Tuesday, March 31, 2009

The Red Heart Pill -- the road to immortality?

The BBC is reporting the story today of a study just published in the British medical journal, The Lancet, about the 'polypill', a 5-in-1-er that combines aspirin to prevent blood clots, a statin to lower cholesterol, and three drugs to lower blood pressure. Meant to be taken by 'everyone over 55' (a pill that everyone takes forever -- a pharmaceutical dream), the original aim was to lower heart disease by 80%.

A drug trial in India suggests that the pill has the desired effect, and is well tolerated with no downside. The reaction to this by the medical profession seems to be mixed, with many questioning the ethics of offering a pill to do what diet and exercise can already do. (Oddly, few question the ethics of these drugs taken separately, nor suggest that more money should be put into figuring out how to make health education effective.)

To us, however, a more important point is one related to a major theme of this Blog, that of causal complexity in life. The problem is known as that of competing causes, and there is nothing arcane about it. It is that if this pill actually works and becomes widely used (the BBC reports that the estimate is that incidence of heart disease and stroke will be halved, saving millions of lives), the long term effect will be to allow huge numbers of people to survive farther into old age, where they will inevitably become arthritic, mentally deficient, and will get diseases like cancers and other non-cardiovascular diseases that will be just as lethal and even more expensive, for longer, than the heart disease they didn't die of in middle age.

This is another angle on biological complexity: there is no free lunch. One can't oppose measures that increase the length of healthy life, but that doesn't mean the competing cause problem won't become a serious one. We know this clearly from what has happened in the last couple of generations as many of us have lived long enough to do complexity Blogs, once infectious diseases and other causes of early death were brought under control.

The competing cause trap also relates to what is called the 'dependency ratio', the number of people that each working-age person must support. This number is already a heavy burden, and we know that it will get dramatically worse (e.g., who will pay for Social Security for all the elders?) even without any polypills leading to yet more people to survive to become socially dependent.

Besides supporting the elderly, there will also be a problem of less resources for those here and elsewhere in the world whose needs, at young ages, are vital -- nutrition, vaccination, and so on for hundreds of millions for whom living long and hale enough to get heart disease is just a dream.

There are no easy escapes from complexity problems of this sort. Here the good of the individual competes with the good of society.The problem is what to do about it, and there the answers must come from science but also from society as a whole.

Sunday, March 29, 2009

Big Lobbying Week

This past week saw pushes on both sides of the Atlantic for funding for new mega-genomic projects. On the European side, this lobbying is for EU-wide national biobanks, of millions of peoples' records including personal health information and (of course) DNA samples. On the American side, it's to get federal funding for more large-scale genetics. Mass emailings are going out to anyone on potentially relevant science list-serves, asking them to get in touch with the incoming secretary of Health and Human Services. In both cases, the advertized benefit of these huge and expensive genomics projects is a revolutionary 'personalized medicine,' a cause that seems somewhat unsavory given that it will mainly be for wealthy patients, in an era when many millions are without basic living resources including health care.

Personalized medicine is code for a high-technology approach to genetics, to tailor treatment to each individual by predicting their susceptibilities (and potentials?) to suggest molecular interventions. Lifestyle advice is also mentioned, but the real push is genetic, and it's based on a faith in strong genetic determinism, because if individual genotypes don't have high predictive power, the dream of revolutionized medicine won't become a reality. And so this past week was a big one for lobbyists for the belief system that holds (sometimes explicitly, sometimes implicitly) that genes determine everything in life, which often goes hand-in-hand with the belief that anything organized about life has to be due to natural selection (for brevity, we are exaggerating--but not all that much). Inherent in both of these related beliefs is an assumed fundamental inherency about organisms and their traits. Such views have a history of being rationales for various sorts of inequality, but also discrimination, sometimes of the worst kinds. So this isn't just societally neutral science, and it would be naive to believe that such misuses of science are just historical relics.

Commercial interests as well as the self-interests of academics and the bureaucratic portfolios of science funding agencies are transparent in these efforts. An objective never stated publicly as such is to lock up huge amounts of funds, for open-ended time periods. That will certainly keep the vested interests in the pink of professional health for decades.....but will it keep the public that pays for it in the pink of health?

