hospital, but of the Wessex Regional Health Authority. After that e were run successively by the Dorset Area Health Authority and the East Dorset District Heath Authority. Then Wessex was abolished and we were part of the South West Region, run from Bristol, a town 100 miles away with no public transport link and a two hour drive by car. Then we had the Somerset and Dorset Strategic Health Authority based at Taunton, a small town 70 miles away, again with no public transport link and three hours away by car down country bumpkin roads. The purchasing and providing of health care was split so that we became dependent on ‘fundholder’ general practitioners while we became a ‘Foundation’ Trust. Then fundholders went and we had small Primary Care Trusts which soon amalgamated into large Primary Care Trusts and we dropped the ‘Foundation’ and became a NHS Trust. Soon we are to have Polyclinics rather than GP surgeries or perhaps in addition to. Small hospitals have become GP hospitals and will soon become the base for the Polyclinic.

Despite all these changes the same people are running things. Job titles have changed but the function stays much the same. Every reorganization is accompanied by a new logo and new headed notepaper. So please! A moratorium on reorganization!

Berwick has special praise for British General Practice or as we must now call it, Primary Care. This has changed from a reactive service to a proactive service. Last week I received an invitation to have a pneumovax inoculation. I don’t have weak lungs, I have never smoked, I don’t get chest infections, but I am 65. The GP obviously gets paid a bonus for every 65-year old he recruits to the program. It costs me nothing so I might as well go, but what’s next? Routine colonoscopies every year? Free hot water bottles for the winter months?

Berwick recognizes that the NHS is not perfect and has some prescriptions for us.
1 Patients should keep their own records and be involved in their own illnesses – nothing about me without me.
2 No more restructuring. Hear! Hear!
3 Keep it local.
4 Concentrate on Primary Care.
5 Don’t put your faith in market forces
6 Avoid supply driven care like the plague
7 Develop an integrated quality assurance system.
8 Heal the divide between doctors managers and politicians.
9 Train healthcare workers for the future not the past. I agree I was trained to look after TB and rheumatic heart disease, conditions that beset Britons in the 1930s.
10 Be a Heath service not a Disease service.

I believe in miracles

Last night I watched an old war film. The captured flyers had spent a year in a prisoner of war camp somewhere in northern Germany. Under the cover of a vaulting horse they had tunneled out of the Stalag and with forged papers they had crossed the country by train to the nearest port. They were holed up in a small hotel while trying to contact Swedish seamen. When they go out they realize that they are being followed. They try to give him the slip, but he is still there. How would you pray in these circumstances?

The authorities are looking for you. You have managed to keep below the radar. Every night you sleep in a different bed and some nights in no bed at all. You have many loyal friends who support you, but only a very few who know where you will lay your head tonight. Although your position seems precarious, in reality you have enormous strength. Your father has ready and prepared thousands of crack troops who could rescue you from danger at a moment’s notice. All it needs is one radio call. This isn’t World War II with a crackly wireless and long and ponderous flights from England; this is instant access with communications loud and clear. This is ‘Beam me up, Scottie’ instant transportation.

You hear a crowd gathering. In the dark you see torches. The light glints on the body armor. There is no doubt about it; they have come to arrest you. One of your ‘loyal’ supporters has blabbed. Here’s the decision: do you make the call?

The problem is this. You have invested three years in this mission. You always knew it might cost you everything. If you pull out now it would mean abandoning not only your friends, but all those you had come to liberate. Not to make the call means torture and certain death; and not a pleasant death either. This is no quick bullet in the back of the head or lethal injection. This is death by torment and humiliation. It will leave your followers shocked and in despair. If you pulled out they might seem better off. They could go about their business much as before. Some of them would go back to fishing – they were quite good at it. Some might farm, some might trade, and others would take clerical jobs. They would certainly be able to make a living, but they would be living under a malign Ruler who had their distress close to his heart. He would certainly know that he had won a victory, and won it without even a fight.

