Friday, December 21, 2007

Breakthrough of the Year: Human Genetic Variation

Illustrating once again the important, fascinating and challenging issues raised by rapid advances in genetics, Science's editorial on the breakthrough of the year states:

The breakthrough of this year has to do with humans, genomes, and genetics. But it is not about THE human genome (as if there were only one!). Instead, it is about your particular genome, or mine, and what it can tell us about our backgrounds and the quality of our futures.

A number of studies in the past year have led to a new appreciation of human genetic diversity. As soon as genomes are looked at individually, important differences appear: Different single-nucleotide polymorphisms are scattered throughout, and singular combinations of particular genes forming haplotypes emerge. A flood of scans for these variations across the genome has pointed to genes involved in behavioral traits as well as to those that may foretell deferred disease liability. And more extensive structural variations, such as additions, deletions, repeat sequences, and stretches of "backwards" DNA, turn out to be more prevalent than had been recognized. These too are increasingly being associated with disease risks.

High-throughput sequencing techniques are bringing the cost of genomics down. The few "celebrity genomes" (e.g., Watson's and Venter's) will soon be followed by others, we hope in an order not determined by wealth but by scientific need or personal medical circumstance. Our natural interest in personal genealogy, accompanied by worries about our health, will create an incentive structure that even now is creating a sometimes dubious niche market for having one's genome "done."


Thursday, December 20, 2007

Study on Fragile X Syndrome

Fragile X syndrome is the most common form of inherited mental impairment. It is a sex-linked genetic disease and is more prevalent and severe in males. It is estimated that approximately 1 in 4000 males have fragile X (and 1 in 6000-8000 females). The condition is caused by a mutation in a gene on the X chromosome.

The National Fragile X Foundation describes the impact this inherited condition has on males:

The majority of males with fragile X syndrome will have a significant intellectual disability. The spectrum ranges from learning disabilities to severe mental retardation and autism.

In addition, males have a variety of physical and behavioral characteristics. However, no male has all of these characteristics.

Physical features such as enlarged ears, long face with prominent chin, and large testicles (in post pubertal males) are common. Connective tissue problems may include ear infections, mitral valve prolapse, flat feet, double-jointed fingers, hyperflexible joints and a variety of skeletal problems.

Behavioral characteristics in males include attention deficit disorders, speech disturbances, hand biting, hand flapping, autistic behaviors, poor eye contact, and unusual responses to various touch, auditory or visual stimuli.

At present there is no cure for fragile X. But the latest issue of Neuron has a promising report entitled "Correction of Fragile X Syndrome in Mice" by Gül Dölen et. al. Here is the abstract:

Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.

The BBC also has the scoop here.


Monday, December 17, 2007

Main Menu (Dec. 2007)

White House Statement on Negotiating the Problem of Climate Change

Pressing ethical and social issues are often extremely complex and difficult to even fully comprehend, let alone resolve. And appreciating these complexities helps us gain a better understanding of the competing interests and positions at stake in a particular issue or dispute. The issue of climate change is no different.

Reasonable disagreement concerning how the world ought to respond to climate change is not a disagreement about whether the end in question (i.e. reduce global warming)is desirable, rather it is a dispute over what constitutes the most effective and fair *means* for achieving that desirable outcome.

No doubt people will react to the Bali Roadmap in different ways (e.g. some may see it as a success, others might think it is not good enough, etc.). But I doubt that anyone could deny the fact that the solution to this dilemma is neither simple nor self-evident. And so the various procedures we witnessed over the past week or so,....discussion, debate and compromise...are the procedures that must precede any sage policy-decision on such an important and yet complex issue. And the Bali Roadmap is really just that, a *roadmap* to yet further discussion, debate and negotiation on these issues.

One gets a sense of the enormity of the complex stakes at play here from the latest Press Release from the White House (here). Here is an excerpt:

There are many features of the Decision that are quite positive, including those provisions recognizing the importance of developing clean technologies, financing the deployment of those technologies in the developing world, assisting countries in adapting to climate change, exploring industry sector agreements on emissions, and addressing deforestation.

The United States does have serious concerns about other aspects of the Decision as we begin the negotiations. Notably, the United States believes that, in three important ways, we have not yet fully given effect to the principle of common but differentiated responsibilities that is a pillar of the UN Framework Convention on Climate Change.

First, the negotiations must proceed on the view that the problem of climate change cannot be adequately addressed through commitments for emissions cuts by developed countries alone. Major developing economies must likewise act. Just as the work of the IPCC has deepened our scientific understanding of the scope of the problem and action required, so too empirical studies on emission trends in the major developing economies now conclusively establish that emissions reductions principally by the developed world will be insufficient to confront the global problem effectively.

Second, negotiations must clearly differentiate among developing countries in terms of the size of their economies, their level of emissions and level of energy utilization, and sufficiently link the character or extent of responsibility to such factors. We must give sufficient emphasis to the important and appropriate role that the larger emitting developing countries should play in a global effort to address climate change.

