Showing posts with label principles of life. Show all posts
Showing posts with label principles of life. Show all posts

Friday, January 18, 2013

Burrowing into the unending nature vs nurture debate

Behavior modules
Two interesting stories about behavior this week.  You've probably read about the mouse that builds its nest in a stereotypical way.  The Nature paper (Weber, Peterson, and Hoekstra) describing this was reported in The New York Times, as a story about how genes control complex behavior. 

The research was motivated by the question of how genetics influences the evolution of complex behaviors, but the researchers also wonder whether the environment influences variation in heritable behavior, and whether many or few genetic changes affect behavioral evolution.

The authors describe the burrow built by oldfield mice as having a long entrance and escape tunnels, and they say that the length is consistent wherever these mice build them, although tunnel depth depends on the soil in which they build.




Deer mice make a smaller, simpler burrow, and when the two species are interbred in the lab, the offspring reproduce the more complex burrow of the oldfield mouse, though with varying length.  First generation backcross mice (offspring of the interbreeding then bred with the parental strain) build burrows of varying length, and not all built escape tunnels, which suggests to the researchers that these behaviors are separately determined. 

The researchers then looked for genetic loci that might be influencing these behaviors and found three different loci that seem to contribute to tunnel length, and another that influences the building of escape tunnels.  As explained in the NYT:
All complicated behaviors are affected by many things, Dr. Hoekstra said, so these regions of DNA do not determine tunnel architecture and length by themselves. But tunnel length is about 30 percent inherited, she said, and the three locations account for about half of that variation. The rest is determined by many tiny genetic effects. As for the one location that affected whether or not mice dug an escape tunnel, if a short-burrow mouse had the long-burrow DNA region, it was 40 percent more likely to dig a complete escape tunnel. 
Well, if tunnel length is about 30 percent inherited (and there is variation in tunnel length; average length is 181 cm, with a standard deviation of ±53), and the three locations account for about half of that variation, or perhaps 15% of the variation in tunnel-building, then the rest of the causation is not due to a few major genes.  Though, if it's 70% non-genetic, then one wonders how the environment specifies that a tunnel will have an escape hatch.

The authors conclude that "discrete genetic modules" control complex behaviors and that, "Together, these results suggest that complex behaviours—in this case, a classic ‘extended phenotype'—can evolve through multiple genetic changes each affecting distinct behaviour modules."  One could challenge this rather strong genetic-determinism view.  But how genes (much less environments) determine this type of thing is interesting and challenging to think about.

Overcoming behavior modules
Manduca sexta, or Hawkmoth;
Wikimedia Commons
The second story this week is from a paper in Science reporting that while the hawkmoth seems to innately prefer the nectar of night-blooming flowers, it can learn to collect nectar from other sources.  These moths seem to innately prefer flowers that give off a specific class of aromatic compounds, or at least the aromatics of their preferred flowers are processed similarly by the moth's olfactory response.

But the researchers wondered whether olfactory response necessarily reflects the moth's preference.  To test this, they exposed naive moths to paper flowers scented with different classes of compounds from those they generally prefer.  The moths were then observed to visit flowers emitting these scents at similar frequencies to those they innately prefer.  The authors conclude that "olfactory conditioning provided moths with flexibility in their foraging behavior but did not extinguish their innate preferences for scents from the moth-pollinated flowers." They suggest that "olfactory conditioning may operate in an olfactory "channel" separate from, but parallel to, that involved in the innate responses."  Modularity again. 

So much for exquisitely fine-tuned co-evolution of flower and pollinator. 

Glass half full/half empty
There's something for everyone here. The mouse researchers conclude that behavior is modular and evolves by the mixing and matching of genetic modules. Maybe, but there's plenty of non-heritable influence on mouse burrowing behavior as well, if tunnel length is only "about 30 percent inherited."

Modularity is a fundamental principle of life, and the idea that behavior, as well as morphological traits, can be modular is certainly a possibility -- every 4th grade class has its clown and its bully and its teacher's pet, after all.  But this doesn't mean that it must be genetically determined.  It could be, but the evidence isn't yet there. Maybe the non-mapped variation has to do with general cognitive function and how an animal scopes out its environment and decides what would be a good strategy for living in it.

We are all ultimately reducible to genes, in the sense that they are the basis of who and what we are.  But, as the hawkmoth study shows, the fact that even a lowly moth can easily overcome "innate" behavior with a whiff of something it wasn't born to crave is yet further evidence that organisms are inherently adaptable, a fundamental principle of life.  Given that environments can change quickly and unpredictably, that's a good thing. 

Monday, December 17, 2012

Principles of life exemplified (again): cell membrane domains

Principles of life
As regular readers know, one of the core ideas we present in our book, The Mermaid's Tale, is that there is a basic set of principles that explain life in the short term (development), the long and extremely long term (evolution) and the simultaneous (ecosystems).  These principles are being used implicitly or explicitly in biology labs around the world as researchers design and interpret their experiments because they derive from everything we know about life.  That they work everywhere and at all time scales isn't our invention, we just happened to have drawn up the list.  (We've blogged about this before, e.g citing examples of the principles in action.)

