Thursday, November 30, 2006

Manchester Talk

I am writing this blog on my (return) train journey from Manchester to Oxford. Yesterday afternoon I presented my “Genetic Justice” paper again, this time to MANCEPT in the Department of Politics at Manchester University. It was great to get the chance to visit my old department again. I was a Lecturer at Manchester in 2002/3 before leaving the UK to take up the position back in Canada.

For this particular presentation I was given a very generous amount of time to talk-- 60 minutes for the presentation itself and 60 minutes for questions. This proved very useful as I was able to address some of the methodological issues I address in the book and elaborate, in greater detail, on some of the empirical considerations and constraints that arise in the context of direct somatic interventions like gene therapy.

When I have presented this paper before the central issue raised in the question period has tended to focus on whether the sufficitarian position might be able to provide just as useful, if not a more useful, framework than the pluralistic prioritarian one I advance. And as I noted in a previous post I am now investing a good deal of thought and time into critically examining that issue.

But yesterday’s feedback raised a new host of issues for me to consider. A number of people noted that there seemed a tension in the way I framed what a theory of genetic justice is a theory about and the details of what I took a defensible theory of genetic justice to entail. The concern was that, on the one hand, I believe the distribution of our genetic endowments warrants special treatment or attention in its own right (hence the reason for claiming we need a theory of "genetic justice"). And yet, at the same time, I went to great efforts in the presentation to argue that a theory of genetic justice must be placed in the larger context of a theory of societal fairness (e.g. when it comes to decisions concerning the allocation of scarce public funds, etc.). So this raised some confusion in terms of what, exactly, was going on here.

These questions were very helpful as I myself am still sorting out the finer details of what the proposed aim of my project is. At one level, I think the genetic revolution raises a number of unique challenges for theories of social justice (especially resource-based accounts) and I think we simply cannot adopt a kind of “add, shake and stir” approach to the issue. That is, simply add our genetic constitutions to the list of things to be distributed and then churn out some prescriptions via those distributive principles we endorse for the regulation of socio-economic inequalities (e.g. Rawls’s difference principle, or fair equality of opportunity, sufficiency, etc.). But I do think it is worthwhile to see how the logic of particular theories, like luck egalitarianism or left and right variants of libertarianism, could push us towards particular prescriptions concerning the regulation of biomedical research (not because we should accept these conclusions, rather we should reject the underlying theories!).

I want to reject these “first-order” normative theories, in large part, because they will ill-equip us to address the real challenges that the genetic revolution has thrust upon us. First-order theories “seek to resolve moral disagreement by demonstrating that alternative theories and principles should be rejected” (Gutmann and Thompson, 2004: 13). What I am really after is what Gutmann and Thompson call a “second-order” normative theory. That is, “a theory about other theories in the sense that it provides ways of dealing with the claims of conflicting first-order theories” (Gutmann and Thompson, 2004: 13).

So the potential dilemma for me is this: my stance on prioritarianism poses a potential tension with my taking the line that I merely want to develop a second-order (rather than first-order) normative theory. Of course it is true that the second-order theory of deliberative democracy itself acknowledges important first-order procedural and substantive values (like freedom, equality and utility). But what is truly distinctive about a second-order theory is that it does not champion any one of these principles as “the” principles of justice. It does not serially order them or give any absolute priority over other political values. A second-order theory is more interested in how we could reasonably balance these competing values when such conflicts arise, and so it takes these values to be both morally and politically provisional. This notion of provisionality is really what I am after in my examination of genetics and justice. Genetics and justice is a great example of an applied topic that is rapidly advancing in a way that warrants our taking such a provisionalist and pluralistic stance.

I want to consider how the genetic revolution will compel us to re-consider the moral landscape- the chance/choice distinction, the limits and scopes of reproductive freedom, the basis of intellectual property rights, and the duty to prevent harm, who we define as the “least advantaged”, and our attitudes towards aging, etc. Of course these dilemmas are not all unique to genetics. But what I think is novel and interesting is how the issue of genetics, and genetic intervention in particular, brings these various concerns together in a vivid fashion. And I think it is imperative that normative theories keep pace with these scientific advances, that our normative theories evolve in the appropriate fashion as the moral landscape shifts in various ways.