Well, as I am sure you know by now, Jesus never made that call. It was one of those prayers that Jesus never prayed. When Satan desired to sift Peter like wheat, Jesus never prayed that Peter be declared off limits for the Devil. He never prayed that Peter would be so strong as to resist the evil one. He prayed that his faith would not fail. It seemed to fail, as Peter denied his Lord, but the sifting got rid of Peter’s undesirable characteristics: his arrogance, his bombast, his violence, his boasting. The man whose vain bluster claimed that if all deserted, he would stay steadfast; the man whose violent temper struck off the servant’s ear; the man who swore blind that he never knew him, became the writer of the letter that recommends to his followers that they “live in harmony with one another; be sympathetic, love as brothers, be compassionate and humble. Do not repay evil with evil or insult with insult, but with blessing.” (I Peter 3:8)

It is clear that Jesus was well aware of what was going to happen to Jerusalem in AD 70. In Matthew chapter 24 he makes it plain that disaster was coming. As we now know Jerusalem was sacked and the Temple destroyed in AD 70 by Titus, the Roman general soon to be Emperor. How Jesus felt for Jerusalem! Luke tells us that he wept over the city and what was in store for it (Luke 19:41). Matthew tells us of his anguish, “O Jerusalem, Jerusalem, you who kill the prophets and stone those sent to you, how often I have longed to gather your children together, as a hen gathers her chicks under her wings, but you were not willing.” (Matt 23:37) But he never prayed for God to spare the city. He advises the dwellers of the city to flee to the mountains, but the destruction of Jerusalem is a given.

God’s answers to prayers may not be intelligible to us. The atheist scoffs, “If your god were all powerful and all loving as you claim, he would not allow the suffering that we see every night on the ten o’clock news. Either he is all loving but powerless or he is powerful but doesn’t care. Or more likely he is a figment of your imagination.”

What do we say to the child sexually abused by her father? What do we say to the young mother whose breast cancer has spread to her bones? What do we say to the children of missionaries who have been hacked down in one of the world’s trouble spots? What do we say to the mother whose daughter has killed herself? That God could intervene but he tolerates evil? That he recognizes the arbitrariness of suffering but has to put up in it? That he understands wicked and oppressive regimes, but has to stand by and do nothing?

What do we say when they ask for a miracle? Pray that my handicapped baby will walk. Pray that my wife won’t die of her brain tumor. Pray that brutal and abusing husband will love me again as he used to.

I believe in miracles, but they are miracles. They are rare exceptions to God’s laws that mean that up is up and down is down and that water flows from up to down and 2+2=4. Miracles can’t be turned on like a tap. If prayer worked like magic you would not dare put one foot in front of another in case someone, somewhere had prayed that paving stone away. No, God’s answers must be altogether more subtle.

Has God done nothing to alleviate the suffering of the world? He gave us his Word to tell us how to live. He sent us his Son to cancel our sin. He sent us his Spirit to live in our lives. The foulest oppression, He has experienced. The deepest deprivation; He has known. The greatest disappointment, the most murderous torture, the most fearsome abuse, the most harrowing loss; He has shared in them all.

It was not on the cross where Jesus’ sweat was like drops of blood, but in the Garden beforehand. The writer of the letter to the Hebrews tells us, “he offered up prayers and petitions with loud cries and tears to the one who could save him from death.” (Heb 5:7)

That prayer was answered, but not in the way that you might expect. On the third day he rose again. He was saved from death but not from the suffering. We cannot imagine what transactions took place in those long hours in the Garden, but we know that they were vital. Was it some sort of negotiation? Was it a matter of Jesus reconciling his mind to that of the Father? Was that even necessary or possible? Was the Father rehearsing with Jesus what the final outcome of his suffering would be, for we are told, “for the joy set before him he endured the cross, scorning its shame”. (Heb 12:2)

Jesus continued to pray despite seeing wrongs un-righted. Everyone was looking for him. The previous evening, the whole town had gathered at his door and Jesus had healed many who had various diseases. Instead of starting work on healing the next lot, very early in the morning, while it was still dark, Jesus got up, left the house and went off to a solitary place and prayed. (Mark 1:35)

Jesus hasn’t stopped praying. “He is able to save completely those who come to God through him, because he always lives to intercede for them.” (Heb 7:25) “Christ Jesus, who died – more than that, who was raised to life – is at the right hand of God and is also interceding for us.” (Rom 8:34)

Neither should we.

