Genes&Aging

An Excursion Into Exercise

2007-01-08T04:10:00.000-08:00

I justify this posting on the grounds that exercise is almost certainly a very important factor in aging. What's really fascinating is that the research in this area seems to be absolutely polarized; those who run rats to exhaustion on treadmills generally conclude that long term exercise increases the production of reactive oxygen species (ROS, or free radicals), with the more-or-less implicit conclusion that exercise increases the rate of ageing. The more benign (or possibly just more patient) researchers who have taken elderly Homo sapiens through an exercise regime universally conclude that it improves quality of life, and there seems to be some evidence that it also contributes to increased longevity [1]. Maybe the rats should be allowed to choose not to run to exhaustion?

Anyway...

I'm an expert on getting into a running program. I'm almost as expert at that as I am at giving up alcohol. And since I'm currently back in Brisbane, where the weather is warm and the work pressures are purely internal, I've been running pretty regularly for the past month or so. There are several really obvious differences between running here and in Newcastle. The weather, of course, is the most obvious. In Brisbane I have to set my alarm for 6:30am to be on the road by 7:30, or it's just too hot to run. In Newcastle it's pitch dark at 7:30, and trying to squeeze in a run and still get to work before lunch time is a major hassle. Not to mention running in the cold. Even your ears hurt!

Then there's the setting. In Newcastle I run around Leazes Park, which is actually really pretty, and extremely Victorian, but too small to hold the interest day after day. Plus it was the pond at Leazes Park into which my motorbike was thrown a few months ago, so it still has painful memories, despite the swans. In Brisbane I have a 5K route that runs, for most of the way, past a creek, through bushland. It's cool and shady and replete with water dragons and sulphur crested cockatoos (no swans, though!) and smells of gum trees and hot grass. I swap smug smiles with the other runners and dog walkers, in tacit acknowledgement of our moral and physical superiority over the local slugabeds.

There is a hitch, however. In the past two months there have been 25 sexual attacks, of varying degrees of severity, upon women exercising on Brisbane's footpaths, including a couple in this area. The local government has offered a $50,000 reward for information leading to a conviction, and is advising women not to exercise alone. This morning I'd only gone a kilometer before encountering a very impressive motorcycle cop on my usual path. It's all a bit depressing.

But what really interested me was the way people responded. I do find myself scanning the path ahead, looking for lurkers, and trying to keep tabs on cyclists who overtake me, in case they turn round and turn evil. It does take my mind off the heat, my lungs and my legs, which I guess is some sort of silver lining. But what I really liked was the fact that it seems to have had no effect on the interactions between the early morning exercise community. We still smile and nod, and mouth "Morning", to each other. It's really encouraging to see that most people aren't letting these bastards get to them.

Lets hope they get these guys soon. A few runs to exhaustion on the treadmill will do them the world of good, and I volunteer to take any physiological measurements that might be useful, with a large syringe, as needed.

Jen

[1] Lee, I. M., Hsieh, C. C. & Paffenbarger, R. S. (1995). Excercise intensity and longevity in men. The Harvard alumni health study. Journal of the Americal Medical Association 273(15).

Ageing and Memory

2007-01-01T15:32:00.000-08:00

First up, I have to come clean; this post is a shameless plug for a book written by a good friend and colleague of mine, Janet Wiles[1]. But in the course of writing it I had a quick look at the literature, and found lots of other interesting stuff.

My feeling, for which I have no basis except for experience, is that the major health fear of most younger people is cancer; The Big C. And that's probably fair enough; one in four women and one in three men will contract some sort of cancer in the course of their lives. And there are so many different sorts of cancer, with a multiplicity of causes ranging from DNA damage to viruses to diet. Cancer is scary because it's hard to understand and hard to control.

As we age, however, a new spectre raises its head: Alzheimer's Disease. The prospect of slowly losing our memory and cognitive abilities, the very core of what makes a human being, is not one that any of us can face with equanimity. The fact that some decline in memory and cognition appears to be an inevitable part of normal ageing doesn't help, either; most of the older adults I know (myself included) have wondered, at least in passing, if the fact that they can't find the car keys is a Bad Sign.

Janet's book arose from a survey which she and her co-author (and mum!) carried out, about memory function and concerns about memory in older adults. They used the survey to identify the issues which most concerned older people, and then went back to the literature[2] to identify which phenomena are aspects of normal aging, what might indicate some sort of pathology, and what strategies can help with memory problems [3].

I've always assumed that worries about memory are probably unnecessary; surely cancer is much more prevalent than Alzheimer's? [4]. It turns out that this is not, in fact, the case. There have been several large-scale investigations into the incidence of Alzheimer's. Generally, the incidence seems to be aroun 1% of the population at age 65, rising to around 8% once you're over 85. Interestingly, the incidence at age 80 - 84 is around 3%; there's a big jump once the magic 85th birthday hits. Even so, the incidence is pretty low. However, that translates to a lifetime risk of getting Alzheimer's pretty similar to that of getting cancer; around 25%. The good news is that the relationship between brain changes and disease symptoms is not straightforward; most people age 90 have Alzheimer's-like changes in the brain, despite not having dementia. And some factors, like education, appear to be neuroprotective. So, get educated...

...buy the book!

Jen

[1] Wiles, J. & Wiles, J. (2007). The Memory Book: Everyday Habits for a Healthy Memory. Apple Press. Available from Amazon UK.
[2] Janet is a cognitive scientist, and has in the past spent an unhealthy amount of time with psychologists. Nowadays we've lured her back into the relative sanity of the computer science department.
[3] When the local news in Brisbane did a segment on the book, I got to be interviewed confessing to the world that I can't remember a thing unless I write it down. Thanks, Janet!
[4] And, of course, heart disease or road accidents are far more likely than either.

Ageing Genes Back in the News

2006-12-26T18:49:00.000-08:00

There's an interesting report in yesterday's (26 December) issue of Neurology: researchers in the US have identified a gene which is reponsible both for longevity and for the retention of mental sharpness. "Wow!", thinks I, "my work has been done for me, we can all go home." So I downloaded the paper[1]. Now, I think this is a very nice piece of work, and has some intriguing implications. I have issues, not with the paper itself, but with the way it's being reported.

Looking on Google News[2] yields the following headlines:

"Longevity Gene Also Keeps the Mind Sharp"
"Gene Tied to Longevity Also Preserves Ability to Think Clearly"
"Longevity Gene Also Protects Memory, Cognitive Function"
"'Supergene' Gives Long Life, Clear Mind (I love this one! Does it also enable you to leap tall buildings at a single bound?)
"Study: Gene Tied to Long Life Wards Off Dementia"
...and on, and on.

The most moderate is probably "Gene Tied to Longevity May Protect Brain", but who can really resist "Gene Aids the Elderly"? Or even "Single Gene Could Lead to Longer Life, Better Mental Function"?[3]

OK, so what did they really find?

The study took 158 people aged 99, and looked for the presence of a gene variant previously associated with longevity (CETP VV, a gene whose protein is involved in lipoprotein metabolism). They also gave their subjects a test known as the Mini-Mental State Examination (MMSE), and looked for correlations between MMSE scores and the presence of CETP VV. They did, indeed, find a statistically significant association between the presence of the allele and high test scores; hence the media hysteria. But, of course, the picture is not that simple.

The authors state that "Subjects with good cognitive function had a higher frequency of the CETP VV genotype than those with poor cognitive function (29% vs 14%, p = 0.02)". Further, "those with the CETP VV genotype were twice as likely (61% vs 30%, p = 0.02) to have good cognitive function than those witht the II genotype." OK, those numbers look reasonably interesting, but when you consider that only 43.5% of the group had "good" cognitive function, and only 24% had the "good" allele, it's clear that the gene is not the only factor at work here, by a long shot. In fact, if you translate the percentages into absolute numbers, there were 20 people with good cognition and the good allele, compared with 12 with poor cognition and the good allele. If the traits are independant, you would expect 16 (24% of 43.5% of 158 people) people to have both the good varieties, just by chance. It may be a significant difference, but it's a hardly a "supergene".

In addition, the mechanism of action of the good allele isn't known. The researchers suggest that it may be related to the previously-identified link between CETP VV and low incidences of heart disease, or it may be a completely new pathway. If it's something as simple as increasing blood flow to the brain, then maybe its beneficial effects can be achieved by something as simple as increased aerobic exercise, rather than tinkering with the mode of action of a crucial metabolic pathway.

So, to summarize:

It's a nice paper, and the results are interesting and may direct research into useful areas.
But:
1. It's a small study (158 people)[4];
2. The results are only just statistically significant;
3. Other factors (other genes, environment, nutrition, exercise...) appear to be more important in influencing the phenotype than the gene itself;
4. "Cognitive function" was measured with a single test.

Neither the general public, nor the researchers, nor science itself is done any good by hyping results such as these into news of supergenes which are going to turn us all into centenarian geniuses. It's never that simple.

[1]Barzilai, N., Atzmon, G., Derby, C. A., Baumann, J. M. & Lipton, R. B. (2006). A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 67: 2170 - 2175.
[2] http://news.google.com/news?hl=en&ned=us&ie=UTF-8&ncl=1112251435
[3] Scientific American, how could you?
[4] The results were validated with a larger sample, but it's still a small, preliminary study.

Integrated Functional Networks

2006-12-12T20:36:00.000-08:00

Well, I finally made it Australia, after a flight which I prefer not to remember in too much detail[1]. Today I gave a seminar at the School of Information Technology and Electrical Engineering at the University of Queensland, my old stomping ground.

I haven't been back to Aus for a year, but it feels as if I've never been away, despite the fact that I've done a lot of work in the past year. The seminar was about what I've been doing in Newcastle; integrated functional networks as per the title of this post. I've only been working on this for a year, but I think we're now in a position to identify both the promise and the challenges of this approach.

What's an integrated functional network? It's a network of interactions between proteins within a cell. The interactions are identified by scanning as many as possible of the large data sets that are currently available, generated by lots of different technologies. Different types of interactions are combined using a statistical approach, and the result is a network in which links between genes mean that there is some sort of relationship between those genes. Each link has a weight which reflects the probability that it really exists, given the evidence we have.

These networks are a hot topic of research at the moment, because they take data that is tucked away in big databases and makes them available to biologists with specific research questions. Many of the big pharmaceutical companies are using them to identify potential drug targets, for example. We're hoping to use them to guide research into the genetics of ageing.

So I gave the talk, and got some valuable feedback, and then we went to lunch, which was great, since the people there were all old friends and colleagues. The slides are going to be online somewhere at some stage; I'll post an update when they go up.