We think the list is important because we feel that it is far too widely assumed, even if just tacitly or subliminally, that the only theory about variation in life is the Darwinian theory of competitively based evolution.   This is not to assert that natural selection is unimportant, but we do think that it is far less important or pervasive than the kinds of relationships and properties we have tried to enumerate--indeed, without these coming first, there wouldn't be anything for selection to select for.  One hundred and fifty years of discoveries since Darwin have given us much broader insight into how life works, which we think our list exemplifies.

The principles as we formulate them (annotated here, and of course in our book):
1. Inheritance with memory
2. Modularity
3. Sequestration
4. Coding and interaction
5. Contingency
6. Chance
7. Adaptability
8. Cooperation
This comes up again today because of a paper in the December 7 issue of Cell which illustrates exactly our point about these principles -- they are all around us, and can be used to predict and interpret the kinds of findings in biology that are made all the time.  The paper, "General Protein Diffusion Barriers Create Compartments within Bacterial Cells," Schlimpert et al., describes modularity in the cell membrane of prokaryotes, single-celled organisms without a nucleus, which is similar to that already known in eukaryotes.



In eukaryotes, things that stick off the cellular membrane, like cilia or neuronal axons, 'know' what and where to be because of proteins that are partitioned non-uniformly into specific domains on the plasma membrane through specialized barriers that pick and choose what can pass through.  Schlimpert et al. describe the "protein-mediated membrane diffusion barrier" in the stalked bacterium, Caulobacter crescentus, which, ultimately is "critical for cellular fitness because [such barrier structures] minimize the effective cell volume, allowing faster adaptation to environmental changes that require de novo synthesis of envelope proteins."

Caulobacter have two forms of daughter cell.  'Swarmer' cell with flagellum for moving; 'Stalked' cell, with adhesive organelle, for adhering to surfaces. Swarmer cells soon differentiate into stalked cells (Wikipedia).
Like eukaryotes, prokaryotes also segregate proteins in the cytoplasm, the interior of the cell, into specialized "micrcompartments."  This is important, because different kinds of functions and reactions need their own local environmental conditions (e.g., pH, particular proteins or other molecules), without interference from other stuff in the cell.  So they do share this local organizing principle, but that prokaryotes also had protein-mediated diffusion barriers that determined the organization of the membrane was not previously known. Schlimbert et al. demonstrate this by showing that the stalk-cell body boundary behaves differently from the rest of the cell membrane, as molecules that are allowed to diffuse through the rest of the membrane cannot pass through this boundary.  The work is described in much detail in the paper, but for our purposes here, these are the important points:
Unlike in eukaryotic cells, these diffusion barriers not only laterally compartmentalize cellular membranes but also limit the free diffusion of soluble proteins, thereby providing a significant fitness advantage. Diffusion barrier formation in Caulobacter therefore represents a thus far unrecognized mechanism to optimize the growth of a prokaryote by restricting protein mobility within the cell.
Principles in action
This one very specific example of a microorganism in action illustrates very nicely some of the basic principles we've proposed. In particular, modularity, sequestration and adaptability.  If one were to have hypothesized ahead of time how prokaryotic membranes were organized, the idea that they were composed of specialized domains -- modules -- would have been an obvious first guess, and not just because that's how eukaryotic cell membranes are organized but because that's how all of life is organized.  And, modularity goes hand-in-hand with sequestration, but sequestration that isn't complete because some communication between the inside and the outside of the cell is essential.

Schlimpert et al. write that the presence of the cell membrane domains allows "faster adaptation to environmental changes that require de novo synthesis of envelope proteins."  Again, no surprise that adaptability is enhanced by membrane modularity, as adaptability is one of the most important traits that organisms have evolved, and probably one of the earliest because it's so ubiquitous.

As for the rest of our list of principles, they are simply inherent in the mechanics of life, and so of course in Caulobacter. Inheritance with memory is so basic that it's a given in terms of how organisms reproduce; memory being embodied in DNA.  Coding and interaction are fundamental to how all genes are expressed, and how receptors receive signal and so on, and because life is a 4 dimensional process, contingency is equally inherent; every step of development and of maintaining homeostasis or reproducing depends on what has come before.  Life also is inherently random and dependent upon cooperation; among genes, cellular organelles, micro compartments and so on.

So, again, a simple set of principles predicts and explains a tiny piece of life, because all of life shares a common ancestor; descent with modification for the last 3.5 billion years has given us the incredible diversity of life we see around us, but it hasn't changed the fundamentals.

Monday, October 29, 2012

The microbiome: competition or cooperation, adaptation or adaptability?

We're just now getting around to blogging about a Perspectives piece in the Oct 12 Science called "Animal Behavior and the Microbiome" by Vanessa Ezenwa et al. It's an overview of current thinking about the role microorganisms play in animal behavior.  The Human Microbiome Project documenting the extent of such organisms in humans, and the essential role these guys play in human health and disease, has found that the genes in the trillions of microorganisms with which we share our bodies outnumber ours by 100 to 1.

