Why don't the immune cells in our body run amok and attack our own tissues? Well, sometimes they do, resulting in autoimmune diseases like type I diabetes mellitus, pernicious anaemia, vitiligo, etc, but mostly they are kept in check.
The way this happens is through an elaborate system of checks and balances. The first of these occur in the thymus- the site of development and maturation of T cells, where they migrate soon after they are formed in the bone marrow.
In the thymus, young T cells come in contact with the body's own antigens- called "self antigens"- on the natural residents of the thymus- the epithelial & stromal cells. These antigens are recognised when they are "presented" to the maturing T cells, gift-wrapped in MHC molecules- also known as HLA, the major determinants of transplant success in allogenic transplants. T cells that recognise these MHC-self antigen complexes are selected to survive- a process called positive selection.
However, the thymus does not contain many antigens, which are sequestered in far-flung tissues of the body- the pancreatic antigens, for example. When the mature T cells are released into the circulation, there is a real danger that these would then attack the body's own tissues, mistakenly interpreting the hitherto hidden self antigens as foreign.
Why doesn't this happen?
This is because of need for co-stimulation. The mature T cell with its receptor bound to hitherto unfamiliar antigens carried on self MHC proteins is like a loaded gun....but with its safety-catch on. Co-stimulation is that safety catch.
I had alluded earlier to the fact that for T cells to recognise antigens, these must be carried in the groove of self MHC molecules. These molecules are in turn part of specialised cells called antigen presenting cells (APC).
When APCs, carrying the self MHC molecule, holding the antigen in its embrace, meets and binds to a T cell receptor, the T cell asks- "Is that all you have got for me? Where's your co-stimulation molecule?"
Every mature T cell constitutively expresses a marker called CD28. The ligand (something that it ligates) for this is something called B-7, present on APCs. There are two types of B7- B7-1 (also called CD80), and B7-2 (also called CD86). Only when a CD28 on T-cell binds to a B7 on an APC does the T cell become activated. Since this is required in addition to the T cell receptor recognising the putative (foreign) antigen bound to a self MHC molecule in the APC, the process is called co-stimulation.
The nice bit is that co-stimulation molecules on APC- B7- does not become expressed until the APC meets an invading pathogen. These pathogens have certain patterns- lipopolysaccharides on gram negative bacteria, for example- that are called pathogen associated molecular patterns or PAMPs. The PAMPs bind to certain probes on APCs that recognise them- called pattern recognition receptors or PRRs. The most well known PRRs are a group of primitive receptors called Toll-like receptors (TLR), characterised only recently from fruit flies.
Thus when the TLR or a similar PRR on the APC recognises a PAMP on an invading pathogen, B7 becomes expressed on the APC. The APC is now "licensed" to activate a mature T cell. The safety catch is off.
This principle has been exploited in medicine through a drug called Abatacept, used successfully in the treatment of Rheumatoid arthritis. Further attempts at exploiting the phenomenon backfired when volunteers at a drug trial in London became critically unwell after administration of an experimental drug. More on that soon.
Saturday, 13 March 2010
Monday, 8 March 2010
Why Aren't Women Men?
Why indeed? A woman has XX, men have XY. The Y chromosome is much smaller than the X chromosome, and virtually useless. It carries only around 100 genes. OTOH, The X chromosome contains several important genes, such as the hemophilia gene, the gene that controls the excretion of phosphate by kidneys, and the dystrophin gene, abnormalities in which accounts for Duchenne's Muscular Dystrophy.
If the X chromosome is so important, how then do men manage with only X chromosome, while women need two? The surprising answer is that soon after birth, a woman randomly inactivates one X chromosome in every cell of hers. It might be the paternal X chromosome or the maternal X chromosome that's inactivated, but not the same X chromosome in every cell, as otherwise women would be as prone to X linked disorders as men.
This is done by an extra-genetic mechanism called epigenetics- usually by methylation of cytosine bases in DNA, where they occur next to guanine bases- a pairing known as CpG- p stands for the phospate in the deoxyribose sugar that joins up nucleotide bases like cytosine and gunanine in the DNA. This has the effect of shutting off genes which are downstream of the methylated CpG unit.
Epigenetics is an amazing phenomenon and may explain some of the most amazing events seen in the inheritance of acquired traits. More on that later.
If the X chromosome is so important, how then do men manage with only X chromosome, while women need two? The surprising answer is that soon after birth, a woman randomly inactivates one X chromosome in every cell of hers. It might be the paternal X chromosome or the maternal X chromosome that's inactivated, but not the same X chromosome in every cell, as otherwise women would be as prone to X linked disorders as men.