Third, the negotiations must adequately distinguish among developing countries by recognizing that the responsibilities of the smaller or least developed countries are different from the larger, more advanced developing countries. In our view, such smaller and less developed countries are entitled to receive more differentiated treatment so as to more truly reflect their special needs and circumstances.

Accordingly, for these negotiations to succeed, it is essential that the major developed and developing countries be prepared to negotiate commitments, consistent with their national circumstances, that will make a due contribution to the reduction of global emissions. A post-2012 arrangement will be effective only if it reflects such contributions. At the same time, the United States believes that any arrangement must also take into account the legitimate right of the major developing economies and indeed all countries to grow their economies, develop on a sustainable basis, and have access to secure energy sources.


Sunday, December 16, 2007

Genetically Engineered Mice Not Afraid of Cats

The Guardian reports about the story of a genetically engineered mouse that has no fear of cats. Here is a sample:

The Tokyo University professor has just unveiled mutant mice that have lost their innate fear of cats.

Rather than flee or freeze when confronted with their feline enemy, the mice sniffed and even played with them, blissfully unaware of the potential dangers.

Kobayakawa developed the fearless mice by shutting down receptors in their olfactory bulb - the area of the brain that processes information about smells - which would normally induce panic as soon as they get so much as a whiff of a cat.


Saturday, December 15, 2007

Globe Story "The Boy in the Moon" (Part 3)

Following on from my previous post, and updating this post, Part 3 of Ian Brown's moving story "The Boy in the Moon" is now posted on the Globe site here. Here is a sample from this compassionate and insight piece of journalism from an obviously loving and caring father:

Walker makes people cry too. It can happen any time and to almost everyone who meets him, eventually.

They aren't tears of loss, or pity. I think they're tears of gratitude.

The handicapped remind us how dark life can be — every life, not just the handicapped ones. Born out of darkness, to head immediately toward that other darkness, with only a blink of light between. That was how Samuel Beckett put it. Most of his characters are legless, or confined, or without reason for hope.

So when Walker does anything to suggest there's a point to his life besides pain and isolation, it seems particularly brave. For a boy like Walker, an ornament on a Christmas tree is like the ark of the covenant. Even if my son is trying not to succumb to pain, and suddenly finds it bigger than him, and is stricken with grief at his defeat, at least he had hopes of beating it. There's a cup of grog for the undefeated, as a friend recently put it.

I think that's what the weeping is about. Walker has the same effect as the ballet: They both can reveal the larger shape of the world.

....Walker was saved by medical technology. I am grateful, but under my gratitude lurks a terrifying question: What would have happened if nature had been left to take its course? We saved his life, but is it a life he finds worth living?

....The biggest challenge, I find, is to be optimistic. Not about Walker — he takes care of that — but about his future. The longer I spend in the world of my son's disability, the more people I meet who rise to that challenge. They are some of the most impressive people I've ever encountered.

...I only wish I could believe in his God as well. Because the truth is, I do not see the face of the Almighty in Walker, and it would demean him to try. Instead, I see humanity, the face of my boy. Walker is no saint and neither am I. I can't bear to watch him bash himself every day, but I can try to understand why he does it. The more I struggle to face my limitations as a father, the less I want to trade him. Not just because we have a physical bond, a big simple thing; not just because he's taught me the difference between a real problem and a mere complaint; not just because he makes me more serious, makes me appreciate time and Hayley and my wife and friends, and all the sweetness that one day ebbs away. I have begun simply to love him as he is, because I've discovered I can; because we can be who we are, weary dad and broken boy, without alteration or apology, in the here and now. There is no planning with this boy. I go where he goes.

...Not long ago, I had a dream about Walker. He was in his new house and I was visiting. He was very, very, very happy: He still couldn't speak, but he understood everything and could instantly convey all he wanted to say, in murmurs. After our visit, he walked me to the door of his house to say goodbye, and stood there, beaming. His housemate Chantal, or his other friend Christa Lee, or some combination of the two, was behind him. It was clear she was his girlfriend. That pleased me: I knew he had finally found someone to love and someone to love him, not just in the public way everyone loves Walker, but in a way only he could understand — his own private love, at last, to give and receive. And he loved me, and I loved him, and we both knew it. He smiled as I said goodbye, and gave me his blessing. He had forgiven me for his life. But in the end it was just a dream.

Many thanks to Ian Brown for sharing this story with us.


Screening for Hypercholesterolaemia

This story in the Times and this one in the Guardian report about HFEA's decision to permit a couple to screen their embyros for familial hypercholesterolaemia (FH), a condition that increases the risk of heart attack and can result in death during childhood.

Here are a few excerpts from the two stories:

From the Guardian:

A couple who have a milder form of the disorder are seeking permission to have their embryos screened by Paul Serhal, of University College hospital, London, according to the Times.

They have a five-year-old daughter, who was born with the serious homozygous form of FH and fear any other children they have could also be affected.

The decision may reignite controversy over parents' rights to create "designer babies", as the procedure may also identify a milder form of the disease that is affected by lifestyle and can be treated with drugs.