Smoking and drinking

A painter and decorator has been fined £30 for smoking in his own van because it was deemed to be a workplace. A passenger in his van, who had also just lit up, received a £30 fixed penalty notice as well. They are victimes of 'passive smoking' legislation

This particular report is in the Guardian, but it is in all today's newspapers. It happened in west Wales near Aberystwyth, which is about as alien a place that you can get in Britain, but that's mo excuse. The police had stopped the van on the suspicion that it was unroadworthy and you can imagine that he must have them a bit of cheek, but this is a prime example of the pettifogging bureaucracy that has crept over the country and the intrusive interference of the 'authorities' in the lives of the general public.

I imagine this decision will be thrown out on appeal, but it is yet another example of the police getting too big for their size twelves.

Now I have been a campaigner against tobacco. I pity those who were captured by the tobacco barons when they were young and have been addicted to the weed ever since. It is harder to stop smoking than to get off heroin. Most smokers want to stop and I am all for the health service giving them all the help they need. But in my working life I found it pretty easy to avoid passive smoke. Legislation that keeps smokers out of pubs seems to ignore the fact that people go there to drink, and that the alcohol is doing them more harm than the smoking.

I remember being confronted by a patient in my clinic with a raised MCV. The mean cell volume is a good warning sign of alcoholism and so it proved. He was a big fat man with a red face, cigarette stained fingers and beery breath. Aged about 45 he had married for a third time, on this occasion to a 23-year old who came in with him and with their baby. She clearly recognized his ill health and pleaded with me to make him better.

The cause of his problem was easy to diagnose: he drank too much and smoked too much. I told him that he would have to stop smoking and stop drinking. I spelled out all the consequences and agreed with the wisdom of the advice, though he couldn't see how he could manage to stop both at once. Brain-washed as I was about the evils of smoking, I suggested that he started with that and left the alcohol problem until later.

He didn't turn up to his next appointment a month later, but his wife did, or I should say his widow. She told me that he had died the previous week of gastric bleeding from esophageal varices. "Why didn't you get him to stop drinking first?" she screamed at me. I doubt that I could have done, but I should have taken his drinking history more seriously. I should have immediately investigated his liver.

Since then the problem has gone from bad to worse. Earlier this week we heard that there were more than 800,000 people admitted to hospital each year with alcohol-related illnesses and injuries in the UK — four times the official figure. When my daughter was a young doctor on the medical wards, alcohol was one of the major reasons for hospital admissions.

The night club business in Bournemouth has been booming, but I heard yesterday that the company that owns the night clubs is talking about going into liquidation. There are no fewer late night revellers spilling out onto the streets at 4 am, but the credit crunch has meant that rather than going out in the evening to drink the youngsters are going out drunk. Alcohol is so much cheaper at the supermarkets that the youngsters are drinking at home first and then going out. Supermarkets are using alcohol as a 'loss-leader' to draw in customers and don't seem to be much concerned that shoplifters are targeting the whisky counters.

Most countries have realized the necessity of limiting the sale of alcohol, but the drinks industry persuaded Tony Blair to make it more easily available. I wouldn't dare suggest that a sweetener went to Labor Party funds, but were one to be discovered I would not be surprised. The EU has made it impossible to restrict the importation of low-tax alcohol from France. Some individuals make a daily trip in a white van and return with it stuffed with alcohol, claiming that it is 'for personal use'. 'Booze cruises' are big money.

Cannabis has been in the news recently because of the risk of its inducing psychotic episodes, especially in young Afro-Caribbeans. Cocaine usage is rife among the fashionable party-goers and heroin addiction is a major cause of crime as addicts steal to feed their habit; but all these are minor players compared to alcohol. Over 2000 people a day admitted to hospital! We lose between 2000 and 3000 people are year to traffic accidents. In Iraq and Afghanistan together, fewer than 300 soldiers have died since hostilities began.