From the sublime to the ridiculous: tonight's the University Staff Club Trivia Night finals, and my (ex) team is competing. I'll be there to cheer them on (and maybe drink a champagne or two!).

[1] Why do the nutters always want to talk to you at 2am when you're trying to watch "Finding Nemo"?

Dubai, or not Dubai?

2006-12-09T09:55:00.000-08:00

I'm officially in transit to Australia, to spend Christmas with my family. I'm actually in Dubai, which has its pluses as well as its minuses.

I left home at 8:00am Friday, to catch an 8:30 train to London. Arrived 12:00; another hour on the train to Heathrow and then 45 minutes in the Emirates check-in line. When I actually got to the desk it was a little galling to find that I'd actually been in the wrong line; my first leg was with Virgin Atlantic. Still, these things can happen to anyone! I moved to the Virgin line, and finally managed to check in. Seven hours from leaving my front door to walking through security, and I haven't even boarded the plane.

We did board - eventually. Only about an hour late, but enough to make us miss the connection to Brisbane. So I'm spending the night in Dubai. An interesting city.

At first they were proposing to put us up at the Marriott, but it turned out that all they had were executive rooms, at an equivalent of $500US per night. "Oh, yes!" I was thinking. "At last, the life I should be living!" Alas, it was not to be. We're at the Arabian Park, a perfectly adequate hotel, but not exactly the high life.

They think big in Dubai. The buildings are big (although some are cool and curly, but not many). The roads are big, and the traffic is appalling. I went to a (big) shopping mall to get some money from an ATM, only to come face to face with a dilemma. I have no idea what the currency is, or how it translates to dollars (Australian or American) or pounds. So I'm looking at the ATM, and it's teling me that I can withdraw up to 3,000 somethings. The minimum is 200; I choose to go with 600, which is the second lowest option. I may just have cleaned out my bank account, and made it impossible to pay the rent this month; or I may have about two pounds in my purse, and will be totally humiliated when I have to pay my internet access bill in the morning. It's these little nuances that make international finance so interesting.

I'm currently in bed, with a wake up call booked for 4am. With any luck I'll be home in another 12 hours, but I have Singapore to negotiate yet. The way my recent trips have gone, I'm not optimistic, although I gather you can make a good living as a street theatre artist at Singapore airport, so all is not necessarily lost. One of these days I'll get back to doing science...

Cheap wine and a 21-day growth

2006-12-04T15:11:00.000-08:00

Yes, it's red wine revisited. I've previously mentioned the depressing finding that you need to drink 300 glasses of red wine a day in order to get mouse-verified levels of life-extending resveratrol. Tempting, but impractical, not to mention expensive, even if you go for one of the co-op's cheaper options. But this week's Nature carries a report that it might not just be resveratrol that is the essential longevity-promoting ingredient in red wine. Apparently there's another set of chemicals, irresistably named "oligomeric procyanidins", abundant in wines from Nuoro province, Sardinia, and southwest France, which appears to act against blood vessel constriction. And people from these regions apparently have "higher than normal average longevity". As a loyal Aussie, and a long-term devotee of Australian reds, this news disturbs me.

So should we move from the Brown Brothers Merlot to one of those French wines with the unpronounceable names? Maybe. There seems to be some evidence that the Tannat grape, which is grown in these areas, is particularly rich in procyanidins. But another factor seems to be the fermentation process; apparently traditional wines in these regions undergo a 21-day fermentation process, in which the juice remains in contact with the skins and seeds (and seeds are where the procyanidins lurk). Most wine has a shorter fermentation process, and so the wine ends up absorbing less of the active ingredients.

I have to admit I've never tried wines from Sardinia. Maybe it's time to give them a go. Any recommendations?

Creating Life

2006-11-21T09:26:00.000-08:00

The reason I haven't been posting much lately (well, the excuse I'm giving, anyway) is that I've been doing the writing for which I'm paid: a conference paper on integrated functional networks and two book chapters, one on gene networks and evolutionary computation, and one on synthetic biology. They are all, of course, little masterpieces, carefully crafted and polished [1], but I was particularly inspired by the last-mentioned.

I volunteered to write the chapter because I'm interested in synthetic biology, didn't know a huge amount about it, and wanted an excuse to learn. The ultimate aim is simple, if ambitious: to create life from scratch. The intermediate aims are to engineer the genomes of existing organisms to produce specific, predictable behaviour. We already have a field of genetic engineering, of course, but it tends to be pretty restrained. Dropping a cold-resistance gene from a deep-sea fish into a banana genome so Inuit can grow their own banana sundaes[2] is one thing; producing a lawn of bacteria which acts as a photographic film[3] is quite another. I started out quite skeptical about whether it was possible to do anything large-scale and significant, but ended up pretty impressed with the possibilities.

We're nowhere near creating life from scratch, of course. Although a virus (polio) has been created by simply building a chromosome from its published sequence[4], it did need the cytoplasm from an existing cell in order to reproduce. And viruses are as simple as you get, to the point where some people deny they're alive (although I think that's ridiculous - they have obviously evolved from more complex creatures; can you evolve from being alive to not being alive?). But it's a very impressive start.

I think there's huge scope for computational intelligence and machine learning approaches in this field, and I'd love to work on it. Manybe once I've cured cancer and ended ageing...

[1] And thankfully now the problems of their respective editors, instead of me.
[2] Sadly, to the best of my knowledge, not yet done. My next grant, perhaps?
[3] Levskaya, A., Chevalier, A. A., Tabor, J. J., Simpson, Z. B., Lavery, L. A., Levy, M., Davidson, E. A., Scouras, A., Ellington, A. D., Marcotte, E. M. & Voigt, C. A. (2005). Engineering Escherischia coli to see light. Nature 438: 441 - 442.
[4] Cello, J., Paul, A. V. & Wimmer, E. (2002). Chemical synthesis of Poliovirus cDNA: Generation of infectious virus in the absence of natural template. Science 297: 1016 - 1018. And they just ordered the DNA from commercial producers. Very cool.

Eat, Drink and Be Merry

2006-11-20T01:46:00.000-08:00

It's no longer a problem, according to research published in Nature last week. At least, that's how it's been widely reported in the press. The magic potion resveratrol, as found in red wine, has been shown to counteract many of the health impacts of a bad diet, in mice. So, as long as you have a nice cab. sav. with your Big Mac, you'll be fine.

Of course, the reality is not quite so rosy. For one thing, the amount of resveratrol the mice were given is many times higher than most people get out of wine - a glass of wine contains 0.3% of the dose the mice were given (adjusted for body size, of course). That means you'd need to drink around 300 glasses of red per day to get the same benefits. Some brave souls have tried, but oddly enough good health doesn't seem to increase with increasing alcohol consumption. Clearly, the merlot-with-your-cornflakes approach isn't going to cut it.

Resveratrol is readily available over the internet, and is believed to be safe. Since we don't know the mechanism of action, however, this may not be the case if it's taken for long periods of time. And, of course, humans may not necessarily react the same way as the mice. People aren't mice; it would be a pity to turn them into guinea pigs.

So I reluctantly put down the fries and head out for a run. I can always have a glass of red when I get back, just to be on the safe side.

Mitochondria and Aging

2006-10-18T13:15:00.000-07:00

So, why are mirochondria interesting from an aging point of view? They are the site of the tricarboxylic acid cycle (TCA cycle, or Krebbs cycle, as it was known when I was an undergrad, lo these many years ago). The TCA cycle is the heart of energy generation in the cell; it produces a molecule called adenosine triphosphate (ATP) which is the energy currency of the cell. Converting ATP to ADP (adenosine diphosphate - one phosphate less!) releases energy, and lots of reactions within the cell use this fact to acquire the energy they need. So mitochondria are absolutely essential to the cell.

But there's no such thing as a free lunch. The process of generating energy also generates lots of other things, including the ominously named Reactive Oxygen Species (ROS), more widely known as free radicals. These molecules are, not surprisingly, highly reactive, and interact with lots of other molecules in the cell, causing untold havoc, some of which is believed to contribute to the aging process. So mitochondria are the embodiment of the oldest joke in the world, which is usually applied to women: can't live with them, can't live without them.

Mitochondria are essential (and really, really cool). And even apart from their role in aging, there are lots of other reasons we should be interested in them. I'll post some of them tomorrow.

Mitochondria

2006-10-13T14:19:00.000-07:00

Even in a multicellular organism, individual cells display a surprising amount of, well, individuality. Every cell has a distinct identity, and the majority are able to perform most, if not all, of the functions of free-living unicellular organisms . So distinct are cells that the cell doctrine of biology—the concept that all organisms are made up of cells—has been described as the fundamental paradigm of modern biology and medicine. The focus of biologists upon cell biology (there is a whole subfield of biology which goes by this name, and is perceived by its proponents as absolutely crucial to an understanding of life) has led to major breakthroughs in biology, but as we have seen, cell architecture is only fundamental to life at one particular scale . Vital interactions take place at subcellular levels, while multicellular organisms are very much more than the sum of their cells.

It is generally accepted that the cells of multicellular organisms evolved from independent single celled bacteria. Further, most biologists now believe that eukaryotic cells arose from the fusion of several different types of single celled organisms. This theory, known as endosymbiosis, was originally proposed in the nineteenth century, after the development of microscope allowed biologists to observe that cellular organelles bear a remarkable resemblance to free-living bacteria. The theory was not widely accepted amongst biologists until after it was espoused and publicized by the biologist Lynn Margulis in the 1960s. Since then, genetic analysis has confirmed that the DNA of organelles is in many ways more similar to that of bacteria than to that of the nucleus of the cell in which the organelle resides.

Basically, the theory suggests that eukaryotic cells evolved as a result of “lunch gone wrong” about 1.4 billion years ago. Bacteria prey upon smaller bacteria by engulfing them in an invagination of the cell membrane, which eventually pinches off to form a sac, or vacuole, inside the cell. Digestive enzymes then break down the contents of the vacuole and the hapless prey is consumed. It appears, however, that this process is not always foolproof. Some small bacteria, originally destined to be lunch, seem to have sidestepped the digestion process and taken up residence in the cytoplasm of the would-be diner. Whether they were originally harmful to their unwitting host is unknown; most probably the vast majority were. However, some tenants possessed abilities which were usefully complementary to those of the host—the ability to convert sunlight into useable energy via photosynthesis, for example, or to carry out other chemical reactions which were not in the host’s repertoire. The engulfed bacteria also benefited from the relationship, gaining advantages such as being part of a larger organism and therefore safer from predation, and having access to a steady supply of food. A partnership was established, and over time became not just beneficial but mutually necessary to the participants. From an uneasy admixture of predator and prey, the eukaryotic cell was born.

