A relatively common problem in clinical practice is the young subject with hypertension in association with hypokalaemia and metabolic alkalosis. Physicians should resist the temptation of labeling this subset as "Essential Hypertension". A definitive diagnosis can be achieved with a bit of perseverance.
As medicine evolves, new paradigms displace old ones. Primary hyperaldosteronism was thought to be exceedingly rare. Not so. It is now recognised that 10-15% of subjects with hypertension have primary hyperaldosteronism. This is particularly true in young subjects, subjects with a strong family history of hypertension and those with hypokalaemia.
Yet, too much reliability has been placed on the presence of hypokalaemia as a marker of this condition. In fact, less than 50% of subjects with primary hyperaldosteronism have hypokalaemia. The rest are normokalaemic. Therefore it is important to have a high index of suspicion in young subjects, those with a strong family history of early onset hypertension, those with family history of stroke before age 40, and those with refractory hypertension, i.e. subjects whose BP remains uncontrolled despite three anti-hypertensives, including a diuretic.
The assessment should begin by measuring the ratio of plasma aldosterone to plasma renin activity (PRA). A ratio of >30 with an absolute concentration of aldosterone of>415 pmol/l and in particular, a completely suppressed PRA is virtually diagnostic of primary hyperaldosteronism.
The most common cause of this condition is idiopathic adrenal hyperplasia (IHA), causing bilateral hyperplasia of the adrenals, accounting for 65% of cases. Around 30% of cases are due to unilateral adrenal adenomas. The other 5% comprises 3 rare disorders- hereditary hyperaldosteronism types 1,2 and 3.
Type 1 hereditary hyperaldosteronism is a fascinating condition. Also called glucocorticoid remediable aldosteronism (GRA), this rare autosomal dominant condition is due to the fusion of two genes- CYB11B1 and CYB11B2, whereby the enzyme aldosterone synthase comes under the control of ACTH. Thus, aldosterone is made in the zona fasciculata rather than zona glomerulosa and is suppressible by steroid therapy. Half of these subjects have a normal serum potassium.
Type 2 is simply an inherited predisposition to adrenal adenoma or hyperplasia.
What if the plasma renin and aldosterone are both raised? Think of renovascular hypertension, renin secreting tumours, coarctation of aorta and subjects on diuretics.
Then there are those whose plasma renin and aldosterone are both suppressed. These subjects have a non-aldosterone related cause for their hypertension such as hypercortisolism due to Cushing's syndrome, Syndrome of Apparent Mineralocorticoid Excess (SAME), or excessive liquorice intake, certain causes of congenital adrenal hyperplasia such as 11-beta hydroxylase deficiency, deoxycorticosterone secreting tumours and Liddle's syndrome.
Two inherited conditions deserve special mention. SAME is a rare autosomal recessive condition due to inherited deficiency of 11-beta hydroxysteroid dehydrogenase deficiency. This is a renal enzyme that converts cortisol to inactive cortisone. When this enzyme is deficient or inhibited by liquorice, or overwhelmed by excessive production of cortisol, as in Cushing's syndrome (particularly due to ectopic ACTH production from small cell or other tumours), cortisol is freed up to act on the mineralocorticoid receptors and mimic the action of aldosterone. These patients tend to have a very low serum potassium.
The other inherited disorder with suppressed aldosterone and renin levels is Liddle's syndrome. This is an autosomal dominant condition where epithelial sodium channels responsible for reabsorption of tubular sodium at the expense of potassium remain constitutively open due to inability to remove the beta or gamma subunits of these channels. The removal of these channels from the tubular epithelium depends on an uniquitin ligase called Nedd, which is defective in Liddle's patients. Intuitively, direct potassium channel blockers such as amiloride and triamterene work well in the treatment of hypertension in Liddle's syndrome, while aldosterone antagonists such such as spironolactone do not. It's worth remembering that as in GRA, over half of subjects with Liddle's syndrome have normal serum potassium.