So I suppose the apparent tension in my project is perhaps unavoidable. I want the second-order theory I defend to be the one philosophers (as well as others) champion over the rival first-order theories of genetic justice that I think are likely to emerge in these debates. Yet the conclusion of my argument is that philosophers need to exercise a greater degree of humility given the diverse range of empirical considerations that are involved in these issues. And there is a fine line between saying a political philosopher has an important enough role to play that he should write (and people should read) his book on genetics and justice and at the same time say his contribution is minimal and conclusions tentative and provisional. These are the same concerns I faced with my previous book on a virtue-account of distributive justice.

In many ways my approach to these issues runs against the standard convention in applied ethics and political philosophy. Typically one starts with a particular first-order theory (e.g. utilitarianism, Rawlsian justice, libertarianism, etc.) and then one looks at how it applies to a particular issue (e.g. global justice, multiculturalism, etc.). I am starting the other way around. I am looking at a range of practical predicaments which the genetic revolution has (and possibly will) raise and then I search for and construct a theoretical framework that can do justice to the complexity of the issues and stakes involved in them *and* provide us with some normative prescriptions for addressing these challenges. And I am doing this from a largely agnostic stance concerning which overarching first-order theory of distributive justice is the correct theory to endorse. But my fence sitting is not dishonest, I really do not have an overarching theory of distributive justice. It is true that in this book I assume that some resource-based theory of justice is the one we are functioning within, one that grants some room to the traditional concerns of liberal democracies (such as liberty, protection of the vulnerable, respect for democratic law making, etc.). But these weak assumptions are, I believe, consistent with the premises of a second-order theory.

So I am very grateful to the audience at Manchester. I really enjoyed and appreciated the detailed questions and the conservations that followed over a pint and dinner.


Tuesday, November 28, 2006

Differences in Schooling Abilities

Today's Globe and Mail has an interesting (short) piece on differences in schooling abilities among young Canadian children. Gender, affluence, parental encouragement and exposure to sports all have an impact on a child's schooling abilities.

Here are a few excerpts from the article:

In general, girls are more ready to learn at the age of five, says a Statistics Canada report which assessed children's readiness for school and then traced back two years looking for earlier behavioural hints. At five years old, girls have better communication skills, attention and self-control levels, and are more independent in dressing, while boys display more curiosity.

....Children from lower income households didn't understand as many words, couldn't communicate as well, had lower knowledge of numbers, and lower attention and co-operative play rates. But the family's affluence had no impact on work effort, curiosity, self-control and independence of dress and cleanliness.

More important than income was positive interaction with parents. Children who talk to their parents and receive largely positive feedback — being encouraged to do one thing, instead of discouraged to do another — rated higher in communication, curiosity and co-operation.

This last paragraph (which I put in italics) is very important for parents and society to bear in mind. The most important thing we can provide our children with is love and encouragement at home. That, perhaps more than anything else, will help equip our children with the best possible start in life.


Monday, November 27, 2006

The Priority View: Some Thoughts

In a previous post I noted that I am not an egalitarian in the sense of what most contemporary analytic political philosophers take that term to denote. That is, I am not committed to the view that something (e.g. welfare, resources, etc.) ought to be distributed equally. Having said that, I do align myself with the side of the political spectrum (i.e. the left) that feels inclined to object to existing socio-economic inequalities and believes something should be done to address this unfairness.

So what is grounding these intuitions if it is not some variant of egalitarianism?

Perhaps it is prioritarianism or some commitment to the doctrine of sufficiency. But just to clarify things -- recall my comments on virtue theory-- I am not searching for some over-arching metric of distributive justice to hang my hat on. I have a pluralistic view on these issues. (recall this). Rather, I am interested in cases where appeals to a prioritarian principle might be more useful and attractive than appeals to rival distributive principles- like utilitarianism, egalitarianism or sufficiency.

