Monday, March 30, 2009

Appreciating the Impact Natural Selection Has on Our Lives

As this year marks the bicentennial of Darwin's birth I felt inspired to write the following rather lengthy post.

I begin by recalling two rather vivid memories I have that are separated by approximately twenty years in time:

Memory #1. 1978

The last shoe lace is tied tight. The light spring jackets are all buttoned or zipped up. Then there are a few seconds of anxious waiting... wait for it....wait for it....
All of the kids in my grade 2 class, including myself, storm out of the classroom. Within two minutes the once empty and quiet playground is now filled with laughter and life. Kids playing tag, ball hockey, skipping, etc. For the next 15 minutes every child is on the go. Recess is a time for play. It is the highlight of the school day for kids everywhere. Few sights in life fascinate me as much as watching children play. The joy on their faces. The connectedness they have to "living in the moment".

Memory #2. 1998

It is 5pm and dinner time at the nursing home. This is the first time I have visited my grandmother since she moved from her apartment to a nursing home. Indeed, it is the first time I have ever set foot in a nursing home. The residents of the home line up for dinner service. A large crowd of residents (the majority are women) now consume the main floor which has the dinning area. Some of the residents can stand in the long line unaided. Most have walkers, and others are confined to a wheelchair. Witnessing this scene has remained vivid in my mind over the years. In particular I have always been struck by the disconnect that seems to exist between the world "inside nursing homes" and the "outside world". The former is a place people come to visit loved ones and family. And it might be a place they themselves spend the final years of their own lives. But it is a place people seldom discuss. It is a place rarely portrayed in the media or in works of art, etc. The elderly and their plight are very much marginalized from our culture. And this is unfortunate for many reasons (though I won't detail all the reasons here today).

I find reflecting on these two distinct memories is helpful to me in many ways. The stark contrast between the health and vitality of people during the different stages of the human life cycle sparks the obvious question- why are things this way? Why is it that most (though not all) school-aged children have the energy and vitality I described above; and yet most (though not all) adults over the age of 85 suffer from one or more illness or disease?

According to the CDC stats on death rates, approximately 14.5 children (ages 5-9) per 100 000 will die this year. But for adults ages 80-84 6,712.9 per 100 000 will die. This means that the death rate for seniors (in this age bracket) is 463 times higher than it is for children (in this age bracket). But why is this so?

Before jumping to that answer consider some more details of the specific causes of death for children and seniors and some more why questions.

Drawing on these older stats (which conveniently contain the 10 leading causes of death by age) we see that for children ages 5-9 the top cause of death is accidents. So things "out there" in the external world (speeding cars, swimming pools, etc.) are the greatest threat to the survival of children in the United States. But what kills most Americans when they are over the age of 85? Heart disease is #1, then cancer, then cerebrovascular diseases, then chronic lower respiratory diseases, followed by diabetes and AD.

But why is it that the greatest single threat to the life of people when they are young are "external" factors; and yet the greatest threat to the life of aged persons are "internal" to us (i.e. chronic diseases)?

When this "why?" question is asked as a comparison between these different aged groups of humans (rather than, say, just two individuals of the same age) it helps focus our attention on the evolutionary causes of morbidity and mortality. Why do humans age the way we do? A way that fills us with life and energy at age 8, but brings disease, frailty and/or (usually) death by age 88?

The answer to understanding why we age the way we do is in fact related to the answer of another why question- why we reproduce. In other words, the health and vitality we have when young is directly linked to the failing health we have at more advanced ages. To appreciate this link we must appreciate why any species would reproduce.

Why should a species, any species, reproduce? I was reading this interesting paper last week. And the imperative to reproduce is linked to the inevitability of death. Given the extrinsic risks that permeate our environment (e.g. predation, starvation, etc.) the solution to escaping death is reproduction. Species that can successfully reproduce will continue on, while those that can't eventually become extinct. So prioritizing reproduction (rather than maintenance of the soma) is beneficial in the kind of world we have tended to inhabit. Humans are here today because we have been pretty successful (so far, in our relatively short evolutionary history) at successfully reproducing under the external threats we have faced.

The importance of reproduction thus leads to a tradeoff between investing physiological resources into reproduction, resources that could otherwise have been used to maintain the health and vitality of a parent. Because of the pervasive risk of morbidity and mortality, humans typically died either during their pre-reproductive or reproductive periods. So life expectancy before the 19th century was below the age of 30 and that had always been the case for humans.