Since at least some of these are necessary for life, one offshoot of learning about this is to ask what 'the' human genome really is.  Most bacteria we know of, like the ones in our gut, have to do with rather prosaic, if vital, physiology such as digestion.  These are interesting and important, but they don't involve more sensitive issues such as our personal identity -- our behavior.  The role of microbes in animal behavior is just beginning to be understood, and it may be more profound than had been thought. 

Kudzu bug; Wikipedia
For example, as described in the paper, "the Kudzu bug (Megacopta cribraria), an agricultural pest, is born without any symbionts (species with which both have a mutually necessary affiliation for survival). After birth it acquires a specific symbiont from bacterial capsules left by its mother. If these capsules are removed, the bugs show dramatic wandering behaviors, presumably to search for symbiont capsules left with nearby eggs."

Or, bumble bees acquire gut microbiota either through contact with nest mates or by feeding on feces containing the microbiota required by the gut. Bees without these microbiota were more susceptible to a bumble bee parasite, Crithidia bombi. Fruit flies that share the same diet-acquired microbiota are much more likely to mate with each other than with those that don't.  And then there's the zombie ant, infected by killer fungi, and the rats -- and cat ladies -- infected by Toxoplasma gondii, both of which we described here.  The examples go on and on.

But what does the recognition that we don't go through life alone mean for the usual understanding of social context, ecosystems and the evolution of behavior?  It's tempting to suggest that these are examples of exquisitely fine-tuned co-evolution, and the usual darwinian interpretation would be that every organism is out for itself, selfishly hijacking another's gut, brain, feces, nasal passages, skin, eyes, now manipulating their behavior -- any and everything -- to make a living.  And needing to out-compete all the other microbes fighting for the same territory.  But don't get too greedy or you'll kill your host and then you're in trouble too.  (Reminiscent of how humans feel about climate change -- we have to save the planet so we can continue to exploit it ourselves.) 

But this is rather a stretch, really, and depends on fitting the facts to a preconceived view of the purpose of organismal interactions (apply our take on why people believe microbes will be found on Mars here).  And that preconceived view is that life is all about selfishness, exploitation and competition.

But there's an alternative view, and that is that what this represents is cooperation, one of the fundamental principles of life that we've often written about here and in our book MT.  It's a principle that requires abandoning the long-held belief in the primacy of "survival of the fittest" because that very rarely happens.  A better description would be "failure of the frail" -- it's only the weakest organisms that can't reproduce; most everyone else does just fine.  Plus, much of survival depends to a large degree on luck and has nothing to do with genes or competition or your ability to outwit your neighbor.

So, this Russian doll kind of life-within-life-within-life that's being catalogued is an ongoing documentation of the centrality of cooperation in life.  There's surely some adaptation going on -- the bumble bee is better off without Crithidia bombi than with, but 10-20% of worker bees in hives in the field have been shown to be infected and bees have carried on; it's only now that they're bombarded with infection with multiple parasites and more that it's a problem.  But the bee did not evolve to be infected with gut microbiota to fight off C. bombi, the bee evolved with the ability to host gut microbiota and to fight off the parasite, however that happens. 

Further, some infection was survivable, and the parasite didn't need the bumble bee because it's an equal opportunity infector, infecting other insects.  This brings up another fundamental principle of life, and that's adaptability.  Because it's ubiquitous, we believe adaptability is a characteristic of life that was present very early in evolution. So, humans can't live without a gut full of microbiota, but the species that we host are widely variable, they change when we're ill or pregnant, we can kill them off in great numbers with antibiotics, can add more with probiotics or natural exposures, and we're fine.  The same has to be true for other organisms.

One can say that what's here has to work, or at least to have worked successfully enough in the past to be here today.  But that's only a part of the biology, and there has been a tendency to focus more on how that evolved via competition, than on the interactions themselves.  How cooperation works is turning out to be an elegant but complex business.  Even if Darwinian explanations are 100% correct -- and there are reasons to temper such a view -- understanding how such things work today is in itself a challenge, and a very interesting one at that.  Though, perhaps our very interest in it is because of some microbe in our brains, that makes us sympathetic to the lives of microbes...

Monday, October 22, 2012

Life on Mars: Why microbes?

Tropes of our time
When the proponents of costly explorations of Mars start justifying these projects, they usually reduce the reason to the objective of finding life there.  That's good space-travel-as-Disney imagery that will get the public to open up their wallets.

In fact, even the most hyperbolic NASA proponents don't promise 'advanced' life like humans (or, even, little green men) there.  No, they are always referring to microbes, so tiny that we can't see them from telescopes or cameras aloft in orbiting spacecraft.  We have to land, and indeed we have to land guys with shovels to find it.

The argument that Mars life must be primitive is based on the geological history of Mars which suggests that it and the Earth originated at similar times, but about 4 billion years ago the smaller Mars settled down to a nearly atmosphere-free, more hostile environment unlike the hospitable environments here.  But if life had begun on Mars at about the same time as it seems to have begun here, so the tale goes, it would have reached a comparable stage of primitive forms, the kind that evidence from 3.5 billion year old rocks shows was then here on Earth....life that the newly hostile Martian environment killed off.  At best, if there are any surviving forms, they'll have to be hiding, protected, under the ice or huddling inside rocks.