We should get our priorities right. Sales of alcohol should be restricted to those over-21, and it should not be on open display of supermarket shelves. I would prefer that sale of alcohol for consumption off the premises be confined to licensed premises with a barrier between customer and product and with very restricted hours of opening.

Most people like a drink and we certainly don't want to go back to prohibition, but that does not mean there should be so little restriction on the availability of alcohol. Liberty is fine, but the present drinking culture hurts not only the individual consumer, but his wife and children, his neighbor and almost everyone else in society. If you have a national health service, you have an interest in not paying for other people's recklessness.

New Trials

No blogging yesterday as I was at the UK CLL group's clinical trials meeting. This was a good chance to review what was happening in the UK. Currently we are without a major change. LRF CLL4 has been analyzed and published with its concusion that the combination of fludarabine and cyclphosphamide gives more responses and longer remissions than either fludarabine of chlorambucil as single agents, and rather more surprisingly that these two drugs cannot be distinguished by their performance. However, none of these drugs gives a longer overall survival compared to the others when used as first line treatment. There are 5 of 6 other spin-off papers due from that trial, mainly about the prognostic factors, but also about the comparison of oral and iv fludarabine.

The next trial has been a long time in coming because the Germans have rather stolen a march on us, and have already asked the next major question, which is does the addition of ritiuximab improve results. Although this will be the subject of a major paper at ASH, we know from heavy hints from the Roche website that the answer will be a very high response rate (perhaps 95%) much longer remissions (4-5 years?) and no improvement in overall survival.

So what is there left to do with conventional drugs? There is the Ron Taylor question: do we need such large doses of rituximab? And there is the Spanish question: is there a place for mitoxantrone?

Our next trial is going to address these, starting, we hope, early next year. The randomization will be between FCR and FCMr. F=Fludarabine, C=Cyclophosphamide, M=mitoxantrone (at a small dose, 6mg/sq m), R=full dose rituximab, r=minidose rituximab (100mg). At the same time we will conduct a randomized phase II study comparing FCR with FCMR.

We currently have a randomized phase II study looking at chlorambucil versus chlorambucil plus rituximab in patients though unfit for fludarabine and are looking at a randomized phase III study looking at chlorambucil with or without ofatumumab.

Several centers are also taking part in the international study comparing FCR with FCR plus lumiliximab.

The consolidation study with Campath is continuing but is recruiting poorly perhaps because of the 6 dearths in the American study. It is clear that eradication of minimal residual disease should only be undertaken in centres experienced with the problem.

The 17p- trial (Campred) is almost complete and it is touch and go whether it will be ready for ASH. A new trial adding Revlimid is being designed. Revlimid is also the drug of choice for early stage, poor risk patients.

On the horizon are some Treanda trials: R-Bendamustine v R-chlorambucil might be attractive as long as they chose a proper dose of chlorambucil. An SMZL comparing splenectomy and FR might have difficulty recruiting even if it were pan-Europe. We might join the CALGB mini-allo trial.

Wedding Anniversary

Today is our 41st Wedding Anniversary. To celebrate I bought Diane a couple of boxes of DVDs of BBC plays featuring Judi Dench and Helen Mirren, and she bought me a biography of Charles Wesley. Shows what serious people we are. Then this afternoon we went for a walk in the New Forest. We went to Rhinefield and followed the Tall Trees Trail. Here are some of the tallest trees in the forest including Douglas Firs, oaks, beeches, silver birch, cedars and redwoods over 100 feet high. The trees date from about 200 years ago, though there is an arboretum planted about 50 years ago with less mature specimens.

Summer has arrived and temperatures are in the eighties, so the shade of the trees was very welcome. How fortunate we are to live in such a beautiful part of the world!

Why pray?