In subjects with high aldosterone:PRA ratio, the next test is salt loading to see if the serum aldosterone levels are suppressible. This can be done as an inpatient after infusing IV saline, or as an outpatient, after loading for 3 days with oral salt tablets. Subjects with primary aldosteronism will not suppress their aldosterone levels after salt loading.
Such subjects should then have a CT scan to pick up an adrenal adenoma putatively responsible for the excess aldosterone. If the CT does not show an adenoma, and irrespective of the CT results in subjects over the age of 40, most authorities would recommend that patients should have adrenal vein sampling for aldosterone:cortisol ratio to distinguish functional adenoma from IHA. Subjects under 40 with an obvious adenoma on CT should be directly considered for surgical adrenalectomy. Conversely, those with IHA would benefit from medical management with spironolactone.
Acknowledgement: uptodate.com
Monday, 1 April 2013
Saturday, 23 July 2011
Restaurant Maths
I was at a dinner the other night at a restaurant when we moaned about the fact that the rectangular table was so long that those of us at one end could hardly speak to those at the other. Restaurant designers are acutely aware of the fact for a given perimeter, a circle occupies the greatest area of all possible shapes.
Talk therefore turned to circles and my colleague said the volume of a sphere is obtained by integrating the area of a circle.
I did a quick differentiation in my mind- 4/3 pi r^3 differentiates to 4 pi r^2, so it was easy to prove him wrong.
I just found out why- the area of a sphere is given by 4 pi r^2.
But hey, did you know this? For a cone, sphere and cylinder, where radius equals height:
Volume of a cone= 1/3 pi r^2. h= 1/3 pi r^2.2r= 2/3 pi.r^3 X 1
Volume of a sphere= 4/3 pi r^3= 2/3 pi. r^3 X 2
Volume of a cylinder= pi.r^2.h= pi.r^2.2r= 2/3 pi.r^3 X 3
Therefore the volume of equiradial cone, sphere and cylinder has a ratio of 1:2:3.
The relationshiip between the cone and cylinder is a bit obvious, but I had no idea that you could make a sphere out of 2 cones or a cylinder out of 1.5 spheres. Did you?
Talk therefore turned to circles and my colleague said the volume of a sphere is obtained by integrating the area of a circle.
I did a quick differentiation in my mind- 4/3 pi r^3 differentiates to 4 pi r^2, so it was easy to prove him wrong.
I just found out why- the area of a sphere is given by 4 pi r^2.
But hey, did you know this? For a cone, sphere and cylinder, where radius equals height:
Volume of a cone= 1/3 pi r^2. h= 1/3 pi r^2.2r= 2/3 pi.r^3 X 1
Volume of a sphere= 4/3 pi r^3= 2/3 pi. r^3 X 2
Volume of a cylinder= pi.r^2.h= pi.r^2.2r= 2/3 pi.r^3 X 3
Therefore the volume of equiradial cone, sphere and cylinder has a ratio of 1:2:3.
The relationshiip between the cone and cylinder is a bit obvious, but I had no idea that you could make a sphere out of 2 cones or a cylinder out of 1.5 spheres. Did you?
Sunday, 26 June 2011
The Worm That Won Three Nobels
Meet Caenorhabditis elegans, or simply C.elegans. Roundworm extraordinaire, 1 mm long. Multicellular eukaryote. Superstar.
Simple to study, it was the organism that has 35% homology (similarity) to human DNA. The prototype organism, where apoptosis- programmed cell death- was studied. Apoptosis is the reason why the cells of your immune system wither and die in an orderly fashion after killing the bad bugs, rather than running out of control and killing you off instead. When things go wrong with apoptosis, bad things happen- like autoimmune diseases, or cancer. Brenner, Horvitz & Sulston walked with the Medicine Nobel for this work in 2002.