I am now investing a good deal of thought into this issue as it has important consequences for my project on genetics and justice. In that book I am developing a pluralistic prioritarian account of genetic justice (see here). And I want to contrast that theory with a sufficitarian theory and the principle of a genetic decent minimum. So I need to clarify my thoughts on some of these issues and I hope this post will help me make sense of where I stand.

This term I have also been involved in a prioritarian reading group (with members of the CSSJ) which has been very helpful in helping me sift through some of these issues. Today we read Campbell Brown’s very insightful and interesting paper “Priority or Sufficiency… or Both?” which is published in the Oct 2005 issue of Economics and Philosophy. Brown’s article provides a useful synopsis of the different variants of prioritarianism and sufficientism (absolute vs weighted) and he makes a compelling case for a hybrid account called Threshold prioritarianism. This is a mixed view that: “in some cases it gives only weighted priority (i.e., where better off and worse off occupy the same side of the sufficiency threshold), and in other cases it gives absolute priority (where the better off and worse off occupy different sides of the sufficiency threshold) (Campbell p. 217).

I like the idea of the hybrid view as it provides one with a more flexible scheme than the absolute views do. However, I am hesitate to endorse the threshold priority view, in the context of genetic justice. Before I explain my hesitation to endorse it let me summarise what I think would be entailed by this view. (It is important to note that I am applying this view in a way different than that proposed by Campbell- he functions within a version of maximising consequentalism and welfarism).

What this hybrid view would maintain, when applied to a resourcist-metric that includes our genetic constitutions as part of the currency of justice, is that we should give a priority to those who are worse off. More specifically, those whose genetic constitutions place them below the threshold (lets say, for the sake of argument, “normal species functioning”) have an absolute priority over those who enjoy normal species functioning when it comes to making decisions about the different possible regulatory frameworks we could adopt for biomedical research. And when the decision is between benefiting members on the same side of the threshold—either victims of one disease vs another, or between different people whom all possess decent genetic constitutions- the worst off (defined in relative terms) have weighted priority. This means we consider how worse off they are, the number of people in this category and the magnitude of the benefits in question. I really like the idea of weighted priority but not absolute priority. I guess I am a weighted prioritarian across the board (in the context of genetic justice).

So when developing my critique of the sufficitarian position I could write a brief section outlining this hybrid position, which would suggest a bridging strategy between the two positions. Where they really differ, and this might be useful for me to also address, is when everyone is above the sufficiency threshold. The prioritarian can still be concerned with relative inequalities whereas the sufficitarian will not. And this could be important if one expands the concern to regulating genetic enhancements (though it goes too far into the realm of ideal theorising which I try to avoid in the book).

Furthermore, when it comes to making decisions concerning whom to benefit when the potential recipients are all below the threshold (e.g. victims of different genetic diseases) both the sufficiency and threshold priority view invoke weighted priority. So they probably end up endorsing the same policy decisions I want my across-the-board weighted policy to endorse. But I do think my position will have some virtues these other versions will lack.

Firstly, for my position, there are no circumstances where absolute priority ought to be conferred upon the least advantaged (even if they are below a threshold). That was a major shortcoming of Rawls’s principle of maximin. Secondly, the sufficiency position and the threshold view both have to grapple with the issue of how we define what the “minimum threshold” actually is. The fact that there is no hard and fast division between therapy and enhancement means that advocates of the sufficiency and threshold priority view will face difficulties that the pluralistic prioritarian can dispense with more readily. And I think this is another important benefit of that position.


Friday, November 24, 2006

Gendicine (update)

Gendicine, as I noted in a previous post, is the world's first commercially approved gene therapy and is available in China. Today's issue of Science has a useful update on Gendicine entitled "Splicing Out the West?" (subscription needed). Here is a brief excerpt:

As these projects advance in China, gene therapies in North America and Europe are struggling to complete premarket clinical tests. After a U.S. patient died in a 1999 gene therapy trial and two children in French trials developed leukemia in 2002, the U.S. Food and Drug Administration (FDA) tightened controls on experiments, says James Norris, head of the U.K.-based International Society for Cell & Gene Therapy of Cancer. Western companies say they are making progress but have not yet brought a single gene therapy to market.