We think the evidence is clearly that it won't, and for several reasons. First, hundreds of diseases really are genetic. Cystic fibrosis and muscular dystrophy are well-known examples. They are actually quite complicated, but at least the genes are known, good targets for research, and tests for at least their major genetic variants with high predictive power are already available: they do not require targeted, sequestered funds nor nationwide biobanks. Secondly, even for complex traits, like cancer or diabetes, the majority of cases are manifestly not genetic in the usual sense. Thirdly, sequestered, targeted research pots are not needed to stimulate research into these common and important diseases: investigators will initiate research proposals to work on those problems that will compete just fine in the peer-reviewed system.

Actually, the scientists organizing and proposing these efforts know very well that they are unlikely to deliver their proposed benefits. They know, too, that when one mega-project ends, self-interest drives the need for a successor. That's the nature of the game these days--and not only in genetics by any means--it is largely what vested interests are all about, and naturally those who will gain are not going to speak against locking up hundreds of millions of funds for countless years to come to fund their playground. And we've not mentioned the many issues of confidentiality and other kinds of abuse of private information.

Of course genes are important. The overall genetic contribution to most biological traits in any species is substantial. That's why embryos can start as single cells and turn into predictable adults, resembling their parents, and so on. Clearly genomes play a major, if not the only, role in this. This is 'molecular' and materialistic causation. There is nothing mystical about it.

But prediction and understanding in science are more than making such statements about a genomic role in biological traits. Living organisms--even individual cells--are highly complex, with countless interacting factors, each variable in the population, and affected by contingency and chance. And there is the 'environment', which from any gene's point of view includes everything else, including the rest of the individual cell's genome. That means that we may not be able to have usefully high individual (personalized) prediction based on any one gene or its variants, or even on any reasonably enumerable set of them. And that is what the evidence, of which there is a huge amount, has clearly shown.

We'll comment at a later date on this lack of individually predictive determinism, and why looking from the 'gene' (itself an increasingly elusive notion these days) on up to the organism and its diseases, is not a cost-effective way to invest health resources. Science is a good thing to invest in, and large health data bases can be, too. But investment should be in proportion to the problems that need solving, not the research curiosities (or interests) of a small group of privileged people called 'scientists'. The history of such glowing promises by geneticists is older than many who will chance across this posting, and while there is a clear and important role for some large-scale genomic resources, biobanks and dreamy promises for gene-based 'personalized medicine' are highly exaggerated, self-interested lobbying tools that need to be recognized as such. When you see ads like the one linked to above, you should ask why would anyone need to pay for such ads? Who has what to gain? If as scientists we just want to keep the large-scale genomic industry in business, at least let's say so honestly and be done with it.

Societally responsible science requires that people speak up about the facts as they are known. The integrity of science depends on truthfulness, and there should be resistance when facts are distorted or dissembled, or exaggerated promises made, out of this kind of self-interest, especially when the target is public funds. At least, that is how we see what is going on in this regard today.

Thursday, March 26, 2009

Taking science on faith

There's a news story this week in the journal, Nature, entitled "Classical behavioural studies flawed".

"One of the most famous experiments in biology isn't the solid piece of work it's usually portrayed as, say Dutch researchers who have replicated the study. Instead, it's more like an anecdote that became slightly more legendary each time its author retold the story.

The work in question was done in 1947 by the Dutch researcher Niko Tinbergen on the begging behaviour of herring-gull chicks. At the time, the dominant idea in animal behaviour was that learning was all-important. Tinbergen argued that animals co into the world with instincts already adapted to their environments." (The photo is taken from the Wikipedia article on herring gulls.)

Tinbergen's idea became a classical textbook study that guided much of the conceptual thinking in the field of 'ethology' as it was then called, and led to much Darwinian and hence genetic determinism and what has become evolutionary psychology. The finding was that chicks hatch with the instinct to peck at red, the color of a spot on the adult herring gull's bill, to coax their parents into feeding them. His experiments, however, showed that chicks were more likely to peck at any color other than red. Over the course of writing up the results for 10 different publications, he slightly altered the way he described his results so that he explained away those findings -- he said, for example, that he had showed them red more often than other colors and he presumed that this caused them to become acclimated to it -- but he always concluded that they prefer red. He wasn't making up data -- he was explaining away results he didn't like. The Nature authors in fact conclude that he was essentially correct (arguments about such studies will be left for another day), but of course he didn't know that at the time.