The specific sequence of steps that Margulis proposes to have occurred during evolution are as follows:

1. A sulfur and heat-loving archaebacterium merged with a swimming bacterium to form the first nucleated single celled organism (protist). This swimming protist eventually evolved mitosis, the process of cell division;
2. The protist merged with an aerobic bacterium (a purple bacterium or proteobacterium, whose descendants eventually evolved into mitochondria, the energy factories of the cell);
3. In some lineages, that commune engulfed photosynthetic bacteria (cyanobacteria) to form swimming green algae, the ancestors of today's plant cells.

The basic eukaryotic cell had been born, and continued to evolve and diversify into the whole spectrum of eukaryotes—single-celled and multicellular—that surround us today.
This sequence of events is now widely accepted. Eukaryotic cellular organelles still carry their own DNA, although often in a fairly rudimentary form, and the genes they carry have been demonstrated to be closer in sequence to genes from free-living single-celled organisms than to the genes in the nucleus of the cell in which they dwell. Further, there are minor differences in codon usage between organelle and nuclear DNA . The evidence appears to be clearly on the side of endosymbiosis.

Antagonistic Pleiotropy

2006-10-10T03:02:00.000-07:00

The term itself is enough to warrant a blog post, but the concept underneath is just as cool, and a damn sight easier to understand. 'Pleiotropy' is simply the phenomenon of a gene affecting more than one trait. It's easy to see how this can happen; a transcription factor (such as p53) can turn on dozens of other genes, each of which has its own effect (or effects; the target genes may themsleves be pleiotropic!). And many (most?) genes produce proteins which end up in several different cellular compartments, performing multiple functional roles. Pleiotropy has been documented ever since the concept of a gene existed; Williams (1957) cites Bridges & Brehme (1944) as identifying mutations charmingly called glass and sparkling in Drosophila. They were named for the effect they have on the adult eye [1], but they also affect the colour of the malpighian tubules[2] in the larva.

Antagonistic pleiotropy, as the name suggests, occurs when a gene affects multiple traits in opposite directions. As early as 1957, George Williams suggested that antagonistic pleiotropy might be the root cause of ageing [3]. He proposed that genes that confer a selective advantage to young creatures will be selected for even if they are disadvantageous in later life, since damage to the organism post-reproduction is invisible to natural selection. It's a neat idea, and in my opinion part, but not all, of the story.

So, is there any evidence for genes which act in this manner? There are lots of papers on the subject, and quite a scattering of potential candidates (I haven't done a proper review - I have too many other reviews on my plate at the moment!), but a recent paper that caught my eye was about differential ageing of males and females in Drosophila[4]. The author suggests that since mitochondria and X chromosomes spend more of their time in females than in males, they will tend to undergo selection which is beneficial for females, even if the adaptations are not so good for males. Mitochondria are well known to be important in ageing, so this sort of effect might explain why females tend to live longer than males[5]. I always liked mitochondria; they are truly fascinating [6]. And I like them even more now that I know they're on my side!

[1] I don't know about you, but when I think about "a pair of sparkling eyes", I rarely have fruit flies in mind.
[2] A sort of invertebrate kidney system.
[3] Williams, G. (1957). Pleiotropy, natural selection and the evolution of senescence.Evolution 11:398 - 411. Available online at http://www.telomere.org/Downloads/Williams_searchable.pdf
[4] Tower, J. (2006). Sex-specific regulation of aging and apoptosis. Mechanisms of Ageing and Development 127(9): 705 - 718.
[5] I hadn't realised that fruit flies showed the same pattern of survival as humans; I wonder what other organisms do?
[6] I went to add a link to my previous post on mitochondria, only to find I haven't made one. So the next topic will be...

Supercentenarians

2006-10-07T13:59:00.000-07:00

A new Supercentenarian Research Centre has just been established in Pittsburgh[1]. A supercentenarian is not, apparently, a 100-year-old with their underpants on the outside, but a person of at least 110. According to the article from the Washington Post, although the number of centenarians is increasing, the number reaching 110 is not, a statistic which I find somewhat odd. Obviously, your chance of dying increases with every year after young adulthood, but if increased longevity is due to environmental factors, you'd expect it to apply to all age groups. They're looking for donations, and hope to eventually become a funding body, making grants to projects which look very much like the IL's 85+ study.

For the record, there are currently 76 people in the world who are verified to be 110 or older. The Washington Post made no mention on their choice of costume.

[1] I don't know why all the articles I read mention the location; it's like the way newspapers always give people's ages when mentioning them. Completely irrelevant, most of the time. Mind you, I just did it, too.

Telomeres in the News

2006-10-06T03:54:00.000-07:00

There's an interesting article in Monday's Life Style Extra about a link between osteoarthiritis and ageing. The link is, apparently, via the telomeres, which are the bits at the ends of chromosomes. Over time the telomeres get shorter, so telomere length can, according to some, be used as a measure of biological age. In the study being reported, people with arthritis had telomeres siignificantly shorter than their less-afflicted peers. The suggestion is that osteoarthritis leads to increased oxidative stress within the cells, as does ageing.

It's an intriguing idea, and not, on the face of it, improbable. I do have a problem with people using "ageing" as a synonym for "telomere shortening"; they are clearly related, but not the same thing. Just about everything[1] ages, but not all organisms have associated telomere shortening.So they are related, but not identical, concepts. To be fair, the article does make this clear; it's just the headline that is a tad dramatic. "Osteoarthritis causes oxidative stress which shortens your telomeres by an amount equivalent to 11 years worth of normal levels of oxidative stress" isn't as catchy as "Arthritis ages you by 11 years"!

There's no hint as to what the mechanism aould be, and I couldn't find the original report, because the links on the researcher's web page are all broken. Interesting observation, though.

[1] There are a couple of organisms which are not supposed to age, but I think the jury's still out, really.

Bio M&S Day, Guelph

2006-10-02T10:30:00.000-07:00

I have to say, "Guelph" is just the coolest name for a city. Given that I've lived in (and, in fact, given birth in) Wagga Wagga, this is high praise!

So, last Saturday was the Bio M&S day in Guelph. Half a dozen speakers addressing various aspects of computational intelligence in bioinformatics, and an audience of maybe 10 - 15 [1] people from a wide range of backgrounds. I hope the audience got something out of it - I had a fantastic time, and found the whole day very enjoyable, even though I was jetlagged out of my mind.

Most of the speakers (including me) had presented at CIBCB in the previous couple of days, so I was familiar with the work, but it was really nice to have full hour-long talks instead of the 15 minutes you get at a conference. I'm starting to understand what Gwenn Volkert is doing with Hidden Markov Models and Kay Weise on modelling RNA secondary structure. Paul Higgs also gave a really interesting talk on the evolution of biased codon usage in mitochondrial genomes. Mitochondria are amazingly cool: important in ageing, which is fortunate for me, but just downright cool in their own right. I posted a long rant about mitochondria in the blog I kept for my last job, which is now offline. I'll repost it here at some stage. Everyone should know and love their mitochondria[2]!

My talk was on gene networks (surprise, surprise!) and seemed to go down ok. I enjoyed it, anyway, so there was at least one person in the room who was awake! That didn't last, of course...it was a long, but thankfully uneventful, trip home. I slept most of the afternoon, which is a bad idea; heaven knows if I'll sleep tonight. Back to work tomorrow.

[1] I didn't count!
[2] I can feel a tshirt coming on...

CIBCB Day 2

2006-09-29T21:03:00.000-07:00

I woke up this morning at 5am in Toronto. It's now midnight, and I'm in Guelph. A long day, but a very interesting one. I'd like to say it's made the last few days worth it, but I don't think my sense of humor has recovered yet.

The 5am start was because I wasn't sure how to get from the hotel where I was staying to the Renaissance downtown. Turns out that all metro systems are pretty similar, and I made it without too much hassle[1]. Today's schedule was two parallel sessions, so I didn't see everything, but I think I managed to catch most of the bits that interested me.

I chaired the first session, on gene networks, and gave the last talk in that section. Most of the talks were about reverse engineering gene networks from microarray data. Since I'm in the middle of a review which covers this area, I was particularly interested. It's a topic which is a natural for a computational intelligence approach, since the problem is desperately underdetermined; there's just not enough data to solve it. Added to which there are multiple networks which will produce the same gene expression pattern, the structure of the actual networks is unknown, and DNA-protein interactions are certainly not the whole story, and it becomes apparent that the problem is non-trivial.

My opinion, which was not substantially altered by today's talks, is that it can't yet be done. Current algorithms work pretty well on small, artificial networks, but don't scale to realistic network sizes, and the networks they produce cannot be properly validated. It's still an interesting area, though, and well worth working on. The insights and algorithms developed now may well be much more practically valuable when applied to the larger, more complete data sets which undoubtedly be generated over the next few years.

There were good sessions in the afternoon on Biological Theory and RNA structure and function. The latter was mostly algorithms for predicting RNA secondary structure from sequence data. Since we're starting to realise just how important RNA is, I think we'll be seeing a lot more of this sort of work in the next few years. And RNA structure might be easier to predict than protein structure, which is another largely-unsolved problem with huge biological implications[2].

Went to dinner tonight with a group of female bioinformaticians, an occurrence which is as rare as it is enjoyable. Then the train to Guelph, and, hopefully, some sleep in preparation for another day of talks tomorrow.

[1] Apart from the hotel desk clerk, but we won't go in that...
[2] Or then again, it may not.

Still in Transit

2006-09-28T17:38:00.000-07:00

It's not the first time I've woken up in a room full of strangers who are carefully not looking at me, with my face adhering to black vinyl and a chair arm sticking into my back, but the last time was 20 years ago, and I have to confess I'd be perfectly happy if the next time is 20 years in the future. Still, a night spent in gate lounge 5F was not as bad as I'd feared. Breakfast in Murphy's pseudo-Irish Pub was a bit surreal, though [1], not least because it appeared to be full of Geordies.

To add insult to injury, the plane was delayed by nearly an hour. If it had been delayed that much yesterday, I would have caught it! I made it to Toronto in the end and am currently ensconced in a hotel, showered, chip-fed and manicured[2]. I've missed the first day of the conference, but fortunately my talk is tomorrow. I'm chairing the session, too, and it starts at 8:30, so something tells me tomorrow is not going to be a lot less frantic than today. At least it will contain some science, though!