Some see this as a sign that China is catching up with, or even surpassing, the West. "I think the future of gene therapy will be in China," says Andre Lieber, a gene therapy researcher at the University of Washington (UW), Seattle. But he warns that recent claims of success should be read with caution. There is a "problem" with interpreting clinical studies done in China, Lieber says. Often the primary data are published only in Chinese--raising a barrier to nonspeakers--and even when they appear in English, critical information may be missing.

Intellectual-property rights may be problematic, too. Some researchers in the West have questioned claims of independent innovations made by Chinese drug companies; this could limit sales outside China. Finally, critics argue that the Chinese regulatory system is not rigorous and that Gendicine, for one, was approved with scant evidence of efficacy. With drugs to treat cancer, "the bar is a lot lower than in the United States to get approval," says Frank McCormick, director of the University of California, San Francisco, Comprehensive Cancer Center.


Thursday, November 23, 2006

Human Genome and Global Variation

A new study in today's issue of Nature (available free here) suggests that there can be significant genetic differences between people. These differences involve what are called 'copy-number variants'.

You can learn more about CNVs, and their potential role in the development of disease, by taking a look at the Copy Number Variation Project site at the Sanger Institute.

Here is the abstract of the new study in Nature:

"Global variation in copy number in the human genome"

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

News@Nature also has an overview of the findings here. That story contains a useful "Same But Different" summary chart with the following information which is useful to have on hand:

3,080 million 'letters' of DNA in the human genome

22,205 genes, by one recent estimate

10 million single-letter changes (SNPs) — that's only 0.3% of the genome

1,447 copy-number variants, covering a surprisingly large 12% of the genome

About 99.5% similarity between two random people's DNA



Tuesday, November 21, 2006

Medical Sequencing

The National Human Genome Research Institute issued this press release yesterday, noting that a new era of sequencing for cancer and other medical purposes has begun. Here is a brief excerpt:

"Genomic sequencing has already made a substantial impact on both biological and medical research. A major focus of the next phase will be medical sequencing, which involves using sequencing technologies to identify genes that contribute to common human diseases, most of which have so far eluded gene hunters," said NHGRI Director Francis S. Collins, M.D., Ph.D. "These discoveries will shed new light on the biological pathways involved in human health and disease, which in turn will lead to better strategies for diagnosis, treatment and prevention. It is gratifying that our sequencing centers are going to play a major role in bringing the promise of personalized health care closer to reality."

....Over the next four years, the centers in NHGRI's Large-Scale Sequencing Research Network will utilize existing technology to continue large-scale sequencing of important targets. Almost half of the sequencing capacity will be dedicated to medical sequencing. The sequencing centers will also pursue new ways to increase the speed and lower the cost of DNA sequencing by testing and implementing several new technologies, which could potentially revolutionize large-scale sequencing and expand the use of genomics in medical research and health care. The combined sequence output from the centers, using current technologies, is expected to be about 12 billion DNA base pairs per month - the equivalent of four human genomes.

....Other medical sequencing projects will use DNA sequencing to: discover new genes that are involved in common diseases; identify the genes responsible for dozens of relatively rare, single-gene (autosomal Mendelian) diseases; sequence all of the genes on the X chromosome from affected individuals to identify those involved in sex-linked diseases; and survey the range of variants in genes known to contribute to certain common diseases. The start of each project will depend on a number of factors, including the strategic selection of specific diseases and the availability of patient samples with appropriate informed consent.

Science has a report on the news release here.


Saturday, November 18, 2006

Globe Story on Cancer

Today's Globe and Mail has a gripping narrative story entitled "Cancer: A Day in the Life".

Here is a brief excerpt about the story:

There are 153,100 new cases a year in Canada, about 420 a day, and each day also brings an average of 193 cancer deaths, more than 70,000 a year. But those numbers hide a more complex tale, one that includes thousands of shaken families, excruciating loneliness, yearning loss and deep transformation.

Today, launching a special series, The Globe and Mail looks at the disease from that vantage point — choosing one day, entirely at random, to present a panoramic view of how profoundly Canadian lives are shaped by cancer.