We pray because Jesus prayed. A simple enough answer. Christians follow Christ. The Bible records more than a dozen of Jesus' specific prayers as well as his teaching and parables on the subject. We can see that it was his practice to pray regularly and for long periods. Five times the Gospels mention his practice of praying in solitude. He prayed in the Garden, he prayed on the cross. He seldom prayed for himself. The request that this cup be taken from him is perhaps the only occasion and that was modulated by "not my will, but thine." He often prayed for others: for children brought by their mothers, for the people by the grave of Lazarus, for Simon Peter whom Satan sought to sift, for those who were crucifying him. At times of special importance he intensified his prayers: at his baptism, all night before choosing his disciples (was it Judas that gave him so much trouble or was it Peter?), on the Mount of Transfiguration, and especially before his death. His prayer could be exuberant as when the 70 returned from their mission. He prayed that his disciples would receive the Counsellor; he prayed in his great High Priestly prayer of John 17 for all of us believers who would come after him.

Did he get everything he prayed for? Do we? The answer is no, or at the best, not yet. When I said he prayed for us, what did he pray for? He prayed for unity. "That all of them may be one, Father, just as you are in me and I am in you." At the last count there were 34,000 distinct denominations and sects. Is that an answered prayer? Much as I dislike ECUSA and all that they stand for, you can see where Rowan Williams is coming from and why he prays for unity. We should pray for the Anglican Church that they will come home to Christ.

I suggest that on that long night before he chose the twelve, he prayed for Judas. He certainly prayed for Peter, that his faith would not fail. We know that Peter's faith failed him three times before the cock crowed. The Bible tells us that Satan has asked to sift him like wheat. As for Judas Luke tells us that 'Satan entered Judas'. We are in a spiritual warfare. We face supernatural forces. Sometimes Satan wins the battle. We know that he is a beaten foe, but he won't lie down just yet. He means to take as many casualties with him as he can.

Like his ancestor Jacob before him Jesus wrestles in prayer. We must do the same. Prayer is hard work. Despite our wish to be spared Satan's attacks God permits them. We cannot fathom that. Why was Satan permitted to smite that good man Job? Why didn't Jesus restrain Satan when Peter slunk into the courtyard and warmed bis hands by the brazier? He was bravely there when others had fled. Why wasn't he protected? And Judas? Poor Judas. Jesus' friend and companion those three years on the road. Why would he not spare his friend from this harrowing? Why did he allow this evil possession?

We know now why. We know why Jesus died. It seemed a cockeyed plan at the time, but Jesus had to die. He had to be betrayed. He had to be denied. No rescue plan could be allowed to interrupt the proceedings. The just must die for the unjust. There was no other way. There was no other good enough. God knew what He was doing.

We may be perplexed at God. Why doesn't He answer my prayers? Why doesn't He do what I want? Prayer reconciles us to the will of God.

If He is going to do what he wants anyway, why should we pray? I don't know. I only know that in some mysterious way his plans are accomplished because we pray. How do I know? Because Jesus prayed and even though his prayers appeared not to be answered, God's will was accomplished and millions were saved.

"SICKO"

I finally got to see "Sicko", Michael Moore's tirade against the American Health Insurance industry. It is, of course, a polemic rather than a documentary and therefore it can't be expected to tell the truth, but it does make some valid points.

One point was that being part of what Americans call a socialized medicine system doesn't have to impoverish doctors. Cuban doctors may work for cents but British doctors are very well paid. There are certainly multi-millionaires, but most of these have a private practice income outside the NHS. Nevertheless, there are a lot of NHS doctors taking home $200,000 a year or more.

He raved about the French system, but French taxes are very high and you have to put up with the natives taking to the streets every so often and disrupting public services. If you want a government servant to come and do your laundry during your maternity leave you have to pay for it some way.

One of the cases that he highlighted was the unwillingness of an insurance company to pay for a bone marrow transplant in a man metastatic kidney cancer who had failed high dose interleukin-2. They claimed that it was an experimental approach. Well, you can be certain that it is not available on the NHS unless it is as an experimental approach. Should Insurance Companies be expected to pay for medical experiments? I know that the NHS stem cell transplant program does fund the large transplant centers at a rate so that they can do a certain number of experimental procedures every year. The NIH also has a program of experimental transplant procedures at no cost to the patient. But such programs are run under the direction of the doctor in charge and there is no obligation that any particular patient should be taken on. In answer to the question, "Are you doing this for me, doctor, or am I doing it for you?" the answer is very much the latter. As an aside it is very unlikely that the patient would even have got high dose IL-2 under the NHS since this is not a NICE approved treatment and no-one in the UK is doing any research on it.