"This obnoxious disease can cause cardiovascular accidents at a very early age," Serhal said. "Some people would think twice about using embryos that they know have a risky gene, and others would say you shouldn't screen out a condition that can be managed..."

There are two forms of FH. The mild - or heterozygous - form affects about one in 400 people but can be controlled with cholesterol-lowering drugs. About one in 250,000 people inherits two defective copies of the gene and develops the more serious of homozygous FH. Sufferers can experience angina by the age of six.

An HFEA spokeswoman indicated it may only permit screening for the more serious form of the disease.

And from the Times:

Critics argue that the test will allow couples to destroy embryos that would have had a good chance of becoming children with fulfilling and reasonably healthy lives.

The test will also create an unprecedented moral dilemma for some couples, as it could show that they have produced no embryos completely unaffected by the disease. This would force them to decide whether to implant embryos that they know have a genetic risk of premature heart disease and death, or to throw them away and deny them a chance of life.

It's very unfortunate that both stories refer to screening for FH as "designer babies" (the Times article is titled "Designer baby fear over heart gene test"). This kind of sensationalist journalism only impairs informed, reflective debate on what is a very serious issue. Rather than being an issue of a parent's right to create "designer babies", the right at issue here is the right to minimize the risk of death and disease for one's offspring. Far from being trivial, this is a fundamental right and freedom.

Undergoing IVF and screening the embryos before making a decision of which, if any, of the embryos to implant does not mean a parent is creating "designer babies". Rather, these parents face the following decision: (1) do they implant embryos that have the gene for the disorder or (2) those embryos that don't have the gene. Or, if all the embryos have the gene, (3) do the parents decide not to implant any of those embryos. Denying the parents the opportunity to screen simply means the decision the parents face becomes: do you opt for reproduction when you know there is a high probability you will have a child with this disorder? None of these embryos would even exist (and thus they would not be discarded) if parents are not permitted to screen as I assume the parents would only opt for IVF if they could screen for the gene in the first place. So prohibiting screening for FH will not save embryos that would otherwise be discarded.

If one is tempted to find such reasoning persausive then just look at things this way: for those parents that decide not to have another child, because they don't want to risk having a child with FH, the decision to prohibit the screening of embryos for FH has closed off the only chance they [i.e. these potential people] have of coming into existence. But of course there is not a high probability that any embryo implanted will result in a live birth anyways. So this line of reasoning is faulty in many respects.

Furthermore, I was puzzled about the way the Times described the decision parents may face if they discover that all their embryos have this gene. These parents must decide whether they want any of the embryos to be implanted. But this is hardly an "unprecedented moral dilemma". Such a decision shares many parallels with the decisions parents face when them decide to have an abortion after a prenatal screen detects an abnormality (though one could argue that the decision to abort is an even tougher moral dilemma).

It is unfortunate that, when it comes to something as important as a parent's reproductive freedom, the onus is on the parents to convince HFEA that their interest in having the test is not iniquitous. Whereas the onus should really be on the government to show that an intrusion on a parent's reproductive freedom is justifiable. Add to this the fact that journalists often impair, rather than enhance the quality of, public debate on such issues by invoking sensationalist sentiments like "designer babies" and the prospect of deliberative democracy looks unlikely. This is why I believe it is better to view such screening technologies as falling within the scope of reproductive freedom and thus a "constitutional essential". To limit this freedom we must have demonstrable evidence that a pressing and substantial harm will likely occur to an identifiable group or individual. And this simply does not happen in the case of permitting parents who undergo IVF to screen embryos for a genetic disease like FH.


Thursday, December 13, 2007

Nature Technology Feature on RNAi Therapeutics

Last year I linked to this animated tour through the process of RNA interference (RNAi). Andrew Fire and Craig Mello won the Noble Prize in Medicine in 2006 for their discovery of RNAi. RNAi is natural mechanism for silencing gene expression.

The latest issue of Nature has a "Technology Feature" on RNAi therapeutics entitled "Small RNAs: Delivering the future" by Nathan Blow. Here is a sample:

The remarkable ability of short sequences of synthetic RNA to interfere with messenger RNA and thereby silence the activity of specific genes has proved incredibly helpful to geneticists wrestling with genetic function. And the push to harness this RNA interference (RNAi) for therapeutic use is now beginning to make headway. In the six years since the first paper reporting RNAi gene silencing in mammals was published1, at least six therapeutic programmes based on the concept have moved into clinical trials.

....Getting a small RNA to interfere with the right messenger RNA in the correct tissue and cell type at a safe, therapeutic level by systemic administration requires an exquisite degree of control — creating the need for different delivery vehicles and potentially even specialized targeting strategies. Animal studies2 have shown that it is possible for siRNAs delivered systemically to silence target genes. "What we have learned over the past couple of years is that systemic delivery of RNAi can be achieved, and there are a variety of methods that can be used to achieve it," says Maraganore. But he is also quick to note that there is no simple solution.