This is done by an extra-genetic mechanism called epigenetics- usually by methylation of cytosine bases in DNA, where they occur next to guanine bases- a pairing known as CpG- p stands for the phospate in the deoxyribose sugar that joins up nucleotide bases like cytosine and gunanine in the DNA. This has the effect of shutting off genes which are downstream of the methylated CpG unit.
Epigenetics is an amazing phenomenon and may explain some of the most amazing events seen in the inheritance of acquired traits. More on that later.
Saturday, 10 October 2009
Laboratory of Molecular Biology, Cambridge- 14 Nobel Laureates
Quite amazing, isn't it? How many more would it have had, had UK not had an arbitrary retirement age of 65 for its scientists?
Here's the list
14. Venkataraman Ramakrishnan 2009 Chemistry
American. Awarded joint prize for elucidating the structure of ribosomes.
13. Sir John Sulston 2002 Medicine/Physiology
British. Awarded joint prize for genetic regulation of organ development and programmed cell death.
12. Robert Horvitz 2002 Medicine/Physiology
American. Awarded joint prize for genetic regulation of organ development and programmed cell death.
11. Sydney Brenner 2002 Medicine/Physiology
South African born. Joint prize for genetic regulation of organ development and programmed cell death.
10. John Walker 1997 Chemistry
British. Gained prize for explaining "the enzymatic mechanism underlying the synthesis of adenosine triphosphate".
8&9. Fred Sanger 1958 and 1980 Chemistry
British. Awarded first prize for work on structure of proteins and a joint prize for base sequences in nucleic acids.
7. Georges Köhler 1984 Physiology/Medicine
German. Awarded joint prize for work on immune system theories and developing monoclonal antibodies.
6. Jim Watson 1962 Physiology/Medicine
American. Awarded prize for joint discovery concerning the molecular structure of nucleic acids.
5. Cesar Milstein 1984 Physiology/Medicine
Argentinian born. Awarded joint prize for work on immune system theories and developing monoclonal antibodies.
4. Francis Crick 1962 Physiology/Medicine
British. Awarded prize for joint discovery concerning the molecular structure of nucleic acids.
3. John Kendrew 1962 Chemistry
British. Awarded joint prize with Max Perutz for their studies of structures of globular proteins.
2. Max Perutz 1962 Chemistry
Austrian born. Awarded joint prize with John Kendrew for their studies of structures of globular proteins.
1. Sir Aaron Klug 1982 Chemistry
Lithuanian born. Awarded prize for work on crystallographic electron microscopy and nucleic acid-protein complexes.
Here's the list
14. Venkataraman Ramakrishnan 2009 Chemistry
American. Awarded joint prize for elucidating the structure of ribosomes.
13. Sir John Sulston 2002 Medicine/Physiology
British. Awarded joint prize for genetic regulation of organ development and programmed cell death.
12. Robert Horvitz 2002 Medicine/Physiology
American. Awarded joint prize for genetic regulation of organ development and programmed cell death.
11. Sydney Brenner 2002 Medicine/Physiology
South African born. Joint prize for genetic regulation of organ development and programmed cell death.
10. John Walker 1997 Chemistry
British. Gained prize for explaining "the enzymatic mechanism underlying the synthesis of adenosine triphosphate".
8&9. Fred Sanger 1958 and 1980 Chemistry
British. Awarded first prize for work on structure of proteins and a joint prize for base sequences in nucleic acids.
7. Georges Köhler 1984 Physiology/Medicine
German. Awarded joint prize for work on immune system theories and developing monoclonal antibodies.
6. Jim Watson 1962 Physiology/Medicine
American. Awarded prize for joint discovery concerning the molecular structure of nucleic acids.
5. Cesar Milstein 1984 Physiology/Medicine
Argentinian born. Awarded joint prize for work on immune system theories and developing monoclonal antibodies.
4. Francis Crick 1962 Physiology/Medicine
British. Awarded prize for joint discovery concerning the molecular structure of nucleic acids.
3. John Kendrew 1962 Chemistry
British. Awarded joint prize with Max Perutz for their studies of structures of globular proteins.
2. Max Perutz 1962 Chemistry
Austrian born. Awarded joint prize with John Kendrew for their studies of structures of globular proteins.
1. Sir Aaron Klug 1982 Chemistry
Lithuanian born. Awarded prize for work on crystallographic electron microscopy and nucleic acid-protein complexes.
Friday, 8 May 2009
A British goodbye for TATA?
Jamshedpur boy- born and schooled. Of course I'd be a fan of TATA. The greatest Indian company that ever was. Not because of the immense profits they boast of, but because of the ethical bedrock on which those profits were made.
