development through research??

15 years ago, when Chief Khunchai first took a job managing a malaria clinic on a remote stretch of the Thailand-Myanmar (still Burma at that time) border, there weren’t year round roads, there was no electricity, no telephones, and the endemic guerilla warfare between the Karen and the Burmese didn’t pay much attention to the international border.  A Karen military base was just over the mountain on the other side of the river.  Sometimes when fights broke out, mortars would fly across the river and land near the clinic.  It wasn’t personal; such things don’t always stop at international borders.

Moei River - the international border between Thailand and Myanmar

In the hot season temperatures regularly exceed 90° Fahrenheit, at midnight.  Without electricity, every degree above 80 is obvious.  There is a constant trickle of sweat behind your ears and down your lower back, and you eventually stop mistaking this feeling for mosquitoes and other insects that want your blood.

In the wet season, everything is permeated by the omnipresent moisture.  Pencils won’t write on paper, which has been collecting moisture from the rain and from your sweat, and pens make thick smudges on anything they touch.  Records are hard to keep.  The landscape is almost fluorescent green during this season.  The dichotomy between inside and outside is a false one.  Even the walls grow green with algae, plants and vines work their ways into the cracks and struggle for a nook or cranny to fill and exploit.

In this part of the world, the sun goes down at a consistent time pretty much year round – 6:30.  But this malaria clinic is surrounded by sharp mountain peaks and karst rock formations, and these geological entities hide the sun more quickly.  If work was to be done after 5pm or so, it was done by candle.  Malaria diagnoses would have to wait until tomorrow, when the light from the sun could be used in the small circular mirror that illuminates the slides and lenses in the microscope.

microscope for detecting malaria

Contacting the outside world could be done using military styled radios, through a tall antenna that stretched out of the top of the clinic.  This was handy in case people needed to be evacuated because of flooding, fires, or fighting to relay information about the epidemiological situation, or to request shipments of dwindling medical supplies.  A lighting rod was placed at the other end of the building to keep people from getting barbecued during storms.

a storm over the Moei

Over the years, Chief Khunchai has become a much respected member of society.  He knows almost everyone in the district in some way or another, and he holds a lot of political weight.  His office gets nicer over time.  Still the chief of a malaria clinic, he looks back on those days with little nostalgia.  He shudders a little when he tells me about working by candle light and having to worry about the fighting.  Yes, today things are quite different.  

He now manages a new malaria clinic about 35 miles south of the one he started at.  This malaria clinic has electricity.  At first this meant an electric microscope and lights, and that work could be done at night.  It also meant fans, which make work much more bearable during certain times of the year.  Even more recently, it meant that sealed doors could be installed in the main room and office so that wall AC units could also be installed.  AC isn’t frequently used, but it is very nice to turn the units on when there are special guests (usually political superiors) visiting.  

There are at least three different large malaria projects running in the district, and each of these projects has hired staff that are housed at the clinic.  A room was built on to the back so that they would all have desk and computer space.  A little data entry and a lot of facebook and youtube happen in that room.  

In the same period of time, malaria cases appear to have decreased, even while the population of the area has increased.  This is especially the case with regard to cases in Thai nationals.  Most cases here are in Myanmar nationals or Karen people with no nationality.  In fact, it is entirely possible that today there are more malaria-related personnel in Thailand than there are cases of malaria in Thai people each year.  That is, I think, a very strange thing.  

I begin with this story so that I can paint a picture of a kind of situation that I think has occurred in many parts of the world.  Malaria persists in places where “development”, for whatever reason, hasn’t extended.  One (I) could easily argue that such “development” is actually destructive in many ways, but it is hard to argue that life for many people hasn’t become easier.  And malaria cases have gone down at the same time.  

At least some of that development must be a direct result of the research cash that flows in from major malaria research projects and initiatives.  Those data entry people in the back facebooking can now purchase relatively nice motorcycles; some of the managers might even buy cars.  It’s not just the malaria clinic that has changed, there are also new restaurants, roads that are mostly good (or equally bad) year-round rather than only being traversable during the dry season, and more recently, a 7-11.  I joke that next year there may be another 7-11 across from that 7-11, but you may not understand unless you’ve recently visited Bangkok.  All of these things have associated workers who in turn buy stuff from places that also employ people.  In this part of the world, and I think in other parts too, malaria is mostly a “rural” disease.  It exists in places without 7-11s and year-round roads.  As you pave the ground for those roads and build concrete jungles, this particular disease tends to go away.  

And I find in this all a great irony.  

I’ve previously heard jokes that the best way to get rid of a disease is to try to study it.  I think this means I’m not the first to notice what is happening.  

The malaria industry is huge and there is a lot of money in it.  Frustratingly, much of that money winds up getting wasted through corruption and through things that ultimately aren’t necessary for what I think really matters: helping people who are sick with malaria, or even better, getting rid of malaria.  

For that matter, a question I’ve increasingly worried about over the last several years is: Should we really be setting up an industry, a vast network of jobs, that are all geared toward halting a disease?  Will these people really be motivated to stomp out the very thing (in this case, malaria) that keeps their own lives, at least economically, afloat?  Is that why people heatedly argue that we should be trying to control malaria rather than just get rid of it??!  Even more-so, while I can see the value in having electricity at a malaria clinic for diagnosis purposes, is AC, more space, new desks, etc. all relevant for combating the malaria problem?  

But perhaps there is another way to look at this too.  That is, perhaps all those research dollars that get pumped into malaria research do actually work.  I think they really do.  I just don’t think they work in the way that any of us really intend for them to.  They wind up spurring the local economy, they boost peoples’ economic well-being, and then in some cases and for some extremely complex reasons, people who move out of deep poverty are no longer faced with the immediate health consequences of that poverty.  For them, malaria isn’t any longer an immediate danger.  They can sit in a nice office, preferably behind a nice fan and in front of a nice computer screen, and check boxes on the computer that correspond to a malaria patient’s age and sex (or to a “like” button on someone’s post).  After half a life’s worth of work in less-than-ideal conditions, maybe it is more than OK that Chief Khunchai no longer has to dodge mortars or work by candlelight.  Hell, maybe he deserves the occasional AC – I certainly convince myself that I do.  

Sometimes I’ve gotten quite riled-up by the ways I see malaria research dollars getting spent but maybe I’ve completely missed the point.  Maybe all that really matters is that those dollars with the malaria name on them wind up having the effect that (I think) we all ultimately want.  Even if the functional mechanism behind this cause and effect has basically nothing to do with the one(s) that many of us think matters.      

*** I know several "Chief Khunchais" - but this name is of course made up

Change on the Thai-Myanmar border

It’s been several weeks since I last posted about moving my family to Thailand for my dissertation work.  We’ve all adapted quite well to our new home and I’ve yet to hear rumors of familial mutiny.

We’ve made a few trips to the closest city, Mae Sot, and once to a big malaria meeting in Guilin, China.  It is a strange feeling to come home to a place that seemed quite foreign only a few months ago, but now feels quite familiar.  When I told some people that we’d be moving to Thailand until at least March 2014, several commented on how long that seemed.  Now it seems like it is nowhere near long enough.  Each passing week I learn something new about the place, a new type of food, the names of mountains, villages and schools hidden down little dirt roads.  I have the Thai consonants and most of the vowels memorized and, now that I can read a little Thai, new worlds have opened.  Months of field work are certainly better than weeks, but it feels like a lifetime is necessary for me to really understand this place.

I haven’t left but I already miss the Moei River and the Dawna Range.  This place has certainly changed me and I think I’m safe in saying it will leave lasting impressions on my family too.