The thrust of the Nature story is that we shouldn't call this sloppy science because science was less rigorous then. Even Darwin's work would be pummeled if it were to be peer reviewed today. While that's probably true, it's only partly true. Modern criteria for inference and study design were not invented last year, but have been around for some time. Darwin did not have many of the tools, such as statistical methods, that we use but (as Mendel, Morgan, and many others, including epidemiologists showed) systematic, well-controlled inferential study designs were certainly known.

Good science or not, this is an example of how scientists, who are supposed to always be open to having their results falsified, indeed who (it is often taught in class) go out of their way to falsify their 'hypotheses', in fact tend to cling tightly to their conclusions in spite of contradictory results. Even in the era of 'more rigorous' science, if not significant, results are often described as 'nearly significant' or 'suggestive'. Outliers are discarded. Forced, post hoc reasoning is often offered to explain away weak results or exceptions, and of course the problem always warrants further study. But science is a human endeavor -- more often than scientists like to admit, results are taken on faith.

Germany's Most Wanted Serial Killer!

DNA is sensitive and a great forensic tool, since every one of us is unique. But most DNA comes from someone who actually exists. Phantom DNA is only in one's imagination....or is it?

Today there's a story about Germany's most wanted woman, a serial killer for whom the German police have been searching for 15 years. The same DNA was found at many of this woman's vicious crime scenes, something like 40 in all.

Unfortunately, it now appears that there is no such person! Or at least that this person isn't the serial killer the police have been looking for for so long. It seems that the cotton swabs used to collect the DNA may have been contaminated by DNA from a worker at the swab factory.

This points out one of the problems with amplifying minute amounts of DNA: contamination. Contamination plagued studies of ancient DNA for quite some time, and still makes aDNA work a game for experts rather than amateurs. People concerned about bioethical and societal issues involved in forensic DNA (and millions of CSI fans, presumably), raise the issue of contamination, and the German experience shows that the problem can be an insidious one.

Wednesday, March 25, 2009

Are biobanks a good investment?

This week sees a push to establish a Europe-wide biobank. Biobanks are repositories of huge troves of biological samples; DNA, tissues, other kinds of specimens, and the masses of accompanying information, DNA sequence and health data, that researchers hope will make sense of it all. Everyone seems to need a biobank, and many millions of dollars and pounds and euros have been committed to their creation and maintenance, for decades to come.

The claim is that these databases will be revolutionary (our term, but that's the spirit of what's being suggested), by inaugurating an era of 'personalized medicine', in which treatment is tailored to the specific patient. Of course, intelligent and conscientious doctors have always practiced 'personalized' medicine: if a given therapy seems not to be working, they adjust or try something else. But what is being promised now is that the personalized approach will be based on targeting therapies to individual genetic variation (though environments are mentioned, tailored lifestyle advice is nothing new).

Of course, success at this would be a bonanza for pharmaceuticals, but there is a more subtle issue than profit-seeking (largely at public expense) that underlies the idea of making hundreds of thousands, or even millions, of DNAs available, along with extensive biomedical information, to the private sector. At least one thing that would really be profitable compared to combinations of drugs affecting only modest numbers of individuals, is to find a 'blockbuster' drug (like statins, or baldness remedies, or--of course--the next Viagra). A great incentive, but one that private industry should fund on its own.

But one doesn't have to be cynical about private self-interest to raise questions about the scientific merits of biobanking, nor does one have to stress the potential invasion of privacy and other bioethical issues (insurance, employment, psychological impact of genetic disease forecasts, genealogical ancestry, parentage, gene-patenting, etc.).

The idea that a biobank will provide dramatic health improvements is based on a belief in genetic determinism that, despite occasional caveats and denials, is the reason that genotyping could have the high predictive value that's being touted. If stochasticity (randomness), complexity, and environmental effects predominate in the production of important biomedical traits, then genetic risk effects will be small to modest, predictive power too contingent on other unmeasured factors, and statistically unstable over time.

We already know about major disease traits is that they clearly are not due to a few, much less one, genetic mutation, except in a small minority of instances. Here, we're not speaking of the many essentially single-gene diseases, whose causal genes are already identified--there is no need for big biobanks for them.

The problem of understanding genetic causation has been a challenge, and ever-increasing sample sizes have very clearly been showing that we cannot use reductionistic approaches to dissect all (or, probably, even the majority) of genetic risk factors for common complex diseases. We know, in fact, that most are most heavily the result of lifestyle changes.