He also showed a case of a citizen of Detroit hopping across the border to take advantage of the free Canadian system by pretending to be the 'common-law' wife of a Canadian citizen. The first visit had to be aborted as the cops turned up. And why not? Moore seemed to be endorsing a criminal offence. Defrauding the Canadian taxpayer is no way to improve US medicine.

The truth is that whatever system of health care you have, there are flaws in it. Pharmaceutical companies have produced drugs that are more expensive that people can afford. We should see these drugs in the same way that we would see any other expensive product - a house or a yacht, for instance. I could afford a yacht if I really wanted one. I would have to arrange some way of paying for it over a period, and I would have to work out how much I would use it. Perhaps I would do it as a timeshare or perhaps rent one when I needed one.

For medicine I would also work out whether it was value for money. It is a certain as snow in Greenland that one day I am going to die. If someone offered to extend my life, I would want to know for how long, what the chances were and what it would cost in both suffering and cash.

In the UK NICE has declared that if you get a year of good quality life with a 100% certainty for $60,000 then the community will pay. If it is more expensive than that it won't. Though it is not so overt as that elsewhere, I believe that a similar value is put on human life in other Western communities. In a free market it should be possible for someone to put a value on their own life and if necessary to pay the difference, or if they can haggle with the supplier.

In reality, most communities enter into an arrangement that spreads the cost. Only a small proportion of the people will ever need Herceptin, but it might be you. Therefore, you a buy a ticket for the lottery hoping you never win, but if you do, you won't be left unable to cope. Those who don't buy a ticket are taking a risk. The trouble is that there are lots more products like Herceptin and therefore a lot more lotteries. Some people can't afford all the lottery tickets that they need. Even when the lottery organizations (insurance companies) offer you deals (ten tickets for the price of seven) there are still many people priced out of the market and some people who buy a cheaper product that quibbles when required to pay out (you didn't buy it from a recognized agent; you didn't tell us you had two left feet; you never said your grandmother was a communist). So the government steps in with safety net provisions. The argument for a national system is that if the government is going to have to underwrite the thing anyway it is going to turn out cheaper to run the whole thing than to licence a load of crooks to skim off the profits and leave you to pick up the difficult cases.

I have spent today haggling with a car dealer over a replacement for my 15 year old Mitsubishi Space Wagon. The trouble is that I want a particular model and I can't find another one nearer than 75 miles away and that is no cheaper. The dealer knows that, of course, which is why he has priced the car where he has. It's like that with Big Pharma. They know that there is a $60,000 threshold, so they price their drugs a bit above that. They are trying to drive prices up. The only thing that will bring them down is competition, but if they have a unique product why would they want to reduce their price? You might say, "You'd be better off selling some drugs for $60,000 than none at all." but they might reply, "Very well we'll sell it in Germany."

In fact, while the American market is so profligate, prices will never come down. Even if you can beat them down to $60,000, they are likely to make up the difference by raising the price for a different product that currently retails for less than $60,000.

'Sicko' over-eggs the benefit of other systems of health care and unfairly criticises the American system and there is absolute no need to. The following piece of doggerel exemplifies the attitude:

You cannot hope to bribe or twist
Thank God, the British journalist,
But seeing what the man will do
Unbribed, there's no occasion to. (Humbert Wolfe)

Michael Moore is a journalist and the three rules of journalism are : Make it juicy; Make it brief; Make it up.

Who do you believe?

