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Cystic Fibrosis Channel (CFTR) in the cell membrane; ivacaftor works on the outside of the cell to increase the ease with which chloride ions can move through the channel formed by CFTR protein that spans the cell membrane many times

It seemed like a major medical miracle at the time: the defective gene which causes cystic fibrosis (CFTR gene which stands for Cystic Fibrosis Transmembrane Conductance Regulator) was identified and the world was waiting for the next step, perhaps a quick cure for the disease which many hoped would be realized shortly after discovery of the offending gene. After all, knowledge of the gene and the amino acid sequence of CFTR seemed like overcoming the major hurdle and the rest would be easy–a drug designer game–no problem. The CFTR gene identification however, was in 1989 and, although improvements in palliative therapeutic methods over the past forty years have dramatically prolonged the survival rate of those  afflicted with the disease (from an average age of 11 years to 37), no magical cure had emerged more than twenty years since the gene was first discovered. Now, very recently, the drug VX-770 (ivacaftor) was introduced that seems to offer a breakthrough for at least one subclass of patients with Cystic Fibrosis. As it turns out, Cystic Fibrosis is a disease that contains many different mutations of the CFTR gene, and only the mutation known as G551D, which has defective CFTR proteins that reach the surface of the cell are responsive to the drug (ivacaftor works by enhancing the transport of chloride through the CFTR channels, which improves the ability of the channel to participate in normal fluid regulation, reducing the sticky mucous secretions that, in the respiratory system, create a high risk of infection and restriction to normal air flow and oxygen exchange).  The G551D  mutation only accounts for 4 to 5% of the Cystic Fibrosis population. But the hope is that this drug will also help other mutations of the gene if they have at least some CFTR channels that make it to the surface of the cell.

Most of the cystic fibrosis patients have defects in the protein such that they never get placed in the cell membrane, because they are not folded properly and not recognized by the cell “as suitable for service.” Once the CFTR protein is properly placed in the cell membrane, it works by allowing chloride ions to more readily traverse the ion channel that they form, typically moving from the inside to the outside of the cell (with sodium and water coming through other channels) to provide a less viscous secretion into the respiratory tracts (other organs besides the lungs are similarly affected). Thus, while no single drug is likely to  relieve the entire panoply of cystic fibrosis mutations, this first step using ivacaftor has proven very promising in clinical trials. It is a novel drug that was created by twenty years of intensive research and new discoveries along the way that verified how complex a problem we face in generating a suitable cure, even if the structure of the disease-causing protein has been deciphered. VX-770 (ivacaftor) was developed by a method known as High Throuput Screening (HTS) in which 228,000 chemically diverse drug-like compounds were screened using a cellular assay for identifying CFTR potentiators. A multiple author paper was published in PNAS in 2009 and the results of a successful clinical trial were reported in the November 3, 2011 issue of the New England Journal of Medicine.

While this promising new drug gives us all reason to celebrate and enhance our hopes for future developments in this dreaded disease, we must also sober up for the struggle ahead, because this new drug (ivacaftor) does not address the central problem faced by the majority of patients with cystic fibrosis. About 90% of cystic fibrosis patients suffer from a form of the disease in which they do not produce a CFTR protein that partitions across  the cell membrane and would thus not be amenable to ivacaftor treatment. In a way, the drug works like hooking up your hose to a power washer, which increases the pressure and flow of water, but would not work without a source of water and the plumbing necessary to bring it to the device. The task ahead for the majority of cystic fibrosis patients is more sobering when compared to the achievement with ivacaftor and the subset of patients with G551D. Indeed a more complete cure, covering the entire spectrum of the cystic fibrosis patient population will very likely have to come from a gene replacement  strategy. But we have good news on that front as well: we have already had success with therapeutic gene-replacement approach in treating diseases such as Leber’s Congenital Amaurosis, through the injection of a single dose of adenovirus into the eye which had a copy of a healthy gene that replaced the defective RPE65 gene. RPE65 is required to regenerate the visual pigment (rhodopsin) that is necessary for the first step in capturing photic stimuli. Thus the patients with this deficiency were blind from an early age. Now the treated subjects can see and this mode of therapy will spread to eventually include many different forms of blindness, including retinitis pigmentosa, one of the major causes of human blindness.