[1] I've always been concerned that my scrambled eggs are not as light and fluffy as they could be. But at least I don't do that to them!
[2] I've broken a fingernail, though...is this really worth it?

Traveller's Tales

2006-09-27T09:35:00.000-07:00

I'm on my way to the IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology, in Toronto. Something tells me it's going to be another one of those trips...

I was up at 5am, after a disturbed night's sleep; I never sleep well when I'm afraid of missing the alarm. Bathed, dressed, packed, fed, on the metro by 7, which wasn't too bad. Arrived at the airport to find that only one bag was allowed, but I had a laptop and a handbag. Put the laptop in the handbag, various important, delicate and almost certainly soon-to-be-stolen-or-smashed items [1] into the laptop bag, and checked it in.

And then the flight from Newcastle to Amsterdam was delayed due to bad weather. The flight itself consisted of two hours in the gate lounge, 45 minutes sitting on the runway, then 50 minutes in the air, enlivened by a dry cheese sandwich. I'm so glad I had that double gin at 8:30am... Upon arrival, we were told that those Toronto-bound had missed the connection. After half an hour in line at the transfer desk (a doddle, compared with those at the end of the line, but I can do a mean sprint from arrival gate to transfer desk, even in high heels) I was told that the next flight is tomorrow afternoon. And because the delay was due to weather, the airline won't pay for a hotel. So it's a night in the gate lounge for me, and I'll miss the first day of the conference.

Mr Lloyds-TSB grudgingly parted with 50 euros, via a handy ATM (not a given, three days before payday!), so I'm in a bar, paying airport prices for average chardonnay, and plotting. Apparently there are recliner chairs in some lounges, so at some point I'll go try and intimidate someone into vacating one. Not that I expect to sleep. I wonder what the crime rate is in Schipol airport?

[1] Including the power supply for the laptop, so this connection is strictly a limited option. I'll try and save half an hour's worth of battery for 3am, when things are most likely to get desperate.

Are We Evolving?

2006-09-25T02:16:00.000-07:00

I don't ask this with the aim of engaging any creationists[1], but because it is a legitimate question to ponder. There are two schools of thought. One argues that Homo sapiens is no longer evolving, since the advent of modern medicine means that we can keep alive-and even reproducing-people who would otherwise die. On the whole, proponents of this view seem to think it's a bad thing. They skate perilously close to eugenics, with the (usually implicit) view that those of us with "bad genes" should at least have the decency to die, leaving the gene pool nice and tidy. "Bad genes" are apparently a lot like pornography - "I can't define it, but I know it when I see it!" The only certainty is that those bemoaning the rise of the genetic underclass have no doubts about the goodness of their own genes.

Exactly the opposite point of view is held by those who believe that the amazing developments in practical genetics over the last 50 years or so mean that, not only are we evolving, but we can control the direction of our own evolution. Media stories [2] about the potential and problems of "designer babies" are rife. If any of these reporters had actually tried introducing a desired gene into a eukaryote (and yes, I have!) they'd be a lot more circumspect. That's not to say that we'll never be able to design tall, blonde, intelligent, beautiful offspring to order[3], but I seriously doubt whether we're yet directing our own evolution.

I suspect the bottom line is that we're just as subject to the vagaries of natural selection as any other species. We really don't understand the day-to-day mechanics of natural selection; the concept of "fitness" is about as vague as you can get, and in practice is measured in terms of reproductive success. For a species with a generation time as long as humans (15 - 20 years), there just hasn't been time for us to affect evolution in any significant manner, whether by medicine or by genetic engineering. I'd be willing to lay odds we're still evolving.

[1] I have colleagues who are more than capable of doing this - go for it, Matt!
[2] Even my favourite, New Scientist, has been known to succumb to designer baby hysteria.
[3] I produced tall, blonde, intelligent, beautiful offspring the old fashioned way, and it seems to be working so far. A bit less tall would have been good, though, so they couldn't lean on me when they feel patronising.

Camels

2006-09-24T08:55:00.000-07:00

OK, this has absolutely nothing to do with ageing (I don't even know the lifespan of a camel, offhand), but this has got to be one of the coolest photographs I've ever seen:

Check it out!

Death is the Price you Pay for Sex

2006-09-23T01:19:00.000-07:00

At least, that's what Lynn Margulis says. Between you and me, I've never really understood what she meant, but it sounds vaguely evolutionary-theory-PC, so I just nod knowingly. But according to Reuters, 40% of Brits would give up on sex if it meant living to 100, so it looks as if quite a proportion of the population isn't prepared to pay the price.

Now the disclaimer: the Reuters article says it's research done by Mori on behalf of BUPA, but I can't find anything about it on either of their websites. So it's impossible to judge what sort of questions were asked or what the results mean. I assume, for example, that by "living to 100" they mean a healthy, active 100[1]. And the sample demographics might be interesting; I should imagine a group of nuns would be much happier giving up sex in favour of longevity than a group of prostitutes.

But despite the caveats, it's an interesting question. From an evolutionary point of view, once you've reproduced you might as well die (unless you can help perpetuate your genes by being a grandparent)[2]. But people are amazingly selfish, and seem to prefer to stay alive. But giving up sex? This is where we need the text of the survey. Did the respondants really mean they'd be prepared to sacrifice the chance to reproduce, or just that they'd give up going to the Bigg Market on Saturday nights? Given that 94% apparently said they wouldn't give up their friends or family in order to make the century, I'd guess the latter. And, let's face it, that's not such a big sacrifice.

The alternative, of course, is to live fast, die young and leave a good-looking corpse.

[1] Although they won't get a telegram from the Queen; apparently she sends cards these days!
[2] This is a shocking simplification, and I'm ashamed of myself. I'll do a proper posting on it later.

You're Getting Sleepy...

2006-09-21T07:14:00.000-07:00

Interesting review in Nature today about the interplay between sleep and weight gain. There seems to be an increasing amount of evidence indicating that people who are short on sleep tend to gain weight. This seems a bit weird, until you realise that the areas of the brain that control fatigue and sleep overlap with those that control appetitite. So you won't necessarily get fat if you're sleep-deprived (a relief, I'm sure, to all our hard-working students!), but you will tend to get the munchies. The answer, as it is so depressingly often, is not to give into temptation. Sigh.

So, this lead me to wonder...is there a link between sleep deprivation and longevity (I would expect it to be negativbe, if it exists). I did a quick search on Google Scholar (where have my scholastic pronciples gone?!) and it seems, not unsurprisingly, that there hasn't been a lot of research in the area. There's an article intriguingly titled "Mammalian sleep, longevity, and energy metabolism" in Brain, Behaviour and Evolution from 1974, but my library doesn't carry that one. I might order it on interlibrary loan, of I ever get around to returning thebook on the history of RNA that's nearly a year overdue. If I set foot in the actual, physical library I expect sirens to wail and lights to flash, while armed guards appear from behind the stacks. Or maybe I'm just being self-aggrandizing here! Anyway, if I can find it I'll post a summary.

Offhand, I'd be willing to bet that there is a relationship between hours of sleep and general health, which would translate, at least to some extent, to longevity. Whether there's a more direct connection, like that between sleep and appetite is less certain, but would be an interesting area of research.

Lasker Awards

2006-09-17T02:00:00.000-07:00

The 2006 Lasker Awards for Basic Medical Research has been awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for the prediction and discovery of telomerase. Fantastic!

Telomerase is the enzyme which maintains the (surprise, surprise) telomeres. These are the bits on the ends of the chromosomes. Every time a chromosome is copied the telomeres get shorter, and it is widely believed that this contributes to the ageing process. When the telomeres get too short, it appears, the cell dies. Telomerase is generally not active in adult cells, so one form of anti-ageing therapy might involve activating telomerase.

This is, unfortunately, a dangerous thing to do. Cells with active telomerase are immortal, and the type of immortal cells we know best are, of course, cancer cells. It turns out that cancer cells do have active telomerase; once again, cancer is the flip side of ageing. So any intervention based upon telomerase would have to take into account all of the complexities of the system, which we are just beginning to understand. It's a very active area of research, and a fascinating one.

What's Wrong With "Old"?

2006-09-16T10:18:00.000-07:00

I've just been watching Saturday afternoon TV (I know, but I'm trying to avoid working on a very overdue paper!) and was confronted with Jane Fonda selling face cream. Now, leaving aside the fact that none of these creams actually do anything, what really annoyed me is the way that the clearly-surgically-enhanced Ms Fonda refers to the skin which has benefited so much from this elixir (as opposed to plastic surgery) as "very mature". In the ad she mentions, with commendable sang-froid, that she's 68. Why the euphemism? Jane Fonda is old. Mature as well, but why boggle at "old"? It seems to be the ultimate crime in our society. It's OK to have lots of years under your belt, as long as you've had enough work done that you look like Barbie. And never use the o-word.

A great illustration of this attitude is the recent appearance at some awards show [1] of Charlie's Angels, who are now in their 60s. Lots of media coverage raving about how good they still look. If you're a devotee of plastic surgery, they're poster children. And I'll bet not one of them would label themselves "old".

Well, I have sympathy with that. But the problem lies, not with the fact of ageing, which is inescapable [2], but with the pandering to the perception that only young-looking women are attractive. Given that assumption, "old" is a killer word: if you're old you're a non-person. It applies to men, too, but less so. We all think Sean Connery is gorgeous, and most of us would admit he's old. But we still probably wouldn't use the word!

Life isn't about sex. Personal value shouldn't be about sexual attractiveness. There's nothing wrong with being old - the alternative is much worse![3]

[1] Sorry, wasn't paying attention. Something media-related; I'm pretty sure it wasn't the Nobels.

[2] Until my research centre sorts it out, of course!

[3] And actually, I happen to think that old women can be gorgeous, too, but then, I have a vested interest!

Longevity Records

2006-09-14T04:04:00.000-07:00

If the Guinness Book of World Records says it, it must be so...the Seven-figure pygmy goby Eviota sigillata is officially the shortest-lived animal on the planet, strutting its stuff on the world's stage for a mere 59 days at the most, of which three weeks are spent as larvae, leaving two weeks into which to cram its entire reproductive life. It takes me longer than that just to get a date...

For completeness, I should point out that the world's lonhest lived animal (and indeed, longest lived organism) is the Hexactinellid sponge Scolymastra joubini, according to the Human Ageing Genomic Resources website. It cheats, though, (the sponge, not the website) by living in the Antarctic, where the very low temperatures keep metabolisms slow. The site admits that the estimated maximum age of 15,000 years may be an overestimate, but even so, it's a long, long time to hang around the Ross Sea. Puts Departmental Meetings right into perspective!