That's a pretty powerful belief in parallel histories up to that point, as if life is nearly inevitable.  It seems like quite a stretch, but that's not all.  Even purportedly knowledgeable scientists speak of carbon and oxygen and so on in Mars rocks, in the context of noting that these are the building blocks of life, and especially of DNA.  This shows how deeply the flash-words, or 'tropes' of our time control our thinking, although we know that it's by far more likely that RNA came first (here on Earth, at least).  But this is how current science is embedded in current culture.  RNA has very similar molecular contents, but the implied idea is that a DNA-based protein code must be the way life works.  That's how it is here, and it's the core of current life science, so it must be that way there, too!

NASA will be peeking with great Curiosity everywhere it can look for anything it could claim suggests life, and eventually exploratory vehicles will try to bore down to find life, shivering modestly, in or under the Martian ice.  Again, we look there because, with its unshielded solar radiation, cold temperature, and little atmosphere, Martian life can't live on the surface--or that is, earth life couldn't--and assuming the same about Martians provides a convenient escape clause for why we we haven't actually seen any Mars life.

Principles of Life
Although our current scientific culture, and its popular image, is centered on or even obsessed by Darwinian competition as the essence of life, there are many other principles that are much more pervasive and important.  We described these at great length in our book MT, and in other papers.  Not only do we argue that cooperation (that is, functionally successful interactions) among many contributing elements is the rule, but the same fact fits with other aspects of life.  Among them are that life, from genes on up, is organized around modular functional units that interact in partially isolated or compartmentalized structures.

The same MT principles are even more deeply, if subtly and even implicitly, at work in surmises about Mars life.  The assumption that we're looking for 'microbes' is that Martians will look like bacteria. This expectation was whetted by the idea, fostered a few years ago, that rod-like remnants of 'microbes' were found in a Mars meteorite named ALH84001, found in Antarctica in 1984. Whether this is biogenetic or biobulldroppings is beyond our expertise.  But the interpretation that it was life rests to a great extent on the tacit assumption that sequestered modularized structures--cells with internal structures that sequester the inside from the outside--is a universal feature of life, wherever we may find it.

The reference to DNA reflects also the assumption that life at the molecular level is a polymer phenomenon--a string of units (assumed to be nucleotides) that are grouped into local, distinct, functional parts).  That means life is not just a reaction among identical molecules, even a 'cooperative' one like the formation of crystals, but is instead based on cooperative interaction.

These kinds of statements about Mars life show the latent assumptions about life, not just or even not mainly about evolution but about how it must be organized. It is an implicit reflection of the kinds of principles we discussed in MT. 

At the same time, it reflects a lack of imagination or much thought.  It is embedded in our current culture, here on Earth, where we are focused on DNA and bacteria as the primitive detectable form of life, because that's what we see here and that's the current theme of the life sciences.

Could life be other than something than this?  And here we mean something beyond the question of whether life must involve carbon or water, etc.  Rather, we ask whether the laws of physics and chemistry mean that to be an evolvable builder of orderly but non-homogeneous complexity--forms built up with variable subunits, the way we are built of cells, organs, organ systems, and populations--must be based on spatial relationships among polymer-like molecules, whose combinatorial presence enables structures to be built.  If that is the case, it is probably a rather profound truth.

And yet, can that be the case?  It would seem not likely, since even our understanding of life as it happened here is that it arose merely as chemical reactions in a primordial soup in some lakes, ponds or oceans.  That is, it was initially some open reactions, not encased in membrane compartments, not diversified based on an array of 'instruction' molecules (RNA or proteins).
 
If not, if there could be very different ways of what we would classify as 'life', then we could be in for some startling surprises as space is explored. And it would show how rooted human thinking is in its cultural context, no matter how objective science tries to be.

Monday, April 23, 2012

Brains are like jelly....and they're fluid, too.

Intelligence is malleable?
Two pieces in the April 22 New York Times Sunday Magazine suggest that the idea that intelligence is fixed at birth has been greatly exaggerated.  We can get smarter if we work at it.  According to one piece, we have to exercise our fluid intelligence, and in the other, we have to exercise our bodies.

Fluid intelligence lifting weights
In 2008, two psychologists, Susanne Jaeggi and Martin Buschkuehl, published a paper in which they reported that young adults who play a challenging game requiring concentration can improve their "fluid intelligence", which the NYT article defines as "the capacity to solve novel problems, to learn, to reason, to see connections and to get to the bottom of things."
Psychologists have long regarded intelligence as coming in two flavors: crystallized intelligence, the treasure trove of stored-up information and how-to knowledge (the sort of thing tested on “Jeopardy!” or put to use when you ride a bicycle); and fluid intelligence. Crystallized intelligence grows as you age; fluid intelligence has long been known to peak in early adulthood, around college age, and then to decline gradually. And unlike physical conditioning, which can transform 98-pound weaklings into hunks, fluid intelligence has always been considered impervious to training.
The inflexibility of fluid intelligence has been the explanation for why we can't do better on I.Q. tests over our lifetimes.  Though, the pesky little problem of the Flynn effect, the sustained increase in I.Q. scores over decades in much of the world, has been a thorn in the side of those who hold that I.Q. is fixed.  And, even if people have never actually settled on what intelligence actually is, the idea that at least we know it's fixed, and that most studies show a considerable amount of heritability, has lead many to believe there must basically be due to the genotypes we're each born with.