Big changes, little changes…

Things along the Thai-Myanmar border appear to be changing a lot.  To be fair, things here have always been in flux and that probably has a lot to do with this region's special place in malaria research.  Development has lagged in this region because of a half century worth of fighting between one of the major ethnic groups, the Karen, and the Burmese military.  Despite this political and military uncertainty, at least one place has emerged as an economic center in this part of the world: Mae Sot.  

Though it is nowhere near being the largest city in Thailand, it is one of the most multicultural.  Walking down its streets you see long-bearded Muslim men, Indian men with long, curled mustaches, Burmese and Karen people in beautiful sarongs (longyi) and frequently wearing thanaka on their faces, and a few NGO workers scattered about.  Thai street vendors sell noodles and soup in front of beautifully decorated pagodas and small street shops selling roti and samosas flourish across the street from a large mosque.  

The city is a center of trade, linking Thailand to not only Myanmar but also India and China.  Much of that trade is in illegal goods or through illegal channels, also lending to an interesting city vibe.  We are just south of the infamous Golden Triangle.  However the opium business here is apparently being exchanged for methamphetamine* and human trafficking thrives.  Early in the mornings there are several downtown stores that specialize in precious stones, especially jade, and they are always crowded with an interesting lot.  Crowds of the above described people, also including wealthy looking Thai men wearing enough protective amulets to make you wonder why they need so much protection, hover around brightly lit stalls.     

Since we’ve arrived here the Myanmar government has opened Karen State for tourism.  Previously some people were allowed to visit, but only after flying deeper into the nation, never over the border.  On the other side of the Thai-Myanmar Friendship Bridge lies the city of Myawaddy, and until now tourists were allowed to visit there only during daylight hours and were not allowed to travel deeper into the nation from this point.  That has now changed.  Also, over the last several years, there have been plans in place to connect Mae Sot to Moreh, India.  There are systems of roads across Myanmar currently, but they haven’t been kept in good repair in many areas.  The new push is an effort to create a new economic zone, with Mae Sot playing a key role.  

Where I live (Mae Tan), north of Mae Sot, things are apparently changing too.  People and goods have always moved back and forth across the Moei River.  The frequency (and legality?) of those movements appear to have changed.  Every day people come over from Myanmar and make their way down to the fresh market.  Some return on boats with bags of rice, eggs, fruits and vegetables.  Some carry toy trucks and bikes back across the border.  Sometimes suspicious trucks, full of cargo that I can’t see, make their way down to the river port around midnight.  This morning there are several full sized trucks, backed up to the river port, in full daylight, all while the border guards are on duty.  This is something new.  

But many people who’ve been a part of the conflict in this area or who have kept up with it are suspicious of some of these changes.  There is a questionable peace deal that has halted most armed conflicts between the Karen and the Burmese military.  However, not everyone has signed on to this deal, and for that matter, there is real question about whether or not it was actually a peace treaty or if it was just an agreement to begin considering a peace process.  Regardless, the Burmese military has come in to Karen state with new ease; they have paved roads and have resupplied their military bases.  If these changes aren’t well-intentioned, and given what continues to happen up in Kachin State many people are quite unsure, the Burmese military now appears to have a strategic upper hand.     

What will these changes mean for the ecology of infectious diseases?

I think it’s much too early to know, but I have some opinions.   While most of this region has a malaria problem, Mae Sot does not and has not for several decades.  An expert on malaria who has lived in this area for as long, told me in passing that when things like highways, concrete, and air conditioners arrive, the malaria seems to go away.  If economic changes are on the horizon, and they appear to be, then perhaps malaria will only continue to be a problem in small isolated pockets in this area.  Those trucks that I mention above are full of concrete bags which are being toted across the river.  It looks like environmental change is well on its way and I have quite complicated feelings about this.  

As someone who comes from a place with lots of luxuries that are either rare or nonexistent in the tropical world (running water, running water that you can drink, few deadly infectious diseases, etc.) I always feel like a hypocrite when I think that others shouldn’t go through some form of industrialization.  “Don’t cut all of your trees down.  We did that and now I wish we had them back” is an easy thing to say while sitting in front of a fancy computer in a climate controlled room.  The U.S. certainly wiped out malaria, but did we do so at a great environmental cost?  I don’t really know.  I hope that the answer to halting malaria isn’t that we must cut down all of the trees.  

Also, I’ve spent the last four years of my life focusing almost entirely on one infectious disease: malaria.  There are at least two reasons for this focus.  The first is that it is a major threat to global public health.  The second, and perhaps more practical, reason is that malaria isn’t something that you can really understand by just dabbling in it.  It is such a complicated disease that you really need to jump in and get wet from the literature, the laboratory work, and the field work to really be competent in it.  But in the hypothetical future when malaria is no more a problem for this part of the world, there will remain other infectious diseases.  Malaria mosquitoes don’t like concrete and streets, but dengue fever mosquitoes do.  Tuberculosis and HIV thrive on pioneer highways like the one that is soon to join Mae Sot to India.  Even if changing the environment does fix the current malaria problem, it won’t fix the current infectious disease problem: that is a problem of competing risks. 

Leafing through Nature or, How does development work?

We have some mature oak trees in our yard.  Last week, the winds and rain associated with the hurricane blew down googles of leaves, blanketing our yard (and we've already raked 3 times!).  But looking at the leaf-litter, I noticed the two leaves in the picture below.  Both were from the same tree.  Yep, that's a 1-foot ruler.

 

This isn't actually the tree (can't get a good camera angle on it; plus, we haven't had any snow yet), but the point can be made from this pic I grabbed from the web.  The arrows show, figuratively, that our two leaves, one normal size, one quite huge, fell from different parts of the tree (I had no way to know the exact relationships in the case of the real leaves).

Now, this tree started as a single cell, the embryo in some lucky acorn at least 50 years ago (this tree was already big when we moved here 30 years ago).  How can this same genome generate such massively different leaves?  What this means is that the leaf, the phenotype, cannot be predicted from the genome.

Note in the first picture that the pattern of the leaves is the same, basically the same toothy oaky structure of side growths, with a major vein going into each 'tooth' of the leaf.  But the details vary, which means that except for the basic structure, they too cannot be predicted from the genome.  None of the 23andLess promises, nor those of the Director of NIH, can change this.  Could the difference be due to environment? 

Genes and environments
Now we can at least ask about genes interacting with environments, such as temperature, water supply, sunlight and so on, that can differ in different parts of the tree, so some leaves get better living or growing conditions than others.  Of course, these cannot be predicted from the acorn, so personalized treenomic medicine isn't possible.  But worse, of course, at the acorn stage we don't have any way to know the future of dry and wet seasons, cloudiness, and the like.

And, sorry to say it, but in fact in this case it was not true that the large leaves were all on one side of the tree, and the small leaves from elsewhere on it.  Before they fell, the leaf sizes were distributed across the tree.  So nothing so simple, from what we know to measure at least, could account for this.

So in a way this makes such predictions essentially impossible, even in principle.  The solo genome of the acorn is not a predictor of more than the general features of the tree:  its overall branching and root structure, general shapes of its leaves, types of flowers and flowering time, nature of its bark--that sort of generic oakiness.  We could tell it will not grow to be a hemlock or a maple!

Explaining the similarities
But there are ways to account for the major aspects of similarity between these two very different leaves.  Those are the general principles of organization, gene action, and development, that we refer to as 'cooperation' among interacting factors--genes, signal molecules, cell surface receptors, cells, and so on.  In the book MT, we describe various processes that are driven by genes but not contained within any gene.  These processes of interaction involve timing effects, branching, and differentiation among cells.  That for example is how the veins branch and growth occurs along them in a leaf.

