In this class section, Dr. Gilbert Chu, Stanford School of Medicine Professor of Medicine and Biochemistry, discusses DNA and recombination.
Dr. Pizzo begins with an introduction for Dr. Chu.
The three R's are replication, recombination and repair. Replication copies DNA, recombination rearranges DNA and repair repairs DNA.
DNA polymerase copies the DNA (template), which then needs a primer to get started the other way. The process involves nucleotide base pairs, A-G-C-T. How these are arranged instructs the cell on what kind of protein to make. Next he displays the replication fork.
The DNA synthesis happens only in the 5' to 3' direction. The two DNA strands are antiparallel. Leading strand synthesis is continuous. Lagging strand synthesis is discontinuous.
The three R's are replication, recombination and repair. Replication copies DNA, recombination rearranges DNA and repair repairs DNA.
DNA polymerase copies the DNA (template), which then needs a primer to get started the other way. The process involves nucleotide base pairs, A-G-C-T. How these are arranged instructs the cell on what kind of protein to make. Next he displays the replication fork.
The DNA synthesis happens only in the 5' to 3' direction. The two DNA strands are antiparallel. Leading strand synthesis is continuous. Lagging strand synthesis is discontinuous.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNAReplication.html
The replication is actually a two step process - first copying the opposite and binding pair and then creating a new strand that is opposite/complementary to the copy. That is A is copied as T and and G is copied as C. The copy is then paired with T to A and C to G.
So ATGC is copied as TACG, which then can generate the original sequence by pairing with its opposite, ATGC.
Next up is recombination, which rearranges the DNA. He uses a Mr. Potato Head as an example, which is funny. Recombination allows for new protein creation - think back to the jumping genes and transcription factors that Sapolsky covered. There are two basic types - homologous recombination and site specific recombination.
Homologous recombination repairs DNA double strand breaks. For example you could have a yellow strand and a red strand that have similar DNA sequences. The yellow strand experiences a disaster - a double strand break. The information is all screwed up - but it's able to locate a nearby strand that has the same DNA code as it - and use this as a template for repair. Through strand invasion - and by way of hydrogen bonding - the 3' pair goes out to get info. DNA polymerase then copies the needed info (missing bases).
This is what it would be like if you and the driver next to you both experienced a flat tire. You pull off the road and are able to watch him replace his tire with a spare tire. You, in turn, can copy his actions and replace your tire.
These DNA strand breaks are going on all the time. Oxygen free radicals are floating around making these breaks all the time. Cosmic rays. X-rays. Some plants create poisons that can cause these. Chemotherapy involves double strand breaks that kill off cancer cells a little bit faster than normal cells. The immune system makes these breaks on purpose (back to Sapolsky and jumping genes, the MHC and all those scary diseases).
This only happens during replication times and the strands must be approximately 95% or more homologous. Replication is accurate - 1 error in every 10,000,000 bases.
Without repair, you get mutations. On average you have to mutate about 6 very important genes to get a cancer. Cancer isn't one disease or type; it's proliferating cells that have mutated to the point where they are running the wrong program. When these cells begin interfering with the functioning of other organs, you get the possibility of death.
Young people get the cancers that require only 1 hit. Breast cancer, colon cancer, prostate cancer, pancreatic cancer - these are areas where 6 mutations are required.
Rad51 and BRCA2 proteins promote strand exchange. The Rad51 molecules load onto the protected DNA and assist with the strand invasion. BRCA2 helps load Rad51 on. It's assisted in this process by BRCA1.
BRCA1 and BRCA2 mutations cause breast cancer. Affected individuals carry one mutant and one normal allele of BRCA1 or BRCA2. Mutation of the 2nd allele in a breast cell disrupts homologous recombination. And thus defective repair of double strand breaks leads to breast cancer.
And so it's easier to get to 6 mutations because there's inadequate repair going on, so these will be the unfortunate women that get breast cancer in their 20's since it takes less time for the mutations to build up.
Allele is a fancy word meaning we have 2 copies of every gene (except men don't have a back-up copy of many genes due to being XY instead of XX).
When women are tested for BRCA1 and BRCA2, what they're looking for are mutations in either one of the alleles. When a mutation is discovered, the risk of developing breast or ovarian cancer goes up and the affected woman has to make tough decisions, possibly even having the organ removed.
Site specific recombination - retroviral integration. The retroviruses are RNA strands that copy themselves the other way, going from RNA to DNA instead of DNA to RNA to DNA.