For the record, Homo sapiens comes in at #16, which isn't bad going. We're the only species to have our lifespan[1] recorded to decimal precision, too.

[1] 122.5 years

Starving for Longevity

2006-09-06T02:58:00.000-07:00

...or maybe it just makes life feel longer. I'm talking, of course, about caloric restriction, which has been shown to produce significant life extension-up to double the normal life span- in species as diverse as worms, flies and mice. Not only do they live longer, but they appear to age more slowly, developing all those fun, age-related diseases like cancer and atherosclerosis later in life.

We don't really understand the mechanisms involved, so we have no idea whether the same effect will be seen in humans; studies in monkeys and apes only began in the 1980s, so results are just starting to come through. They look promising, but we won't be able to say for certain for another decade or more. But that, of course, doesn't stop people from experimenting on themselves. There's a pretty committed community of caloric restriction practitioners, many of whom are represented by the Calorie Restriction Society. They do preach good nutrition, and talk about some of the risks of practicing calorie restriction, so it looks harmless enough, on balance, although I can't help feeling that going through life trying not to eat is a mindset best left to teenage girls, and quickly outgrown.

But will it work?

There is a school of thought that argues that whatever the mechanism by which CR works, it must have evolved under some sort of selection pressure. And the pressure may well be something along the lines of a short lifespan with a rapid metabolism in an environment where you can't guarantee when you'll see your next meal. Under these circumstances, it makes sense to be able to slow your system down, hence deferring reproduction, under conditions of food scarcity. Mice fit this model nicely, although I'm not so sure about worms.

If, however, this is the underlying rationale for the anti-ageing effects of CR, it might not apply to humans, since we are already big and relatively slow, have a long reproductive lifespan, and evolved in the nuturing plains of Mother Africa. It's all hypothetical, of course, but I find it a moderately convincing line of reasoning. Biology, after all, is all about evolution. So I think I'll steer clear of the CR crowd for now. I'd hate to spend the 32 years I have left hungry, with nothing to show for it in the end.

Food for thought (OK, I know...obvious, but it had to be said!)

Good News and Bad News About Longevity

2006-09-03T23:34:00.000-07:00

We all know that life expectancy is increasing. My Illustrious Leader, in his Reith Lecture in 2001 tells us that 0ver the course of the last half-century, life expectancy has increased steadily by two years each decade. At the start of the 19th century it was around 40; today it is about 75 for a man and 80 for a woman, and still increasing. So that's good news.

But there's bad news, as well. The major aim of gerontologists (apart from finding people able to pronounce the name of their specialization) is to increase the number of years of healthy life lived. The hope is that illness will be compressed into a shorter part of the lifespan; rather than being elderly and frail for 30 of those 40 extra years we aim to be lively octagenarians, getting the arthritis and osteoporosis over with after we've finished mountain climbing and water skiing. But recent statistics released by Australian Institute of Health and Welfare indicate that this may not be the case. They show that as lifespan increases, the proportion of life lived with disability increases. Men can expect to live for 18.6 years with a disability severe enough to affect day-to-day living, while women are looking at a depressing 20.7 years of disability, on average.

Now, according to the life expectancy quiz I did the other day, I can expect to live to 79, unless I mend my evil ways (and there's no sign of that at the moment). I'm currently 47 (and Australian), so I have 11 healthy years ahead of me[1]. Something tells me I might have left that career as a world class Marathon runner too late.

Of course, the bad news doesn't have to continue; this research was done using statistics from 1988 to 2003. There's an awful lot of research being done into healthy aging[2] and the results are yet to make themselves felt. I think most people woud agree that a longer old age filled with pain and medication is not that much of a boon. If we're going to live longer anyway, we desperately need to find out how to live healthier, as well. Right, I'm off for a run!

[1] Yes, of course it's ridiculous to apply population-based statistics to an individual. It's poetic licence, ok?
[2] Obligatory plug for the IL's 85+ Study, which is going to generate lots of lovely data.

Living to 100?

2006-09-01T09:57:00.000-07:00

I've just done the online quiz at http://www.livingto100.com[1]. Interesting, but I'd take its recommendations with a grain of salt. The quiz consists of 40 questions, covering all the sorts of things that you'd expect to be considered important - diet, smoking, alcohol consumption, wearing selt belts, etc. It gives you an estimate of your life expectancy and then some "personalized feedback" which is clearly just canned responses to the options available in the quiz.

The good bits: Most of the questions make sense in the light of what's known about aging, and the recommendations they give are generally valid, although most of them are common sense (eat lots of fresh fruit and vegetables, don't have risky sex...)

I had a couple of problems, though. For a start, the site is clearly commercial. Not a problem, really, but it does make you wonder how unbiased the recommendations are. Further, there are no references to the literature, so no indication why various recommendations are made. One example is aspirin; the site says, and I quote, "if you really don't have a reason to not take an aspirin a day, consider taking one daily. 81 mg of Aspirin per day has been noted to significantly decrease heart disease risk". Now, this is true, but I really don't think it's a good idea to advise individuals to self-medicate based on group studies. As a fit, middle aged, vegetarian, non-smoking female I may or may not benefit from aspirin, but I'd rather be assessed individually than start taking what is actually a quite powerful and surprisingly poorly-understood drug daily for the rest of my life (however short that might be!). And how do I know if I really don't have a reason to take an aspiring a day?

Similarly, the advice to floss every day to avoid heart disease is based on recent, and relatively unsupported, research. It may well be perfectly correct, and it certainly can't hurt to floss, but the advice gives a spurious air of certainty to a finding which is still not solid.

The other bee in Dr Perls' bonnet is screening. Screening for high blood pressure, cholesterol, etc. can be valuable, but it's not a panacea for all ills, and people tend to forget that mass screening tests usually have high error levels. They have to be quick, cheap and non-invasive, and those constraints are rarely compatible with high accuracy and specificity. Might be a blog topic to go into in more depth later! I think the best way to safeguard your health is to be familiar with your body and aware of its functioning, and the risks inherent in whatever lifestyle you choose to lead, so that you can tell when something changes. I'm not anti-screening, but I think measures like the currently-fashionable whole-body MRI or CT screening are at best a waste of money. At worst they can provide a false sense of security, or even add risk by increasing exposure to radiation.

Despite these issues it's an interesting site, and provides generally valid advice[2]. And it was nice to be told I'm a "lean, mean fighting machine"! I'd still love to know how they put a number on life expectancy, though.

Oh, and for the record, I'm only going to live to 79...maybe I should get some of that screening done!

[1] Disclaimer: I have no connection with the site or the good Doctor. I actually came across it via a mention in New Scientist.
[2] I did love the line " Great news that you have not had a heart attack." I thought so, too!

Death of the World's Oldest Woman

2006-08-29T00:22:00.000-07:00

According to the BBC, Maria Esther de Capovilla died on Sunday at age 116. As usual, her relatives ascribe her longevity to any of a variety of healthy practices - eating well, not drinking or smoking, religious devotion - but it really all comes down to chance. Someone has to be the oldest person in the world at any given time, after all! Not that I'm decrying the value of a healthy lifestyle; one of these days I'm going to give it a go myself. But humans are storytellers; we just can't let facts exist without enmeshing them in a web of conjecture. This is how it should be.

I was particularly struck by the information, mentioned in passing in the BBC article, that she spent the last 20 years living with her daughter and son-in-law. I'm sure she was a lovely person, but you can't help feeling for a guy who marries the woman of his dreams and ends up living with the world's oldest and most enduring mother-in-law!

The oldest person ever documented is, of course, Jeanne Louise Calment, who died in 1997, aged 122. It looks like 120-odd is about the human maximum, at least without genetic manipulation (and we have no idea how to do that yet). Assuming that most women marry in their 20s, their mothers are likely to be in their 40s, with 80 years at most ahead of them. So sons-in-law worldwide have an upper limit to their years spent housing Mother!

Aging and Cancer

2006-08-22T09:19:00.000-07:00

In a previous life (well, this time last year) I was working on the genetic networks underlying cancer. In this incarnation I'm working on the genetic networks underlying aging (at least, I will be when we've finished building the databases, identifying data sources, obtaining and integrating the data, constructing the networks and having a couple of celebratory pints at the Trent House...) And it's becoming more and more apparent that there really isn't a lot of difference between the two networks.

From one persepctive, of course, that's a trivial observation. All human cells contain the same set of genes, so the Ultimate Network is the same. But of course different genes are expressed in different types of cell, so different subnetworks are actually active in different cells and at different times. And it turns out, perhaps not so surprisingly, that the sets of 'cancer' genes and 'aging' genes[1] have significant overlap.

One of the most downloaded articles from Nature was an editorial called 'Ageing: The price of tumor suppression?'[2], reporting on research published by Tyner et al. in the same issue [3]. The Tyner team found that mice with mutations making the gene p53 (the 'guardian of the genome') more active appeared to have accelerated ageing. p53 is a tumor suppresor gene, and you'd expect that making it more active would be beneficial, in that it would protect against cancer, but the hapless beasties ended up with "reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance". They reason (the researchers, not the mice) that ageing may be a side effect of the natural safeguards that protect us from cancer. Which would mean that combatting ageing by genetic means might just lead to a higher cancer risk. It's like the question all kids seem to ponder: would you rather die by drowning or by shooting?

Confusingly, there's a recent article in Science by Pinkston et al.[4], who found that in C. elegans, everybody's favourite worm, mutations that increase the lifespan also inhibit tumor growth - exactly the opposite of what you'd expect from the mouse models! I'm not sure how applicable this finding is to humans, though; worms don't usually get cancer, so they were genetically engineered to produce tumours, which means that the tumours are probably fairly unlike human tumours. Still it's an interesting finding, and highlights how little we know about the genetics of cell growth and death. Looks like I might be in a job for a while yet!

[1] Of course, there's no such thing as a gene for cancer, or just about anything else, media reports to the contrary. I'm just being lazy and using the usual shorthand for "a gene whose function (or malfunction) impacts the cancer phenotype.
[2] Ferbeyre, G. & Lowe, S. W. (2002). Ageing: The price of tunour suppression? Nature 415:26 - 27.
[3] Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebraniousk, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., Park, S. H., Thompson, T., Karsenty, G., Bradley, A. & Donehower, L. A. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415: 45 - 53.
[4] Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. (2006). Mutations That Increase the Life Span of C. elegans Inhibit Tumor Growth. Science 313:971 - 975.