It was once the case that drug therapy development was by fortuitous accident. The delay between the discovery of the gene and the first drug to target and improve CFTR action points out the difficulty that modern medicine faces: the transition from the era of chemical medicine (where you use the shotgun approach to try a lot of things and if one works you often don’t know why–such as the accidental discovery that antihistamines (chlorpromazine) dramatically improved some symptoms of schizophrenia and led to the elimination of several hundred thousand hospital beds in the 1950s that had been devoted to their care–even though the drug does not cure the disease) to molecular medicine (where the drug is designed to interact with targeted features of the offending molecule, or you replace the gene or prevent its expression)–can be a long, arduous and very painful process, filled with moments of hope and despair much like the medical quest for an AIDS vaccine; it is now more than thirty years since the AIDS virus was first discovered. We keep thinking that we will shorten the delay between discovery and cure, that each new breakthrough towards adopting molecular approaches will allow us to reach a threshold where a new pathway is illuminated to light the way for quickly curing all genetically-based diseases through a magical form of gene replacement therapy, while non-inherited chronic diseases will be cured with greater precision in drug development, like the results with ivacaftor. Each breakthrough like ivacaftor  treatment for cystic fibrosis gives us hope that we are approaching such a threshold and that we are getting closer to a  much broader and wiser view of the disease landscape.  But to get there, we still have to get a lot smarter about biology before any kind of medical avalanche for cures will flood the broad human pathology terrain.

When I was a medical student, during my rotation in medicine as a clinical clerk in my junior year, we admitted a young girl to the hospital with a raging pneumonia caused by her cystic fibrosis condition. It was a life-threatening situation, but she was finally discharged after a long period of antibiotic and pulmonary therapy. She was about 12 and was full of energy with high expectations for her future, though by then she had been admitted many times to the hospital with similar infections and she had obviously been afflicted with the disease from the time of her birth. The disease had also retarded her growth. It seemed like everyone in the hospital went out of their way to greet this young patient, as she was cheerful, charming and expressed with optimism the idea that she might have passed the most dangerous period of her disease and could now look forward to a future with more certainty and plan accordingly. Yet, a year later, I learned that she had been admitted again with another bout of pneumonia and died in the hospital. I never forgot that young patient and I think that experience accounts for my long-standing interest in cystic fibrosis and the CFTR ion channel.

RFM

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Strait of Hormuz (Wikipedia)

Last year, the drums of war began to beat as a result of supposedly new findings suggesting Iran had initiated a program for building a nuclear weapon. I previously wrote on the topic at the time and specifically pointed out the lack of hard evidence supporting such a conclusion: all of Iran’s known nuclear material was accounted for by the International Atomic Energy Agency (IAEA) and none of our intelligence had produced unambiguous evidence that bomb construction was underway. Indeed, our own intelligence estimate as recently as 2010 concluded that Iran was not working on a bomb. Now it seems the Israelis have come to the same conclusion. An article published in Haaretz, a left-leaning Israeli newspaper, began with the following lead: “Israel believes Iran itself has not yet decided whether to make a nuclear bomb, according to intelligence assessment to be presented later this week to U.S. Joint Chiefs of Staff Dempsey.”