....The rapid advancement of RNAi-based therapeutics is leading Polyplus-transfections to explore the manufacturing aspects of delivery vehicles. The company develops and markets DNA, RNA and protein transfection and delivery reagents for both in vitro and in vivo applications. And with RNAi therapeutics on the cusp of entering the clinic, the company sees the need to produce delivery vehicles in bulk under governmental quality specifications or 'current good manufacturing practices' (cGMP) standards. "If you want to be able to get these into the clinics, you have to have cGMP-qualified delivery systems," says Erbacher.


Wednesday, December 12, 2007

PLoS Articles on Aging

The latest issues of PLoS Genetics and PLoS Biology have two interesting studies related to aging. The former contains the research article "AGEMAP: A Gene Expression Database for Aging in Mice" by Jacob M. Zahn et. al. Here is the abstract:

We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different.

And the latest issue of PLoS Biology has "The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age" by Raja Kittappa et. al. Here is the abstract:

Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine.

These two recent studies are excellent examples of the important kind of research being done on aging.


Saturday, December 08, 2007

Learning From Our Mistakes

Our ability to learn from our mistakes no doubt plays a significant role in our psychological and moral development. We all make poor decisions, and our ability to learn from those mistakes increases the likelihood that our lives will go better in the future. And this process never ends, as there are countless dimensions of our lives (e.g. relationships, career, fiscal responsibility, sport, etc.) where we have room to continue to improve and grow. So in one sense, our individual (and collective) lives are really a series of "trial and error" projects. You live and (hopefully!) you learn.

But are we *equally* apt to learn from our mistakes? A study published in the latest issue of Science suggests we are not. In "Genetically Determined Differences in Learning from Errors" the authors contend that people with a particular gene variant (A1-allele carriers) actually have difficulty learning through negative reinforcement. And this might explain why people with this particular allele have an increased risk of developing addictive behaviors.

Here is the abstract:

Genetically Determined Differences in Learning from Errors
Tilmann A. Klein et. al.

The role of dopamine in monitoring negative action outcomes and feedback-based learning was tested in a neuroimaging study in humans grouped according to the dopamine D2 receptor gene polymorphism DRD2-TAQ-IA. In a probabilistic learning task, A1-allele carriers with reduced dopamine D2 receptor densities learned to avoid actions with negative consequences less efficiently. Their posterior medial frontal cortex (pMFC), involved in feedback monitoring, responded less to negative feedback than others' did. Dynamically changing interactions between pMFC and hippocampus found to underlie feedback-based learning were reduced in A1-allele carriers. This demonstrates that learning from errors requires dopaminergic signaling. Dopamine D2 receptor reduction seems to decrease sensitivity to negative action consequences, which may explain an increased risk of developing addictive behaviors in A1-allele carriers.


Friday, December 07, 2007

Importance of a Good Night's Sleep (Update)

Back in March I linked to this study which suggested that a good night's sleep is important for forming new memories. Well, two further studies published this month show the stakes are even higher. The first report is "Carcinogenicity of shift-work, painting, and fire-fighting" in the latest issue of Lancet Oncology. Anyone who has worked shifts (which I did for a couple of summers when I worked in a steel factory) will know that if can wreak havoc on one's life (from sleep and eating habits to social life). This report from researchers at the International Agency for Research on Cancer suggests that shift work can also increase risk of cancer. Here is a sample:

About 15–20% of the working population in Europe and the USA is engaged in shift-work that involves nightwork, which is most prevalent (above 30%) in the health-care, industrial manufacturing, mining, transport, communication, leisure, and hospitality sectors. Among the many different patterns of shiftwork, those including nightwork are the most disruptive for the circadian clock.

Six of eight epidemiological studies from various geographical regions, most notably two independent cohort studies of nurses engaged in shiftwork at night, have noted a modestly increased risk of breast cancer in long-term employees compared with those who are not engaged in shiftwork at night. These studies are limited by potential confounding and inconsistent definitions of shiftwork, with several focused on a single profession. The incidence of breast cancer was also modestly increased in most cohorts of female flight attendants, who also experience circadian disruption by frequently crossing time zones. Limitations of studies in these flight attendants include the potential for detection bias, proxy measures of exposure, and potential uncontrolled confounding by reproductive factors and cosmic radiation.

Several different rodent models have been used to test the effect of disruption of the circadian system on tumour development. More than 20 studies investigated the effect of constant light, dim light at night, simulated chronic jet lag, or circadian timing of carcinogens, and most showed a major increase in tumour incidence. No clear effect was seen for light pulses at night or constant darkness. A similar number of studies investigated the effect of reduced nocturnal melatonin concentrations or removal of the pineal gland (where melatonin is produced) in tumour development and most showed increases in the incidence or growth of tumours.