Because most humans that have ever lived died well before age 65, the force of natural selection only applied to our pre-reproductive and reproductive periods. This explains why most serious childhood genetic disorders, like infantile Tay-Sachs disease, are very rare. A disease that kills humans early in life has little chance of being passed on to future generations. But sadly the same is not true for late- onset diseases, like AD and most cancers.

When it comes to alleles that protect humans from late-life morbidity there is no pressure to select those genes. Unlike our pre-reproductive and reproductive periods, our post-reproductive period was not selected for. Our susceptibility to frailty and disease in late life, unlike our vitality and robustness in early life, is not the outcome of natural selection. As Barnes puts it, "senescence arose from evolutionary neglect rather than evolutionary intent".

This leads me back to my two memories. In the year 2048 the children from my grade 2class will be the age of many of those in nursing homes today. Globally there will be 2 billion humans alive over the age of 60. And this will bring unprecedented levels of chronic disease (cancer, heart disease, stroke, AD, etc.).

If there was something we could do to alter this possible future of unprecedented human suffering and disease from becoming a reality, shouldn't we try to avoid it? To meet these challenges we must foster a Darwinian-based approach to medicine. Instead of feeding the next generation of inquisitive thinkers useless platitudes about the importance of switching off lights to save the world we should encourage them to harness the great potential of evolutionary biology.

Humanity must awaken from its current intellectual slumber (and its accompanying guilt complex about being alive in the first place) if we are to meet the enormous challenges we face this century. Some of the greatest dangers facing our health and economic prospects are in fact the legacies of evolutionary history. To appreciate this we must make the future vivid and have a sense of proportionality.

One doesn't need to be a longevity scientist to know the high probability (indeed certainty) that aging populations will suffer frailty and disease. We all have experiences like memory #2, even though our culture tries not to think about it (out of sight, out of mind).

Given the certainty and severity of the harm of aging you might expect that vast amounts of public funding are being invested in aging research. You might think that the brightest and most talented scientists who long to make the world a better place are being lured into the field. Unfortunately it is very hard to get people to rally behind aging research. This must change. A deceleration of the aging process might make nursing homes a thing of the past. And that would be an enormous achievement that all future generations of humans could enjoy.

To end on a positive note I leave you with yet another sage insight from John Dewey:

Society exists through a process of transmission quite as much as biological life. This transmission occurs by means of communication of habits of doing, thinking, and feeling from the older to the younger. Without this communication of ideals, hopes, expectations, standards, opinions, from those members of society who are passing out of the group life to those who are coming into it, social life could not survive.

Dewey's passage is a nice complement to the spirit of my last post.


Wednesday, March 25, 2009

Science Editorial on the Importance of Science and Enlightenment

The latest issue of Science has this excellent editorial that captures the spirit of my blog and academic research in general:

The authors of the Declaration of Independence and the Constitution of the United States were children of the Enlightenment. They understood the power that flows from combining human reason with empirical knowledge, and they assumed that the political system they were creating would thrive only in a culture that upheld the values of the Enlightenment. And thrive it did, in large part because our people and government upheld those values throughout most of U.S. history. Recently, however, the precepts of the Enlightenment were ignored and even disdained with respect to the manner in which science was used in the nation's governance. Dogma took precedence over evidence, and opinion over facts. Happily, as was made clear by two policy announcements by President Barack Obama on 9 March 2009, the break in the traditionally harmonious relationship between science and government is now ending.

....The recommendations [requested of the director of the Office of Science and Technology Policy]called for to sustain these bold ambitions would place scientific competence and integrity among the core principles of the government's science-based endeavors. For example, they should ensure that the selection of scientists for government positions is based on scientific qualifications and experience [uh, Prime Minister Harper please take note of this!], establish means for addressing instances in which scientific integrity may be compromised, and provide protections for those who draw attention to possible assaults on the integrity of scientific advice.

....The president has taken a large and inspiring step to restore the historically beneficial balance between science and government; we should all now offer to help with the enlightened effort just launched.

As John Dewey put it in 1916 in Democracy and Education, "science is experience becoming rational".