Want to study the function of a particular gene? No problem. Catch a C.elegans, douse it in some double stranded RNA with a complimentary sequence to the bit of DNA you want to study. The dsRNA will home in to the complimentary sequence of the DNA like a long lost brother and join up (hybridise). Result? The protein produced by the gene will be silenced, and presto, because C.elegans stops producing that protein, you know the function of that gene. Cue Nobel for Fire & Mello for Physiology & Medicine in 2006.
Want to label a protein produced by a living organism with a fluorescent biomarker without killing the organism? Try Green Fluorescent Protein or GFP as it's known, first isolated from a jellyfish. Chalfie, Shimomura and Tsien introduced the gene for GFP adjacent to the regulatory sequence (big brother gene) governing the transcription of a certain protein in C.elegans. The protein lit up like Guy Fawkes night under blue light, fluorescing a bright green. It's been used many many times since then to tag proteins, a use that earned the trio, and C.elegans its 3rd Nobel Prize in 6 years, this time in Chemistry, in 2008.
Inspirational worm, C.elegans. Rewarded by my university, the University of Nottingham, with an all expenses paid two week jaunt on The International Space Station to study the effect of zero gravity on muscle. It even has its own social networking site, called- you guessed it- Wormbook.
Simple to study, it was the organism that has 35% homology (similarity) to human DNA. The prototype organism, where apoptosis- programmed cell death- was studied. Apoptosis is the reason why the cells of your immune system wither and die in an orderly fashion after killing the bad bugs, rather than running out of control and killing you off instead. When things go wrong with apoptosis, bad things happen- like autoimmune diseases, or cancer. Brenner, Horvitz & Sulston walked with the Medicine Nobel for this work in 2002.
Want to study the function of a particular gene? No problem. Catch a C.elegans, douse it in some double stranded RNA with a complimentary sequence to the bit of DNA you want to study. The dsRNA will home in to the complimentary sequence of the DNA like a long lost brother and join up (hybridise). Result? The protein produced by the gene will be silenced, and presto, because C.elegans stops producing that protein, you know the function of that gene. Cue Nobel for Fire & Mello for Physiology & Medicine in 2006.
Want to label a protein produced by a living organism with a fluorescent biomarker without killing the organism? Try Green Fluorescent Protein or GFP as it's known, first isolated from a jellyfish. Chalfie, Shimomura and Tsien introduced the gene for GFP adjacent to the regulatory sequence (big brother gene) governing the transcription of a certain protein in C.elegans. The protein lit up like Guy Fawkes night under blue light, fluorescing a bright green. It's been used many many times since then to tag proteins, a use that earned the trio, and C.elegans its 3rd Nobel Prize in 6 years, this time in Chemistry, in 2008.
Inspirational worm, C.elegans. Rewarded by my university, the University of Nottingham, with an all expenses paid two week jaunt on The International Space Station to study the effect of zero gravity on muscle. It even has its own social networking site, called- you guessed it- Wormbook.
Sunday, 30 May 2010
The Versatile Cancer Genes
Elsewhere in this blog, I have referred to how DNA damage can be repaired through a combination of homologous recombination and base excision repair. The well known mediators of homologous recombination are BRCA1 & BRCA2. Women who carry defective BRACA 1 or 2 allele are at increased risk of breast, and in the case of BRCA2 loss, breast and ovarian cancer. Men who have lost a wild type BRCA2 allele are also at increased risk of breast cancer.
It is thought that breast or ovarian cancer develops when the remaining healthy allele becomes mutated in the adult- a process called somatic mutation, to differentiate it from germline mutations, which are inherited.
Those with defects in both alleles of BRCA1 are thought unlikely to survive beyond a very early stage of their life- perhaps succumbing in utero or in early childhood. But what happens to those with two defective BRCA2 alleles at birth?
We didn't know, until now.
An illuminating article in the New England Journal of Medicine reveals that BRCA2 is in fact identical to FANCD1, one of the twenty proteins for whom defective genes have been found in Fanconi's anaemia, an autosomal recessive childhood onset severe anaemia with reduction of other cell lines as well, resulting in an aplastic picture.