Many different kinds of evidence support this view. However, it goes against the current belief system--and that's the right term for it--in genetics as the causal basis of almost anything you want to name (except maybe the reason why stoplights are always red when you get to them). Genetic determinism is already spilling over into behavior, which is a potential social tinder box.

As we go to some lengths to try, at least, to explain in our book, simple, and we would argue often simplistic, ideas about genetic causation may fit current theoretical ideas about genomes and their evolution, and are very much in the interests of business-as-usual. But the evidence is that they are not accurate! Biological traits as a rule involve too many different genetic factors for common, serious diseases to be due to common major mutations. The genomic effects on traits are spread widely across genomes because of the nature of the way genomic functional effects build them during development, maintain them during homeostasis, and throughout their evolutionary history.

Biobanking is based on the idea that individual cases of disease are due to individual ('personalized') genotypes to an extent that justifies locking up huge amounts of research resources, essentially permanently, to build, maintain, and hive off large-scale research projects on. This is not a statement that genomes are not involved in traits, normal or otherwise! There is a difference between trying to understand genetic mechanisms in the traits involved (like blood pressure or neural function), but that requires different approaches such as work with model systems, that do not rest on naturally occurring genomic variation. Even there, even working with inbred animal strains (where there is no variation compared to that in human populations), the same levels of complexity are being found.

The issues of large biomedical databases are not wholly simple, because many good things can come of them. The science itself in terms of accuracy of measurements, technology, and so on, will be of high quality, and we'll have legions of data to play with in our academic and government labs. Certainly some health successes will result, too. But after the fact, claims of success rarely ask what other things could have been done with the resources, that might have had much greater impact. Tying up funds in one large, ongoing effort is a priority decision, in a limited world.

There's no doubt that national disease registries have had importance in public health research and policy in many ways. Computerized record systems and the like, and even the storage of tissue samples and so on, can be important. But that's not the same as doing all the analysis, such as whole genome sequencing, as part of the data base. History shows, also, that such data bases don't collect the relevant data needed, often because it's not known what to collect. What's being lobbied for now, and is almost certain to occur, are large, expensive, hypothesis-free fishing ponds.

In addition to what we think is already known about how genomes work and the complexity of genetic causation, we have seen grandiose promises from geneticists before....long before this. It is in the nature of the science establishment (certainly not limited to genetics!) to lobby in public media and to potential funders for our self-interests. Genetics is our business, and we do genetics every day, but this is about public priorities and public good, not fun for geneticists, at least when paid for on such public-sourced rationales. The focus on genes and the promise that genes will cure everything except stop-light frustration, is a misleading and even distracting way to establish such data.

If you disagree, please let us know where you think we're wrong!

Monday, March 23, 2009

Self-awareness in a cow pasture

Here's a story from the New York Times online today with, if nothing else, a gorgeous picture of a massive slime mold, or Dictyostelium discoideum, found in a cow pasture near Houston. These are amoeba that live separately as single cells until life gets tough, and then they mass together and form a multi-celled organism, with cell to cell communication, that can form a slug that migrates to greener pastures, and a fruiting body that produces spores. Its cells even undergo apoptosis, programmed cell death as needed to sculpt that organism. All of which requires signaling and communication. But what about self-awareness??

Slime molds signal each other with cAMP when it's time to aggregate; our brain cells signal with neurotransmitters. The cells in a slime mold are certainly aware of each other and of their environment in some senses, using receptors and the results of signal reception as their mechanism. They come together as a group, developing internal organization and structure. We might not want to call this consciousness--that is, our kind of consciousness, and it might seem silly even to speak of that. Yet, these Dictyostelia communicate through chemical signaling to work and function together. We might wish to say that they have no self-awareness because they have no central nervous system, whereas we have one and it involves so many cells working together to make 'thoughts'.

Yet how do our brains work, if not by similar kinds of chemical signals? Many kinds of experiments show that consciousness as we experience it is not the basis of our evaluation of circumstances and responses to them; our consciousness comes later, as a kind of monitor (however it works). But many if not most of our brain functions are done without conscious awareness. Nor is our self-awareness due to the large number of communicating cells in our brains, as many kinds of experiments and studies of brain injury have shown. That is one reason consciousness has remained so elusive to science.

So to what extent is it hubris for us to consider our consciousness a higher form of cell-to-cell signaling? Or, in line with the idea that cells, even 'primitive' or 'simple' cells are not so primitive or simple after all. That doesn't mean we understand the different kinds of self-awareness that exist--what about ants, for example?--but it does mean there is a lot to think about, as even the humble slime mold shows.