Retroviruses cause human disease, such as HIV causing AIDS and Hepatitis B causing liver cancer.
The retroviruses undergo recombination with human DNA. They have integrase on them that enables them to pop themselves right onto our DNA and begin using us as the host for their own program.
Drug therapy, such as AZT, works on the integrase in the retrovirus, preventing it from doing its work effectively.
Unfortunately anti-cancer drugs can cause cancer, with an approximate risk of 5%.
This can also be used for our benefit with gene recombination in which retroviruses are used to introduce beneficial gene activity.
Base loss - a cell loses about 5,000 bases from its DNA each day. Base excision repair is responsible for repairing this. PARP-1 protein binds to the DNA gap to accelerate repair.
PARP-1 deficiency can be a problem. Without accelerated repair, a single strand break can become a double strand break when replication occurs. Homologous recombination can save the day (and you can see how there are multiple systems at work here to ensure that the DNA is adequately and accurately repaired.)
However, drugs have recently been developed that inhibit PARP-1 and, as a result, kill of BRCA1 and BRCA2 cancer cells. About 5% of breast cancers are affected.
He mentions that the new drug is an example of how the 3 r's can come together to create an effective drug that has hardly any side effects.
Plasmid DNA within bacteria can be used to create recombinant DNA (recombined DNA). This is done by opening a plasmid and inserting a desirable DNA sequence through a polymerase chain reaction. The recombinant DNA is then introduced to the host cell, which it invades and begins affecting. Because it is introducing desirable DNA sequences, the overall impact is beneficial. Remember that viruses are snippets of DNA or RNA that invade a host and manipulate the host into following the virus's program. By manipulating the virus's program, we can in turn manipulate what it is making the host cell do.
An example is EPO, erythropoieten, which stimulates the production of red blood cells. It binds to the "EPO receptor" on cells in the bone marrow. EPO is actually a red cell precursor (think transcription factor) and when it binds to the receptor, it signals the cell to divide, thus leading to the creation of more red blood cells. Red blood cells, among other duties, carry oxygen.
Natural epo is made by our kidneys. So anybody with kidney disease is at risk for lowered red blood cell counts as a result of reduced epo production by the kidneys.
The upside to EPO is that it treats the anemia associated with renal failure and cancer chemotherapy, it replaces infusion with injection, reduces strain on blood banks, and eliminates the risk of contracting a blood borne illness from donated blood.
The bad part begins with its potential use for competitive advantage in sports. For example, let's say we use cycling as the sport. A cyclist could use EPO injections to increase the red blood cell count in his body. Upping this increases the amount of oxygen available to his muscles. Increasing the amount of oxygen available to his muscles enables him to ride faster and longer than his opponents, thus greatly improving his odds of winning.
(As a side note, its undetectability is a great boon to potential cheaters. However, the flip side is that its undetectability is also a great boon to sore losers. If someone were simply a superior cyclist, he could be accused of doping and would not be able to clear his name solely on negative test results since they would be negative in any case.)
Even worse, bone marrow isn't the only cell type that has EPO receptors. Cancer cells do too, and the EPO injections can fuel the growth of cancer.
Next Dr. Chu presents a couple of examples with implications for health care in the US. In both cases spending more money leads to worse outcomes for the patients, but more money for the pharmaceutical companies.
It begins with pharmaceutical companies educating patients via ads. These ads, and we've all seen them, highlight some alleged health problem, suggest their drug as the solution, and advise you to speak with your doctor about it.
Neulasta stimulates production of white blood cells. It costs $2,500 per injection. With Blue Cross insurance the bill is $6,500. Medicare doesn't pay much more than the $2,500, so doctors and hospitals can't profit as much (which is one reason why the AMA opposes any public option that resembles a single payer or Medicare expansion model - it's too cheap on the cost side).
Amgen makes Epogen and Aranesp. Johnson and Johnson makes Procrit and Eprex. Together the 2004 sales of EPO amounted to $8.6 billion. The market was split - Amgen with the cancer patients, Johnson and Jonson with the kidney patients.
In 2007 Amgen's stock dropped precipitously (from $70 a share to about $50 in a few months' time) because the DAHANCA 10 trial demonstrated that EPO was a disaster for cancer patients. Rather than improving outcomes and lives, it was fueling cancerous growth. Apparently the thinking is that cancer cells are harder to kill when they don't have enough oxygen, so upping the oxygen supply should make radiotherapy more effective (?).