And the latest issue of American Journal of Epidemiology has an interesting study entitled "Do Childhood Sleeping Problems Predict Obesity in Young Adulthood? Evidence from a Prospective Birth Cohort Study". Here is the abstract:

It has been suggested that sleeping problems are causally associated with obesity in early life, but most studies examining this association have been cross-sectional. The authors used a population-based birth cohort of 2,494 children who were born between 1981 and 1983 in Brisbane, Australia, to examine the prospective association between early-life sleeping problems (at ages 6 months and 2–4 years) and obesity at age 21 years. The authors compared mean body mass indices (BMIs; weight (kg)/height (m)2) and persons in the categories of overweight (BMI 25.0–29.9) and obesity (BMI 30) among offspring at age 21 years according to maternally reported childhood sleeping problems. They found that young adult BMI and the prevalence of obesity were greater in offspring who had had sleeping problems at ages 2–4 years than in with those who had not had sleeping problems. These associations were robust to adjustment for a variety of potential confounders, including offspring sex, maternal mental health, and BMI, and several mediators, including adolescent dietary patterns and television-watching. These findings provide some evidence for a long-term impact of childhood sleeping problems on the later development of obesity.

So I hope you all get a good night's sleep!


Thursday, December 06, 2007

"Gene Patents and Justice" Paper

I just finished the proofs for my paper "Gene Patents and Justice" which is forthcoming in a soon-to-be-published issue of Journal of Value Inquiry. Over the past few years I have tried to keep abreast of the fascinating, and complex, issues that arise with respect to gene patents. See, for example, the myriad of issues that are revealed via my "Google Alerts" for "gene patents" a while back.

Developing a moral analysis of gene patents is, I have found, a useful way of trying to determine what justice requires "many-things-considered". When it comes to the issue of gene patents, which values- equality, liberty, priority, etc.- should do the most work in helping us comprehend the "big picture" of the important stakes at risk here and how we can best proceed forward? Here is a sample from the paper:

Intellectual property rights over a finite number of human genes is arguably one of the most important and challenging issues facing policy makers and society in general. Nearly twenty percent of human genes are explicitly claimed as American intellectual property. This represents 4, 382 of the 23, 688 genes in The National Center for Biotechnology Information gene database (Jensen and Murray, 2005) . Patents grant the patentee with rights to exclude others from making, using, selling, offering for sale, or importing patented items for twenty years. Are such rights morally justified? Like the issue of private property in general, we can expect that libertarians and egalitarians will come to different conclusions concerning the stance they will likely take on the issue of gene patents. These conclusions will stem for the different priority libertarians and egalitarians give to the values of liberty and equality, respectively. Libertarians take property rights to be the foundation of a theory of justice; they believe that private property is a natural right. Gene patents are a form of property rights, thus gene patents should be permitted. Egalitarians, in contrast, might hold that the obvious policy to defend is one that prohibits gene patents. They may believe that our genes are part of the common heritage of humanity and thus genetic information should not be appropriated by private industries seeking to make a profit from what is collectively owned. Furthermore, egalitarians might believe that private appropriation of this information will impede our ability to ensure that all people who need genetic interventions will have access to them. The state of affairs that the egalitarian wants to avoid is that where only the rich have access to important therapies and enhancements. To permit gene patents would be to make such a state of affairs a reality.

The libertarian and egalitarian arguments are ill-equipped to help us tackle the central issue which currently dominates policy debates concerning gene patents - how robust genomic intellectual property rights should be. The theoretical position best suited for advancing serious debate about genetics and justice is prioritarianism. In order to take the issue of directly mitigating genetic disadvantage seriously, I argue we should adopt a pluralistic prioritarian position... Consideration must be given to the severity and pervasiveness of different forms of disadvantage, the costs of mitigating them, and the likelihood that the benefits of mitigation will be realised. The fundamental distributive principle that should regulate the development of new genetic technologies is the lax genetic difference principle which maintains that “inequalities in the distribution of genes important to the natural primary goods - health and vigour, intelligence and imagination - are to be arranged so that they are to the greatest reasonable benefit of the least advantaged (Farrelly, 2004).” When applied to the issue of gene patents, the lax genetic difference principle prescribes that there is a conditional moral presumption in favor of gene patents that satisfy a stringent utility requirement. Such a prescription gives due consideration to the interests of the genetically disadvantaged.

Addressing the issue of gene patents from a libertarian, egalitarian and prioritarian perspective helps to illustrate the insights, as well as the limitations, of a philosophical analysis of intellectual property rights. In addition to the weight we should accord to the values of liberty and equality, complex empirical and legal issues arise in the context of these debates, issues that philosophers may not be well suited to address. A defense of a pluralistic prioritarian theory of justice allows us to take the complexities seriously. We can begin to make some progress in terms of determining how stringent the duty to mitigate genetic disadvantage is. Unlike libertarianism, pluralistic prioritarianism provides us with an account of justice that allows us to take seriously the duty to mitigate genetic inequalities. Unlike egalitarianism, pluralistic prioritarianism allows us to balance the duty to mitigate genetic disadvantage with other competing demands of justice. Pluralistic prioritarianism does not require us to take the insular view that mitigating genetic disadvantage is the only requirement of justice. This is an important insight given the facts of pervasive disadvantage, scarcity and the important role environment plays in the development of disease and disadvantage.