The prognosis for science education

We both were judges for the Pennsylvania high school science competition today. We have done this before, and it's a way to take the pulse of American science education. The diagnosis is not so good. The patient is not that far from needing life support. Not many students were involved, even in a big state. They were trying hard, in interesting projects by and large, but many showed a lack of rigorous study design understanding, and many were clearly set up by parents or teachers....or by fancy summer jobs their parents were able to arrange for them, in which they did something they clearly didn't understand very well. Even parental help is OK if our objective is to improve American science, starting at an early age. But many are being left behind; for example, there were no underserved minority students in our sessions.

On the slightly brighter side is that one person among the judges had a BS degree in molecular biology, and is training to become a teacher. Three cheers for her! Let there be more. Also, the organizer is a Dr Dave Kleindienst, who has been dedicating his energies to supporting student science for decades. Every community has one or two of people like him, but what this country needs is a hundred times as many. So, let's encourage bright people including some of our graduate students, to become science teachers!

Sunday, March 22, 2009

Smart bacteria

Last week Ken was at a meeting at the Santa Fe Institute, which was discussing the problem of the traditional concept of the 'gene' in the face of all the new discoveries of DNA-based functions that are very different from simple protein codes. That could be the subject of a future posting, but at the meeting was a well-known microbiologist, Jim Shapiro from the University of Chicago. In the course of conversation, we learned of a recent paper of Jim's that points out how sophisticated even a single bacterial cell is (you can get this from his website: scroll to the bottom and click on the second to last paper, Bacteria are small but not stupid). Indeed, Jim refers to 'cognition' in single cells.

This paper points out how very complex a single cell is, in terms of its internal structure, its diverse ability to sense and evaluate the environment, and its repertoire of responses. He stresses that a cell is not a stupid automaton in that sense. This is wholly consistent with points we tried to make in our book, and is sobering for attempts to boil even more complex traits, like multicellular organisms, into simple genetic causation. Of course genomes contribute to behavior of cells and organisms, but not in ways that are always simple. An important question is how enumerable such genomic effects are, and how 'hard-wired' even single cells are. Like so many other terms one might use, 'cognition' is a word with social or human-specific meanings, but using it for bacteria it is probably an important challenge to our hubris about ourselves. Bacteria may be 'just' bags of chemicals....but so are our brains. Where automated responses end and evaluative, facultative ones begin is not an easy question to answer.

Friday, March 20, 2009

On our title

We chose our title, The Mermaid’s Tale, because we like that it can be thought of as having two meanings. First, of course, it refers to the bodily arrangement of mermaids, but second, it allows us to tell the story of how biological traits, and the creatures that carry them, develop in the short term and what this means on the long term evolutionary time scale. Even religious fundamentalists, who would say they don’t accept the basic principles of evolution, know that there is no such thing as a mermaid. Ironically enough, the reason we, and they, can be so sure is because of the principles of evolution. (Image is an oil painting by John Waterhouse, 1909, now in the public domain.)

The mermaid’s body is said to be made of sections (torso and tail) that are stapled together from different parts of life’s phylogeny, often called the Tree of Life. The ‘Tree of Life’ is a representation of the relationships among organisms: species, like different kinds of cats or goldfish, are placed close together on this diagrammatic representation, because they share a more recent ancestor than other species. Fish and oak trees are very far apart, because they haven’t shared a common ancestor since far into the distant past. But members of similar species often have very similar biology, such as their basic body plan and structures.

The mermaid seems on the surface to be a perfectly plausible species. But it isn’t so. Her parts can’t be found on the same creature because they arose and evolved on lineages, branches on the Tree of Life, that separated from a common ancestor hundreds of millions of years ago. The genetic mechanisms that assemble organisms as they develop have a history that is characterized by sequestration, or isolation – a general principle of life in all its dimensions. In this case, the isolation in different species led to differences in the details of the embryological development of fish with scaly tails but no legs, and of mammals with legs, breasts, and fur, that accumulated over those hundreds of millions of years since they diverged from their common ancestor. The fish tail and the mammal torso now are each built by developmental processes specific to each lineage, each step in development contingent upon what came before – another general principle of life. The processes that build similar traits among closely related species within each lineage are similar as well. Because of contingency, and ‘inheritance with memory’, another basic principle referring to the processes that make offspring resemble their parents and species within lineages resemble each other, although both fish and mammals share many important traits – like having a backbone – they don’t, and can’t have the two basically different body halves that a mermaid does.