You run a poll here of the most respected Indians- and see who comes out on top- it'll be Ratan Tata- industrialist extraordinaire- Tata Sons chairman, and arguably india's greatest philanthroph. Who else would set up an entire plant to manufacture $2000 cars for the masses?
The Tatas are massive anglophiles. The love story dates back to 1907 when Jamshedji Nuseerwanji Tata set up TISCO in a remote village called Kalimati with the blessings of then British viceroy, the Earl of Minto. JRD Tata, the founder of India's first commercial airline, which later became Air India, was spawned of a French mother, and his first language was French. Yet, he studied engineering at Cambridge, and remained a lifelong anglophile despite his close ties to France.
Ratan Tata has simply carried on with that tradition. With india's growing prosperity, the Tatas became one of India's biggest overseas investors. First came Tetley, followed by high profile Anglo-Dutch steel company Corus and finally the jewel in the crown- Jaguar- Land Rover, formerly owned by Ford. All are, of course, British companies.
Yet, with the economic downturn, Britain has treated the Tatas very shabbily. When Tata asked for a £340 million loan to tide them over the difficulties at Jaguar Land Rover, the British government proposed such harsh terms and extreme oversight, that even the normally accomodating Ratan Tata balked. This despite the fact that TATA have bent over backwards to minimise job losses, choosing to cut hours and freeze pay instead.
Today, Tata's investment in Britain has run into further trouble. A Corus steel plant in Teesside faces closure because four long-term steel buyers, including companies in Italy and South Korea, are about to renege on a ten year business agreement.
This is catastrophic for the Tatas. Buffeted by the world downturn, hit by falling car sales and plunging steel prices, they have been losing money in their biggest markets. They need help from the UK government, where their principal investments lie.... and it's not forthcoming.
The reason it's not forthcoming is because the UK authorities have been bitten badly by the almost total collapse of their banks, particularly Royal Bank of Scotland and the Lloyds-HBOS group, which are now majority public owned. Former bank bosses have walked away with millions of pounds in severance and pensions and left behind smoking ruins, requiring massive taxpayer bailouts. The British government has watched impotently and vowed that they won't be taken for suckers ever again. More oversight, greater regulation, more big brotherhood.
Ratan Tata though, is not Sir Fred Goodwin. What Britain does not know is that TATA has an ethical CV that would put the greatest of well run companies to shame. They look after their employees, put welfare before profits, development before short term gain. I know. I was a beneficiary.
How do I tell Gordon Brown or Peter Mandelson though? If the Tatas go down in flames, Britain would have lost one of its most benevolent and caring investors and it'd be an absolute, crying shame.
You run a poll here of the most respected Indians- and see who comes out on top- it'll be Ratan Tata- industrialist extraordinaire- Tata Sons chairman, and arguably india's greatest philanthroph. Who else would set up an entire plant to manufacture $2000 cars for the masses?
The Tatas are massive anglophiles. The love story dates back to 1907 when Jamshedji Nuseerwanji Tata set up TISCO in a remote village called Kalimati with the blessings of then British viceroy, the Earl of Minto. JRD Tata, the founder of India's first commercial airline, which later became Air India, was spawned of a French mother, and his first language was French. Yet, he studied engineering at Cambridge, and remained a lifelong anglophile despite his close ties to France.
Ratan Tata has simply carried on with that tradition. With india's growing prosperity, the Tatas became one of India's biggest overseas investors. First came Tetley, followed by high profile Anglo-Dutch steel company Corus and finally the jewel in the crown- Jaguar- Land Rover, formerly owned by Ford. All are, of course, British companies.
Yet, with the economic downturn, Britain has treated the Tatas very shabbily. When Tata asked for a £340 million loan to tide them over the difficulties at Jaguar Land Rover, the British government proposed such harsh terms and extreme oversight, that even the normally accomodating Ratan Tata balked. This despite the fact that TATA have bent over backwards to minimise job losses, choosing to cut hours and freeze pay instead.
Today, Tata's investment in Britain has run into further trouble. A Corus steel plant in Teesside faces closure because four long-term steel buyers, including companies in Italy and South Korea, are about to renege on a ten year business agreement.
This is catastrophic for the Tatas. Buffeted by the world downturn, hit by falling car sales and plunging steel prices, they have been losing money in their biggest markets. They need help from the UK government, where their principal investments lie.... and it's not forthcoming.
The reason it's not forthcoming is because the UK authorities have been bitten badly by the almost total collapse of their banks, particularly Royal Bank of Scotland and the Lloyds-HBOS group, which are now majority public owned. Former bank bosses have walked away with millions of pounds in severance and pensions and left behind smoking ruins, requiring massive taxpayer bailouts. The British government has watched impotently and vowed that they won't be taken for suckers ever again. More oversight, greater regulation, more big brotherhood.