The Globe's Erin Anderssen spent five months interviewing dozens of patients and families, seeking to represent the breadth of cancer's impact, from toddlers to seniors, mothers to young bachelors. Next, she painstakingly reconstructed each person's unique June 15, building a narrative that runs from dawn through night.

...What you read may sadden and disturb you. It may galvanize and inspire you. It is a window into an all-too-common reality that cries out for understanding.



Thursday, November 16, 2006

Luck Egalitarianism

Any political theory worth defending will be based on some notion of equality (e.g. moral or political equality). But many egalitarian theories of justice subscribe to an additional premise- the notion of distributional equality. This is the supposition that people should be equal in terms of some index of goods (e.g. resources) or wellbeing (welfare).

Following on from my previous post about the virtue of virtue ethics-- I wish to say a few things about what I see as the poverty of contemporary egalitarian theory. More specifically, the theory known as "luck egalitarianism" (LE). There are many variants of this theory, but LE encompasses theories that are premised on the chance/choice distinction which maintains:

Inequalities in the advantages that people enjoy are just if they derive from the choices people have voluntarily made; however, inequalities deriving from unchosen features of people's circumstances are unjust.

Many egalitarians like the chance/choice distinction as it permits them to undercut a common objection to egalitarianism: that egalitarians fail to take personal responsibility seriously enough.

Am I a luck egalitarian? No. I don't believe that all inequalities that can be traced back to choice are just, nor do I believe that all inequalities that can be traced back to bad brute luck are unjust.

Consider first inequalities that can be traced back to choice. In her article "What is the Point of Equality?" (Ethics, 1999- highly recommended!) Elizabeth Anderson provides a number of compelling examples to show that we have a duty of justice to redress some chosen inequalities. Suppose someone engages in a risky leisure activity like sky diving. If, when pursuing this chosen risky preference, they are injured in an accident, do we then have a (collective) responsibility to help them? That is, to provide the medical services necessary to save them. And is this responsibility a duty of justice?

According to the chance/choice distinction we are not obligated to help, as this is a disadvantage that can be traced back to their personal choice. Those who willingly engage in dangerous activities are responsible (according to LE) for their choices. But this doesn't seem right. A civil and fair society will not take such a harsh line on personal responsibility (in these kinds of cases).

The failure of luck egalitarianism, I believe, is its failure to place concerns of responsibility in their proper context and to see the other relevant considerations at play. On some occasions we should hold people responsible for their actions: those who study hard and do well on a test should be rewarded with a high grade and praise. Those who commit crimes should be held responsible and go to jail.

But when someone is in need of life saving medical services it does not matter if the causal story of how they arrived there is one that can be traced back to choice or chance. The most relevant considerations are: how severe is their disadvantage? How urgently do they need treatment? Appeals to notions of personal responsibility are out of place (or at least play a very minimal role) in many situations. But the luck egalitarian cannot make these subtle distinctions and qualifications. A virtue-oriented political theory can. Virtue theorists will reject the claim that all chosen inequalities are just. A number of diverse considerations must be addressed before we can make competent judgments concerning the appropriateness of remedying different kinds of inequalities.

Lets consider now the second horn of the chance/choice distinction- those inequalities that people are not responsible for. Are all of these unjust? Should we attempt to mitigate all such inequalities? Following this logic will lead us to some absurd conclusions. Many, many things in life are unequal and stem from brute luck factors. Some people are taller than others because of the genes they inherit from their parents. Others may have more dating propsects than other people because of their physical appearance. People are born into climates that impact their health and wellbeing in unequal ways. Do we really want to say that all of these inequalities are unjust? Are they all equally unjust? And if they are not, how do we distinguish between the really important inequalities and the trivial ones? The ones that we have a collective responsibility to redress and those we do not. These are the really important questions. And appeals to luck egalitarianism do not get us very far in terms of answering these questions.

The chance/choice distinction may have some intuitive mileage. It may help us explain why we think we should mitigate some inequalities but not others. But when pushed just a little, I think the cracks in the theory are quickly revealed. The real challenge for us is to identify which inequalities we should seek to redress, who should be responsible for redressing them, and how vigorously and at what cost we should be prepared to fight for equality in different contexts. Unfortunately luck egalitarianism detracts us from the truly important questions.