Oddly enough, similar results had already been published in Lancet in 2003.
So ATGC is copied as TACG, which then can generate the original sequence by pairing with its opposite, ATGC.
Next up is recombination, which rearranges the DNA. He uses a Mr. Potato Head as an example, which is funny. Recombination allows for new protein creation - think back to the jumping genes and transcription factors that Sapolsky covered. There are two basic types - homologous recombination and site specific recombination.
Homologous recombination repairs DNA double strand breaks. For example you could have a yellow strand and a red strand that have similar DNA sequences. The yellow strand experiences a disaster - a double strand break. The information is all screwed up - but it's able to locate a nearby strand that has the same DNA code as it - and use this as a template for repair. Through strand invasion - and by way of hydrogen bonding - the 3' pair goes out to get info. DNA polymerase then copies the needed info (missing bases).
This is what it would be like if you and the driver next to you both experienced a flat tire. You pull off the road and are able to watch him replace his tire with a spare tire. You, in turn, can copy his actions and replace your tire.
These DNA strand breaks are going on all the time. Oxygen free radicals are floating around making these breaks all the time. Cosmic rays. X-rays. Some plants create poisons that can cause these. Chemotherapy involves double strand breaks that kill off cancer cells a little bit faster than normal cells. The immune system makes these breaks on purpose (back to Sapolsky and jumping genes, the MHC and all those scary diseases).
This only happens during replication times and the strands must be approximately 95% or more homologous. Replication is accurate - 1 error in every 10,000,000 bases.
Without repair, you get mutations. On average you have to mutate about 6 very important genes to get a cancer. Cancer isn't one disease or type; it's proliferating cells that have mutated to the point where they are running the wrong program. When these cells begin interfering with the functioning of other organs, you get the possibility of death.
Young people get the cancers that require only 1 hit. Breast cancer, colon cancer, prostate cancer, pancreatic cancer - these are areas where 6 mutations are required.
Rad51 and BRCA2 proteins promote strand exchange. The Rad51 molecules load onto the protected DNA and assist with the strand invasion. BRCA2 helps load Rad51 on. It's assisted in this process by BRCA1.
BRCA1 and BRCA2 mutations cause breast cancer. Affected individuals carry one mutant and one normal allele of BRCA1 or BRCA2. Mutation of the 2nd allele in a breast cell disrupts homologous recombination. And thus defective repair of double strand breaks leads to breast cancer.
And so it's easier to get to 6 mutations because there's inadequate repair going on, so these will be the unfortunate women that get breast cancer in their 20's since it takes less time for the mutations to build up.
Allele is a fancy word meaning we have 2 copies of every gene (except men don't have a back-up copy of many genes due to being XY instead of XX).
When women are tested for BRCA1 and BRCA2, what they're looking for are mutations in either one of the alleles. When a mutation is discovered, the risk of developing breast or ovarian cancer goes up and the affected woman has to make tough decisions, possibly even having the organ removed.
Site specific recombination - retroviral integration. The retroviruses are RNA strands that copy themselves the other way, going from RNA to DNA instead of DNA to RNA to DNA.
Retroviruses cause human disease, such as HIV causing AIDS and Hepatitis B causing liver cancer.
The retroviruses undergo recombination with human DNA. They have integrase on them that enables them to pop themselves right onto our DNA and begin using us as the host for their own program.
Drug therapy, such as AZT, works on the integrase in the retrovirus, preventing it from doing its work effectively.
Unfortunately anti-cancer drugs can cause cancer, with an approximate risk of 5%.
This can also be used for our benefit with gene recombination in which retroviruses are used to introduce beneficial gene activity.
Base loss - a cell loses about 5,000 bases from its DNA each day. Base excision repair is responsible for repairing this. PARP-1 protein binds to the DNA gap to accelerate repair.
PARP-1 deficiency can be a problem. Without accelerated repair, a single strand break can become a double strand break when replication occurs. Homologous recombination can save the day (and you can see how there are multiple systems at work here to ensure that the DNA is adequately and accurately repaired.)
However, drugs have recently been developed that inhibit PARP-1 and, as a result, kill of BRCA1 and BRCA2 cancer cells. About 5% of breast cancers are affected.
He mentions that the new drug is an example of how the 3 r's can come together to create an effective drug that has hardly any side effects.