Wednesday, December 05, 2007

Smoking and Social Disadvantage

Just in case one needed yet another good reason to join the fight against smoking...The latest issue of Journal of Public Health has an interesting study entitled "Smoking Cessation and Financial Stress". Here is a sample:

By examining the effect of long-term cessation on financial stress, the study contributes to the growing research on the effect of smoking on social disadvantage and inequality. A recent article based on a survey of a population-based sample from the US, UK, Canada and Australia showed that between one-fifth and one-third of respondents reported to have spent money on cigarettes that they ‘knew would be better spent on household essentials like food’. It was also shown that there is a social gradient in this phenomenon, such that lower income smokers are notably more likely to experience ‘smoking-induced deprivation’ than their well to do counterparts. Thus, campaigns and interventions to encourage smoking cessation among disadvantaged groups are likely to enhance their material conditions and standards of living.

Given recent findings that smoking substantially contributes to socio-economic differentials in mortality in Australia and elsewhere, policies that aim to reduce smoking prevalence among disadvantaged groups are not only likely to benefit the health and financial well-being of these groups, but reduce societal level health inequalities. As such, tobacco control strategies targeting these groups can be viewed as social policy. This indicates the usefulness of a partnership between the tobacco control and the social services sector. Such a partnership has recently been initiated by the New South Wales Cancer Council (Australia) with the launch of ‘Lifting the Burden: Tobacco Control and Social Equity Strategy 2006–2011’, to reduce high smoking prevalence among disadvantaged groups. A focus of this rare strategy is to enhance awareness and understanding of smoking risks among social services agencies and to build their capacity to contribute to tobacco control.


Monday, December 03, 2007

Saving Lives vs Extending Lives

Suppose there are two medical interventions (X and Y) we could provide to a population, but we cannot afford to provide both. So we have to decide which intervention should be the priority.

Intervention X would cure a portion of the population of a particular disease.

Intervention Y would not cure anyone of a particular disease, but it would extend the healthspan of the population by delaying the onset of age-related diseases and disability.

What might we be inclined to say about how important these interventions are. Which intervention should we fund, and why?

To determine what fairness requires in this kind of scenario we would need *much more information* than I have provided here. For example, we would need to know important details concerning the disease in question- like how prevalent the disease is (does it afflict 40% of the population, 0.01% of the population, etc.), how severe it is, how effective alternative treatments or preventative measures might be, etc. We would also have to know how significant the increase in healthy years would be with intervention Y. In other words, the information I provide in this simple case (i.e. X cures a disease, Y extends healthy life) is not sufficient for us to make a sensible judgment concerning priorities. And yet I believe many people will be inclined to do precisely this. Why?

Many people will be inclined to think there is an ethically significant difference between saving lives and extending lives. And thus this distinction is important to consider for it can have influence our attitudes concerning the priority to retard human aging.

No doubt many people will take the view that saving someone from cancer, diabetes or Alzheimer’s disease is so important we should label these laudable aspirations as a “requirement of justice”. And I would agree. However, many people who are willing to do this will also be very hesitant (indeed they might flatly reject) to extend the duties of justice to apply to the effort to retard human aging. And part of the reason for this, I believe, is that they believe we have a duty to *save lives* but not to *extend lives*. So let me explain why I think this distinction is mistaken and should be discarded.

However, before I reveal the folly of this distinction, let me try my best to give the most charitable reading of the insightful sensibilities that underlie the distinction. When we think of a life *saved* we often picture scenarios where someone rescues a baby from a burning building, or a young child is cured of an early onset disease. And in such cases it happens to be the case that the *magnitude* of the benefits conferred upon the recipient are potentially very large. Saving a young child’s life could result in conferring an extra 70 years of healthy living on said individual. And that is a very important benefit. It is important not only because it is 70 years of extra life, but because the recipient in this case is someone who, barring the intervention in question, would be considered among the “worst-off”. To die in the earliest stages of life is to suffer the most tragic of misfortunes. So the imperative to save lives captures both prioritarian sensibilities (the worse off someone is the greater the imperative to help them) as well as considerations of utility.

Consider further the role considerations of utility play in these cases, for doing so reveals how problematic the idea of “saving” a life really is. Suppose we provide a medical intervention to a two year-old child who would otherwise die. However, we know that this intervention will not eradicate the disease, it will merely delay the onset of the disease (and thus death) by 20 years. So when this child reaches that age of 22 they will die. Would we say that, in this kind of scenario, the medical intervention just extended the life of the patient or that it saves their life? What if the intervention would prove effective for 40 years, or 50 years, or 60 years? Or what if, taking things in the other direction, the intervention would only add an extra decade of healthy living, or just 5 years, or even only 1 year. When do we say the intervention saved the patient's life and when does it merely extend their life?

I suspect some of those who will feel committed to the saving/extending distinction are committed to some version of the sufficiency account of justice. That is, they believe that justice only requires us to bring people to some threshold of wellbeing and nothing more. And thus they might be willing to introduce some benchmark, perhaps the average life expectancy, and say that an intervention that brings a patient to that mark has saved their life rather than merely extended it. However, those above this benchmark (i.e. those already above the average life expectancy) cannot, by definition, have their lives *saved* in this sense. Medical interventions can only extend their lives. And extending people’s lives are not as important as saving their lives.