What do you read in the morning? When I start my computer I scan through the sites of The Times, Telegraph, Guardian, Independent and the Mail (the latter for scandal not facts). Then I start reading the blogs and the one I turn to first is Fresh Bilge . Alan Sullivan is a poet of considerable distinction, a yachtsman with an interest in the Earth sciences, climatology and vulcanology, and a CLL sufferer. He posts several times a day and among the most interesting posts are what he calls FB randoms. Yesterday he linked to couple of articles that my readers might be interested in. The first is a piece by Thomas Dalrymple written in 1999 about real and relative poverty, and the second an editorial by a physicist who can understand those math equations that we feel we could understand and when we get to heaven we will understand but in reality have decided that life is too short to understand.

I enjoyed both articles because they concur with my diagnosis that most commentators know more about how to write than how to evaluate data. It is rare to find scientists who can write clearly and even rarer to find writers who understand science.

It is perhaps best to begin every article that you read with the assumption that you are being lied to and then search for who has a vested interest in your believing the stuff you are reading.

Newspapers make their money by attracting advertisers, which they do by selling more copies. People buy newspapers because they like to read 'stories'. My experience with the press is that there are only two stories in medicine - 'breakthrough' and 'disaster'. Every medical story can be tweaked to make it fit the pattern. I don't see why medical stories are any different from stories about politics. All stories are tweaked to make good copy. I'm not saying that bloggers don't tweak their stories, but it is difficult to see how they can make money from doing it.

Dasatinib and CLL

Figure from Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Shaoguang Li. Leuk Lymphoma. 2008 January; 49(1): 19–26
The figure shows: src family kinases (SFKs) directly interact with BCR-ABL resulting in (1) activation of SFKs and (2) augmentation of BCR-ABL kinase activity. Activated SFKs work cooperatively with BCR-ABL in facilitating the growth and progression of leukemia. Several downstream effectors of SFKs have been proposed to mediate the proleukemic effects, such as (3) STAT5, which is known to activate genes involved in growth factor independence, differentiation, adhesion, and DNA repair and (4) AKT, which is key in regulating cell proliferation and survival in BCR-ABL-dependent cells. (5) Active SFKs also phosphorylate certain tyrosine residues on BCR-ABL to create a binding site for GRB-2. This adaptor protein may link the BCR-ABL pathway to Ras, which is known to activate the MEK/ERK oncogenic signaling cascade.

The most startling and important development in targeted therapy has been the use of Glivec (or Gleevec) to treat chronic myeloid leukemia. Even when I was at medical school CML was characterized by the presence of the Philadelphia chromosome. When I was a junior doctor I delighted in correcting a very eminent hemato-oncologist who hadn’t kept up with the news that the Philadelphia chromosome was formed by a translocation between chromosomes 9 and 22 that involved putting two genes, bcr and abl, so close together that they were translated as a single protein. We discovered later that abl was a tyrosine kinase that was switched on and off as the white cell proliferated at the first sign of infection and then died down again when the danger was past. In its elongated form, bcr-abl is a tyrosine kinase fixed in the ‘on’ position. The white cells proliferate without the ‘go’ signal and can’t be switched off. At least they couldn’t until Brian Druker from Portland, Oregon invented STI571, which came to be known as Glivec or imatinib to give it its proper name. Imatinib works by denying bcr-abl its energy supply. In cells, energy is carried around as ATP which needs to plug itself into bcr-abl in order for the tyrosine kinase to do its work. Imatinib blocks the socket where ATP plugs in.

It was hoped that imatinib would be the first of many such inhibitors and that this technology could be adapted to treat other cancers. To be honest that have been other successes, but they have all been in small print diseases or rare variants of common cancers. So far they don’t work for really important diseases. Then came the bad news. Patients with CML started getting resistant to imatinib. It turns out that point mutations in the abl molecule allow the ATP to fuel the molecule again (it sort of widens the socket to allow the fuel cell to plug in. The chemists started messing around with the molecule and came up with AMN-107 (or nilotinib), which works in some cases of imatinib resistance but not in others. It seems to deal with all the abl mutations except one called T315I. BMS-354825 or Dasatinib is more useful, it deals with all the abl mutations except T315I but being a rather different molecule it has a broader spectrum and inhibits other tyrosine kinases than bcr-abl and in particular inhibits src family kinases.