Raven Matrix component of IQ test: fill in the blank square
Wikimedia Commons
So, if Jaeggi and Buschkuehl are correct that fluid intelligence can be improved with practice, a result they continue to demonstrate, this is a challenge to the idea that we're blessed or cursed with innate intelligence.  The idea is that intelligence must be similar to other highly heritable traits, like height, which is also susceptible to environmental effects -- even if within each individual's genetic or other constraints.

Mice lifting weights
The second intelligence story in the Sunday magazine comes at the issue from a different angle.  Mice given the chance to exercise get smarter.  Researchers determined this by giving them before and after cognitive tests, as well as before and after assessments of the structure of their brains.  And, as it happens, people who exercise get smarter, too.  Or at least their brains don't shrink nearly as much as they age as do the brains of sedentary people.
For more than a decade, neuroscientists and physiologists have been gathering evidence of the beneficial relationship between exercise and brainpower. But the newest findings make it clear that this isn’t just a relationship; it is the relationship. Using sophisticated technologies to examine the workings of individual neurons — and the makeup of brain matter itself — scientists in just the past few months have discovered that exercise appears to build a brain that resists physical shrinkage and enhance cognitive flexibility. Exercise, the latest neuroscience suggests, does more to bolster thinking than thinking does.
So, forget personalized genomic medicine, to get smart, just bike (or run) to work, thinking about something profound all the way.

Can this really be true?
Of course, Jaeggi and Buschkuehl have their critics.  Some simply don't believe that fluid intelligence is mutable, and studies continue to confirm this view. But J and B aren't the only psychologists who are beginning to find mutability and as a result, other psychologists are starting to believe their work. But, it's an interesting thing when expert assessment of scientific results depends on belief.  And the word is laced throughout the NYT piece.

Indeed, you're more likely to buy their work if you're not predisposed to think that I.Q. is genetically determined.  Well, and if you think I.Q. is real, measurable, not culturally determined and so on.  And where you come down on these issues seems to be correlated with your politics, at least to some extent.  Rather like where you come down on climate change, or evolution, or the genetics of how people vote.

But let's step away from the politics for the moment, and think about what our particular view of evolution might have to offer here.  Specifically, the idea that seems fairly obvious, that evolution has been consistently good at producing adaptability.  Over and over and over again, so much so that it seems to us to be a fundamental principle of life, organisms have been imbued with the ability to detect, evaluate, and adapt to changing circumstances.  So, to us, it's no surprise that our brains, too, can respond to changing circumstances, can respond to environmental challenges by, say, building new neuronal synapses.  It would be more surprising if it couldn't.  And changes in the brain can involve non-cognitive as well as cognitive intelligence -- that is, it need not involve consciousness as it often does in humans and presumably other animals.

Brains and central nervous systems are, after all, centers of evaluation.  Sensory inputs go there, and are sorted through and evaluated, and decisions made on how to respond to them.  The idea, no pun intended, is that the brain is not a pre-programmed, hard-wired automoton, but allows each unique moment to be sifted and judged, and even more, each moment can leave its mark.  Someone whose cognition is too rigid might be much more likely to be a former someone.

Brains have the texture of jello, but they're fluid as well -- food for thought at least.

Wednesday, March 21, 2012

The plot thickens -- you are what you eat in more ways than one

Your genome on lettuce
Banish the thought that you've got complete control over expression of your own genes.  It turns out that what you eat is also a player.  A paper in the April issue of BioEssays, "Beyond nutrients: Food-derived microRNAs provide cross-kingdom regulation" (Jiang, Sang and Hong), reports that not only do we derive nutrients from food, but that food-derived micro RNAs can affect expression of our genes.  Yet another instance of inter-species cooperation.

Micro RNAs are a relatively recently discovered component of the genome that modulate gene expression.  They silence protein-coding genes by binding to transcribed mRNA and preventing its translation.  As Jiang et al. report, more than 15,000 miRNA loci have been found in 140 species, and are annotated in the miRBase database.  These are miRNAs found inside cells, but recently micro RNAs have been found in blood serum and plasma, urine, saliva and other body fluids.  While RNA is known to be easily degraded and rather fleeting, it seems that these circulating RNAs are highly stable, and resistant to the usual destructive elements; RNAses, and high or low pH or temperature.  And, say Jiang et al., these miRNAs seem to be highly correlated with disease, such as cancers and diabetes, and with tissue injury, which suggests they could be of use as biomarkers.