Sunday, November 12, 2006

The Virtue of Virtue Ethics

A fundamental (no doubt the fundamental) question in normative ethics is: What makes an action or policy the right (or just) course of action? Is it the consequences of an action/policy? Or is it the extent to which an action or policy conforms to a particular principle? In philosophical debates about ethics a great deal of energy has been exerted weighing up the pros and cons of consequentialist vs deontological accounts of ethics.

So where do I place myself in this debate? Of late I have been moving further and further away from both of these positions, and closer towards a virtue-oriented political and personal ethic. That is, I don’t think the rightness or wrongness of a particular action or policy depends (ultimately) on its purported consequences or on its conformity to particular principles. Why not?

Well, with respect to appealing to consequences, there are a couple of problems. Which consequences matter the most (in different contexts)? And *who* decides which consequences matter the most in these different contexts? I what a moral theory that takes these concerns very seriously.

Furthermore, we often have imperfect information concerning the likelihood that particular actions or policies will be followed by particular consequences. What do we do if there are competing claims concerning the proposed efficiency or inefficiency, for example, of particular policies? Policy analysts claim “X” and yet group activists claim “not-X”. What do we do to resolve this disagreement? How do we make sound decisions in conditions of indeterminacy, fallibility, imperfect information and other non-ideal constraints? Whose judgment should we trust to provide us with reliable answers to different difficult questions? Appealing to a consequentialist ethic will not help us navigate many of the challenges we face when making individual and collective decisions in the real, non-ideal world.

Tackling the kinds of concerns I raised above are what I want a moral theory to address. And such concerns are often discarded or sidelined by the desire to formulate some over-arching fundamental currency of welfare- like preference satisfaction, the greatest happiness etc. , which is purported to provide us with the blueprint for creating a more humane society. But the moral terrain is so complex that I doubt consequentialism alone will give us adequate guidance.

How much weight should we place, for example, on greater economic prosperity vs better healthcare, education or national defense? These decisions will impact the life prospects of different citizens as well as non-nationals and future generations. How much weight should we place on the interests of our intimates vs strangers, non-nationals, other species, or future generations?

No doubt consequentialists might retort that all of these are secondary concerns, that they do not distract us from the ultimate concern—that the consequences are what makes an action right or wrong. But for me, these considerations are not simply something that one can resolve by merely fine-tuning one’s favoured version of consequentialism. Rather this quagmire of concerns should be at the forefront of our moral theory. They should inform, in a substantive manner, our moral theory (rather than being something we address as an afterthought).

And what about the appeal to principles? I expressed my related concerns about the principled paradigm here. So you can visit that post to hear my list of complaints against the principled paradigm.

But let me just finish with this final thought- the most difficult decisions we face in life, both as individuals and collectively as a society, are typically decisions we don’t have to answer, once and for all, at one particular moment in time. They are questions we continue to revisit, time and time again (e.g. healthcare reform, the environment, the economy, balancing work and family, etc.). As time goes on the circumstances change, new information comes to light, our moral sensibilities evolve. How we respond to these changing circumstances is really the measure of our moral integrity, rather than appeals to consequentialism or deontology.

We view the moral agent as one who learns from experience, who exercises the appropriate amount of humility, who is willing to defer judgment when faced with tough decisions they are not well positioned to answer, who is willing to consult with others, and who is open-minded. This is all lost if we say— “the right decision is that which promotes the best consequences or moral principles”. Such a vision of ethics is worrisome for a variety of reasons. One concern is that it can delude us into thinking that we can be self-sufficient at living a moral life. That all we need to do, if we want to make the right decision, is get the information about the consequences right, or properly deduce what the principles from some hypothetical original position are.

I believe virtue ethics offers us a much richer and attractive account of morality than its main theoretical rivals.