Now, there are still vastly different cell-distances in the two leaves shown above.  So how can the same genome, even with these process characteristics, generate them both?  One likely answer is that each leaf develops its basic structure--and the basic cell commitment to specific gene expression, when the baby leaf is very small.  Once these things are pre-set, rates of growth can, in principle at least, lead to different numbers of cells in each stage, between each branching event, etc.  Environmental factors can control these rates.

The idea: differentiate very early when the embryo is very small, and let the cells retain their gene-expression characteristics with them as they individually grow.

Still, it's very interesting how this can happen, the flexibility so to speak of what a single genome can do.  Or was it a single genome?

But do the leaves have the same genome, after all?
We say all the leaves in this one tree descend from a single acorn, a single cell with its copies of the Oak genome.  But in fact some mutations occur in every cell division. If they kill the cell, then it has no further bearing on what happens from then on.  But millions if not billions of cell divisions take place from the time the acorn begins to grow and the countless distant meristems that result and from which leaves and flowers grow.  That can be compared to the number of different parent-offspring transmissions that have occurred in the history of the human species.  It means that no two cells actually have the identical genome.  The meristem cells, long separated from common ancestry, are different in a general way as are any two humans.

Most of the genomes are very similar and most mutations have no real effect, but some may, or must.  So it could be that some leaves, or some branches, really are genetically different from each other in ways relevant to things like leaf size.  Maybe that's the reason (with or without additional environmental effects) for this huge difference. 

Personalized tree-nomic medicine, not!
 Could this be predicted in any specific way from the sequence of the genome that preceded the entire leaf?  It's doubtful, because it would be hard to get such a cell, and of course we'd have to do it for thousands of leaves on the same tree to understand the pattern, if any.  Personalized prediction of such small, later-age effects, can surely not be made from the acorn. Yet that is exactly what is promised for humans, relative to late-onset disease, being predicted from a person's 'genome'.

This is not wild speculation.  Your body differs locally in terms of where hairs are located, freckles, age spots, and many other details, for similar reasons--differences arising among your cells during your life.  Mostly they make no difference but if they lead a cell to start dividing too fast, they do matter, and it's called cancer.

So much to contemplate, even while you're just raking your lawn.....

An apt description of how life works: Slop! Part II

In defense of our working description of life as slop, which we posted about yesterday, we suggest here a few principles that we believe apply to life at all levels, and along all time spans, from the immediate to the evolutionary.  The immediate, cellular, developmental level; the organismal level, including interacting organisms; and the evolutionary level, spanning eons.  Hence, the EcoDevoEvo of our blog URL, and which we discuss at length in our book, The Mermaid's Tale.

Evolutionary biologists like laws, models, theorems or rules that explain biological observations and can be used to predict future observations.  Thus, Hamilton's Rule (which we blogged about a few days ago) which explains the perplexing (to a strict Darwinist) behavior of altruism, and which invokes the kinship assessing all-seeing eye of natural selection lest a simple act of kindness go by insufficiently rewarded by the beneficiary.  Likewise almost every trait of an organism from its color to its organ structures is given, or forced to have, a specific selectionistic explanation for its origin.  And of course the theory of natural selection has been used, refined and re-refined to explain all manner of traits and behaviors of individuals and even societies since Darwin's time.  But, despite their rigorous precision in principle, that resemble laws an Einstein would admire, none of these laws/models/rules can explain every instance of X, and often require some hand waving to apply at all.

We think this is because the most general rule, one that applies to all of life, is 'whatever works, works'.  That is, evolution follows no single rules.  As a result, life is a sloppy process, and when you think you've found a rule that works in one instance, life defies you to apply it again in another. It doesn't sound like proper science, but if the shoe fits.....

So, in writing our book and in other things we've written, we've come up with a list of general principles that we think apply very broadly, even given that life is a sloppy process, and even if the principles are very vague or generic by comparison with the formulas for chemical reactions or the action of gravity on the Moon.   And you don't have to take our word for it.  These general principles are used explicitly or implicitly every day in genetics and developmental biology laboratories around the world.  If you are a biologist, you will recognize right away that some or all of them guide your work, even if in an informal way.  We didn't invent these principles, we have simply compiled them -- and we discuss them at length in our book.

1. Inheritance with memory: life is one continuous history, from the beginning 4 billion years ago to now, and cells 'remember' what they've inherited and carry it forth (except for changes, such as mutations in DNA);

2. Modular organization; life is constructed in LEGO mode, with repeated units, like segments, hairs, leaves, and the like.  We have referred in earlier posts to the importance of polymers, long molecules made of different subunits (modular units), whose arrangement contains the 'information' of life.

3. Sequestration: the modules in life are isolated from each other, at least in part.  If life is a history of divergence from common origin, from the beginning, that was possible only because of local, isolated compartments that can be separated enough from other compartments to become different.  Parts of DNA are isolated from each other, cells are, organs are....and you are an organism all your own for the same reason.

4. Coding and interaction;  Life is organized as above, generally because of the signaling interactions among units within and between cells (and beyond).  The key to all of this is combinations of molecules present together in time and place within an organism.  Combinations represent one of many kinds of 'codes', of which the genetic code is only one example.  The dance of such interactions is what causes differential organisms.  

5: Contingency: what's here tomorrow works only from what's here today.  This is the hierarchical nature of combinatorial interactions that we mentioned yesterday.

6. Chance: action without direction.  It is fundamental to life that there is a major component of chance in most aspects of what happens.  Mutation in DNA or the chance transmission of variants from parent to offspring ('Mendel's rules'), and the chance aspects of birth and death, or of winning and losing competition (such as natural selection) are examples at various levels. 

7. Adaptability in the face of changing circumstances.  DNA reacts to its environment (genes are used, or not, depending on whether the DNA is grabbed near them by proteins or other molecules), cells react to conditions via signals of various sorts that they are primed to detect, and so on, up to you, who react to your environment and decide what to eat, when to hold 'em and when to fold 'em, who to woo and who to fear, and so many other things.  Your brain is a hyperactive environment-sensor and decision-maker, and we're all familiar with that (and why some of our closest friends can't ever seem to make up their minds!).  But every cell in your body is doing it all the time, and so are structures within them.

8. Cooperation.  The above phenomena are, as we use the term, examples of cooperation, that is, co-operation, working jointly together.  Sometimes, as among social organisms, this is the kind of socially supportive interactions we usually use the word 'cooperation' for, but the myriad interactions that involve multiple partners (signal, signal detector, cells in organs, and so on) are examples of cooperation in the mechanical and more literal, rather than emotional sense of the term.

Not the least aspect of life that is very general is the lack of precision in these general principles of life:  no matter what might be 'read' in the genes, development makes mistakes -- DNA gets wrongly copied during cell replication, e.g, or during gene expression, or a gene is expressed at the wrong time or place ('wrong' according to what we think are the rules; e.g., A's always pair with T's, and G's with C's in nucleic acids, or this gene is 'for' that, and only expressed here, or there's only one way to build a given trait).  From cell to cell there is variation if you look closely, and the only reason we tend to overlook that variation is what can be called the central tendency, of many cells of a given type, no matter that they vary, together generally produce an acceptable structure (or the individual dies aborning).

Work-arounds have evolved for some of these 'mistakes' -- some DNA copying mistakes are repaired, but not all by any means, which is a good thing for biodiversity.  But others, that aren't repaired, are either fatal to an embryo or survivable, and of the survivable ones, eventually they can even come to look like good ideas; another good thing for biodiversity.  Or, an embryo can survive the mistake, but that same mistake might well spell doom later on, in an unforgiving environment.