The Big Adventure: A Retrospective

2006-08-18T01:20:00.000-07:00

Well, I'm back in Newcastle. It's about 17 degrees, grey, and has rained almost constantly since we got back; something tells me summer is over! To add to my woes someone cloned my debit card in Fortaleza and cleaned out my bank account; I forgot to pay BT before I went overseas and my phone (and hence internet connection!) was cut off; and my motorbike was stolen from the parking lot opposite my flat and vandalized. So the homecoming hasn't been quite as cheerful as it could have been. On the plus side I have a bathrobe with a hotel crest, a bottle of Brazilian rum worth 6 Real (about 2 pounds) and a headful of inspirations, scientific and otherwise. It's been quite a month.

The contrast between the two conferences I went to is fascinating. CEC is an IEEE conference, and as such is full of engineers and computer scientists. In the biology tracks the biological questions are of interest, naturally, but the focus is on algorithms: on turning raw biological data into interesting information. ISMB is dominated by lab-oriented biologists, even though it's the official conference of the International Society for Computational Biology. I got the distinct impression that many of the attendees see bioinformaticians as the handmaidens of "real" biology, rather than as biologists in our own right. There was even a keynote presentation on "Why bioinformaticians need experimental biologists". This is an attitude with which I'm all too familiar, but it's disappointing to see it amongst this community. It needs to be stated that there is some biology-real, honest-to-God biology-that can only be done using a computer. Clearly, we need the lab dwellers and their data, and equally clearly there is a need for computer support for lab biologists, but computational biology is a valid field in its own right. Of course, it's early days yet, and computational biology has yet to prove itself. We need some major breakthroughs, and I think it will be a couple of years before that happens.

OK, off the soapbox and back to doing some of that biology! Or possibly to devising appropriate responses to punk who trash other peoples' motorbikes... Matt's suggestion of red hot knitting needles has a lot going for it.

ISMB 2006 – Day 2

2006-08-08T20:30:00.000-07:00

An interesting day, particularly because it had a couple of more theoretical, evolutionary biology type papers, which I really enjoy. It’s good sometimes to take a step back from the nitty gritty detail with which we work every day and think about the bigger issues in biology. I sometimes suspect I’m an evolutionary biologist manqué, but I really believe, deep down, that all biologists should be.

OK, so – first notable talk (of those I saw!): Christina Chen on ultraconserved elements in genomes. I’m a bit wary of this whole “ultraconserved” business; it seems to me that we really don’t know enough about comparative genomics to state definitively that long stretches (200 appears to be the cutoff) are really completely unchanged between species. And Christina’s research seems to support that. They’ve found that putative ultraconserved regions actually are polymorphic between individuals (although at significantly lower rates than expected) and that there’s no evidence for strong selection on these alleles, because they’re in Hardy-Weinberg equilibrium[1]. And the conclusions? I think we have to be very careful in our interpretation of the meaning of “ultraconserved” regions in genomes. OK, it may not be a brilliant insight, but there’s been a lot of hype in this area lately!

The final plenary was also excellent: Mathieu Blanchette (the Overton Award winner) on “What mammalian genomes tell us about our ancestors and vice versa”. He covered three major issues: predicting transcriptional regulation, the characteristics of CRUNCs (coding regions under non-coding selection), and his Ancestral mammalian genome reconstruction project, in which they’re attempting, with what looks like considerable success, to reconstruct the genome of one of the common mammalian ancestors from the mammalian radiation of 75 million years ago [2]. It’s cool not only in it’s own right, but because it allows comparison between modern mammalian genomes and their common ancestor: as close as we can get to evolution in action.

All in all, a good day, rounded off by a great dinner at (by Fortaleza standards) an outrageous price. Well worth it!

[1] Not that selection is the only factor affecting H-W equilibrium; when I was an undergrad we used to drink toasts to Hardy and Weinberg because the conditions required for their equilibrium are: 1) No selection; 2) No migration; and 3) Random mating. Guess which one we used to drink to?

[2] The Boreoeutherian ancestor, to be as precise as my notes allow. And no, I have no idea what it was.

ISMB 2006 - Day 1

2006-08-07T11:53:00.000-07:00

We dragged ourselves away from the beaches and the bars today to catch a bus to the Fortaleza conference centre at the crack of dawn. There are about 800 attendees, I gather, and they all arrived at around 8am on half a dozen buses. Eight hundred computer scientists who had been deprived of internet access for periods of up to 60 hours (I'd like to hear that story sometime!) arrived more-or-less simultaneously at a venue with wireless access. Which promptly collapsed in a wheezing heap. Matters seem to have improved this afternoon, however; maybe half the delagates are on the beach?

I've been in the Systems Biology stream all day, and it's been excellent. Lots of network talks, most of them addressing the sort of issues that our group wrestles with every day: not enough data, too much data and ill-formed data (usually all at once); the need to make what we know are unrealistic simplifications; computational feasibility. The picture I'm getting is that the field really has advanced over the last couple of years, but there's still an awfully long way to go. The emphasis on biological data (although not necessarily biologically important questions!) is good, too. The origins of the society's journal, Bioinformatics, as Computer Applications in the Biosciences is gradually being lost, although it's taken time.

The second plenary this afternoon looks promising. But maybe I'd better pay attention to the talk I'm currently in...

Update

2006-07-28T13:21:00.000-07:00

Well, I made it. No hijacking, no muggings (yet), but they lost my bags. When the carousel stopped and the official looked at me and shrugged I just had this feelinf of fatalistic acceptance. It could have been worse. It probably will be worse, in due course! They say I can have then back tomorrow (after another taxi trip to the airport and back, for which I'd be willing to bet no-one will offer to pay).

So I finally made it to the beach...dressed in heavy jeans and a distinctly anti-social tshirt after 27 hours in transit. There's a cosmic consiracy here to keep me pale!

Is Southern California Hell?

2006-07-28T10:33:00.000-07:00

It’s certainly hot enough at the moment to qualify. And tree-hugging anti-consumerists would probably embrace the idea. But I’m thinking more pragmatically, not to say selfishly. After the week I’ve just had, I’m starting to believe it is.

I’ve been to California many times, and I generally like it. Palm trees, sun, sand, surfers…just like home. But this time was different. My first mistake was deciding to take the bus from Vancouver to San Diego. I’ve already covered that, so I won’t go into detail. However, after two full days in transit, I was ready for some time on the beach. Except that it was overcast and cloudy the whole three days I was there. Never mind; there are great bookshops and bars, and I managed to fill the time very pleasantly. Come Wednesday morning, and things started to go downhill again.

I was booked on the 10:00am bus to LA. I made it (just) and the trip was uneventful, if a bit tedious. I swear I’m going to take up writing mysteries…some of the junk I’ve read, in desperation, over the last few weeks must have been written as part of a third grade English assignment! Three hours later I’m in LA, facing the next decision. How to get to the airport? I ask around, and it seems the choice is a taxi at around $40, or two buses for $2.50. Call me cheap, but I can think of better uses for $40. Even in California, that’s a fair amount of beer! So I go with the bus option. Two hours, two buses but only one missed stop, and I’ve seen an awful lot of drab real estate and met some…interesting…people. Talking to an American friend later, he assured me that only vagrants take the bus in America. I know what he means. The bus driver was very sweet, though, even if she did forget to tell me which stop to get off at. It just meant I had an extra half hour to talk to her, as we went round the route again.

The metro bus drops you off miles from the terminal, but it only took me 20 minutes to figure out where the shuttles went from and lug my bags over there. Did I mention we’re having a record heat wave? From the airport another shuttle took me to the hotel, where, for the price of a beer, I dined on free bar snacks.

Fast forward to this morning. The hotel insisted that my room was not, as arranged, prepaid, and went ahead and charged it to my credit card. (Actually, I was amazed it went through!). Arguing about this meant that I arrived at the airport with very little time to spare, but fortunately the lines at the check in were moving pretty fast. At the check-in desk I encountered the next check. Apparently, in order to enter Brazil on a visa, you have to have proof of the fact that you’re leaving again. And my return ticket is an eTicket, and I hadn’t printed a copy of the itinerary. I’ve never been deported, and I’m usually pretty open to new experiences, but I still haven’t made it to the beach, and the North Sea is just not the same. The guy behind the desk was very nice about it, but firm – I can’t enter the country on a one way ticket. Somehow I have to show him my itinerary, which I have in my email inbox. I need the internet.

Picture, if you will, a crowded departure area in LA airport at 7:30 in the morning. Amidst the lines of travellers and piles of luggage, in front of desk #14, a middle aged scientist and a uniformed airlines clerk are kneeling on the floor, trying to persuade my laptop to hook up to the network, using the network cable he unplugged from the back of his computer. I think it’s safe to say we caused some interest. After 20 minutes we realized it wasn’t going to work, so he went off to confer with superiors. It was only after he’d got permission for me to go to the gate lounge and use the wireless there that I realized that I did, in fact, have a paper return ticket, at the bottom of my handbag. I have to say, he took it very well!

I’m now en route to Miami. The way today’s going I’m reasonably certain that either the plane will be hijacked or I’ll get mugged on the way to the hotel…

Obedience to Authority

2006-07-25T10:13:00.000-07:00

I spent yesterday evening sitting in the Rock Bottom bar, sampling their microbrews (do they count as microbrews if it's a national chain?) and reading a reissue of Stanley Milgram's classic "Obedience to Authority". It's a totally scary book, and makes you look at human nature quite differently, as does much of Milgram's work[1]. I think he's very much under-appreciated outside the psychology community.

To recapituate quickly: Milgram set up experiments consisting of a 'teacher', a 'learner' and an 'experimenter'. The learner and the experimenter were in cahoots, and the real subject of the experiment was the teacher. The ostensible aim of the experiment was to investigate the effects of punishment upon the learning process, but the real aim was to examine under what circumstances people would obey authority, even when told to do things against their moral principles. The teacher had to read a list of word pairs to the learner, and then punish the learner with an electric shock when the learner got the pairs wrong. The strength of the electric shock increased every time. The learner, although not actually getting shocked, acted increasingly distressed, demanding to be let go (he was strapped in), screaming in pain, an so on.

They varied the experimental conditions in a number of ways, but the results were amazingly consistant. Around 60% of people would inflict pain up to a level clearly labelled 'danger' on the board they were using, if told to do so, even though most of them were clearly distressed by what they were doing. Milgram discusses possible reasons why people behave this way in considerable detail, but the bottom line is: people obey authority, even to the point of doing things they would normally find morally repugnant. And this was just a university-run experiment, for which they were paid $4.50! I should imagine the effect is even stronger for systems with real authority, such as prisons, the police and the armed forces.