I argue, at fuller length, against this sufficitarian position in this paper here, so I wouldn’t elaborate on it further now. But it seems rather bizarre to say that, if you push a pedestrian away from an oncoming speeding car, thus diverting their demise, that whether you saved or merely extended their lives depends on their age. So if the pedestrian is your grandchild you saved a life. But if they are your grandparent you merely extended a life.

Intertwined with these various judgments are, I suspect, attitudes concerning the *quality of life* at stake. So part of the reason why people might be inclined to see extending life as less important than saving lives is that the latter also involves qualitative concerns. So saving a person’s live means the person in question will still have a number of healthy years they can expect to live. But when one talks about extending someone’s life they assume we are talking about extending the last stages of the life cycle, with its frailty and other disadvantages.

But the case for tackling aging is not about extending the last stages of a person’s life (i.e. keeping them in a frail stage for longer). It is about expanding a person’s health span. So extending a person’s live can mean adding disease-free years. Construed in this way, there is no difference (assuming all else is equal) between curing someone of a disease and extending their number of healthy years by retarding aging.

Now the story does get more complicated once we attempt to disentangle the utilitarian and prioritarian concerns that can arise here. If we drop (as I believe we should) the notion of saving people’s lives, and talk instead about extending lives, the utilitarian will place all of the emphasis on the magnitude of the benefits at issue. So an intervention that would extend a person’s healthspan by say 40 years should take priority over an intervention that would only extend a different person’s healthspan by 20 years. But what might the prioritarian say in this case?

For the prioritarian, the magnitude of the benefits themselves will not necessarily settle the issue (though they do matter and should not be ignored). This is so because what also matters is how advantaged or disadvantage the people in question are. So extending the healthspan of someone who can only expect to live to 30 can matter more than extending the healthspan of someone who is expected to live to 80, even if the intervention would confer a greater benefit (in terms of additional healthy years) on the more advantaged person.

So once couched in terms of a pluralistic prioritarian ethic, rather than a utilitarian ethic, one can invoke just the idea of extending people’s lives and do so in a way that accommodates some of the sensibilities of those who feel there is a moral difference between saving lives and extending lives. And once one combines these prioritarian sensibilities with an appreciation of the empirical complexities in this case, like the fact that the most prevalent diseases in the developed world are diseases of aging, talk of retarding aging begins to sound more fair and sensible. Indeed, I believe one can begin to make a persuasive case for describing such a duty as a *duty of justice*.


1 out of every 7 Canadian has a Disability

So says the latest report out of Stats Canada today (entitled "Participation and Activity Limitation Survey").

This story in today's Globe notes that while "one factor in the increase is the aging of the population, Stats Can says this played only a partial role, and that increased social acceptance of reporting disabilities may also be a factor". That may be so, but the chart (see left) from the report illustrates that, in the overall picture of things, aging clearly plays the most significant role in the story of disability. And so we can expect this number to continue to rise as Canada's population ages.

...Actually, as I was looking for some stats on the age of our population I came across this recent report from Stats Canada which notes that "Canada's population continues to age, but it is still one of the youngest of the world's developed nations, according to new preliminary estimates".

There seems to be something odd about the points emphasized in these two Stat Can reports. The first report tries to downplay the role aging plays in disability by noting that other factors explain the increase. That may be true, but it doesn't detract from the fact that, overall, aging is the biggest cause of disability. And then this report on our aging population offers (what I assume is intended to be) some solace by pointing out that we are younger than other developed countries, like Japan. But so what? This fact doesn't mean Canadians should feel content with the status quo, or that we don't need to take the steps necessary to mitigate the disadvantages that come from aging. From these two reports, it seems that there are some "age-deniers" at Stats Canada!

The scientific consensus is in- aging results in lots of bad things (like disease, frailty and death). It has a profound impact on the health prospects of our population and on our economy. And now is the time for us to talk sensibly about what we can do to alter this situation. One could say, to borrow Gore's famous title, aging is "an inconvenient truth". And we cannot afford to ignore it.


Saturday, December 01, 2007

Longevity Pill (Update)

Those following anti-aging research will remember the headlines (like here and here) the Sinclear Lab at Harvard University made with their research on resveratrol, an anti-aging molecule (found in red wine). This article published last year in Nature showed that "resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival....These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing".

This research is fascinating and important stuff! And the latest issue of Nature updates this research. See the scoop here. Researchers have now created compounds that are 1000 times more potent than resvertrol. The MIT Technology Review also has a story here entitled "The Longevity Pill". Here is a sample:

A novel group of drugs that target a gene linked to longevity could provide a way to turn back the clock on the diseases of aging. The compounds are 1,000 times more potent than resveratrol, the molecule thought to underlie the health benefits of red wine, and have shown promise in treating rodent models of obesity and diabetes.