These principles provide a logic to explain why traits have come about.  Yes, you might say wings are naturally selected, and maybe they are (that is, proto-birds had more offspring than animals that weren't airborne at all, and so wings got trendy), but that doesn't tell you anything about how wings came about.  And anyway, maybe wings weren't advantageous at all, they just happened, so your theory of natural selection tells you nothing at all about wings in the end.

Now none of these generalizations are secret or unknown, they are as simple as can be, and they're rather obvious.  There's so much to say about them to show the point that one could, well, write a whole book on the subject.  That's what we did, but even the fact that these general ideas are all around us and easy to perceive, people persist in pushing hard for very precise and rigorous 'laws' that it is almost just as easy to show don't work that way.  We are too wedded to that kind of Galileo/Newton/Einstein science, for historical if not other reasons.

Tomorrow -- er, Monday -- we will take this kind of slopistry from a somewhat different perspective.....

Reversibility: Dollo's 'law' in development and evolution

We recently posted on reports of the re-evolution of traits that had long been lost in evolutionary time.  This seemed to violate Dollo's "law" that evolution was a one-way train that couldn't back up.

When there are people in a population with or without a particular trait, say, eye color, and their children have a different version, we are not perplexed. Contingencies of gene expression or genotype or alleles (genetic variants) in the population can make this happen.  Darwin tried to fit his idea of inheritance with these ideas, mainly by hand-waving.  Now armed with concepts like multi-gene control and recessiveness of alleles, we have no problem understanding how these things happen.

But there are reasons to think that true reversibility of complex traits can't often happen over evolutionary time.  The basis of the argument is that too many genetic changes are required for a complex trait to be constructed and if the trait is 'erased' by mutation (and that is supported in the face of selection), then over time too many other genetic changes (mutations, gene duplications, other uses of genes, etc.) will make it impossible to back-track.

From this point of view, the 'new' version of the trait is physically similar to the old, or to that in a widely distant species, but is due to selection for the same trait that happens to pick up different genes and alleles to get the job done.  But if a pathway has been conserved because it's used for other things in the organism, it may be that simple genetic changes can reactivate that pathway in a context in which it was active long ago.

There has been a similar kind of no-going-back dogma, a kind of Dollo's "law" in developmental genetics.  Stem cells can differentiate into anything, but once that happens, the differentiated cells simply cannot go back to being stem cells.  We now know that this is not accurate. Even a small number of genetic changes in experimental systems can restore various stem-cell states.  This can happen even if the cell being manipulated is highly differentiated.  Is this as surprising or inexplicable as reversals in evolution?

The answer is that it is far less surprising, as a generality.  With some few notable exceptions, all the cells in your body have the same genome. This means that while each cell is of a particular type largely because it uses a specific set, but not all, of the genes in the genome.  There are, so to speak, 'blood' genes, 'stomach' genes, and so on. Gene expression is based on the physical packaging of chromosome regions and the presence of proteins specific to the cell type, that bind to DNA in regions near to, and that cause the expression of the specifically used genes.  But since with few exceptions all the genes still exist in all cells, if one changed these regulatory traits (packaging and so on of DNA, presence of regulatory proteins), one could make the cell do something else.  There may be too many changes in expression needed to make a stomach cell into a lung or muscle cell on its own, but we're looking at cells from the outside, and cells can be engineered to redifferentiate or dedifferentiate by experimentally imposing required sets of change. And in a sense it's why in some instances it only takes about 4 genes being manipulated to bring cells back to a very primitive stem cell type of state.

Evolution is different,  because once a species is committed to a particular direction, its genes themselves as well as their usage have changed, by virtue of mutation and frequency change induced by chance or natural selection.  Thus, spiders and grasshoppers no longer have the same genes so that only the expression pattern would need to be changed to let spiders hop or grasshoppers spin webs.  That is why evolution rarely truly reverses. Sometimes only a few changes would be needed, if basic pathways still exist but have been mutationally inactivated.

On the other hand, most traits have many paths and most genes have many uses, so that there can be many different paths by which some absent trait--or its likeness!--can reappear.  Natural selection and chance could activate some suitable set of genes to make this happen, and how likely it is depends on what environmental constraints are.  And since many developmental genes are highly conserved over long time periods, there can easily be similarities in the genetic basis of reappearance.

We know that some traits, such as complete vs incomplete metamorphosis in some species of amphibians (i.e., whether or not they go through a larval stage), or the pattern of ocelli (middle eyes) in insects, have re-evolved.  And we know that some genes from mammals can induce similar effects even in insects, by replacing or over activating their corresponding insect gene.

So, reversals are of many types due to many causes.  How likely they are, and how genetically they are brought about, are statistical and context-specific questions.  But there are no real mysteries about whether or not they are possible.

Rounding up the evidence on glyphosate

We've blogged a few times (here, e.g.) about the unintended consequences of the widespread use of genetically modified Roundup-resistant plants and, consequently, Roundup (Roundup is an herbicide, and its active ingredient is glyphosate).  Not surprisingly to anyone except Monsanto--the original producers of the stuff, who said this wouldn't happen--Roundup is encouraging the growth of herbicide-resistant weeds wherever it's liberally used, and thus the need for farmers to use more, and more toxic, herbicides, or more labor-intensive horticultural practices to deal with these newly stubborn weeds.  That's evolution for ya.

But other effects are getting some attention too.  A quick check on Google and Google Scholar provides evidence that for more than a decade there have been anecdotal and scientific journal reports of neural, craniofacial, limb and other anomalies in infants born in regions with intensive Roundup use, as well as effects on amphibians and other vertebrates living in or near the fields.  Any organism exposed to water that contains glyphosate-laced runoff apparently is also at risk.

Among many other reports, a 2009 paper finds that glyphosate alone is toxic to cells, and that other chemicals added to the herbicide, supposedly inert, exacerbate the effect.

We have evaluated the toxicity of four glyphosate (G)-based herbicides in Roundup (R) formulations, from 10⁵ times dilutions, on three different human cell types. This dilution level is far below agricultural recommendations and corresponds to low levels of residues in food or feed. The formulations have been compared to G alone and with its main metabolite AMPA or with one known adjuvant of R formulations, POEA. HUVEC primary neonate umbilical cord vein cells have been tested with 293 embryonic kidney and JEG3 placental cell lines. All R formulations cause total cell death within 24 h, through an inhibition of the mitochondrial succinate dehydrogenase activity, and necrosis, by release of cytosolic adenylate kinase measuring membrane damage. They also induce apoptosis via activation of enzymatic caspases 3/7 activity. 

And,

The real threshold of G toxicity must take into account the presence of adjuvants but also G metabolism and time-amplified effects or bioaccumulation. This should be discussed when analyzing the in vivo toxic actions of R. This work clearly confirms that the adjuvants in Roundup formulations are not inert. Moreover, the proprietary mixtures available on the market could cause cell damage and even death around residual levels to be expected, especially in food and feed derived from R formulation-treated crops.

Now a paper in the journal Chemical Research in Toxicology (Aug 9, 2010) reports the teratogenic effects of incubating frog and chick embryos with a 1/5000 dilution of glyphosate, and suggests a mechanism to explain the effect.

The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior−posterior (A-P) axis. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Embryos injected with pure glyphosate showed very similar phenotypes. Moreover, GBH [glyphosate based herbicides] produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly......  A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity..... The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields.

Retinoic acid is a signaling factor that is essential for cell differentiation in the developing embryo, as a regulator of major stages in growth and patterning.  If glyphosate is confirmed to interfere with retinoic acid levels in developing vertebrate embryos, as this study suggests, it's a serious problem for farm workers, people who live in regions where glyphosate is used heavily, or who use water from sources contaminated with glyphosate runoff, as well as any other vertebrate exposed to this stuff.