Wednesday, March 18, 2009

PLoS Genetics Article on Aging Processes in Human and Invertebrate Species

How can the world's aging populations best secure better health and economic prosperity this century? How about funding more important research like this. Here is the "author summary" from the latest issue of PLoS Genetics:

Studies of longevity in model organisms such as baker's yeast, roundworm, and fruit fly have clearly demonstrated that a diverse array of genetic mutations can result in increased life span. In fact, large-scale genetic screens have identified hundreds of genes that when mutated, knocked down, or deleted will significantly enhance longevity in these organisms. Despite great progress in understanding genetic and genomic determinants of life span in model organisms, the general relevance of invertebrate longevity genes to human aging and longevity has yet to be fully established. In this study, we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue. We also show that human genes encoding proteins that interact with human longevity homolog proteins are also changed in expression during human aging. These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity. We also present a collection of novel candidate genes and proteins that may influence human life span.

Aging research: where the action really is!


Phase 2 Gene Therapy Trial for HIV

The latest issue of Nature Medicine has the encouraging results of this Phase 2 gene therapy clinical trial for HIV. Here is the abstract:

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1–infected adults who received a tat-vpr–specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40–48 and 40–100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.


Tuesday, March 17, 2009

Inept Science Minister?

story is an embarrassment to Canadians and a sad reflection of the current health of our democracy.

It may not be surprising that Goodyear is unable to comprehend the evidence in favour of evolution given that his professional "expertise" before entering politics is one that also flouts the scientific evidence (see this and this).

This is a real shame given the great potential science has to improve the health and economic prosperity of Canadians. When those given the responsibility of overseeing and supporting science have little understanding and appreciation of it themselves we undermine the health of our democracy.

John Dewey said it best when he claimed that "science makes possible the systematic pursuit of new ends; it is the agency of progress in action". Given the dire situation of science in the current political climate I fear we may be forfeiting many valuable "new ends", thus resulting in a stagnate and less fertile culture.

Maybe one day I will wake up and it really will be the 21st century. I guess one can dream.....


Sunday, March 15, 2009

Intuition and Cancer Screening

The latest issue of the Annual Review of Medicine has this interesting article on the role of science and intuition in cancer screening. Biases can often mislead clinicians when determining what the efficacy of screening tests alone are. This nicely illustrates the many diverse and complex challenges we face with respect to the duty to prevent harm. Here is a sample:

.... In 1924, the New York Times reported a call to public action by Johns Hopkins surgeon Dr. Joseph Colt Bloodgood, who asserted, “Deaths from cancer would be practically eliminated…if persons afflicted sought medical aid immediately upon the discovery of a foreign growth in any part of the body” (1). He obviously overestimated the potential impact of available early-detection strategies. Nevertheless, the development and application of new medical technologies have accelerated the actualization of this concept.

.... Despite the strength of the messages transmitted to the public about the value of cancer screening, cancer mortality statistics remain sobering. Cancer remains the second most common cause of death in the United States, accounting for 23% of all deaths and dwarfing the third most common cause, stroke, at 6% (see Reference 4, table C). There has been clear progress, but it has been incremental. There has been a decrease of about 10 deaths due to cancer per 100,000 persons per year between 1950 and 2005 (194 versus 184 deaths per 100,000 persons) (5). Population trends reflect a mix of changes in exposures, treatment advances, and screening, so they cannot be used to draw any definitive conclusions about the contribution of early-detection strategies. Nevertheless, the population trends contrast with many public perceptions and clinical intuitions about the magnitude of efficacy of cancer screening.
A core question is, how could Dr. Bloodgood's clinical intuitions and observations have been so misleading? And how can we use scientific methodology to protect us from our strong intuitions? We propose that large-scale randomized trials come to the rescue.

.... Early detection advances what would have been the original date of diagnosis to an earlier point in time, but it does not necessarily follow that the patient's time of death will be delayed. For example, if a particular disease has no known treatment, earlier detection can have no impact on the lifespan of an affected person. In Figure 2a, the two lines represent two lifespans. In the one case, cancer is detected through symptoms, and the person dies at a set point. In the second case, the cancer is detected while asymptomatic through screening. The proportion of the lifespan affected by disease has been extended—that is, the person is a patient longer—but total years of life remain exactly the same.

.... Although clinical intuition is a fundamental “art” of medicine, in the field of cancer screening it is easy to be misled. Powerful, pervasive biases make reliance on experience alone a dangerous strategy. Successful evaluation of early-detection efforts requires strict adherence to the scientific method to protect us from simply ratifying our desires. As Roman playwright Terence noted, “One easily believes what one earnestly hopes for.” We should harness this passion to generate evidence as strong as our messages. At the very least, we should be aware that soundbites can do injustice to complex trade-offs when proposing cancer screening tests to a healthy population.