It is thought that patients with Fanconi's anaemia are very susceptible to DNA damage through cross linking, such as by exposure to radiation. These patients are also susceptible to neoplastic processes such as acute leukaemias, which are curiously much more sensitive to agents such as cisplatin than ordinary leukaemias. It is thought that this is because of their cross linked DNA.
The twenty defective genes in Fanconi's anaemia are thought be responsible for DNA repair through homologous recombination. The process is started off by coming together of two proteins called FANCD2 and FANCI, which then associate with other downstream proteins, one of which is FANCD1....or BRCA2.
It is now realised that those with loss of both BRCA2 alleles through germline mutations develop Fanconi's anaemia, while those with loss of one allele are at increased risk of breast and ovarian cancer in life. Both processes are due to an inherent defect in DNA repair through homologous recombination.
Not surprisingly, defects in some of the twenty genes responsible for Fanconi's anaemia have also been described in other cancers. An innovative way of increasing the susceptibility of such cancers to cisplatin like chemotherapeutic agents is to expose such cells to DNA cross linking agents, as was demonstrated in Fanconi's anaemia.
Another disorder that epitomises the consequences of defective DNA repair is ataxia-telangiectasia, in which the fault lies with a gene described as ataxia-tengiectasia-mutated. Such patients present with immunodeficiency in addition to the obvious symptoms of ataxia & telangiectasia.
It's quite clear that some cancer genes give rise to more than one phenotype...and not just cancers either.
It is thought that breast or ovarian cancer develops when the remaining healthy allele becomes mutated in the adult- a process called somatic mutation, to differentiate it from germline mutations, which are inherited.
Those with defects in both alleles of BRCA1 are thought unlikely to survive beyond a very early stage of their life- perhaps succumbing in utero or in early childhood. But what happens to those with two defective BRCA2 alleles at birth?
We didn't know, until now.
An illuminating article in the New England Journal of Medicine reveals that BRCA2 is in fact identical to FANCD1, one of the twenty proteins for whom defective genes have been found in Fanconi's anaemia, an autosomal recessive childhood onset severe anaemia with reduction of other cell lines as well, resulting in an aplastic picture.
It is thought that patients with Fanconi's anaemia are very susceptible to DNA damage through cross linking, such as by exposure to radiation. These patients are also susceptible to neoplastic processes such as acute leukaemias, which are curiously much more sensitive to agents such as cisplatin than ordinary leukaemias. It is thought that this is because of their cross linked DNA.
The twenty defective genes in Fanconi's anaemia are thought be responsible for DNA repair through homologous recombination. The process is started off by coming together of two proteins called FANCD2 and FANCI, which then associate with other downstream proteins, one of which is FANCD1....or BRCA2.
It is now realised that those with loss of both BRCA2 alleles through germline mutations develop Fanconi's anaemia, while those with loss of one allele are at increased risk of breast and ovarian cancer in life. Both processes are due to an inherent defect in DNA repair through homologous recombination.
Not surprisingly, defects in some of the twenty genes responsible for Fanconi's anaemia have also been described in other cancers. An innovative way of increasing the susceptibility of such cancers to cisplatin like chemotherapeutic agents is to expose such cells to DNA cross linking agents, as was demonstrated in Fanconi's anaemia.
Another disorder that epitomises the consequences of defective DNA repair is ataxia-telangiectasia, in which the fault lies with a gene described as ataxia-tengiectasia-mutated. Such patients present with immunodeficiency in addition to the obvious symptoms of ataxia & telangiectasia.
It's quite clear that some cancer genes give rise to more than one phenotype...and not just cancers either.
Sunday, 23 May 2010
The Hardy Weinberg Distribution
The Hardy Weinberg distribution allows you to find out the prevalence of homozygotes and heterozygotes for given alleles if you know the overall prevalence of the disease.
Thus, say a trait has two phenotypes, a and b. "a" has an allele called p and "b" has an allele called q.
The prevalence of homozygotes for p or q would be p^2 and q^2 respectively. The prevalence of heterozygotes would be 2pq.