But, the paper only notes this in passing, primarily focusing on these miRNAs as signaling factors.
Despite numerous reports of the detection of secreted miRNAs, the exact mechanisms of how these miRNAs are transported and act as signaling molecules are not clear. They have been implicated in stem cell function, hematopoiesis, and immune regulation. Recently, several lines of evidence have suggested that miRNAs are selectively packaged into microvesicle (MV) compartments to function efficiently in mammalian cells. MVs are membrane-covered vesicles and can be released by various kinds of cells.
It may be that being packaged in MVs is what gives these miRNAs their stability, as they are sequestered from RNAses and so on.  And, the packaging process seems to be selective, as only specific types of miRNAs have been found packaged in this way.

Jiang et al. write that "cross-kingdom regulation through miRNA/double-stranded RNA (dsRNA) has been observed in many organisms and engineered systems."  And, it often alters gene expression in the host organism.  Examples include planaria or other parasitic nematodes, which can take exogenous double stranded RNA into their cells, as do insects when fed plants.
For example, when cotton bollworm larvae are fed on plant material expressing dsRNA targeting CYP6AE14, whose gene product helps the insect to counteract the deleterious cotton metabolite gossypol, the transcript level of this gene is decreased and causes larval growth retardation.
It has recently been demonstrated (and we have to take Jiang et al.'s word for it, because the paper by Zhang et al. is in Chinese, unreadable by us) that "mature single-stranded plant miRNAs are present in the serum and tissues of mammals that use plants such as rice as their food sources."  They verified that these are plant RNAs, and that they survived passage through the mouse gastrointestinal tract intact.
Moreover, the authors identified the low-density lipoprotein receptor adapter protein 1 (LDLRAP1) as a target for MIR168a, a plant miRNA that was present at a relatively high level in human sera. The presence of exogenous pre-MIR168a or mature MIR168a miRNA can significantly reduce LDLRAP1 protein level in culture. Furthermore, feeding mice with rice that produces MIR168a reduced the amount of LDLRAP1 protein in liver, which in turn resulted in an elevation of the LDL level in mouse plasma. Both the decrease of LDLRAP1 and the increase of LDL in plasma, however, could be blocked by the addition of an anti-MIR168a antisense oligonucleotide. These elegantly executed experiments not only confirm the role of circulating miRNAs in intercellular communication, but also suggest that miRNAs can transport and function in a cross-kingdom manner.
How miRNAs would survive digestion and be absorbed is a question but without simple answers.  The first issue has to do with how they survive digestion and absorption across the gut.  A second is why we haven't evolved means to detect and degrade them; after all, our immune system is very able to recognize foreign stuff.  Jiang et al. describe the possible conditions under which plant miRNAs can survive this passage, and we won't replicate it here.  Suffice it to say that they note that plant miRNAs are packaged differently from mammalian miRNAs, and that mammalian intestinal epithelial cells 'somehow' ingest plant miRNAs.  They wonder if there's a receptor or some such on the mammalian cell surface that might recognize plant miRNAs and pave the way.  After being taken up by intestinal cells, these miRNAs then are passed to downstream cells, such as the liver, where they are involved in gene regulation.

There's a lot of hand waving going on here, but if true, this is a thought-provoking example of the synergy between organisms.  As this field matures, you can be sure that potential medical uses won't escape pharmaceutical companies.  

Regular readers may notice that in describing these newly discovered miRNAs, we've invoked a number of principles that we think are at the core of life, and that we've recently enumerated on MT -- sequestration, modularity, cooperation, signaling, chance, adaptability.  It's always gratifying when these principles apply in circumstances that were not known at the time we compiled them. 


Whose genome is it, anyway?
But what about evolution?  If we interact with genes (miRNA are coded from the originating species' DNA) from other species, and in at least many cases we depend on that, then perhaps the view of genomes as all contained within a species' cells is misleading.  Perhaps 'our' genome includes that of E. Coli that we need in our gut, or in each location 'our' genome includes miRNAs from foods we depend on for survival.

Normally, one would expect us to lose genetic mechanisms if they are replaced by something else.  If we depend on exogenous genetic information, then mutations in our own genes that do the same thing would have no selective disadvantage and would disappear.  In that sense, the species' genome becomes joined at the proverbial hip to each other.

Far-fetched?  Well, long ago mitochondria and chloroplasts entered cells and evolved from parasite to necessary cellular components.  miRNA and bacterial genomes and so on aren't so thoroughly incorporated (yet), though some viral genomes are.  So there is probably a gradient of intergenomic dependency among species.  This is an extension of predator-prey dependencies, but is similar in concept, just more localized in genes.

Once again, this discovery (if confirmed and shown to be more than trivial) will add to the causal complexity of human traits.

Tuesday, March 13, 2012

Principles of life, in action

We presented a list of principles last week that we think are generic and help explain much of what goes on in life -- during development, between organisms, and over evolutionary time.  They won't tell you which gene is turned on when, or where the enhancer is that controls its expression -- to answer questions such as these, you need different sets of principles.  But, they do, we think, comprise a list of basic observations about life that are shown over and over again to be true.  The proof of that is the gold standard in science: the principles are, implicitly and explicitly, routine underpinnings and assumptions of daily research in the life sciences.