The point here is not to take political sides, but to stress that evaluating the evidence independently, regardless of commercial interest (or, for that matter, tree-hugger interests) is the only way to even have a good chance of preventing major calamities--or, to become confident that they won't occur.  But what we know about evolution and development make it quite conceivable that the problems are real.

The Professor of the Environment

In the Paris EvoDevo meeting that we attended a couple of weeks back, one speaker was the developmental biologist Scott Gilbert. Scott spends his time between Swarthmore and the University of Helsinki, and is the author of the world's foremost text on developmental biology but is also author of a long list of books and articles that put the subject in its historical context.

One point he's been making recently, as in his Paris talk, is that there has been too narrow a focus recently on genes as essentially the only cause of development or its evolution -- genes are not all that's inherited in life. Environmental effects of various kinds can be inherited in different ways, too. Some developmental biologists criticize this message for being 'anti-genetic', but Scott does his own genetics work, and certainly doesn't dismiss its importance.  His examples certainly do not undermine genetics, but simply show, convincingly, that other factors contribute to development and evolution.

We pointed this out in our book Mermaid's Tale as well, and in fact plasticity -- varying responses to environmental factors during development -- was a major theme of the EED meetings. Our gut bacteria (E coli) are vital for survival, and newborns are 'infected' from their mothers or their environment. Gilbert provided numerous other examples. Some fly eggs receive bacteria (Wolbachia) that are needed for their proper gene expression and development (as in the image to the left; Credit: PLoS / Scott O'Neill) -- without that, the egg dies. Maternal uterine conditions can cause fetal gene expression that affects the baby for its whole future life, in terms of things like obesity and blood pressure.

In this sense, laboratory organisms may be in such artificial environments that we don't really get a good picture from them, of how things are out there in the real world.

Since these various kinds of commensalism involve the genomes of more than just the species in question (and other non-genetic environmental factors are also transmitted to or needed by an organism's genome), understanding development requires a broader perspective. Information from the environment can be transmitted 'horizontally' in the sense that it is not transmitted 'vertically' from parent to offspring.

As Gilbert cleverly put it, the environment is not just the sieve of natural selection, deciding who shall live and who shall die. It is a source of information to an organism. And, because response to that information potentially affects survival and evolutionary success, the environment is like a professor: It gives information.....and then gives the recipient a test!

And these tests, like university final exams, determine whether the organism shall graduate!

Every organism is unique, but we all become unique in the same way

We've just run across a 2004 Nature paper by André Pires-daSilva and Ralf Sommer about the evolution of signaling in animal development. This paper, of which we were not aware but should have been, is highly related to some main themes of our book The Mermaid's Tale, which deals with fundamental aspects of how life works including, but not focused on, how it evolved.

The authors write that only seven signaling pathways are responsible for most of the cell-cell interactions that control the development of a single cell into the organism it becomes. They are used repeatedly at every stage of development, and have been co-opted through evolutionary time in the development of new morphological traits and systems.

After millions of years of evolution, signalling pathways have evolved into complex networks of interactions. Surprisingly, genetic and biochemical studies revealed that only a few classes of signalling pathways are sufficient to pattern a wide variety of cells, tissues and morphologies. The specificity of these pathways is based on the history of the cell (referred to as the 'cell's competence'), the intensity of the signal and the cross-regulatory interactions with other signalling cascades.

These ubiquitous pathways are the Hedgehog, Wnt, transforming growth factor-, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. How can the wide diversity of life around us be produced by so few ways for cells to communicate with each other?

Given the flexibility of signalling pathways, research in the past decade has concentrated on the question of how specificity is achieved in any signalling response. There is now clear evidence that the specificity of cellular responses can be achieved by at least five mechanisms, which in some cases act in combination, highlighting the network properties of signalling pathways in living cells.

First, the same receptor can activate different intracellular transducers in different tissues.

Second, differences in the kinetics of the ligand or receptor might generate distinct cellular outcomes.

Third, combinatorial activation by signalling pathways might result in the regulation of specific genes. Several signalling pathways can be integrated either at signalling proteins or at enhancers of target genes.

Fourth, cells that express distinct transcription factors might respond differently when exposed to the same signals.

Fifth, compartmentalization of the signal in the cell can contribute to specificity. The recruitment of components into protein complexes prevents cross signalling between unrelated signalling molecules or targets multifunctional molecules to specific functions.

The idea that a handful of networks can be responsible for most of the cellular 'decision-making' that is development is a beautiful example of core principles of life that we write about. The different ways that cells respond, the different developmental cascades that can be triggered by the same signaling networks, the interaction of different signaling pathways to trigger specific responses, and so forth all demonstrate the importance of modularity, signaling, contingency, sequestration and chance over and over again. How the components of these signaling pathways have evolved -- co-evolved -- is not yet well-understood, but it has to be that the interactions are tolerant of imprecision, and indeed, that tolerance (variation in the affinity of receptor/ligand binding) has been built into the system and leads to the evolutionary novelty.

The keys to this are partial sequestration of components of an organism so that local cells in different parts of the plant or animal can behave in different ways, so they can sense and respond to their environment (by signalling), and the arbitrary combinatorial codes by which signalling systems -- like the ones discussed in the 2004 paper -- work. That the same systems can produce diverse organisms reflects the logic of development, that is, the relational principles by which life is organized. Notch signaling is about the code specified by Notch, its receptor and related proteins, in combination with other such systems--and not by any particular property of the Notch proteins per se.

Every organism is unique, but we all become unique in the same way. It is basically the open-ended use of these very simple processes involving a limited number of components that enables this essentially unlimited diversity of living Nature.

Infant brain and equally naive thinking by scientists?

The program for this week, in our favorite radio program, In OurTime on BBCRadio 4 (applauded recently in The New York Times, and The London Review of Books, so clearly we're not alone!), is about the infant brain. Three psychologists discuss the history of modern ideas on how the brain works and develops, as an infant grows towards fully functional status.

The discussion contrasts a complete tabula rasa (blank slate) view that the infant learns everything from experience, to a totally nativist view that everything is built in. The former was advocated by Jean Piaget, the latter by Noam Chomsky. The discussants went over many intriguing experiments that have been done.

Clearly the way the brain actually develops is in the middle somewhere: the brain has regions that are dedicated to or specialize in some function, such as processing retinal images from the eye, or verbal sounds, or smells. Some parts of the brain regulate things like heartbeat and blood pressure, or secrete hormones. Except when adaptively relocating in recovery from injury, these seem at least generally to be in similar places in different individuals. That is a kind of functional hard-wiring, but it's very generic. It is a regionalization of areas that are set up, so to speak, to learn from experience--to learn sounds, language, the way animate and inanimate objects behave, and so on.

In interesting and important ways, this contrasts sharply with the dream of Darwinian psychologists and similar schools of thought, that want to be able to pry (rather pruriently, we might say) into a person's brain and claim the ability to see what they're really like, rather than how they fancy themselves to be.

The need to find a selective or even essentially deterministic explanation for the evolution of everything and anything mental is strong in our current culture, even if it's manifestly naive. If we are hard-wired for anything, overall, it is not to be hard-wired any more than was necessary. Humans are par excellence the learning and assessing organism, not one pre-programmed for our various tasks and traits. Pre-programmed to be able to scope out a new situation and figure out how to respond to it. That's what human beings are.