Ratan Tata though, is not Sir Fred Goodwin. What Britain does not know is that TATA has an ethical CV that would put the greatest of well run companies to shame. They look after their employees, put welfare before profits, development before short term gain. I know. I was a beneficiary.
How do I tell Gordon Brown or Peter Mandelson though? If the Tatas go down in flames, Britain would have lost one of its most benevolent and caring investors and it'd be an absolute, crying shame.
Friday, 1 May 2009
Applications of Calculus in Medicine....continued
Here's a second example, courtesy mathhelpforum. I recommend this site to anybody who has the remotest interest in Maths. It has some of the best contributors I've seen on math blogs on www, always ready to help out, and with some amazing problem solving skills.
Applications of Calculus in Medicine
I'll be using this part of the blog to illustrate some applications of calculus in Medicine. Here's the first one. To enlarge, please click on the image.
Sunday, 12 April 2009
Race Matters
Nope, this is not going to be a rant on the evils of racism, ethnicism, or any other ~ism. This is simply an attempt at pointing out why your ethnic origins define who you are...medically.
Indians immigrate all over the world. Just like I did. We assimilate into the local populace, pick up their diet and habits, and in due course become creatures moulded in the image of the indigenous population, a process that is known as acculturation.
Yet, at the very core, we remain very different beings- and I am not refering to our undying affinity for cricket and almost ungovernable vice of wasting time on this game.
Consider this, if you are an Asian, you are almost twice as likely to get type II diabetes mellitus than the Caucasian neighbour who lives next door. Despite similar diets and body mass index, you are more likely to suffer from hypertension, and are at a greater risk of suffering from a heart attack. Your neighbour the Scotsman may be drinking 28 units of alcohol a week, at the upper limit of recommendation by the Chief Medical Officer, and getting away with it, except for the odd occasion when he gets pulled over on A66 for deviating off straight lines once too often, and suffers incrimination via a breath test. If you, dear fellow Indian, indulged in similar levels of alcohol consumption, you'd almost certainly suffer meltdown of your liver, or cirrhosis, as it's better known.
The unfairness of genetic wiring doesn't end there. If you put on a stone in weight- 6.3 kg to those uninitiated to the almost insane intricacies of British measures, you'd almost certainly develop osteoarthritis, your knee joints reduced to a slit, hobbling with pain while McBloke next door creaks downstairs with his 15 stone frame on his way to the pub. He'll get his comeuppance too- a decade later. Poor you. As if you didn't have enough to reckon with, with your higher odds of dying from liver, cervical or gallbladder cancer.
If you felt that was bad enough, wait till you hear this. Your skin was designed to make vitamin D, the increasingly important ingredient that ensures bone and muscle health, protects you from various cancers and for Mrs McWife next door, provides a shield against such debilitating conditions such as multiple sclerosis. The problem is, having immigrated to 47 degrees north, your access to sunshine has dwindled to nothing for four months through the winter months, and you develop debilitating aching in your muscles and joints all over. You struggle to get off a low chair. If you came to a jointo-logist like me, I'd measure your vitamin D levels and tell you that they are undetectable because you are simply not making enough big D in your skin. You'd look at me in that aggrieved way, raise your eyebrow and want to know why McNeighbour doesn't have the same problem. Well, two things- firstly, his lighter skin tone lets in more ultraviolet light to maximise the benefits of what little natural illumination there is- but he would, wouldn't he, he was born to this gloom, and this is evolution at work, and secondly, he eats loads of oily fish- salmon, tuna, mackarel and sardines, which you abhor, because they don't remind you of chicken bhuna and lamb karahi.
Have I driven you to the point of despair? Wait, there is some retribution. There are ailments which these annoyingly healthy caucasians suffer, which you, Jo Ahmad, almost have an insurance policy against. Multiple sclerosis, coeliac disease, pernicious anaemia, giant cell arteritis, polymyalgia rheumatica, cancers of breast, endometrium, lung and prostate...the list rolls on and on like a who's who of big bad baddies.
If that makes you feel slightly better about being brown (hey, didn't I warn you this was all about race?) you might be further buoyed to find out if you have a major surgical operation, you are much less likely to die of a deep vein thrombosis lodging in your lung as a clot (pulmonary embolus) some 5 days after the operation. Similarly, you are less likely to get unsightly varicose veins, and despite having overall less bone mass, your mum is less likely to fracture her hip than a Caucasian woman of her age.