It's a really depressing thought. The torturers of the Spanish Inquisition, the witchfinders, the guards in the Nazi concentration camps, the American soldiers in Abu Ghraib were probably all nice, normal people who loved their mums and went to church on Sunday...and found themselves in a situation where they behaved with cold-blooded cruelty to total strangers.

I haven't quite finished the book, so I don't know if he discusses it, but I've heard that many of Milgram's subjects were seriously traumatized by the experiment, and the realization of what they, personally, could be made to do. After this, the ethical rules were tightened, and this sort of research would no longer be approved. He does make it clear, though, that he had no intention of damaging his subjects; before he started he expected that most people would simply refuse to participate once the 'learner' started objecting. Fascinating, disturbing stuff.

[1] Milgram also did the famous 'six degrees of separation' research, which is a significant part of network theory, and so this post is *almost* relevant to my research!

In Transit

2006-07-23T23:51:00.000-07:00

Well, CEC is over. It turned out to be a huge amount of fun - great plenaries (on the whole!), quite a few interesting sessions, and of course the chance to network (it's professional networking, ok? Not just a chance to gossip over a beer!) with interesting people I only get to catch up with at conferences like this. The computational biology sessions, which took up all Thursday, were the highlight for me, of course. I gave two presentations, and actually got some questions, which is always a good sign. Your heart sinks when the session chair says "Thank you! Any questions?" and there's this wooden silence. After a minute or two the chair says "Well, I have one..." and you can see him or her desperately trying to remember what you were talking about. If all else fails "Where do you see this research going?" tends to be trotted out. I've been in that position as session chair myself. Fortunately, it didn't happen this time...lots of questions, to which I may or may not have given comprehensible answers. There were several really nice talks in those sessions, some of which will be useful for a review article I'm writing. I'll talk about that in more detail later.

I spent the last two days on a Greyhound bus. Left Vancouver at 8:30am on Saturday, and got to San Diego at 10:00pm on Sunday. I don't think I've ever been so glad to get into a bath! There's such a lot of gorgeous country down the west coast - one of the reasons why I chose to take the bus - but you get so tired sitting all cramped up for hour after hour that you really don't appreciate it.

I've figured out how to sleep sitting up on a bus, though. There's nothing to it, as long as you have a window seat. You fold yourself up, concertina style, and rest your head against a vibrating glass windowpane, down which a freezing draft is directed by the air conditioning system. Then you wait until all your muscles go numb and your thermoregulatory system shuts down, at which point you can doze lightly, disturbed only by the hugely fat guy beside you turning over and overflowing into your seat, the screams of the inevitable baby three rows up, and the woman directly behind you coughing her drug-resistant TB at the back of your neck. After eight hours of this the sight of a Burger King in the middle of nowhere is suddenly a vision of Paradise, rather than the plastic Hell you previously thought. There's nothing like queuing up for semi-congealed French fries and watery coffee at 6am to make you appreciate life in the salt mines...

I'll be in San Diego for the next few days, and I have two book chapters to write, so if I can tear myself away from the beach I might actually manage to do some work. Failing that, the blog may have to revert to a description of the sufers and bars of Pacific beach!

Self Driving Vehicles

2006-07-21T08:39:00.000-07:00

We had the most entertaining plenary on Wednesday - "Winning the DARPA Grand Challenge", by Sebastian Thrun from Stanford. The challenge was for a totally autonomous vehicle to cross 140 miles of desert in under 10 hours. In 2004 no contestant made it further than about 10 miles, and most people (including me!) concluded that it was currently impossible. In 2005, five teams made it [1] including, of course, the Stanford team, who won $2 million for their efforts. Sebastian gives an excellent talk (he's clearly given it a million times, and knows exactly how his audience will react), and has a fascinating story to tell. Makes you want to get out there and into robotics!

Next year's challenge is to complete a 60 mile urban course, including other moving vehicles, in less than 6 hours [2]. The Stanford team is entering again, and Sebastian is very enthusiastic about the potential for self-driving cars. Listening to him, I was very sceptical...after all, these things are programmed by people like me! (Well, probably not just like me; no-one with any sense lets me anywhere near a Java compiler. I have to lock myself in my office and code when no-one's looking). My gut feeling is that cars driven by people are going to be safer than drive-by-wire. But Sebastian disagrees, and after all, he's the expert.

He also made a point which I hadn't considered, and which brings us, however tenuously, to aging. He discussed how devastating it is to an elderly person to lose their driving licence. It cuts them off from their social circle and, in today's car-oriented society, makes them dependant upon carers. But for the safety of others it often has to happen; we went through this whole business with my husband's grandfather, and I'll bet it happens to most people eventually. But self-driving cars would mean independance for people with Altzheimers, visual impairment, general frailty...all of a sudden it's a very appealing idea. So I'm cautiously on the side of automated cars. As long as they don't let people like me program them!

[1] http://www.darpa.mil/grandchallenge05/index.html
[2] http://www.darpa.mil/grandchallenge/index.asp

Human level intelligence

2006-07-18T17:17:00.000-07:00

Day one of the Congress on Evolutionary Computation, and the theme was artificial intelligence. Talks, panels, a keynote...it's a lovely idea, but I can't help feeling we're being just a tad optimistic here.

We're all engineers here (this conference is run by the Institute for Electrial and Electronics Engineers), so we all share the basic assumption that if a physical phenomenon exists, we can reverse engineer it, given enough time, technology, intelligence and (of course, because we're still academics) money. Intelligence is a phenomenon, arising in complex systems; if we can build a system complex enough, it will be intelligent. I have to admit, I have a lot of sympathy for this attitude. I see no reason why intelligence should be tied to wetware instead of hardware. Reasons may exist, of course, but we don't know them yet, so I think we're justified in exploring the possibilities. But surely it would help if we actually knew what we were looking for?

Intelligence is like pornography: you can't define it, but you know it when you see it. That's the working definition used by most of the computational intelligence community, and it does leave us in an awkward position. Alan Turing suggested the Turing Test as a measure of "human-level intelligence" in 1950(1). The idea is simple: a computer and a human communicate with an interrogator via a keyboard. The questioner can ask anything he likes. The computer passes the test if it can convince the guy on the other side of the keyboard that it is the human. Simple, understandable...and as far from being achieved now as it was when Turing proposed it. Consider industrial robots, 'helpful' computer programs, game bots...is there a skerrick of actual intelligence there?

Even a cut-down version, known as the Loebner Test, was never really convincing. Why has human-level machine intelligence been so hard a problem? I can see a number of possibilities:

1. In some way we don't yet understand, intelligence is a property of brains, and cannot be mimicked on other hardware;
2. Our hardware isn't yet sophisticated enough;
3. Our software isn't yet sophisticated enough;
4. Our working definition of intelligence is so vague / off-the-mark / completely wrong that we're working in absolutely the wrong areas, and missing something really obvious;
5. Some combination of the above.

Obviously, I go with option 5! The feeling around the conference is clearly positive: human-level machine intelligence is just around the corner. Indeed, one talk we had claimed that it's not just around the corner but over the doorstep, and making itself at home in an armchair by the fire, but I have some reservations, so I'm not going to relax just yet. On balance, I go with 2. and 4. We need *much* more complex hardware, and we need to know what we're doing with it. And it's not just around the corner, even if I do quite like the AI who's training me up in Eve Online. She has such a reassuring voice!

No ageing, but I think it's relevant. One of the greatest fears everyone has about the ageing process is its effects on intelligence and memory(2). These are issues worth contemplating by biologists and engineers alike.

(1) Good Turing Test page at http://cogsci.ucsd.edu/~asaygin/tt/ttest.html
(2) Hey, I get to plug a book! Not mine, but by a friend of mine; if you're worried about your ageing memory (I've been worried about mine since I was 19) try The Memory Book: http://www.itee.uq.edu.au/~janetw/memory/

Sleepless in Vancouver

2006-07-17T08:00:00.000-07:00

I'm currently at the World Congress on Computational Intelligence in Vancouver, Canada. The conference starts today, so apart from two free glasses of red wine at the Opening Reception last night I really have nothing to report yet. Should be fun, though; a few old friends, and some interesting looking talks.

Getting here was interesting, to say the least. For some reason, I seem to be a bit disorganized this trip (a state which my friends and family will say is chronic, but they're mistaken). Anyway...I'm going to Fortaleza in Brazil after this, so I needed a visa. Because of delays in funding the flight (there's a world of pain here, I'm just going to gloss over it) I ended up applying for the visa the week before I left. That meant that I had to pick up my passport from the Brazilian Embassy between 3:00 and 4:00pm on the afternoon before I flew out of London. Someone's looking out for me, because it was ready, and I got to spend a very pleasant afternoon on a floating pub on the Thames, with my visa-adorned passport safely in my handbag. Flew out the next morning, and apart from the realisation that the bar at the airport in New York charges $10 for a beer (which I only found out half way through the second one. I was so upset I had to have another one to calm my nerves. Fortunately, there was a special offer - a shot of whatever you choose with each beer for a mere additional $2!) I made it to Vancouver more or less in one piece.

Because the university is not paying for all of this trip, I'm staying at a hostel in downton Vancouver. I arrived at midnight, in a less than lively state, and checked in. I'm in a dorm with three young women, and, quite frankly, it looks (and smells) like a teenager's bedroom. Well, the bedroom of three teenagers. Possibly a teenage boy's dream, but for me the whle setup lacks charm. I made my bed, went through my talk for the conference, and settled down for sleep. At this point it was 2am. On a Friday. By 3:30am the influx and efflux of drunken teenage girls changing their clothes (did I mention it was a teenage boy's dream?) had settled down, and I managed to doze. Until 5am, when some guy starting banging on the door and calling for Angie. Since we didn't seem to number an Angie amongst our ranks, he eventually went away. At 5:30 I decided there was no point trying to sleep, and went for a shower. I could get my own back by snoring, but as far as I'm aware you actually have to sleep to do that. Maybe tonight!

Turns out there's really not a lot to do in Vancouver at 7am on a Saturday, but the staff at the local Starbucks were very nice when, in my stupor, I managed to spill a Grande Americano all over their newly-cleaned premises (and my laptop bag, which now has a pleasantly evocative breakfasty scent that I suspect I'm going to have to live with for a while).

Conference starts today. Not a lot of ageing related stuff, but some interesting talks are lined up. I'm looking forward to it.

Disposable Soma

2006-07-02T14:31:00.000-07:00

I'm firmly convinced that for a biological theory to persist it has to have a catchy name, and the disposable soma theory certainly meets that qualification! Mind you, it's a good theory, too. At this point I should add a disclaimer - it was proposed by my boss(1) in 1977(2) (but that's not why I like it; I'm always happy to critique the boss!).