This is easy to understand. Say if you dip into a bag containing two types of marbles- a & b, whose proportions are p & q respectively. The chances that you pick out "a" first time is of course, p. The chance of picking "a" twice in a row is p*p, and similarly the chances of picking "b" back to back is q*q.
If you picked "a" first, the chance that you'd pick "b" next is of course p*q. If you pick "b" first the chance that you'd pick "a" next q*p. Thus the chance that you'd pick a combination of a & b in two attempts is 2pq.
Let's look at two applications of this.
An African boy has sickle cell anaemia, an autosomal recessive disease with a prevalence of 1 in 500 among Blacks. His sister is getting married to a man of same ethnic origin, and wants to know the odds that her partner, who is unrelated to her, is a carrier.
For an autosomal recessive disorder, cases are obligate homozygotes, and therefore will have their distribution given by p^2. Thus, p^2= 1/500, or p= sq root 1/500= 1/22 (approx).
Thus, the likelihood that her husband would be a heterozygote would be 2pq or 2*1/22*21/22= 1/11 (approx).
Let's take another example. Haemophilia has a population prevalence of 1 in 5000. What's the likelihood that a random female would be a carrier?
Since haemophilia is an X linked trait, the prevalence of the disease is the same as that of the defective allele (since affected boys carry the defective allele on their only X chromosome). Thus, p= 1/5000.
Therefore the chance that an unselected female would be a carrier is 2pq= 2*1/5000*4999/5000= 1/2500.
The Hardy Weinberg distribution assumes that there is no inbreeding among relatives. In practice, many rare disorders express themselves more frequently in communities who inbreed. I'll deal with ways to get around this in another blog entry.
Thus, say a trait has two phenotypes, a and b. "a" has an allele called p and "b" has an allele called q.
The prevalence of homozygotes for p or q would be p^2 and q^2 respectively. The prevalence of heterozygotes would be 2pq.
This is easy to understand. Say if you dip into a bag containing two types of marbles- a & b, whose proportions are p & q respectively. The chances that you pick out "a" first time is of course, p. The chance of picking "a" twice in a row is p*p, and similarly the chances of picking "b" back to back is q*q.
If you picked "a" first, the chance that you'd pick "b" next is of course p*q. If you pick "b" first the chance that you'd pick "a" next q*p. Thus the chance that you'd pick a combination of a & b in two attempts is 2pq.
Let's look at two applications of this.
An African boy has sickle cell anaemia, an autosomal recessive disease with a prevalence of 1 in 500 among Blacks. His sister is getting married to a man of same ethnic origin, and wants to know the odds that her partner, who is unrelated to her, is a carrier.
For an autosomal recessive disorder, cases are obligate homozygotes, and therefore will have their distribution given by p^2. Thus, p^2= 1/500, or p= sq root 1/500= 1/22 (approx).
Thus, the likelihood that her husband would be a heterozygote would be 2pq or 2*1/22*21/22= 1/11 (approx).
Let's take another example. Haemophilia has a population prevalence of 1 in 5000. What's the likelihood that a random female would be a carrier?
Since haemophilia is an X linked trait, the prevalence of the disease is the same as that of the defective allele (since affected boys carry the defective allele on their only X chromosome). Thus, p= 1/5000.
Therefore the chance that an unselected female would be a carrier is 2pq= 2*1/5000*4999/5000= 1/2500.
The Hardy Weinberg distribution assumes that there is no inbreeding among relatives. In practice, many rare disorders express themselves more frequently in communities who inbreed. I'll deal with ways to get around this in another blog entry.
Saturday, 15 May 2010
Forensic Genetics- Righting A 30 Year Old Wrong
Recently, Raymond Towler was freed from a US jail on DNA evidence after being cleared of a rape conviction handed down 29 years ago.
Forensic genetics is still work in progress. However, it's not new. Thousands of 9/11 victims were identified through their DNA after the WTC catastrophe from their remains.