This is also the most parsimonious (simplest and easiest to explain) view of the human mind, if one feels a need for a selective explanation: if you were too rigidly hard-wired, you got caught by surprise and eaten at an early age! You didn't need countless specific selective adventures to weed out vagueness in any and every aspect of your thought. But it's harder to understand neurologically how unprogramming evolved than the 'genes-for' kind of dream. It also isn't as sexy and media-genic a view. Unfortunately, in our society oversimplified determinism and darwinism seems to be the order of the day.

In addition, the anthropocentric explanations of brain function are undermined by the fact that psychologists have shown that many of our traits are found in all sorts of other species, at least of mammals. Things found in dolphins and hedgehogs do not need a human-specific, much less a recent-evolutionary explanation. Such explanations are redundant, not parsimonious--not good science.

How the ability to recognize simple phonetic (sound) contrasts and the like, that is present in other species, led to our ability to build language, symbolic behavior, and all that goes with it, is the core question. Very interesting, but very hard to answer.

Not-so-random gene expression

One of the more perplexing questions about development is how a system rife with randomness--in the timing of gene expression, in whether genes in specific cells actually get turned on when instructed, in genetic variation itself, and so on--so predictably builds a recognizable replica of the organisms that donated their genetic material to the effort. The replica isn't exact, to be sure, as the genetic material comes from two parents with their own unique genomes, and mutations happen, but it's exact enough: a whale won't give birth to an elephant, nor a rabbit to a mouse. Randomness may be built in, but so is stability.

A recent paper in Science (Synchronous and Stochastic Patterns of Gene Activation in the Drosophila Embryo, Boettiger and Levine, July 24, 2009, Vol. 325. no. 5939, pp. 471 - 473) describes a mechanism that may explain some of that stability. Development is a time of rapid and contingent gene expression, demanding that at least a critical mass of cells in a developing tissue respond to signals in the same way, so that the next stage of growth can proceed. But not all cells that receive the same signal respond in the same way, such as by expressing a given gene at a specified time.

A note in the September Nature Reviews Genetics (Polymerase stalling gets genes in sync, p. 590) asks:

How is this variability dealt with in situations in which precise patterns of gene activation are important? A recent study [Boettiger and Levine] suggests a mechanism that can reduce variability in the onset of transcriptional activation in the Drosophila melanogaster embryo and may contribute to the precision of the developmental programme.

One of the initial steps in gene transcription is the recruitment and assembly of the RNA polymerase II complex that then starts the synthesis of new protein. If that complex isn't ready and waiting when a cell receives a signal to turn on a gene, the cell may not respond in a timely way, and the gene won't be turned on when needed.

Boettiger and Levine describe a series of elegant experiments looking at the timing of expression of a number of important 'control genes' in hundreds of fruit fly embryos.

These studies revealed two distinct patterns of gene activation: synchronous and stochastic [meaning random]. Synchronous genes display essentially uniform expression of nascent transcripts in all cells of an embryonic tissue, whereas stochastic genes display erratic patterns of de novo activation. RNA polymerase II is "pre-loaded" (stalled) in the promoter regions of synchronous genes, but not stochastic genes. Transcriptional synchrony might ensure the orderly deployment of the complex gene regulatory networks that control embryogenesis.

The timing differences are significant; synchronous expression of genes in different cells happens within 2 minutes of each other, while stochastic expression varies by as much as 20 minutes. Boettiger and Levine suggest that this may indicate two classes of genes, those for which timing of expression is crucial, and those for which it's less crucial. What controls the pre-loading of the RNA polymerase is not clear, nor how much play there still is in the process--previous experiments have shown that there is considerable variability in expression of the same gene in different cells, including non-expression, so the Boettiger/Levine classification scheme is clearly not exhaustive.

In many ways, randomness is crucial to evolution, but too much randomness during development can be lethal. As the Boettiger and Levine experiments show, evolution has produced ways to rein it in.

Turing the world of science and justice

The Independent ran a story on Tuesday (Aug 18) about a petition being signed by many in Britain, to demand an apology from the British government for its treatment of the late Alan Turing. Richard Dawkins has weighed in as well. Turing was famous for being one of the leaders in developing the regular system by which the British (and the US) were able to read much of the Axis military codes during WWII, by developing mechanical computing means of simulating input conditions for their Enigma machine.

Turing also was a founder of the idea and logic of programmable computers. A Turing machine is a general purpose theoretical concept of how to solve problems that can be very extensive. Many of its principles have been put into practice.

Relative to this blog is that Turing's idea of 'reaction-diffusion' systems was a mathematical model for repetitive patterning such as is widespread in life (hair, leaves, fingers, vertebrae, etc. etc.). Turing showed how complex patterns can be produced by simple interactive processes. You don't need a separate gene for each hair, and tinkering with the process can easily lead to differently patterned hair. We now know from extensive research by many, many of us that signaling systems work this way, and this is how organisms of all kinds are assembled (a major theme in our book, The Mermaid's Tale, that we referred to as 'complexity made simply').

Turing's ideas, modified for practical molecular developmental genetics, are more widespread than is his 1952 paper itself, and most users of the logic of the idea are probably unaware of the paper. But it was a factor in late 20th-century developmental biologists' thinking, expressed in terms like 'morphogens', morphogenetic fields, and the like.

We should be careful about lionizing anyone from the past. In each area in which Turing made major contributions, he had major antecedents. In the late 19th century William Bateson used then-popular field theory and concepts of wave interference patterns to liken such patterns to similar developmental processes in embryos that are responsible for repetitive traits.

In computer science there were Babbage, Holerith, and others, not to mention the Jacquard loom, and at Bletchley Park the Collosus, a punch-tape vacuum-tube based programmable device the British postal service had been using, modified as a German code-breaker.

And Turing was by no means the only major figure to work on Enigma. In fact the code had first been broken well before the war by Polish cryptographers who not only gave their knowledge to the French and British, but who had also invented the machine called the 'bombe' that was a kind of mechanical simulator referred to earlier. And Gordon Welchman who introduced a particular modification to the bombe, called the 'diagonal board', that enabled decoding-simulation of the more complex Enigma the Germans began using later in the way. (We know some of this history since we visited Bletchley Park earlier this summer--when we took the pictures in this post--and subsequently read about it).

The point is simply to place things in proper context. None of us work entirely without history. Even Darwin needs such tempered recognition. This is relevant to the petition mentioned by The Independent. It refers to the fact that Turing, besides being an odd duck in many ways, was homosexual. Today of course that would be no big deal. But that's today. At the time, even in the England he helped save from the Nazis, being gay meant being in the slammer for a number of years (it was like that here in the good ol' enlightened USA, too).

By fluke, Turing was discovered to be gay by the powers-that-be (see the story for details), and he volunteered to undergo hormone 'therapy' rather than jail for his punishment. It had negative effects on him, and for that and who knows what other reasons, Turing bit the poisoned apple -- literally -- and died at age 41.

The petition is for an:

apology from the Prime Minister Gordon Brown, recognising the "consequences of prejudice that ended his career". More than 700 people have signed a petition started by the leading computer scientist John Graham-Cumming on the Downing Street website, including gay rights campaigners, politicians and scientists."

We wholly sympathize and would certainly sign this petition if we were in the UK. However, it strikes us that that's not the right thing to do. Turing actually broke a law that he knew of and was on the books at the time. He was not the only victim of that law, and the majority of his contemporaries in Britain at the time would have considered it a just law, and hence he not a 'victim.'

Standards have changed, and Turing is certainly owed an expression of regret that times were then as judgmental as they were--and we should try to reduce such things today. But one shouldn't have to be a famous genius to warrant retrospective empathy. To apologize to Turing is selectively saying that the way he was treated was regrettable because he helped win the war and invented modern computing theory.