A good article summarizing the significance of this report can be found in Juan Cole’s Informed Comment.  When Iran responded to the new military threats and sanctions by threatening to close the Strait of Hormuz (through which 20% of the world’s oil supply flows) if conflict should break out, the Obama administration decided to ratchet down the threat level and perhaps the article in Haaretz reflects the Israeli willingness to do the same. Obama faces a very tight election this year and does not want to see the cost of oil go up by the Iranians following through with their threats. He also apparently expressed his deep dissatisfaction with the Israelis over the recent assassination of an Iranian nuclear scientist.  Now if we can get Mitt Romney to stop fanning the flames of war  against Iran and lower the tension by a couple of decibels, we might be able to have an election without starting a war in the Middle East. We are truly a gifted nation when it comes to starting wars–we don’t have a problem mobilizing the popular support needed to take us into war–but it’s ending them that seems to give us great difficulty. At least for now perhaps the tension between Iran and the United States/Israel can be lowered and the rhetoric of war eliminated.  Our departure from Iraq has served to reduce friction between the U.S. and Iran, but until we have a peace agreement among the Palestinians and the Israelis, the region will always be a flashpoint. The right wing Likud government in Israel is always sounding the alarm about Iran and we have the habit of believing their intelligence more than we do our own.  The full impact of the Arab Spring has yet to achieve a steady state in the region. But that event also reflects joblessness and economic hardship together with trends in food prices and this is a long and deep economic recession. Each time we increase the tension between the U.S. and Iran, we enhance the position of the hard-line ruling clerics and diminish the prospects of bringing the full-throated Arab Spring to that country. This is the same mechanism we used to prolong the Cold War.

Whenever we attach the word “war” to a conflict, like the “war on drugs” or the “war on terror (ism?)”, we tend to make them into a new version of a never-ending story. Imagine how different it would be if be used the label “skirmish on drugs” or “conflict against terror (ism?).” Wouldn’t those terminology examples make it easier to know when to quit? The word “war” seems to demand a winner and a loser, something we rarely achieve or if we achieved it in Iraq, for example, we did so by utterly destroying their culture and devastating millions of lives–all innocent victims of our shock and awe strategy of warfare. But, when confronted with a “skirmish,” it seems more like a cease fire until you can get the whole thing straightened out by some sort of agreement. I am in favor of any congressional act that would outlaw the use of “war” and reserve that for those circumstances where our nation is truly imperiled by circumstances we didn’t create for ourselves. That would mean we can’t have war against terrorism or a war on drugs or a war on obesity. Furthermore we should extend the ruling so that a President cannot make a judgement about whether a conflict should be viewed as “war.” Like the Constitution, only Congress can declare war. With those rules in hand, we might be able to bring to a much faster resolution the conflicts and wars we start by emphasizing that a war by any other name is a “skirmish,”  and if you lose, it will only be a blemish on your war record, nothing more serious.

RFM

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Wages vs Productivity in America

Les Leopold, writing in Alternet,  has provided an excellent, graph-driven account of why we have an Occupy Wall Street (OWS) movement today. They are demonstrating for the same reasons that each of us might offer about the financial condition of our country and why we see so little opportunity for job prospects now and into the future. For those people that have jobs, they are finding it difficult to make ends meet, many are  loaded with student loan debt and and large numbers of Americans are being evicted from their homes, with many others teetering on the brink of foreclosure.  Government has not only failed them, but participated in the actions that reduced employment opportunities to a shadow of what is needed for a healthy society. The government bailout has been directed to the wealthy, many of whom caused the economic meltdown in the first place.  Our culture and economy have been hollowed out by those still in charge, yet these same players continue to generate new high risk investment “instruments” and still send jobs overseas. If the OWS demonstration doesn’t grow into a national crescendo, it’s because we will allow it to fail–it is our turn to step in, support the  movement and facilitate their energy to build a national consensus for making a new economy that works more effectively for people, with enhanced wages, reduced costs for education (do you remember when tuition at the University of California was free until Ronald Reagan introduced tuition charges which have now soared to all time highs?), reversing our expensive, privatized culture and do so with a progressive tax base that stabilizes our society and allows us to rebuild a very broken economy–one that includes vitality in its support of a stable, social safety net. These are not impossible goals. The economy needs to work for all of us, from top to bottom and for too long we have neglected the latter in favor of the former.  We need our country back, the one we assumed we had all along, the one that slowly eroded without our notice because of the small incremental steps that were  too subtle for human detection. In retrospect however, we went over a cliff.