Human clinical trials to test the compounds in diabetes are slated to begin early next year, according to Sirtris Pharmaceuticals, based in Cambridge, MA, which developed the drugs. "As far as I'm aware, this is the first anti-aging molecule going into [testing in] man," says David Sinclair, a biologist at Harvard Medical School, in Boston, and cofounder of Sirtris. (See "The Enthusiast.") "From that standpoint, this is a major milestone in medicine."

The new drugs target an enzyme called SIRT1, which belongs to a class of proteins known as sirtuins that have been shown to lengthen life span in lower organisms. Sinclair and others theorize that activating these enzymes, which play a role in cell metabolism, mimics the effects of caloric restriction--a low-calorie but nutritionally complete diet that dampens disease and boosts longevity in both invertebrates and mammals.

The first anti-aging molecule is going to be tested in a human!!....

O brave new world
That has such people in't.


Silenced Genes

An excerpt from another interesting story in today's Globe:

Remember biology class where you learned that you inherited one copy of a gene from your mother and a second from your father?

There is a twist: Some of those genes arrive switched off, so there is no backup if the other copy goes bad, making you more vulnerable to disorders from obesity to cancer.

Duke University scientists now have identified these “silenced genes,” creating the first map of this unique group of about 200 genes believed to play a profound role in people's health.

More intriguing, the work marks an important step in studying how our environment – food, stress, pollution – interacts with genes to help determine why some people get sick and others do not.

“What we have is a bag of gold nuggets,” lead researcher Dr. Randy Jirtle said about the collection of “imprinted” genes. The team's findings were published online Friday by the journal Genome Research.

Next comes work to prove exactly what role these genes play. “Some will be real gold and some will be fool's gold,” Dr. Jirtle added.

Usually, people inherit a copy of each gene from each parent and both copies are active, programmed to do their jobs whenever needed. If one copy of a gene becomes mutated and quits working properly, often the other copy can compensate.

Genetic imprinting knocks out that backup. It means that for some genes, people inherit an active copy only from the mother or only from the father. Molecular signals tell, or “imprint,” the copy from the other parent to be silent.

Dr. Jirtle compared it to flying a two-engine airplane with one engine cut off. If the second engine quits, the plane crashes. In genetic terms, if one tumour-suppressing gene is silenced and the active one breaks down, a person is more susceptible to cancer.


The Weather

This story is depressing.

Hmm, coupled with this story, it makes one wonder how tough it must be to be in the business of trying to predict something that is, well, so unpredicatable!


Moving Globe Story on Child with CFC

Today's Globe has this moving story entitled "The Boy in the Moon" (part 1 of 3). The story is written and narrated by Globe reporter Ian Brown. His 11 year-old son, Walker, has CFC, a very rare genetic condition (it is estimated there are around 200-300 people worldwide with CFC). You can learn more about CFC from this web site. Here are a few details about the condition from that site:

What is Cardiofaciocutaneous (CFC) syndrome?
CFC syndrome is a rare genetic condition that typically affects the heart (cardio-), facial features(facio-) and skin (cutaneous). It is seen with equal frequency in males and females and across all ethnic groups. Children with CFC syndrome may have certain features that suggest the diagnosis, such as relatively large head size, down-slanting eyes, sparse eyebrows, curly hair, areas of thickened or scaly skin, and small stature. Most will also have a heart defect. While there is a wide spectrum of severity in CFC syndrome, most individuals will have some degree of learning difficulty and developmental delay. There are several characteristic facial features that are evident in CFC syndrome that may overlap with other conditions, particularly Noonan Syndrome (NS) and Costello Syndrome (CS). Therefore, accurate diagnosis is essential for proper medical management.

What causes CFC?
CFC syndrome is caused by a mutation (change) in one of our genes. Genes are the instructions which tell our body how to develop and function properly. If there is a change in one of our genes, it can affect how the gene is supposed to function and how the body develops. Recently, three different genes have been found to be associated with CFC syndrome (BRAF, MEK1, MEK2). Most individuals with CFC syndrome (87%) have a mutation in the BRAF gene and 13% have a mutation in MEK1/2. Molecular genetic (DNA) testing for mutations in all of these genes is clinically available.

Here is a sample from Ian's story:

The hard part is trying to answer the questions Walker raises in my mind every time I pick him up. What is the value of a life like his — a life lived in the twilight, and often in pain? What is the cost of his life to those around him? "We spend a million dollars to save them," a doctor said to me recently. We were sitting in her office, and she was crying. "But then when they're discharged, we ignore them."

Sometimes, watching him, it's like looking at the moon: You see the face of the man in the moon, but you know there's actually no man there. But if Walker is so insubstantial, why does he feel so important? What is he trying to show me?

To answer that question, I decided to look again at the life he had lived, and the way we had helped him live it — first at home, later in a special community for children like him. I climbed into a car and drove across the continent to meet other children with his syndrome.

All I really want to know is what goes on inside his off-shaped head, in his jumped-up heart. But every time I ask, he somehow persuades me to look into my own.