In a way that demeans the apology. We owe expression of regrets about our human failings firstly to ourselves, so we won't repeat them, and then to everyone who fell victim, chimney-sweep and code-breaker alike. We should be touring the entire world, not just Turing's world of science, in seeking out injustice.

I still smell a rat! (Episode II)

So each olfactory neuron (ON) expresses only one of its 2000 olfactory receptor (OR) genes on its surface and hence can only react (bind to) a limited range of odorant molecules. The combination of ONs that can bind to an odor molecule is a combinatorial expression code for the brain: the combination of signals is remembered when it first occurs and recognized when sometime later the same smell is encountered.

But how does this 'map' from nose to the brain?

In ways not yet understood, the receptor molecule on the surface of each ON helps guides the axon from the nose through the base of the skull into the brain. There it meets a structure called the olfactory bulb. Neurons expressing the same OR may be located in different parts of the nerve, but their axons recognize each other, and bundle together, as their axons migrate to one or two specific locations in the olfactory bulb. These locations are called glomeruli. A glomerulus is a kind of neural knot of axons from all the ONs that express the same OR and hence that respond to the same odor molecule.

From there, neurons travel to various parts of the brain. Their routes are not precise and there is no longer a simple correspondence between the neural endings in a given part of the brain and the odor molecules they respond to. The brain can remember which ONs fire for a given odorant, but there's no spatial map that corresponds to the spatial pattern of the ONs in the nose. Instead, the brain simply remembers where 'lemon' is, and we each have this little factoid in different parts of our brains.

Now it was thought that evolution had programmed a fixed location for each glomerulus, so that in some sense there would be at least a map of where in the olfactory bulb axons from cells using the same OR would travel to. There is logic in terms of the development of brain terminals for sound and sight information, since for example, light travels from a tree, lion, potential mate in an orderly way. But there's no such natural order to odors, and glomeruli-like units are not found in other sensory systems. So why would such a system be needed and how did it evolve?

Recent work reviewed by Zou et al, the paper we referred to in our previous post, shows that it may be true that axons expressing the same OR molecule do recognize each other and bundle together. They end up in a glomerulus in the olfactory bulb. But it's not the same place in different individuals, even different genetically identical mice from the same inbred strain. The idea of forming a glomerulus, as a kind of developmental ordering that clusters similar neurons together, and may increase the signal strength as a result, seems to be programmed. But a particular location is not.

By requiring less specific order, and one forced on a system of information (odors) that didn't have any natural order, the olfactory 'wiring' system may thus have been easier to evolve. But it means that odor responses would be somewhat less stereotypical, less precisely evolved, and that we respond to odors more as a result of experience than hard-wiring.

In fact, Zou et al. report that some studies have shown that the wiring that's observed depends in important ways on olfactory experience--the usage of the neurons--during early life. Since each animal's experience is different, it's no surprise that the results also differ.

This picture does not make complex traits simple, but it helps show how complexity can be made simply. Tractable, reasonable processes can end up generating complex structures by assembling them bit by bit in stages during development. Olfactory organization is an example.

Further, this story shows that environments and their associated variation and stochasticity affect the traits we all bear--even when they are programmed genetically to develop by orderly processes. In that way, even inbred animals--like human identical twins--can be different from each other.

The brain and the braincase, and much more, too

In our book The Mermaid's Tale, we make the point that, in thinking about how the diversity of life arose, people often place too much emphasis on evolutionary time scales compared to the more immediate timescale on which life is actually lived. We note that no two species in nature, no matter how distant or how different their genomes, are any more different than a brain and the braincase that encloses it. Yet the brain and the braincase are made with cells having the same genome, very closely related in terms of cellular descent (from the single fertilized egg), and that in fact interact extensively with each other. This figure, from a simulation done by Brian Lambert, programmer extraordinaire with our group, illustrates how signal interactions among 3 layers, an outer epithelium, a pre-bone layer of mesodermal cells, and an underlying dural layer usually thought of as the outer layer of the brain, produce the different tissues of the brain and skull.

The difference is not in the genomes in any of the cells involved in the development of the head, of course, but in the way their genomes are used. Indeed, in research that we are doing in collaboration with Joan Richtsmeier and others here, and Mimi Jabs at Albert Einstein University in New York, we are finding the intricate way in which these two structures develop through intimate interactions of cell layers that often express similar genes. It is not even clear whether the cells of the future braincase, or those of the future brain, are 'in charge' of this process, and the very concept of a pure hierarchy of control is probably most often a misperception that may derive from our broader culture, in which we do have bosses and the bossed, and natural power hierarchies.

This cooperative kind of interaction based on signaling is essential to life, indeed we would argue that life is signaling. That means that contrary to ideas since Mendel's work on peas was rediscovered in 1900, genes per se are not as much the key to life as gene usage, and also the somewhat Lamarck-like fact that cells, if not organisms, do change--in this case their gene expression and hence their differentiation and behavior, as a result of experience (their cellular context), and these changes are inherited by their descendant cells in the body of the organism.

This is not the place to go on in detail about that--it's a major part of our book. But we are triggered to discuss the subject because a new paper by Dimas et al. in Science Express ("Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner", Dimas et al., published in Science Express online, July 30, 2009), has compared regions of the genome in which variation among individuals differently control expression of genes in several different cell lines from the individuals that were tested. The findings are, first, that each cell type has its own regulatory regions distributed across the genome. This is no surprise because each cell, such as different types of blood cells, does different things and must do that via hundreds of different expressed genes. There is variation because these individuals vary, just as you and we do. But the greater variation, as with the brain and the braincase, is among very closely related cells in terms of their gene expression.

Dimas et al. also found that regulatory regions used in only one of the tested cell types tended to cause lower levels of expression, and to be farther from the genes. Why this should be, if it is a finding that holds up in future work, is anyone's guess, but may reflect some aspect of evolution related to the cell type. Another finding was that the great majority, up to around 80%, of regulation is by control elements that only affect one of the tested cell types.

So cells differentiate to make organs, and that's what makes you as an organism. Evolution leads to differences, to be sure, but at least as interesting is the way that cells act as organisms of their own, and evolve--yes, evolve in the true sense of the word--very rapidly and by cooperative communication, rather than competition, among each other. In fact, in the book we call the developmental process of cellular differentiation cytospeciation.

These issues are important far beyond their basic interest. For example, the whole idea of using stem cells to develop replacement tissue as therapy for diseases depends on making the same starting cells become different, a singular challenge. Indeed, it's less of a challenge to produce a whole new animal with stem cells than to direct the differentiation of the cell types needed to make a single organ. But, the more this can be done with the patient's own genome, the more likely it will work.

But, some day it may be possible to take your adult skin cells, and turn them into brain or braincase, to repair damage acquired during life.

The Centrality of Cooperation in Life: a first installment

A recent story in the New York Times science section about the importance of cooperation in ant colonies reminded us that we've been focused on things like disease and genetic causation in our blog for a while now. So we thought it was time to get back to other things, such as the importance of cooperation in all of biology, not just to ants.

Cooperation was in the subtitle of our book, and for a reason. Ever since Darwin's Origin of Species, whose 150th anniversary is rightly being celebrated this year, there has been what we think is an excessive belief that competition is central to the nature of life. In biology, this ethos is largely about the way that Darwinian evolution, with its stress on competition among individuals within a population, with its genetically determined winners, losers, inherent goods and bads, has fit the nature of our industrial culture's worldview. It is a convenient way to rationalize and hence justify self-interested gain by a few against the many.

Nobody can deny that there is competition in life, in the sense that some individuals do better at reproducing than others. Species have their day, and fade as other species flourish. It's an important mechanism for biological change and was a brilliant insight of Darwin, as well of others in his time (Wallace's attention was more on group competition against environmental limitations, than on individual competition). It helped demystify the origin and nature of life and its diversity.