New Therapy Improves Memory and Learning Under Stress

Here is an interesting News Report from Stanford University about a new therapy that could offer hope to patients who suffer from the severe neurological side effects of steroids. Neuroscientists have designed a gene that enhances memory and learning ability in animals under stress. Here is an excerpt from the story.

The goal of the study was to see if rats treated with gene therapy would perform differently than normal rats during the water maze tests following exposure to stress. To administer gene therapy, the researchers anesthetized the rodent, inserted a syringe into its hippocampus and injected a genetically engineered virus with DNA containing the chimeric gene. Once injected, individual copies of the virus penetrate the hippocampal neurons, thereby delivering the chimeric gene and activating it in the rat's brain. The new gene then transforms harmful corticoids into helpful estrogens—a process that should hypothetically block the animal's negative behavioral response to stress.

....Stress tests were conducted before the animal received training, immediately after training and 24 hours later. "This taps into three different domains and three different timings—the effects of stress on learning, on storing learned information as memory and on retrieving that memory," Sapolsky explained.

The results were clear: When stress was applied 24 hours after training, the rats infected with the chimeric gene swam to the area of the missing platform faster, and spent significantly more time looking for it, than the normal rats did.

"These results are pretty fantastic," Nicholas said. "They suggest that this gene therapy not only blocks the deleterious effects of glucocorticoids but actually enhances spatial memory and learning through estrogen-controlled events, even in the presence of stress. Seeing this enhancement effect was pretty exciting. It's the best we could have hoped for."

The Stanford story also has a link to an interesting video (under Related Info). And the study was published in the Nov. 8th issue of Journal of Neuroscience. Here is the abstract of that article:

"Enhancing Cognition after Stress with Gene Therapy"
Andrea Nicholas, Carolina D. Munhoz,Deveroux Ferguson, Laura Campbell,1\ and Robert Sapolsky

Hippocampal function is essential for the acquisition, consolidation, and retrieval of spatial memory. High circulating levels of glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, have been shown to impair both acquisition and retrieval and can either impair or enhance consolidation, depending on experimental conditions. In contrast, estrogen can enhance spatial memory performance and can block the deleterious effects of GCs on such performance. We therefore constructed a chimeric gene ("ER/GR") containing the hormone-binding domain of the GC receptor and the DNA binding domain of the estrogen receptor; as a result, ER/GR transduces deleterious GC signals into beneficial estrogenic ones. We show here that acute immobilization stress, before acquisition and retrieval phases, increases latencies for male rats in a hidden platform version of the Morris water maze. This impairment is blocked by hippocampal expression of the ER/GR transgene. ER/GR expression also blocks decreases in platform crossings caused by acute stress, either after acquisition or before retrieval. Three days of stress before acquisition produces an estrogen-like enhancement of performance in ER/GR-treated rats. Moreover, ER/GR blocks the suppressive effects of GCs on expression of brain-derived neurotrophic factor (BDNF), a growth factor central to hippocampal-dependent cognition and plasticity, instead producing an estrogenic increase in BDNF expression. Thus, ER/GR expression enhances spatial memory performance and blocks the impairing effects of GCs on such performance.


Wednesday, November 08, 2006

Neanderthals and the Gene Regulating Brain Growth

The gene Microcephalin (MCPH1) regulates brain size. There is an interesting article in this week's Proceedings of the National Academy of Sciences which suggests that this adaptive allele may have come from an archaic Homo lineage. The article is freely available online here. Here is the abstract:

"Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage" by Patrick D. Evans et. al.