Monday, March 09, 2009

Main Menu (March 2009)

Recent posts on "In Search of Enlightenment" include:

(1) Aging Research and Making the Future Vivid

(2) Globe Story on Cancer Prevention

(3) The Parallels Between Apologism and Theism


Thursday, March 05, 2009

POLS 250 Trailer

Next year I will be teaching the yearlong required theory course here at Queen's (POLS 250). The class size is approximately 250 students. Students wondering what we might be covering in the course can view this trailer below (just click play)

Whoever said theory was dry and removed from the real world?! :)


P.S.- the latest issue of Academic Matters has this excellent article which encompasses my own sentiments towards teaching intro theory.

Monday, March 02, 2009

Aging Research and Making the Future Vivid

This post is also posted on the Women's Bioethics Project here.

In this post I try to make the case for getting those interested in bioethics and issues pertaining to women to join the cause of supporting the basic science that could lead to a deceleration of human aging.

At first blush the proposition that those interested in the health and welfare of women should support aging research might sound counterintuitive. When we hear the phrase "aging research" we might automatically envision the kinds of products we currently see advertised on TV, like "anti-aging" creams that promise to restore the youthful appearance of skin, hide wrinkles, etc. Such products reinforce demeaning ideals of "womanhood"-- that a woman's self-worth can be reduced to her physical appearance and thus every woman should do everything she can to present herself as "youthful" and conceal the signs of aging. Those are not the interventions, and that is not the message, I am talking about. Far from it.

By "aging research" I mean the scientific field of biogerontology which studies the biological processes of aging. And by an "anti-aging" intervention (which is currently hypothetical... there is nothing you can currently buy that decelerates aging) I mean a pharmaceutical that decelerates the rate of molecular and cellular damage caused by aging. An intervention could do this be mimicking the effects of calorie restriction (without actually requiring a restriction of calories). A deceleration of the aging process would delay many of the common diseases and conditions associated with aging (like heart disease, cancer, stroke, AD, etc.) and possibly compress morbidity and mortality. Thus people would enjoy more years of disease-free life than that possible given the current rate of aging for most humans.

When I talk to people about my interests in this area there are a number of reservations and concerns they have. Let me briefly identify, and address, two of them: (1) many feel that talk of retarding human aging sounds like mere science fiction; and (2) many express the viewpoint that it is distasteful to worry about decelerating aging when there is so much poverty and disease in the world. I will very quickly address (1) and then focus on (2), with particular reference to the situation of women.

Talk of retarding human aging will strike many as either pure science fiction, or, at best, the prospect of an "anti-aging" pill is a long, long ways off. This is a common reaction and one that would have been more reasonable to hold 20 or even just 10 years ago. But over the past decade amazing progress has been made in the field of longevity science which makes the prospect of a genuine anti-aging pill becoming available in the next 5-10 years a real possibility. In fact there are a number of human clinical trials currently underway involving resveratrol (an anti-aging molecule present in red wine) and Sirtris has trials for more concentrated compounds.

So the first hurdle for these products is to establish if they are safe and effective treatments for the diseases of aging. If so, they could be pursued as a preventative intervention to protect people (including all future generations) from the diseases of aging. By decelerating the rate of aging during adulthood we could reduce our risk of disease and death in late life, thus extending the number of healthy years humans could expect to live.

OK, so back to my main goal of encouraging those interested in the issues facing women to champion this area of scientific research. This brings me to concern (2). One might wonder why, given all the pressing issues facing women in the world today, that they ought to add aging and longevity science to the list of things to address. "Is it really a priority?" one might ask. "Is it a priority in a world with disease and poverty?"

This is a fair question. And the answer is "YES!". Why? Because most disease in the world today is caused by aging. Now you won't find data from the World Health Organization that states that explicitly. But what you will find are the data concerning the proximate (rather that evolutionary) causes of morbidity and mortality. But behind the proximate causes of most human deaths (like cancer and heart disease) are the biological processes of aging. In other words, it is not a coincidence that most people who suffer disease and death today are over age 60. The vulnerabilities of late life reflect the tradeoff that natural selection has made between the fitness of a parent and reproduction. Natural selection favors a strategy in which organisms invest fewer resources in the maintenance of somatic cells and tissues that are necessary for indefinite survival of the individual (source).