However, it's not the whole truth about life. Instead, we think, a focus on competition draws disproportionate attention to the long-term historical aspects of life, even if the Darwinian explanation is accurate!, rather than what we can easily see every day before our very eyes. What we see everywhere, every day is mainly cooperation: among molecules within each of our cells, among cells within each individual, and among individuals. In a deep biological sense, if not in one that fits the value-loaded human word 'cooperation', even predator and prey must cooperate: both must be present for each to survive.

Classical evolutionary theory, and a lot of popular science writing based on it, assumes competition to be the fundamental force in life. But absolutely as essential to life is necessity for cooperation at all times and at all these levels--among genes in genetic pathways, among organelles in cells, among cells and tissues and organs, and in ecosystems among organisms within and between species.

And, our focus on cooperation leads us to a different view of natural selection and its importance in evolution. As we say in The Mermaid's Tale, natural selection does happen, but it depends on a lot of if's. For example, if a species over-reproduces, and if there is variation in the next generation, and if some of that variation leads its bearers to do better in a given environment, and if that's due to the inherited genome, and if the environment remains stable for long enough that this variant is favored consistently, and if the favored forms reproduce successfully, as do their offspring, and if they produce more offspring than organisms without the favored variant, then these favored organisms may become more common, due to natural selection. That is, they will be better adapted to their environment. But, all these if's must co-occur for natural selection to be an important force in change. If they are sporadic, or varying in nature and intensity, then their relative importance diminishes in relation to other aspects of life, including chance. Indeed, distinguishing chance from natural selection is no simple challenge.

No matter, to understand life in a deep sense one really has first to understand the nature of the countless cooperative interactions on which it is based. How those interactions change over long time periods of generations of cells, organisms, species, and ecosystems is important. But the interactions, and how they organize life, come first.

Genetic perceptions and(/or) illusions?

If as we tend to think, genes are not as strongly deterministic as seems often to be argued, then why do humans always give birth to humans, and voles to voles? Isn't the genome all-important, and therefore doesn't it have to be a blueprint (or, in more current terms, a computer program) for the organism? Even the other ingredients in the fertilized egg are often to a great extent dismissed in importance, because at some stage they are determined by genes (for example, in the mother when she produces the egg cell).

It's true that most people enter this world with the same basic set of parts, even if each part varies among people. But, in many senses the person is not predictable by his or her genome. You get this disease, other people get that one. You are athletic, others are not. You can do math, others can do metalwork. And so on, but most often a genetic predisposition for these traits can't be found.

We have made a number of recent posts about that genotype to phenotype connection problem. You generally resemble your relatives, which must be at least partly for genetic reasons, but the idea of predicting much more than that about your specific life from your specific genome is not working out very well, except vaguely or, it is certainly true, for a number of genetic variants with strong effects, that are often rare or pathological. In the latter cases are the genetic causes of diseases like muscular dystrophy or cystic fibrosis.

But these facts seem inconsistent! How can your genome determine whether you are an oak, a rabbit, or a person....and yet not determine whether you'll be a musician, get cancer, or win a Nobel prize? Is the idea of genetic control an illusion?

Yes and no. Part of the explanation has to do with what we refer to in our book as 'inheritance with memory'. Genomes acquire mutations and, if they aren't lethal, they are faithfully transmitted from parent to offspring so that some people have blue eyes and some have brown, some have freckles and others don't.

Over time, differences accumulate in genomes, and with isolation of one kind or another, lineages diverge into different species, and then differences continue to build up over evolutionary time. When millions of years later you compare a rabbit to a person (much less to a maple!), so much genetic variation has accumulated that there is clearly no confusing these different organisms. The genes, and the result of their action are unmistakable.

What happens at each step during development of an embryo reflects the cumulative effect of many genes, and is contingent on what has already happened. Thus, step by step by step in a developing rabbit embryo the rabbit foundation gets laid and everything that happens next basically depends on getting more rabbit instructions, because, except for genes that are very similar (conserved) across species, they are the only instructions that the cells in the embryo can receive.

Variation is tolerated but within limits--some rabbits have very floppy ears and some don't, but none have elephant ears or a rack of antlers (as in the jackalope pictured here) or can survive a mutation that gives it, say, a malfunctioning heart. So, you get a continuum of rabbit types, but because of how development works, a newborn rabbit can't veer very far from 'rabbitness'.

The same is true for humans--among those whose ancestors were separated on different continents, during thousands of generations, genetic variation arose and accumulated in these populations, and it's often possible to tell from a genome where a person's ancestors lived. That is, that person's genome's geographic ancestry.

When the subject turns to variation within a species or a population, however, the scale of variation that we are studying greatly changes. Now we are trying to identify genetic variation that, while still compatible with its species and population, and with successful embryological development, contributes to trait variation. Relative to species differences, such variation is usually very slight. But, it happens because, within limits, biology is imprecise and a certain amount of sloppiness (mutation, in this case) is compatible with life. In fact, it drives evolution.

What does this mean about the genetics of disease, or other traits that are often of interest to researchers, like behavior, artistic ability, intelligence, etc.? Culturally, we may make much of these differences, such as who can play shortstop and who can't. But often, these are traits that are not all that far from average or only are manifest after decades of life (e.g., even 'early onset' heart or Alzheimer disease means onset in one's 50s). Without even considering the effects of the environment, it is no surprise, and no illusion, that it is difficult to identify the generally small differences in gene performance that are responsible.

Of course, like a machine, there are many ways in which a broken part can break the whole machine, so that within any species there are many ways in which mutations that have major effects on some gene can have major effects on the organism. Mostly, those are lethal or present early in life. And, many mutations probably happen in the developing egg or sperm rendering that cell unable to survive--that's prezygotic selection. But even serious diseases are small relative to the fact that a person with huntington's disease or cancer is, first and foremost, a person.

Weiss and Buchanan, 2009

So, there may seem to be an inconsistency between the difficulty of finding genetic causes of variation among humans, and the obvious fact that genetic variance is responsible for our development and differences from other species. A major explanation is the scale of difference one is thinking about. Just because genes clearly and definitively determine the difference between you and a maple tree--and it's easy to identify the genes that contribute to that difference--that does not mean that the genetic basis of the trait differences between you and anyone else is going to be easy to identify. Or between a red maple and a sugar maple. Or that genetic variation alone is going to explain your disease risk or particular skills.

And there's another point. In biomedical genetics we are drawing samples from billions of people, whose diseases come to the attention of specialty clinics around the developed world, and hence are reported, included in data bases, and are put under the genetic microscope for examination. This means that we systematically identify the very rarest, most aberrant genotypes in our species. This can greatly exaggerate the amount of genetically driven variation in humans compared to most, if not all, other species.

However, it must be said that even the instances of other species (such as a hundred or so standard lines of inbred mice, or perhaps a few thousand lines of fruit flies or Arabidopsis plants (as in the drawing), from which much of our knowledge of genetic variation is derived), finds similar mixes of genetic simplicity and complexity. In other words, one does not need a sample space of hundreds of millions to encounter the difficulty of trying to predict phenotypes from genotypes.

So while this is true, it's also true that some variation in human traits is controlled by single genes, and those behave at least to some extent like the classical genetic traits that Mendel studied in peas. This variation arises in exactly the same way variant genes with small effects that contribute to polygenic traits arises--by mutation. But, the effects of mutation follow a distribution from very small to very large, and the genetic variants affecting the extreme are easier to identify. Some common variants of this kind do exist, because life is a mix of whatever evolution happened to produce. But complex traits remain, for understandable evolutionary reasons, complex.