The very first use of forensic genetics was in 1986 in the UK. Two women, raped and murdered in Leicester in similar fashion 3 years apart, triggered an arrest. The suspect (bizarrely, as it turned out) confessed to the first murder, but not the second. The police approached Sir Alec Jeffreys at Leicester University, the then Professor of Genetics, for help. Based on DNA analysis from the murder scenes, the suspect was acquitted. A second man, Colin Pitchfork, was subsequently found guilty of both murders. He had escaped justice initially by volunteering his friend for a DNA sample he purported to be his own.
So how does DNA fingerprinting work? There are several techniques, but the most useful one makes use of short tandem repeats (STRs) present in the DNA sequence, usually comprising 4 bases such as GATT. The length of a STR is unique to each person. Each STR of course occupies a certain locus on a given chromosome, and as each chromosome is paired, each person possesses two STRs for a given locus, usually of varying length. Part of a sequence is denoted with a point (for example GATT GATT GATT GATT GA would be denoted as 4.2). If there are 4 repeats of GATT on one cheomosome, and 7 repeats on its allele, that is denoted as 4/7.
The USA has a national DNA database called CODIS, which contains around 5 million DNA fingerprints, a number similar to that held in the UK. CODIS is based on 13 different STRs, giving a likelihood that a given sequence will be matched of 1 in 1 trillion. The UK uses 10 STRs, giving a likelihood of match of 1 in a billion.
The frequency of a given allele in the population is given by the Hardy Weinberg equation. For a homozygous allele p, the frequency is given as p^2, while for heterozygous alleles p & q, the frequency is 2pq. To find the probability that all the STRs present in a given person could be replicated in another person, you multiply the probability of finding each STR in a given ethnic group. Therefore, the more STRs you use, the greater the certainty that no two individuals would have the same profile.
Sometimes DNA from victims can be badly degraded because of time elapsed, making STR analysis difficult or incomplete (say 8 STRs possible instead of 13). Under such circumstances, geneticists exploit single nucleotide polymorphisms (SNPs). These are single base differences that occur every 100 to 300 bases within the human genome. Two out of every 3 SNPs involve replacing a C with a T. By using enough SNPs, usually around 70 where C and T are likely to occur equally often, you can make it virtually certain that a profile cannot statistically belong to another human being on the planet. Thus, if all 70 SNPs were to occur independently, the likelihood of a match would be 2^70, or around 10^21. In practice, though, many of these do not assort independently, a phenomenon called linkage dysequilibrium, which still leaves us with a very high likelihood.
A third technique is to use mitochondrial DNA, which is inherited from the mother. This is highly preserved from one generation to the next, and it is thought that 5% of all Caucasians have the same mitochondrial DNA. It therefore lacks the discriminatory power of STRs. It doesn't degrade easily however, and has been used to solve historical mysteries, such as the one used to disprove Anna Anderson's claim to have descended from the Romanov family. The same investigation also showed that Prince Philip, the Duke of Edinburgh, was a descendant of the Russian Romanovs.
Forensic genetics is still work in progress. However, it's not new. Thousands of 9/11 victims were identified through their DNA after the WTC catastrophe from their remains.
The very first use of forensic genetics was in 1986 in the UK. Two women, raped and murdered in Leicester in similar fashion 3 years apart, triggered an arrest. The suspect (bizarrely, as it turned out) confessed to the first murder, but not the second. The police approached Sir Alec Jeffreys at Leicester University, the then Professor of Genetics, for help. Based on DNA analysis from the murder scenes, the suspect was acquitted. A second man, Colin Pitchfork, was subsequently found guilty of both murders. He had escaped justice initially by volunteering his friend for a DNA sample he purported to be his own.
So how does DNA fingerprinting work? There are several techniques, but the most useful one makes use of short tandem repeats (STRs) present in the DNA sequence, usually comprising 4 bases such as GATT. The length of a STR is unique to each person. Each STR of course occupies a certain locus on a given chromosome, and as each chromosome is paired, each person possesses two STRs for a given locus, usually of varying length. Part of a sequence is denoted with a point (for example GATT GATT GATT GATT GA would be denoted as 4.2). If there are 4 repeats of GATT on one cheomosome, and 7 repeats on its allele, that is denoted as 4/7.