The enormous and unprecedented disease burden the world will experience this century makes vivid the human toll of this tradeoff. Take the year 2005, the latest year that one can easily find the stats from the World Health Organization. Approximately 55 million people died in 2005. Of that number, 35 million died of chronic disease. That number is twice the number of deaths due to infectious diseases (including HIV/AIDS, tuberculosis and malaria), maternal and perinatal conditions, and nutritional deficiencies. That is a staggering figure. Furthermore, between the years 2005-2015 WHO estimates that 220 million people will die from chronic disease, most of them (144 million deaths) in lower middle income countries like China and India. The diseases associated with aging are not, contrary to popular perception, only a problem for people living in the developed world. Indeed, being vulnerable to disability and frailty is a much greater disadvantage if one lives in a poor society with no decent health care or pension, as the link between income and "ability to work" is much more direct. So the chronic diseases associated with aging are a problem for all societies, not only the richest countries in the world.

I don't want to fixate too much on the global figures for chronic disease but some brief comparisons with other events in human history will help us get a sense of the magnitude of the problem of chronic disease. It is estimated that between the mid-14th and mid-17th centuries, the "Black Death" plague killed approximately 25 million people. This means that the current deaths caused by chronic disease in just one year is equal to the number of total deaths caused by three centuries of the "Black Death" plague! The 220 million deaths caused today by a decade of chronic disease is closer to the scale of death from a few decades of small pox. In the twentieth century small pox is estimated to have killed between 300 and 500 million people. By 1980 small pox had been eradicated thanks to the small pox vaccine.

Could we vanquish chronic diseases like heart disease and cancer this century, like we did small pox last century? To make serious headway against chronic disease we must understand the ultimate (that is evolutionary) and not just proximate cause of disease. There is no virus that is responsible for all cancers, heart disease, stroke, AD, etc. But if we better understand the biological processes of aging we may be able to modify the rate of aging so that we reduce our risk of disease and death in later life. So tackling aging is an issue of preventative medicine. An anti-aging pill that slowed down the molecular and cellular damage of aging would extend the period of healthy life humans could expect to live.

In order to appreciate the great benefits this could confer upon women, especially women in poorer countries, consider the facts of this report:

Women comprise the majority of the older population in virtually all countries, largely because globally women live longer than men. By 2025, both the proportion and number of older women are expected to soar from 107 to 373 million in Asia, and from 13 to 46 million in Africa.

And.....Osteoporosis and associated fractures are a major cause of illness, disability and death, and are a huge medical expense. It is estimated that the annual number of hip fractures worldwide will rise from 1.7 million in 1990 to around 6.3 million by 2050. Women suffer 80% of hip fractures; their lifetime risk for osteoporotic fractures is at least 30%, and probably closer to 40%. In contrast, the risk is only 13% for men.

To fully appreciate the benefits of an intervention that decelerates human aging we must make the future health prospects for women in the world today more vivid. In particular we need to consider what the situation of those vulnerable today will be in the decades to come-- like the 373 million older women who will be living in Asia by 2025. These women will be vulnerable to the chronic diseases and disabilities of aging. But we could reduce these risks if we could decelerate human aging.

One of my favourite Ted Talks lectures is this one by Harvard psychologist Dan Gilbert. It is a brilliant presentation, outlining how our decisions are skewed by a variety of limitations and biases.

At the end there is an apt question from biogerontologist Aubrey De Grey concerning how these cognitive limitations impact our ability to see aging for the threat that it actually is. Gilbert responds by noting that humans can imagine the near future much more vividly than the far future. That is why we are more likely to address the problems of today rather than those of tomorrow. And this is a real problem for humanity given that the health problems facing 2 billion persons over age 60 by 2050 will be enormous.

To get people to make more sage decisions about the far future we need to provide them with details. We need to help them become psychologically connected with the future. The more detail people have about the far future the more likely they will make decisions about it like they do the near future (though we don't always do the latter well either, but that is the subject for another post! :)).

So my plea for getting those interested in women's health and welfare to get behind aging research is one that seeks to make vivid the threat that senescence poses to the health prospects of women this century. Senescence will likely cause more disease and disability for women this century than any other cause. Senescence not only threatens our health and survival by increasing the risk of fatal diseases (like heart disease and cancer), but also one's ability to contribute to their communities and families. Aging research is thus a vital component of developmental economics. The sooner we increase public support and funding for this science, the sooner we will be able to reduce the risk of morbidity and mortality for the world's aging female populations.