Abstract: At the center of the debate on the emergence of modern humans and their spread throughout the globe is the question of whether archaic Homo lineages contributed to the modern human gene pool, and more importantly, whether such contributions impacted the evolutionary adaptation of our species. A major obstacle to answering this question is that low levels of admixture with archaic lineages are not expected to leave extensive traces in the modern human gene pool because of genetic drift. Loci that have undergone strong positive selection, however, offer a unique opportunity to identify low-level admixture with archaic lineages, provided that the introgressed archaic allele has risen to high frequency under positive selection. The gene microcephalin (MCPH1) regulates brain size during development and has experienced positive selection in the lineage leading to Homo sapiens. Within modern humans, a group of closely related haplotypes at this locus, known as haplogroup D, rose from a single copy 37,000 years ago and swept to exceptionally high frequency (70% worldwide today) because of positive selection. Here, we examine the origin of haplogroup D. By using the interhaplogroup divergence test, we show that haplogroup D likely originated from a lineage separated from modern humans 1.1 million years ago and introgressed into humans by 37,000 years ago. This finding supports the possibility of admixture between modern humans and archaic Homo populations (Neanderthals being one possibility). Furthermore, it buttresses the important notion that, through such adminture, our species has benefited evolutionarily by gaining new advantageous alleles. The interhaplogroup divergence test developed here may be broadly applicable to the detection of introgression at other loci in the human genome or in genomes of other species.

Nature News also has a report about the findings here.


Tuesday, November 07, 2006

HIV Gene Therapy

Human immunodeficiency virus (HIV) is the virus that causes AIDS. According to the latest WHO Aids Epidemic Report (Dec. 2005, you can download it here) the number of people living with HIV is 40.3 million. This includes 2.5 million children under the age of 15. Last year alone 3.1 million people died from AIDS. And since it was first recognized in 1981, AIDS has killed more than 25 million people. This makes AIDS “one of the most destructive epidemics in human history”.

This story from the BBC News reports that the preliminary tests of an HIV gene therapy are encouraging. The Penn Medicine Press release is available here. Below is an excerpt from the BBC report:

Researchers at Pennsylvania University treated five patients, who had not responded to drugs, with disabled HIV. It carried added genetic material that blocks HIV reproduction and as a result HIV levels in the patients' blood either stabilised or decreased. The research raises the prospect that gene therapy might provide an alternative to antiretroviral drugs.

The long-term effectiveness of the drugs is under threat from the growing problem of drug resistance. Researcher Dr Carl June said: "Gene therapy has long been discussed as an alternative treatment for HIV. The goal of this trial was safety and feasibility and the results established that. But the results also hint at something much more.

…They [the patients] were given a single infusion of their own immune system T cells that had been removed from their blood, purified and genetically modified to carry the manipulated version of HIV. Each patient received around 10 billion T cells - between 2% and 10% of the total number in an average person.

The disabled HIV gene used by the researchers was modified to carry an antisense RNA molecule, which scrambles the process of reading genetic information and is designed to sabotage the process HIV uses to reproduce itself inside infected cells.

…Dr Bruce Levine, who also worked on the study - published online in Proceedings of the National Academy of Science - said: "Just because this has produced encouraging results in one or two patients doesn't mean it will work for everyone. We have much more work to do."

Dr George Schmid, a specialist in HIV at the World Health Organization, said it could take many years to determine whether the technique was safe and effective, but he said the results were "encouraging".


Friday, November 03, 2006

Body Temperature and Life Expectancy

Want to live longer? Maybe you just need to "chill out", literally! This news report from Nature notes that a recent study found that mice cooled by half a degree below normal had a life expectancy 20% longer. That is the equivalent of 7-8 additional human years. Here is a snippet from the report [and what is truly fascinating is how they lowered the temperature of the mice]:

The result implies that chilling human blood could also stretch out our lifespan, if a safe way can be found to do it. "Maybe from the point of view of survival, 37 is not exactly optimal," says lead researcher Bruno Conti of the Scripps Research Institute in La Jolla, California.

....Conti's team managed to cool down mice using genetic engineering. They used a gene called uncoupling protein 2, which diverts the cells' mitochondria from their usual task of making chemical energy, and instead prompts them to release energy as heat.

They inserted this gene into a group of brain cells in the animals' hypothalamus and near to the region that senses and controls body temperature, much like a thermostat. The gene effectively heated up the thermostat and, as a result, tricked the rest of the body into cooling down by 0.3 to 0.5 °C.

....So if 36.5 °C helps animals to live longer, why wasn't it selected for through evolution? The cooler temperature probably has no selective advantage because it stretches out life after reproduction, and does not affect the ability of animals to have children and pass on their genes. And although Conti's mice appeared normal, it's possible that the lower body temperature actually causes subtle health problems.