The USA has a national DNA database called CODIS, which contains around 5 million DNA fingerprints, a number similar to that held in the UK. CODIS is based on 13 different STRs, giving a likelihood that a given sequence will be matched of 1 in 1 trillion. The UK uses 10 STRs, giving a likelihood of match of 1 in a billion.
The frequency of a given allele in the population is given by the Hardy Weinberg equation. For a homozygous allele p, the frequency is given as p^2, while for heterozygous alleles p & q, the frequency is 2pq. To find the probability that all the STRs present in a given person could be replicated in another person, you multiply the probability of finding each STR in a given ethnic group. Therefore, the more STRs you use, the greater the certainty that no two individuals would have the same profile.
Sometimes DNA from victims can be badly degraded because of time elapsed, making STR analysis difficult or incomplete (say 8 STRs possible instead of 13). Under such circumstances, geneticists exploit single nucleotide polymorphisms (SNPs). These are single base differences that occur every 100 to 300 bases within the human genome. Two out of every 3 SNPs involve replacing a C with a T. By using enough SNPs, usually around 70 where C and T are likely to occur equally often, you can make it virtually certain that a profile cannot statistically belong to another human being on the planet. Thus, if all 70 SNPs were to occur independently, the likelihood of a match would be 2^70, or around 10^21. In practice, though, many of these do not assort independently, a phenomenon called linkage dysequilibrium, which still leaves us with a very high likelihood.
A third technique is to use mitochondrial DNA, which is inherited from the mother. This is highly preserved from one generation to the next, and it is thought that 5% of all Caucasians have the same mitochondrial DNA. It therefore lacks the discriminatory power of STRs. It doesn't degrade easily however, and has been used to solve historical mysteries, such as the one used to disprove Anna Anderson's claim to have descended from the Romanov family. The same investigation also showed that Prince Philip, the Duke of Edinburgh, was a descendant of the Russian Romanovs.
Sunday, 9 May 2010
Synthetic Lethality- Strategies To Target Cancer
One way of targeting cancer cells is to aim for an antigen that's only present in cancer tissue and not in healthy tissues, for example with monoclonal antibodies to the epidermal growth factor called Her/neu present in certain breast cancers, through a now well known agent called Herceptin (Trastuzumab). However, this approach only works with a few cancers. Another ingenious approach is to exploit a phenomenon called Synthetic Lethality.
The DNA we all are made of undergoes thousands of breakages in every cell cycle. If this is not repaired, sooner or later, we'll all develop cancer. To ensure that this doesn't happen, nature has introduced more than one mechanism, a sort of backup that is termed redundancy in medicine. If one mechanism fails, there will be another that will repair the damaged DNA. Redundancy has to be there, because otherwise we'll simply cease to exist.
Here's where the opportunity for fighting cancer comes in. Nature's two most important methods of repairing DNA are through an enzyme called PARP1, which removes the defective DNA base pairs, allowing the defective bit to be repaired, and through a process called homologous recombination, where new DNA is generated from existing DNA. Remember, DNA has two strands, and all the info required to generate a fully functional DNA ribbon is present in any one strand.
This is no big deal and is not unique to human beings. For thousands of years, bacteria have repaired faults through homologous recombination. In 2007, two American & one British scientist were awarded the Nobel Prize in Medicine for describing this phenomenon and its applications in more detail.
Now we come to the nity-gritty. Most people will know by now that one of the biggest risk factors for breast and ovarian cancers is the presence of mutations in two vital genes called BRCA1 and BRCA2. These tend to run in families and increase the risk of these cancers severalfold.