I do not intend to be the purveyor of gloom, so let me remind you that nurture is as important as nature. If you exercise regularly and run 30 or so miles a week, your risk of developing diabetes, high blood pressure, suffering a heart attack and ending up with debilitating osteoarthritis are substantially diminshed despite your genetic handicap, although not altogether eliminated. Your cheery white family next door might similarly consider cutting down on alcohol and red meat and thus substantially reducing the risk of colon, breast, and oesophageal cancers. You might even consider taking this acculturation thing one step further by resolving to consume those disgusting oily fish a couple of times a week and boosting your vitamin D stores.
Don't do it all too quickly please. You wouldn't want to put me out of business now, would you?
Indians immigrate all over the world. Just like I did. We assimilate into the local populace, pick up their diet and habits, and in due course become creatures moulded in the image of the indigenous population, a process that is known as acculturation.
Yet, at the very core, we remain very different beings- and I am not refering to our undying affinity for cricket and almost ungovernable vice of wasting time on this game.
Consider this, if you are an Asian, you are almost twice as likely to get type II diabetes mellitus than the Caucasian neighbour who lives next door. Despite similar diets and body mass index, you are more likely to suffer from hypertension, and are at a greater risk of suffering from a heart attack. Your neighbour the Scotsman may be drinking 28 units of alcohol a week, at the upper limit of recommendation by the Chief Medical Officer, and getting away with it, except for the odd occasion when he gets pulled over on A66 for deviating off straight lines once too often, and suffers incrimination via a breath test. If you, dear fellow Indian, indulged in similar levels of alcohol consumption, you'd almost certainly suffer meltdown of your liver, or cirrhosis, as it's better known.
The unfairness of genetic wiring doesn't end there. If you put on a stone in weight- 6.3 kg to those uninitiated to the almost insane intricacies of British measures, you'd almost certainly develop osteoarthritis, your knee joints reduced to a slit, hobbling with pain while McBloke next door creaks downstairs with his 15 stone frame on his way to the pub. He'll get his comeuppance too- a decade later. Poor you. As if you didn't have enough to reckon with, with your higher odds of dying from liver, cervical or gallbladder cancer.
If you felt that was bad enough, wait till you hear this. Your skin was designed to make vitamin D, the increasingly important ingredient that ensures bone and muscle health, protects you from various cancers and for Mrs McWife next door, provides a shield against such debilitating conditions such as multiple sclerosis. The problem is, having immigrated to 47 degrees north, your access to sunshine has dwindled to nothing for four months through the winter months, and you develop debilitating aching in your muscles and joints all over. You struggle to get off a low chair. If you came to a jointo-logist like me, I'd measure your vitamin D levels and tell you that they are undetectable because you are simply not making enough big D in your skin. You'd look at me in that aggrieved way, raise your eyebrow and want to know why McNeighbour doesn't have the same problem. Well, two things- firstly, his lighter skin tone lets in more ultraviolet light to maximise the benefits of what little natural illumination there is- but he would, wouldn't he, he was born to this gloom, and this is evolution at work, and secondly, he eats loads of oily fish- salmon, tuna, mackarel and sardines, which you abhor, because they don't remind you of chicken bhuna and lamb karahi.
Have I driven you to the point of despair? Wait, there is some retribution. There are ailments which these annoyingly healthy caucasians suffer, which you, Jo Ahmad, almost have an insurance policy against. Multiple sclerosis, coeliac disease, pernicious anaemia, giant cell arteritis, polymyalgia rheumatica, cancers of breast, endometrium, lung and prostate...the list rolls on and on like a who's who of big bad baddies.
If that makes you feel slightly better about being brown (hey, didn't I warn you this was all about race?) you might be further buoyed to find out if you have a major surgical operation, you are much less likely to die of a deep vein thrombosis lodging in your lung as a clot (pulmonary embolus) some 5 days after the operation. Similarly, you are less likely to get unsightly varicose veins, and despite having overall less bone mass, your mum is less likely to fracture her hip than a Caucasian woman of her age.
I do not intend to be the purveyor of gloom, so let me remind you that nurture is as important as nature. If you exercise regularly and run 30 or so miles a week, your risk of developing diabetes, high blood pressure, suffering a heart attack and ending up with debilitating osteoarthritis are substantially diminshed despite your genetic handicap, although not altogether eliminated. Your cheery white family next door might similarly consider cutting down on alcohol and red meat and thus substantially reducing the risk of colon, breast, and oesophageal cancers. You might even consider taking this acculturation thing one step further by resolving to consume those disgusting oily fish a couple of times a week and boosting your vitamin D stores.
Don't do it all too quickly please. You wouldn't want to put me out of business now, would you?
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