Plasmid DNA within bacteria can be used to create recombinant DNA (recombined DNA). This is done by opening a plasmid and inserting a desirable DNA sequence through a polymerase chain reaction. The recombinant DNA is then introduced to the host cell, which it invades and begins affecting. Because it is introducing desirable DNA sequences, the overall impact is beneficial. Remember that viruses are snippets of DNA or RNA that invade a host and manipulate the host into following the virus's program. By manipulating the virus's program, we can in turn manipulate what it is making the host cell do.
An example is EPO, erythropoieten, which stimulates the production of red blood cells. It binds to the "EPO receptor" on cells in the bone marrow. EPO is actually a red cell precursor (think transcription factor) and when it binds to the receptor, it signals the cell to divide, thus leading to the creation of more red blood cells. Red blood cells, among other duties, carry oxygen.
Natural epo is made by our kidneys. So anybody with kidney disease is at risk for lowered red blood cell counts as a result of reduced epo production by the kidneys.
The upside to EPO is that it treats the anemia associated with renal failure and cancer chemotherapy, it replaces infusion with injection, reduces strain on blood banks, and eliminates the risk of contracting a blood borne illness from donated blood.
The bad part begins with its potential use for competitive advantage in sports. For example, let's say we use cycling as the sport. A cyclist could use EPO injections to increase the red blood cell count in his body. Upping this increases the amount of oxygen available to his muscles. Increasing the amount of oxygen available to his muscles enables him to ride faster and longer than his opponents, thus greatly improving his odds of winning.
(As a side note, its undetectability is a great boon to potential cheaters. However, the flip side is that its undetectability is also a great boon to sore losers. If someone were simply a superior cyclist, he could be accused of doping and would not be able to clear his name solely on negative test results since they would be negative in any case.)
Even worse, bone marrow isn't the only cell type that has EPO receptors. Cancer cells do too, and the EPO injections can fuel the growth of cancer.
Next Dr. Chu presents a couple of examples with implications for health care in the US. In both cases spending more money leads to worse outcomes for the patients, but more money for the pharmaceutical companies.
It begins with pharmaceutical companies educating patients via ads. These ads, and we've all seen them, highlight some alleged health problem, suggest their drug as the solution, and advise you to speak with your doctor about it.
Neulasta stimulates production of white blood cells. It costs $2,500 per injection. With Blue Cross insurance the bill is $6,500. Medicare doesn't pay much more than the $2,500, so doctors and hospitals can't profit as much (which is one reason why the AMA opposes any public option that resembles a single payer or Medicare expansion model - it's too cheap on the cost side).
Amgen makes Epogen and Aranesp. Johnson and Johnson makes Procrit and Eprex. Together the 2004 sales of EPO amounted to $8.6 billion. The market was split - Amgen with the cancer patients, Johnson and Jonson with the kidney patients.
In 2007 Amgen's stock dropped precipitously (from $70 a share to about $50 in a few months' time) because the DAHANCA 10 trial demonstrated that EPO was a disaster for cancer patients. Rather than improving outcomes and lives, it was fueling cancerous growth. Apparently the thinking is that cancer cells are harder to kill when they don't have enough oxygen, so upping the oxygen supply should make radiotherapy more effective (?).
Oddly enough, similar results had already been published in Lancet in 2003.
http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_02_JohnsonJohnson-Procrit.htm
The thing is it's called the EPO receptor because it was first identified in bone marrow cells. But there's no law that says it can only be found on bone marrow cells. "Cancer" cells also have an epo receptor and in some cases rather than helping alleviate patients' suffering, epo induces cancerous growth. Not a great deal for $8.6 billion a year. Those cancer cells that have the receptor will respond by growing. Dr. Chu states that the FDA knew about it - well, the caption above is a link to their site with exactly this info, a full report from May 2004.
So let's go back to Professor Sapolsky's lectures on DNA. Recall that all cells have the DNA in them, but certain sections of the DNA serve as a sort of instruction manual for what the cell should do. Free floating hormones and transcription factors come along and activate strands of the DNA instruction booklet, leading to gene expression in one or multiple locations. Thus when a transcription factor, which is what epo essentially is, comes along and pings a cell, it activates that DNA instruction sequence. This is all well and good if it's a bone marrow cell that was always designed to be activated for this purpose. But activate a replication sequence in another cell that isn't supposed to get hit by epo and you have yourself a transcription factor promoting cell growth in a cell that wasn't supposed to have that string of DNA activated.