Evidence is accumulating that imatinib resistance in accelerated phase CML and Ph-positive ALL is caused by the activity of src family kinases. Upregulation of Lyn and Hck (see previous article) has been observed in blasts from patients with imatinib-resistant CML. It was later found that while imatinib effectively reduced activation of BCR-ABL and consequently downstream activation of SFKs in specimens derived from patients with imatinib-sensitive CML, this agent had no effect on SFK activation in samples from resistant patients despite BCR-ABL inhibition.

Dasatinib is the the only dual SFK/BCR-ABL inhibitor approved in the United States and Europe for the treatment of patients with imatinib-resistant or -intolerant CML and Ph+ ALL. This orally available tyrosine kinase inhibitor is structurally unrelated to imatinib and has a 325-fold greater activity against native BCR-ABL in vitro as compared to imatinib. Several animal studies have indicated that dual SFK/BCR-ABL inhibition with dasatinib is advantageous in CML and Ph+ ALL. Dasatinib was able to recover the antitumor activity lost with imatinib treatment as a result of BCR-ABL–independent Lyn activation. It also induces complete remission of Ph+ ALL, and significantly prolongs survival of CML in mice. It was found in mice that SFKs are required for the progression of CML to lymphoid blast crisis, suggesting that treatment with dasatinib could potentially delay the transition of CML from chronic phase to lymphoid blast crisis. Although dasatinib does not kill leukemic stem cells, studies in mice with ALL suggest that the cytostatic effects of dasatinib on this cell population could prevent leukemic transformation and afford long-term control of the disease.

Clinical trials have shown that dasatinib induces rapid and deep responses in imatinib-resistant patients across all phases of CML and Ph+ ALL. While it is clear that the more potent activity of dasatinib against native and mutant variants of BCR-ABL is partly responsible for its clinical efficacy in imatinib-resistant CML, BCR-ABL–independent effects appear to play a role as well. Dasatinib has shown activity in imatinib-resistant patients with no detectable abl mutations.

Could its activity against SFKs be useful in other diesases? In particular, could it be useful in CLL? A paper just published online from Veldurthy and colleagues which include Michael Hallek suggests that dasatinib might have a role in the treatment of CLL.

It was already known from a JCI paper published in 2005 that CLL cells express Lyn protein between 2.5- and 5-fold more than normal B cells while in contrast, Src, Fyn, Fgr, and Lck levels were similar in normal and leukemic cells. Lyn distribution analyzed in normal B cells by confocal microscopy appears punctate and random across the plasma membrane whereas a more intense and coalescent fluorescence revealed that an abnormal amount of Lyn was present in the plasma membrane of leukemic cells, seemingly concentrated in lipid rafts. In contrast to normal B cells, Lyn tyrosine kinase is constitutively (ie switched on all the time) active in CLL cells, as demonstrated by remarkable kinase activity in the anti-Lyn immunocomplexes. These findings did not correlate with the expression of ZAP-70 or with the presence or absence of somatic mutations. In contrast, tyrosine kinase activity was undetectable in immunoprecipitates obtained in parallel experiments with anti-Src, anti-Fyn, anti-c-Fgr, and anti-Lck antibodies. Whereas stimulation of the BCR of normal B cells increases the amount of Lyn ninefold, no such increase is seen in CLL. It appears that the increased amount of Lyn is at least in part responsible for the defective apoptosis of CLL cells.

Veldurthy et al show that incubation of CLL cells with dasatinib markedly reduces tyrosine phosphorylation and also the downstream signalling pathways involving MAP kinase, Erk1/2, Akt and p38. Incubation with dasatinib increased apoptosis, an effect that was not inhibited by p53 deficiency or functional loss, but the effect of dasatinib was greater in CLLs with unmutated rather than mutated IGHV genes. The combination of fludarabine and dasatinib was additive.

One caveat to this exciting news. When CLL cells were co-cultivated with the bone marrow stromal cell line, HS5, a degree of protection was provided against dasatinib induced apaotosis, suggesting that the CLL cells might be safe from such an attack when residing in lymph nodes or bone marrow.

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.