We have a long way to go before we achieve a sense of national focus on the right target and the means to achieve these objectives.  But the OWS movement got the place right.  The financialization of America has been a bad turn of events, not a good one. The wages vs productivity in America  graph [taken from lepold's article]  illustrates what happened to the wages of the American worker over the past several decades and why there is an Occupy Wall Street movement gaining momentum today.  Throughout most of our history [United States] there existed a tight relationship  between worker productivity (economic output per hour of labor) and wages (weekly wages in the graph have been inflation adjusted to 2008 dollars).  When expressed in this way, you can see how the wages and productivity  tracked one another, but began  to deviate in the late 1960s, at which time wage earners’ weekly income  fell flat ,though productivity continued to grow: on this scale the highest weekly wage was $746 a week in 1971-1972 ($2008), but could be, in today’s $ more than $1000 per week had the relationship between productivity and wages continued at it’s pre-1960s relationship.   What happened quite simply was that management stopped rewarding workers for their increase in productivity and started to use the additional profits from gains in productivity to plow them back into the organization, reporting them as increased profits which led to enhanced value for publicly traded stock. A rise in the value of the stock enhanced the personal gain of management and made them look like geniuses, when all the while it was in reality a transfer of wealth from workers to management. Stock purchases increasingly became part of the CEO salary picture and eventually could be back-dated to insure a handsome golden parachute. Simultaneous with the development of the golden parachute for management, the gold watch for employees  went the way of the Dodo bird. The wild merger mania that occurred during the Reagan years led to a decrease in plant efficiency, compensated by downsizing, robbing retirement packages and selling off assets of companies. Mergers led to a decreased competition and upward movement of prices. Eventually local stores would be replaced by Wal-Mart, whose low wages were supplemented by the social safety net at public expense. Wall-Mart continues to be a government-subsidized operation and has contributed to the third world-like feminization of labor.

The figure on the right, also from Les Leopold’s article in Alternet  illustrates how the loss of worker’s compensation helped to elevate the top 100 CEO salaries based on the average worker’s annual salary. Here you see an explosive growth in CEO salary from 45x in 1970 to 1723x in 2006. You can argue that this massive salary increase was created by taking the salary deserved by workers for their increased productivity and then diverting it into corporate income and stock values.  This change did not happen by accident. It happened when the neoliberal movement began to change the nature of our economy and culture, to emphasize free market conditions and globalization, as national borders began to melt and multinational corporations begin to emerge with huge influence on the laws that regulated business and capital markets. The flaw that exists today in Wall Street is continued belief in the idea that a free market is a perfect instrument and, in time, will solve all problems. These same neoliberal capitalists also express the idea that a financial crisis is good once in a while to wipe the slate clean and get a fresh start. Increasingly, from the dotcom crisis of 2001 and the Great Recession of today have reduced labor costs substantially. The Republicans are voting to maintain the current crisis to further reduce labor costs of the American work force. Indeed, for each crisis created by capitalism, a labor surplus is created which allows the capitalist class to manipulate working conditions further by having an excess of labor such that labor lowers their demands and becomes more pliable.

Rate of top 100 CEO salaries per average worker annual salaries

Did it ever occur to you that despite the fact that for decades we have been aware of the salary inequities between men and women, who earn less for the same work, the situation has not really changed, despite social pressure to establish gender equity in salary. That is the nature of neoliberal policy–keep women’s salaries as low as possible and move more women into the work force, thus reducing total labor costs. We may want to think that the feminization of our work force was done in the name of gender equity, a noble cause,  but neoliberal policy means that a net reduction in labor cost is achieved when more women enter the work force, such that maintaining women’s salaries below their male counterparts reduces labor costs as the proportion of the work force increases in female representation. If you look at the global labor situation, where a more informal manufacturing has taken place in some industries, such as making shoes or clothing in third-world countries, often localized in Export Processing Zones (EPZs),  more and more women have entered the work force, some with children, who can adapt to  flexible hours of work consistent with their needs for child care, particularly in single parent families. Neoliberal strategies for cheap female labor have also led to slave labor prostitution among very young women and this is a growing world-wide problem, which is also found in the United States.

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