The EPO discussion broadens into an examination of the fee for service model of medicine. In this model, doctors are paid for what they do, what tests they order and what drugs they administer. This sets up a scenario in which treatments and drug prescriptions can be undertaken as much for the profit they provide as for any medical need (this was one of the selling points for HMO's - by only approving evidence based treatments, you reduce the costs associated with unnecessary treatment and thus drive down the overall cost of health care, and, theoretically, health care insurance.) He'll later recommend a book, On the Take by Jerome Kassirer, that examines the issue in depth (it's an excellent read).
A further break down looks like this. Pharmaceutical companies sponsor research and pay doctors in a variety of ways for trying out and/or endorsing their products. They also make significant contributions to the AMA. The AMA is involved with the establishment of proper treatment protocols, including what drugs should be prescribed. Going off label opens doctors and patients up to insurance company denials and doctors to questions of malpractice (regardless of whether the listed drugs are really what's best). So doctors benefit by taking handouts from pharmaceutical companies and are punished for deviations from the established path. This is fine as long as the drugs are ok, but when they aren't, people can be hurt. Vioxx will be described as an example - a fine drug when prescribed for the right patient but when over-prescribed (including to people at risk for heart attacks) it was fatal. Finally research protocols are an issue - often large trials are run on ideal candidates and higher risk subjects are excluded. In essence drugs are tested on the healthiest subjects available, approved and then given to the sickest ones too. This can have fatal consequences (viewers of ER will recall this was part of the beef between Benton and Vucelich - Benton being concerned that the constant unreported dropping of patients skewed the results and made the treatment appear better, and the risks lower, than was actually the case).
High drug costs yield high administration costs which equal big profit. For oncologists. And we wonder why end of life treatment eats up so many health care dollars.
By the way, this is what the "death panels" argument was really about. Sarah Palin couldn't care less if old people are left to die. But implementing evidence based, regulated medicine for end of life care will produce a lot of evidence that expensive treatments are often only as effective as placebos and give very little value in relation to their costs. Especially when those costs are analyzed in comparison to what they could have bought for other patients. Thus there's a risk that "death panels" would reject extremely expensive treatments that yield little for patients. Doing so would cost pharmaceutical companies billions of dollars in annual sales. There was never a true concern that President Obama would want to kill all the 82 year olds (bear in mind the accusations raised against him came from the same camp that would like to cut back on social security and medicare benefits...), but there was a huge concern that he might implement policies that refused to pay $6,500 for cancer causing EPO shots.
While that particular practice is out, it was no outlier. Kassirer offers numerous examples in his book.
Vioxx - a pain relieving drug that causing significantly less GI distress than its counterparts, including naproxen. 8 trials with independent end point committees demonstrated an overall 3.88 fold increase risk for heart attack from Vioxx use (8 trials without end point committees demonstrated a 0.79 fold increase). The Victor study was undertaken to see if Vioxx could reduce the risk for colon cancer (aspirin does this and is believed to do so by working on the Cox-2 receptor).
Here's how that works:
An inflammatory experience occurs and the body begins a stress response. The Cox-2 enzyme triggers prostaglandins in inflammatory cells which leads to pain, heat and swelling (and polyps in the colon - so stopping that reduces the risk of colon cancer recurring). On the other hand, the Cox-1 enzyme is also involved, but it does important things, helping with blood platelets (for blood clots) and mucus production for the stomach lining. Aspirin and Naprosyn block both Cox-1 and Cox-2 pathways. Thus you get relief from swelling (such as from arthritis) but you also have stomach problems. Vioxx, on the other hand, only hits the Cox-2 pathway, so it reduces the swelling without interfering with the housekeeping activities of Cox-1 enzymes. But this means that platelets will continue to form and one of the major protective benefits of aspirin - reduced stroke risk due to fewer blood clots - is lost in the exchange and a patient who was at risk for a stroke or heart attack will continue to be at risk, thus resulting in an increased heart attack rate in Vioxx patients viz-a-viz aspirin patients.
Returning to the costs of care versus quality of care, he shows charts that the US spends more per capita while only ranking 28th in the world in outcomes. Again, this is expensive treatments that don't really help. Also, this is people depending on drug treatments rather than lifestyle changes.
So let's go back to Professor Sapolsky's lectures on DNA. Recall that all cells have the DNA in them, but certain sections of the DNA serve as a sort of instruction manual for what the cell should do. Free floating hormones and transcription factors come along and activate strands of the DNA instruction booklet, leading to gene expression in one or multiple locations. Thus when a transcription factor, which is what epo essentially is, comes along and pings a cell, it activates that DNA instruction sequence. This is all well and good if it's a bone marrow cell that was always designed to be activated for this purpose. But activate a replication sequence in another cell that isn't supposed to get hit by epo and you have yourself a transcription factor promoting cell growth in a cell that wasn't supposed to have that string of DNA activated.