Interestingly, however, it was discovered not so many years ago to great surprise, fish and mammals, torsos and scaly finned tails, despite their deep separation in evolutionary time, do share many aspects of the basic processes of development, even while differing in the specifics. The way many of the same genes and genetic mechanisms are used are quite similar in both lineages. Indeed, we share some of this with insects and worms, and we share many of the same basic types of mechanism even with plants – though the vast majority of the specific genes used in those mechanisms are totally different. This is an important aspect of the discussions we hope to hold on this site.

Darwin’s basic insight about the unity of life, descended from a common ancestor, has been confirmed many times over by the lessons of genetics and developmental biology. There’s something deeply satisfying about that.

Thursday, March 19, 2009

What genes are 'for' continued: testis expressed gene 2?

Genes often get their names from a single function, or from a disease or disorder they’ve originally been associated with (except for fruit fly genes, which get great, but usually totally uninformative names like sonic hedgehog or sevenless or bride of sevenless or cheap date – which are not only entertaining, but their being uninformative is probably better than the restrictive and potentially misleading names given to everyone else). In humans, we’ve got things like ‘Testis-expressed’ genes, or breast cancer genes (BRCA), or immune genes, and so on. A lot of information about what these genes do goes missing when we rely on this kind of naming, an indication of just how much we’re still prisoners of Mendel’s single-gene, single-function approach (he didn’t know of genes per se, of course).

Here’s a picture of the expression in a mid-gestation mouse of a gene called ‘CFH’, or complement factor H, a protein that’s secreted into the bloodstream and that is involved in the complement pathway of the immune system that reacts to the detection of pathogen-infected cells.

The picture is from a very useful database called GenePaint (GenePaint) that is in the process of cataloguing expression of more than 20,000 genes in the developing mouse. Zooming in on such pictures shows the specific cells that are expressing the gene – choose your favorite gene and check it out on GenePaint yourself. Here, we’ve labeled various structures (and it’s in fact a figure we’ve used in a paper of ours in the Feb 2009 issue of BioEssays (vol. 31: 198-208.)).

The picture is of a transverse section showing the results of an ‘in situ hybridization’ experiment looking for expression of the CFH gene in a 14-day old mouse embryo. Imagine you’re looking at a profile of the embryo, it’s sliced into many thin sections and the sections are put onto a microscope slide and then bathed in a solution that contains an RNA ‘probe’ that binds to CFH message in whatever cell the gene is expressed. The probe is treated so that it will turn purple wherever it binds, so the dark purple in this picture indicates where the CFH gene is expressed.

The interesting thing is that this ‘immune gene’ is expressed in lots of unexpected places in the developing mouse. It’s clearly more than an immune gene, and must have something to do with function that’s not yet known. The same can be said of most genes.

Here’s another picture, with in situ results again from GenePaint, but annotated by Sam Sholtis, lately of our lab, now a post-doc in Jim Noonan’s lab at Yale.

Panel A shows expression of Hap1, huntingtin associated protein, clearly not just about brain cell function, and panel B shows expression of Tex2, testis-expressed gene 2, clearly not restricted to the testes -- the insets show that they are strongly expressed in developing teeth, as well as elsewhere. Sam was interested in genes expressed in developing teeth, and if he had restricted himself by gene names or the literature about them, he would never have looked at the two genes in this figure.

Whatever these (and most) genes do, it is inaccurate at best to think of them as genes ‘for’ some specific thing. Their expression as seen in such figures as these could be incidental and without functional importance, but more commonly there is some function that we can identify if we but look for it. It is accurate to say that these genes contribute to the particular structures in which they’re expressed in these embryos, but it may not be accurate even to say the genes are ‘for’ this set of structures. That’s because this is just one instance of one embryo, at one stage of development, in one inbred (and hence rather artificial) strain of laboratory mice, under one set of circumstances. Who knows what other structures or molecular processes might depend on or involve these same genes?

Genes-for thinking works when a mutation has a strong effect, as in, say, many genetic diseases of childhood such as cystic fibrosis or Tay Sachs disease. But it fails us when we’re trying to understand complexity. It is first of all a major problem to overcome gene-for thinking, which has been entrenched by the history of discovery in genetics that goes all the way back to Mendel, and which is so appealing since we like to find simple causes of things. It is much more challenging to determine how to think of organisms if not in gene-for terms.