A couple of papers in last week's Science describing how bacteria adapt to changing environments illustrate this nicely. In their paper, Nicholas et al. undertook to explore changes in the 'transcriptome' (suite of genes expressed at any given time) when the bacterium, Bacillus subtilis, underwent environmental changes, 104 in all, in controlled conditions in their lab.  That is, they set out to characterize 'transcriptome plasticity' in this critter.  They catalogued the genes expressed in every set of conditions, and found 'highly correlated changes in expression', in response to conditions.
Of the previously annotated coding sequences (CDSs), only 186 (4.4%) were not expressed under any condition. Most of these CDSs were of unknown function and predicted to originate from horizontal transfer (SOM 3 and table S3). The 30% of the CDSs most highly expressed under each condition were defined as “highly expressed” (SOM 3). Eighty-five percent of all CDSs were highly expressed in one or more conditions (fig. S3A), but only ~3% (144) of all CDSs were highly expressed under all conditions, indicating that most B. subtilis genes are differentially expressed. Genes in the latter group encode proteins with essential functions and enzymes involved in glycolysis, iron sulfur metabolism, and detoxification pathways.
That is, a small percentage of genes were always expressed, another small percentage of genes never expressed, and the large majority of genes were highly expressed in at least one environment.  These facts show the modularity of genomes and differential combinatorial context-specific usage,  which implies various kinds of internal compartmentalization (effectively, the sequestration of components), even in  simple bacteria.

They also analyzed promoter regions, and discovered that about 46% of all genes can be transcribed from more than one promoter.  And:
We comprehensively mapped transcription units (TUs) and grouped 2935 promoters into regulons [reglators of groups of genes] controlled by various RNA polymerase sigma factors [transcription initiation factors in bacteria that facilitate RNA polymerase, the enzyme that enables the stringing together of nucleotides into RNA, to bind to gene promoters], accounting for ~66% of the observed variance in transcriptional activity. This global classification of promoters and detailed description of TUs revealed that a large proportion of the detected antisense RNAs arose from potentially spurious transcription initiation by alternative sigma factors and from imperfect control of transcription termination.
That is, a considerable amount of transcription is imprecise (what we've called 'slop').  For example,  transcription of coding regions often extended beyond the boundary of the gene, and this produced antisense RNA (asRNA), rather than protein-coding RNAs.  But, they propose that these 'spuriously' produced asRNA's may actually have a biological role, sometimes in gene regulation.  Thus, slop turns out to be an important part of life.  And gene regulation is a combinatorial phenomenon that involves some sorts of context-specific balance among factors.  Combinatorial causation (one can say via 'Boolean' logic if one is familiar with computerese) is fundamental even to bacterial life and eology.

Among other things, the authors conclude that their analysis "revealed that asRNAs generated by inefficient control of transcriptional events might be a drawback of [transcriptional plasticity], though they might contribute to the creation of previously unknown regulatory functions."

Buescher et al. also analyzed changing conditions on Bacillus subtilis, in their case, food -- glucose and malate, sources of carbon for these bacteria -- to try to understand the interaction of regulatory and function networks in the cell.  As described in the commentary to these two papers, Buescher et al found that:
Most genes were differentially expressed, and 127 out of 154 transcription factors changed their activity during one or both shifts. Changes in carbon metabolism during both shifts were mediated largely by altering the abundance of a small number of proteins. Although both nutrients are preferred carbon sources for B. subtilis, adaptation to glucose availability was slow and largely controlled transcriptionally, whereas adaptation to malate was fast and primarily regulated posttranscriptionally.
And,
To achieve adaptation, B. subtilis makes some compromises. The observations of Nicolas et al.suggest that transcriptional plasticity is often associated with imperfect control, leading to the generation of antisense RNAs. This may arise due to aberrant termination of transcription, or spurious transcription initiation while using alternative sigma factors. Similarly, the results from Buescher et al.suggest that, depending on the prevailing environmental condition, the preferential uptake of one carbon source over the other might confer condition-specific evolutionary advantages in growth. This is achieved by active regulation or constitutive expression of several genes—two distinct strategies, neither of which is advantageous per se. Thus, to adapt to changing environments, B. subtilis makes a trade-off between the implementation of complex regulatory programs and imprecise regulation.
So, how does this illustrate our principles?  Here's the list again, briefly, but the annotated list is here.

1. Inheritance with memory
2. Modularity
3. Sequestration
4. Coding and interaction
5. Contingency
6. Chance
7. Adaptability
8. Cooperation

Inheritance with memory is why B. subtilis, as any organism, are what they are generation after generation, and why they have predictable responses to environmental changes. Modularity is obvious throughout; regulatory regions, genes, cells themselves are all modules.  And cells are sequestered, but not completely, which is why they can detect the environment and respond to changes.  Coding and interaction are fundamental aspects of gene expression,  of course, and which genes are expressed is contingent upon environmental conditions.  Chance comes into the picture in how reliably gene transcription takes place (not always reliably), and indeed, in what environment the bacteria must respond to when.  And it all involves cooperation among genes, regulatory elements, and so on.

We think it's important and worthwhile to try to itemize principles like these, not because we feel we have made any sort of 'discovery', but because in the search for principles of life, there are twin thrusts, one being molecular biological reductionism, and the other being overly simplistic deterministic effectively one-gene or gene-for causal and evolutionary thinking.  The latter leads to a focus on competition when the principles in the format that we try to enunciate them show how much more life depends on cooperative (coordinated, jointly functional) rather than competitive interactions.