How do you think the BRCA gene works? It codes for homologous recombination. "Defective" families carry one copy of the faulty gene and one healthy copy (called the "wild type allele"- in genetics, "wild" refers to the natural, healthy copy.) They only develop cancer when the healthy gene somehow undergoes a new mutation. The lifetime risk of such cancer is around 40% for carriers of the BRACA1 gene and around 20% for the BRCA2 gene. In desperation, many such poor women undergo "preventative" mastectomy or oophorectomy at a relatively young age for peace of mind.
Yet, now a study suggests that there is a way out of such terrible solutions. Remember the PARP1 enzyme I mentioned, the other part of the double act of DNA repair? When cancer develops in the BRCA mutation carriers because of an acquired defect in the remaining wild type gene, the cancerous cells become totally dependent on the PARP1 enzyme for DNA repair. Yet, the other, non-cancerous cells in the cancer sufferer are not dependent on PARP1 alone because they still have one functioning, healthy copy of the BRCA gene. Therefore, it follows that if you can target the PARP-1 in these women through a pharmacological agent, the cancer cells, having no means to repair their DNA, will die, while the healthy cells will be unaffected.
That's what synthetic lethality means. Two genes are said to be in a synthetic lethal relationship if defect in one can be compensated by the other. However, if both are defective, the cell will die.
Hats off to the cancer researchers. In a few years, it seems, we'll be able to beat familial breast & ovarian cancer, a task that once seemed insurmountable.
The DNA we all are made of undergoes thousands of breakages in every cell cycle. If this is not repaired, sooner or later, we'll all develop cancer. To ensure that this doesn't happen, nature has introduced more than one mechanism, a sort of backup that is termed redundancy in medicine. If one mechanism fails, there will be another that will repair the damaged DNA. Redundancy has to be there, because otherwise we'll simply cease to exist.
Here's where the opportunity for fighting cancer comes in. Nature's two most important methods of repairing DNA are through an enzyme called PARP1, which removes the defective DNA base pairs, allowing the defective bit to be repaired, and through a process called homologous recombination, where new DNA is generated from existing DNA. Remember, DNA has two strands, and all the info required to generate a fully functional DNA ribbon is present in any one strand.
This is no big deal and is not unique to human beings. For thousands of years, bacteria have repaired faults through homologous recombination. In 2007, two American & one British scientist were awarded the Nobel Prize in Medicine for describing this phenomenon and its applications in more detail.
Now we come to the nity-gritty. Most people will know by now that one of the biggest risk factors for breast and ovarian cancers is the presence of mutations in two vital genes called BRCA1 and BRCA2. These tend to run in families and increase the risk of these cancers severalfold.
How do you think the BRCA gene works? It codes for homologous recombination. "Defective" families carry one copy of the faulty gene and one healthy copy (called the "wild type allele"- in genetics, "wild" refers to the natural, healthy copy.) They only develop cancer when the healthy gene somehow undergoes a new mutation. The lifetime risk of such cancer is around 40% for carriers of the BRACA1 gene and around 20% for the BRCA2 gene. In desperation, many such poor women undergo "preventative" mastectomy or oophorectomy at a relatively young age for peace of mind.
Yet, now a study suggests that there is a way out of such terrible solutions. Remember the PARP1 enzyme I mentioned, the other part of the double act of DNA repair? When cancer develops in the BRCA mutation carriers because of an acquired defect in the remaining wild type gene, the cancerous cells become totally dependent on the PARP1 enzyme for DNA repair. Yet, the other, non-cancerous cells in the cancer sufferer are not dependent on PARP1 alone because they still have one functioning, healthy copy of the BRCA gene. Therefore, it follows that if you can target the PARP-1 in these women through a pharmacological agent, the cancer cells, having no means to repair their DNA, will die, while the healthy cells will be unaffected.
That's what synthetic lethality means. Two genes are said to be in a synthetic lethal relationship if defect in one can be compensated by the other. However, if both are defective, the cell will die.
Hats off to the cancer researchers. In a few years, it seems, we'll be able to beat familial breast & ovarian cancer, a task that once seemed insurmountable.
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