The EPO discussion broadens into an examination of the fee for service model of medicine. In this model, doctors are paid for what they do, what tests they order and what drugs they administer. This sets up a scenario in which treatments and drug prescriptions can be undertaken as much for the profit they provide as for any medical need (this was one of the selling points for HMO's - by only approving evidence based treatments, you reduce the costs associated with unnecessary treatment and thus drive down the overall cost of health care, and, theoretically, health care insurance.) He'll later recommend a book, On the Take by Jerome Kassirer, that examines the issue in depth (it's an excellent read).
A further break down looks like this. Pharmaceutical companies sponsor research and pay doctors in a variety of ways for trying out and/or endorsing their products. They also make significant contributions to the AMA. The AMA is involved with the establishment of proper treatment protocols, including what drugs should be prescribed. Going off label opens doctors and patients up to insurance company denials and doctors to questions of malpractice (regardless of whether the listed drugs are really what's best). So doctors benefit by taking handouts from pharmaceutical companies and are punished for deviations from the established path. This is fine as long as the drugs are ok, but when they aren't, people can be hurt. Vioxx will be described as an example - a fine drug when prescribed for the right patient but when over-prescribed (including to people at risk for heart attacks) it was fatal. Finally research protocols are an issue - often large trials are run on ideal candidates and higher risk subjects are excluded. In essence drugs are tested on the healthiest subjects available, approved and then given to the sickest ones too. This can have fatal consequences (viewers of ER will recall this was part of the beef between Benton and Vucelich - Benton being concerned that the constant unreported dropping of patients skewed the results and made the treatment appear better, and the risks lower, than was actually the case).
High drug costs yield high administration costs which equal big profit. For oncologists. And we wonder why end of life treatment eats up so many health care dollars.
By the way, this is what the "death panels" argument was really about. Sarah Palin couldn't care less if old people are left to die. But implementing evidence based, regulated medicine for end of life care will produce a lot of evidence that expensive treatments are often only as effective as placebos and give very little value in relation to their costs. Especially when those costs are analyzed in comparison to what they could have bought for other patients. Thus there's a risk that "death panels" would reject extremely expensive treatments that yield little for patients. Doing so would cost pharmaceutical companies billions of dollars in annual sales. There was never a true concern that President Obama would want to kill all the 82 year olds (bear in mind the accusations raised against him came from the same camp that would like to cut back on social security and medicare benefits...), but there was a huge concern that he might implement policies that refused to pay $6,500 for cancer causing EPO shots.
While that particular practice is out, it was no outlier. Kassirer offers numerous examples in his book.
Vioxx - a pain relieving drug that causing significantly less GI distress than its counterparts, including naproxen. 8 trials with independent end point committees demonstrated an overall 3.88 fold increase risk for heart attack from Vioxx use (8 trials without end point committees demonstrated a 0.79 fold increase). The Victor study was undertaken to see if Vioxx could reduce the risk for colon cancer (aspirin does this and is believed to do so by working on the Cox-2 receptor).
Here's how that works:
An inflammatory experience occurs and the body begins a stress response. The Cox-2 enzyme triggers prostaglandins in inflammatory cells which leads to pain, heat and swelling (and polyps in the colon - so stopping that reduces the risk of colon cancer recurring). On the other hand, the Cox-1 enzyme is also involved, but it does important things, helping with blood platelets (for blood clots) and mucus production for the stomach lining. Aspirin and Naprosyn block both Cox-1 and Cox-2 pathways. Thus you get relief from swelling (such as from arthritis) but you also have stomach problems. Vioxx, on the other hand, only hits the Cox-2 pathway, so it reduces the swelling without interfering with the housekeeping activities of Cox-1 enzymes. But this means that platelets will continue to form and one of the major protective benefits of aspirin - reduced stroke risk due to fewer blood clots - is lost in the exchange and a patient who was at risk for a stroke or heart attack will continue to be at risk, thus resulting in an increased heart attack rate in Vioxx patients viz-a-viz aspirin patients.
Returning to the costs of care versus quality of care, he shows charts that the US spends more per capita while only ranking 28th in the world in outcomes. Again, this is expensive treatments that don't really help. Also, this is people depending on drug treatments rather than lifestyle changes.