Wednesday, March 18, 2009

If genetic causation is complex, why should risk factors be any less so?

Every day, it seems, the forces of biological simplism -- the hunger for, and vested interest in simple answers to complex questions -- suffer a setback. Today, it's large-study results that show that screening for a simple marker for early prostate cancer detection seems to be ineffective ( New York Times prostate cancer article ). It may be harmful in the sense of leading to the detection of benign cases, and then some intervention with its associated risk of morbidity. Earlier this year somewhat similar results appeared for mammographic screening for breast cancer. The point is not to coldly denigrate attempts at early detection, but to show the importance of recognizing nature's complexity. Those who suffer from cancer--and we all know such people, and many of us will be such people--deserve all the care and concern that can be mustered. But can we think of better ways to approach this genetically complex problem? Is standard reductionism, trying to identify individual risk factors, or even single risk factors, the way to go? Or will some smart young researcher give us the benefit of conceptually innovative ideas?

For most risk factors, genetic or otherwise, the situation is similar: cholesterol, blood pressure, even obesity have complex and poorly understood associations with subsequent disease outcomes, and with prior genetic risk factors. It is already known, however, that the most effective way to head off chronic diseases is not to smoke, get exercise, and eat a moderate, balanced diet (including even to have a drink now and then!).

But, that conceptually innovative idea is not going to come anytime in the next month or so -- biology is on holiday. This is not like France, where everyone goes to the seaside in August. No, it's because of our 'stimulus' package's ad hoc grants program. Like lemmings to the sea, or hogs to the trough, every scientist and his relatives (living or deceased) is charging headlong for the new money. Whether this is a moral way to spend these funds is an open question. But everyone's now too busy putting together their hoped-for bonanza grants to do any actual scientific work. Ironically, the stimulus package's 'challenge grants' may turn out to be a NON-work initiative for science!

Presumably, the crush will end and we'll all get back to work. One can predict that, due to the gold rush the funding percentages won't be any better, and they may be worse for this 'easy money'. Time will tell.

The gene 'for' concept

Although people know better, we see papers or discussions daily that effectively refer to findings of, or searches for the gene(s) 'for' some particular trait. The gene 'for' obesity, or autism or aggression. Or the gene responsible for the evolution of the trait. The gene 'for' what makes us human. When the trait is reasonably simple, and a genetic variant's effects in some population is fairly strong, this makes literal sense. From a standard Darwin evolutionary perspective, or a standard developmental perspective the ideas also seem to make sense. There are in fact traits and diseases that are basically attributable to single genes, as Mendel showed with his work on peas in the 19th century, and many have found thereafter. But this kind of thinking can be misleading and often -- or maybe usually -- is.

Many, many areas of the genome contribute to a trait. In a population or species, most if not all regions of the genome are subject to mutation and usually vary at least in some individuals. Some are 'genes' in the usual sense of coding for a protein, but other genome areas are inv0lved in different kinds of function, such as controlling the expression of protein-coding genes.

With lots of variation in lots of factors, and the complicated patterns of cells in an embryo or individuals in a species, it's likely that many, rather than one or even just a few, of these varying elements contribute to variation in an embryo or variation in a species over evolutionary time. A single gene many contribute to a trait, but they are often misleadingly thought of as being 'for' it, as if they play a special role.

This becomes all the more important when it is considered that most elements in the genome, and in particular most protein-coding regions ('genes' in the usual sense of the word), have many different uses even within the same species -- even within the same organ or system at any given time and/or during its development. So is a gene expressed in teeth, limbs, and gut a gene 'for' teeth? And if the homologous gene in flies -- that 'tooth gene' -- is expressed in (say) limbs and brains in vertebrates, is it now a limb gene? a brain gene?

Gene-for thinking is often decried by authors of reviews and overviews (including ourselves). But it's a hard habit to break, and few of us can claim to have made that break, that conceptual break, as cleanly as we ought (though Ken was just at a meeting with a very prominent microbiologist who said he hasn't used the word gene when talking about genetics in class in 20 years -- he sets the bar high). There are many ways to consider a genetic element that contributes to many different things in a given individual and/or in different species. Altering the gene may affect multiple traits, and its effects may be more important in some individuals or species than in others. Likewise, it may change in evolution because of selective effects on only one of the traits in which it's used. Disentangling these issues is not easy. But it's clear that we need to, and that linear thinking of DNA as beads on a strings is a limited way of thinking -- in many ways, we're prisoners of Mendel. Yet, thinking in the many higher dimensions of development and evolution is by no means easy, though it provides exciting prospects for those who enjoy the challenges of biology -- on all its time scales.