So, the basic question is "why age"? Why not live forever?

The first issue is that, in the wild, creatures almost never die of old age. You get eaten, or run over, or die of disease long before the grey hairs start to intrude. So, if you, as an organism, can take it as read that you're going to die, it makes evolutionary sense to maximise the spread of your genes. The ones you carry will die with you, but you want as many copies as possible out there. Given that you have a limited energy budget (as every dieter is well aware), the question becomes - how much do you expend on repair of the inevitable damage that's done to cells and chromosomes, and how much on reproduction? The disposable soma theory addresses exactly this question.

And the answer, of course, is different for different organisms with different lifestyles. You can live fast, die young and leave a beautiful corpse (and a lot of offspring), like the many sea creatures who contribute to the plankton layer; or put lots of time and energy into a small number of babies, as humans do. The best strategy depends on your lifestyle and evolutionary niche. Since the soma (body) is inescapably disposable, all the issues of game theory come into play - which is another story, for another time.

(1) OK, one of my bosses. As a minion in the university hierarchy I have an elegant sufficiency of bosses, and just as I think I have them all tabulated, I find there are more. One of the joys of academia, I guess...

(2) Kirkwood, T. B. L. 1977. 'Evolution of ageing', Nature vol. 270, p.301 - 304.

Paved with good intentions

2006-06-27T13:11:00.000-07:00

I sincerely hope I'm not actually on the road to Hell (although the streets around the hospital where I work part of the time can be pretty unpleasant!), but my good intentions of posting regularly here certainly didn't pan out. Such is life...let's see how it goes.

I've been pretty busy for the last few months. Several paper deadlines, finishing off old projects from my last job, lending a hand to the experimentalists (of which more anon) and a new project. The latter is, of course, the most exciting, so I'll describe it briefly.

I do network analysis, and to date I've been mostly working on structural networks - that is, networks based upon evidence of physical interactions. Protein-protein interactions within the cell, genetic regulatory interactions, and (one of my minor triumphs) social networks on the internet. That was a triumph because it was perfectly valid research-I even published a paper on it-but it also was the perfect excuse for spending work hours on IRC. Not quite as good as that project on the ecology of spiders living on tropical beaches that I have in mind, but entertaining! It was a great data set, too.

However, structural networks have their limitations. Biological interactions come in all flavours, even if you restrict yourself to interactions occurring within a cell, and a single type of network can only capture a subset of the important interactions. It makes a lot of sense to combine different types of interaction data into a single network of functional interactions. Doing this raises lots of issues, however: what data do you include; how do you deal with missing data; how do you estimate the reliability of data sets; how do you combine different types of evidence in a proncipled way? And, of course, once you've built your network, what do you use it for; what sort of insights can it give that, say, a protein-protein interaction network won't? Needless to say, I have at least the beginnings of ideas about all of these questions, and I'll go into the issues in more detail later. For now, I'm starting on database design and data collection, using the impossibly charismatic Bacillus subtilis as a test organism. Anyone who can point me to any sort of data on intracellular interactions in B. subtilis feel free to let me know!

Back to flogging the cluster, before the IT guys realize I'm hogging it and come to tell me off...

A small celebration

2006-03-02T06:59:00.000-08:00

A much-delayed post here, because I've been sweating over a conference paper for the last couple of weeks. Deadline yesterday, and we met it! Albeit with my co-author in Australia staying up until 2am to finish the stats, and becoming decidedly monosylaabic in the process. But the main thing is that it's done and submitted and out of my hands.

In the paper we look at the relationship between network motifs and network dynamics. The seminal paper in this area was published in 2002 [1], but the idea has really taken off. Basically the idea is that a large complex network can be broken down into small network motifs consisting of three or four nodes, which carry out a very specific task - being a logical 'and' gate or providing negative feedback control, or whatever. The hope is that if we can characterize enough of these motifs we will be able to get a handle of the way large networks behave by looking at the way their motifs behave.

This is a lovely idea, and offers the first real hope of being able to understand the way in which things like genetic regulatory networks operate other then simply prodding them and seeinghow they respond. Statistically over-represented motifs have been found in lots of different kinds of networks, biological and otherwise, and the fact that the same motfs can be found in very different networks means, according to some researchers, that they are evolutionarily conserved.

However, when you're looking at groups of three or four nodes there just aren't that many combinations in which they can occur. In addition, looking at huge numbers of nodes and the links between them means that you have to interpret your statistics with caution; if the chance of a particular combination occurring is 1 in a thousand (0.001, usually considered statistically significant) you only need to make 500 observations to have a good chance of seeing that combination. Ans with large nets we're looking at lots of combinations! So while I think the network motif idea is a very neat one, and I'd like it to be the basis for useful analysis, I think it remains unproven.

In out study we took a reverse approach and generated computational networks with and without interesting dynamic behaviour and then looked to see what the structural differences between them were. There was certainly no increase in numbers of motifs, although we did see a few. What did change dramatically was the numberof feedback loops in the networks. Since feedback loops are known to be important in the generation of network dynamics, this makes sense, and we're continuing to follow it up.

We concluded that you can have interesting dynamic behaviour without the presence of network motifs. This doesn't mean that real networks don't have them, but it does mean that they don't have to have them, and hints that the relationship between network topology and dynamics is not going to be easily untangled. But we're working on it! Fingers crossed that the paper gets in...

So, this was a bit of a diversion from aging, but I'll get back into it next week, when my brain is less full of triads and simple cycles.

[1] Milo, R., Shen-Orr, S., Itzkovitz, S., Kashtan, N., Chklovskii, D. & Alon, U. (2002). Network motifs: Simple building blocks of complex networks. Science 298: 824 - 827.

Theories of Aging

2006-02-15T02:12:00.000-08:00

There are three major theories of aging: that is it programmed; antagonistic pleiotropy (don't you just love that term? Should be a band name...); and that is the result of accidental damage accumulating over time. I discussed the first theory in my last post, so I'll look at the other two theories in this one.

Sir Peter Medawar (who won the Nobel Prize in Physiology or Medicine in 1960 "for discovery of acquired immunological tolerance" (along with Sir Frank Macfarlane Burnet, who was Australian - did I ever mention I'm Australian?)) suggested in 1952 that because organisms are exposed to constant sources of DNA damage such as background radiation and toxic chemicals, repair systems will eventually be overwhelmed. As mutations accumulate the cells become less and less capable of maintaining normal metabolism, and eventually they age and die.

A different take was presented by George Williams in 1957. He reasoned that natural selection operates far more strongly on young organisms in the reproductive phase of their life cycle than it does when they have already survived to adulthood and reproduced. So genes which produce traits which are beneficial in early life but damaging in later life (hence the 'antagonistic') are likely to persist and spread in a population. 'Pleiotropy' simply means the control by one gene of several different traits, in this case those that benefit the young and impair the old. So under this theory aging is the price we pay for youthful fitness benefits.

In 1977 Tom Kirkwood propsed the 'disposable soma' theory of aging, which pretty much subsumes the other two theories in a pretty neat way. I'll cover disposable soma in more detail next time; right now I'd better get back to a conference paper I'm writing.

Genes for Aging?

2006-02-08T11:03:00.000-08:00

The suggestion that aging might be genetically programmed was first made by Alfred Russel Wallace in 1889. He suggested that "Natural selection…in many cases favours such races as die almost immediately after they have left successors" (Wallace, 1889). The idea is predicated upon the existence of group and/or kin selection; organisms which die free up resources, and if their rate of dispersal is low, the organisms which will benefit from these additional resources are highly likely to be kin.

There are some theoretical problems with this approach; for a start, it invokes the spectre of group selection, which is anathema to most evolutionary biologists. The idea that individuals will sacrifice themselves "for the good of the species" was still being taught when I was in high school (and we don't need to go into how long ago that was; it's enough that I'm still alive!), but is generally discredited today. The major problem with it is that the system is open to cheaters - mutant individuals who accept the sacrifices of others without doing their share. Because cheaters get more resources, they can reproduce more, and cheater genes will spread through the population. Apparent instances of suicidally altruistic behaviour such as birds alerting the rest of the flock to the presence of a predator via an attention-attracting call, can be explained in terms of individual, rather than group good. For a very nice introduction to the research in this area, I highly recommend Matt Ridley's book "The Origins of Virtue".

So group selection segued into kin selection, via William Hamilton in 1964. If, instead of the spoecies as a whole, your sacrifice benefits your genes by preserving copies of them - for example, those in your close kin - the sacrifice might be worth it. And the theory does seem to hold in many situations; you can use it to generate hypotheses which can be tested in the field or lab. But there is always a tradeoff between the benefits to the genes in the original owner, and those in the kin. There's an excellent page on the topic in the Stanford Encyclopedia of Philosophy.

I think that for us to be able to say, with some confidence, that aging is programmed, we need much more evidence than we currently have.

What is aging?

2006-02-02T01:32:00.000-08:00

OK, maybe the updates won't be as frequent as I'd hoped! A couple of weeks ago we had an induction week for the new research centre I'm working for. The idea was for everyone involved to get to know each other, and discuss some basic issues in aging research. And the most fascinating question that came up, to my mind, was the simplest: what is aging?

A lot of people (in the literature as well as in general conversation) confound aging with longevity. If you're extending lifespan, the unspoken assumption goes, you must be slowing aging, right? Well, maybe. But you're not directly observing the aging process, so longevity remains a proxy. And yet we have strong gut feelings that there is such a thing as a rate of aging. You only have to look around you to see that some 40-year-olds look older than others. But we're interested in cells, and while it's easy to keep track of the chronological age of cells (how long since last division, how many times the population size has doubled, etc.), there's really no way to visually pick a young-for-its-age cell from its more hard-living fellows. So we turn to biomarkers, a topic I'll have some coherent thought on soon. Probably.

Hello

2006-01-18T04:48:00.000-08:00

Finally back in the real world...I used to have a blog here called Cancer Dynamics, which has been shamefully neglected. But I have an excuse! I've moved jobs and even countries, and the whole process has been a bit distracting. I'm now working on computational modelling of the ageing process. I'll be doing the same sorts of things that I was before - simulation models using agents, evolutionary computation, etc., but I'll also be working closely with other modellers and wet lab biologists to generate and analyze data. It's going to be a fun ride.

This blog is therefore going to be pretty much a continuation of the previous one, although I hope it'll be updated a bit more frequently. So it'll contain musings on my research, on what I'm reading, and what's going on in the wider community. You never know, someone might even read it some time...