Tuesday, March 17, 2009

Evolution and development compared

The fact of shared developmental processes is a profound indicator of the importance of general principles, or logic, in the construction of organisms. The life sciences were transformed by the exciting realization, due to Darwin and Wallace, that complex life has gotten here by way of historical processes, and the discovery of genomes as the storehouse of accumulating information that makes that possible. But too great a focus on the evolutionary time scale, and hence on changes in DNA sequence over long time periods, tends to pull attention away from the means by which genomes operate in the here and now. Developmental processes are somewhat different from the processes of evolution, though all are based on general principles of life, which we'll describe in a later post. This table is a way in which we think these two aspects of life might be compared.

Evolution is about change in genomes over many generations, while development is about differential use of genes in the same genome in a single lifetime. Evolutionary change is open-ended and unpredictable while development is so predictable that a trout never spawns a frog -- or even a salmon, although of course each new organism is unique. Both kinds of change are contingent on what's here now, but the constraints on development depend on environmental triggers and gene usage signaled by a single genome.

Saturday, March 14, 2009

Introduction to The Mermaid's Tale

We are Ken Weiss and Anne Buchanan, researchers in evolutionary biology, anthropology, and developmental and human genetics in the Department of Anthropology at Penn State University. We are frequent co-authors, and maintain our own web pages at www.anthro.psu.edu. Many of the ideas we'll discuss here are from our recent book, The Mermaid's Tale: Four Billion Years of Cooperation in the Making of Living Things (Harvard University Press, 2009).

We'll be exploring the way that genes and genomes affect life on all its dimensions; the ecological, developmental, and evolutionary. The history of biology, and in particular the discovery of evolution by Darwin and Wallace, and the discovery of genes by Mendel, has led to our current understanding of life. It allowed research strategies to develop that led to the greatest explosion of knowledge ever produced by science.

Yet, it's been restrictive. This history has led to an understanding of genes that reflects only a slice of the whole story. A simpler and, more specifically, deterministic understanding than the truth. For example, history has encouraged the notion of genes as codes for proteins, but DNA does much, much more than that and its other functions are largely ignored (even though they are understood to be important). Adding to this complexity, recent research has made it apparent that it's no longer clear what a gene even is.

Likewise, in explaining how traits arise, the usual view has been a simpler, probably simplistic, view of genetic determinism and natural selection than is the whole truth. It's easy to suggest scenarios of adaptive selection as if they were testable (which they rarely are) by implying that the adaptive traits are precisely “genetic” (or natural selection couldn't have produced them). But, when we try to identify the genetic causal basis of traits, we usually can't account for more than a fraction. This and other evidence suggest that selection is typically far weaker and less specific than its reputation.

The creation of evolutionary stories has had a strong pull on biology and other areas of modern society, because oversimplified explanations can be so appealing and easy to understand. These stories can seem so plausible that they are offered as if they must be true. This owes in part, we think, to the collapse of the understanding of deep time when thinking about evolution, that takes place when one compares ancestors or contemporary living species, and to treating them as though they in effect arose quickly, systematically, and as if driven by a continuous, fine tuning force (natural selection). That was in essence Darwin's view, but it is not actually accurate in most cases.

We think that a key fact to a broader and more accurate view of life is to see the interaction of a huge number of components. We refer to this as “cooperation” as a counter-weight to the usual theme of “competition” that is usual in strict Darwinian perspectives. It is because of many interacting components – within cells, between cells, within and between tissues and organisms -- each of them subject to mutation-driven change and chance, and each of them tolerant of variation, that life on all of its time scales, the unimaginably long evolutionary dimension, the short dimension of development, and the simultaneous one of ecology, has been possible.

So, we'll post our thoughts our reactions to papers in journals, books, and other triggers, as we hope to generate some discussion on these issues. We believe they're important to understanding life generally, as well as to understanding the genetic prediction of traits, disease risk, improving agriculture and biomedicine, concepts such as “race”, and to the use of darwinian concepts that are applied to other areas of life such as markets, social inequality, religion and others.

We hope this interests you much as it does us!