Thursday, March 8, 2012

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.....

Wednesday, March 7, 2012

An apt description for how life works is: Slop! Part I

From Darwin's time to the present, theories advanced to explain the nature and evolution of life have generally attempted something that is law-like, precise, mathematical, and universal.  But they all have essentially failed--not as apt descriptions of aspects of life or instances of evolution, but as generalizations with the kind of precision expected of 'science'.

Genetics, being molecular, strikes many as the underlying domain where the precise laws of life occur.  If molecules and energy are the fundamental constituents of all of existence, then this must be so about life as well.  It seems to many to be a reasonable deduction that whole organisms must therefore be complex embodiments of the diktats of their genomes.  What is written in the DNA is often treated, even despite some casual caveats to the contrary, as written in stone: your fixed destiny!

But upon close examination this is just not how things generally are.  The causal aspects of life comprise a spectrum, a panorama ranging from very strong causation that largely fits the dreams of simple theoretical biology, to a large amount (we would say certainly the majority) of causation that is aggregative, cooperative, weak, statistical and hence probabilistic, and for which we do not have rigorous theory of the kind that chemists do.

In fact, since life began just as some sort of bubbling chemical reaction in the primeval 'soup', it has become 'life' rather than just a chemical reaction, because it developed sequestered regions (that eventually became cells, organs, organisms, and species) that internally had various interactions but became both isolated and different from other such regions.  The patterns of difference were generated by the evolutionary processes whose key characteristics include that it has no plan, and no pre-set direction.  There is no theory for what will evolve, only some generic processes.

At the level of individual molecules, molecule A interacts with molecule B just as is taught in chemistry class.  There is no violation, that we know of, of the laws of chemistry just because the molecules are found in a living cell.  Molecules are molecules.  The same individual biochemical reactions can in fact be produced in the proverbial test tube, and those of us in life science research achieve such miracles routinely every day.  But there are so many different types of molecules, at different concentrations, times, and locations even within a single cell, that the net results are not so simple.  They don't just add up like the sums of the prices on your grocery list.

For one thing, there are always chance aspects to whether two molecules will bump into each other or interact (as taught in chem class).   But things are not uniformly distributed even within a cell, the way they are in class.  Unlike a soup, there's nobody to stir them to make them mix evenly.  Life is in a sense about not mixing evenly.  So a very large number of probabilistic aspects of chemistry are relevant to the net result.

The overall result is different from a simple sloshing solution for very key reasons that go beyond just differences in concentration of ingredients.  This is that living reactions are hierarchical: what happens now depends on what happened just before, which depends on what happened just before that, in a chain that goes back 3.8 billion years of continuous contingencies!  Some individual reactions are, again as they teach in chem class, reversible.  But the hierarchy from conception to death, or differentiation of cells from one state to the next, is typically not reversible (for example, making stem cells from other types of cells is a form of such reversal, but engineered from the outside, not by the cell itself).

Any major biological function is a mix of such hierarchies with their own complexities, time relationships, and contingencies.  In some situations there are ways of going back, but in many this is not the case.  In particular, it's generally not the case with evolution: commitments get made, hierarchies get established, and they are too interwoven for Nature to do much backpedaling.  But the origin of these complex, hierarchical wefts and warps was haphazard in that, unlike a human weaver, it had no pattern or future use in mind (it had no mind!).  Hierarchies build up over time, that become too complex to be viable if they were to 'try' to reverse course.

Then why do things seem so orderly -- so tempting to develop nice, neat equations for life the way Einstein had a ridiculously simple equation for the entire universe (e=mc^2)?  Or the simple formula for water (H2O), so simple that we can tell where in the vastness of space water may exist just by knowing the formula?  The reason, in a phrase, is that while life is sloppy in the above ways, it is divided into units with enough members, and the members are closely related enough, that there are what can be called 'central tendencies'.  Individuals who are each a mix of huge numbers of components, like molecules of a certain kind, or copies of a protein coded by some gene, each variable but only up to an extent, can themselves vary among each other, but only up to an extent.  Humans vary, but not enough to ever be confused with rabbits.  Body temperature varies but only within a recognizable mammalian range (and when too far off, we can understand why it is a 'disease').

So, orderly slop is the order of the day for much of life.  The orderliness is rather loose, not at all like the orderliness of water molecules, the speed of light, or the pull of gravity.  It follows general principles generally, and at various levels follows basic physical and chemical principles rigidly.  But life is an evolutionary phenomenon based on divergence and difference.  It is not like a crystal that may grow, but only within very constrained bounds.

This is why, unsatisfying as it may seem to someone suffering from physics envy, the laws of life are frustratingly elusive--even if there are such 'laws'.  And yet, if one stops expecting and starts understanding, life is very orderly and understandable, taken on its own terms.  That's what makes it life!

What one would expect, and what one sees very clearly, is that the soup became slop:  very organized in some ways, wholly consistent with the laws of physics and chemistry, but not orderly and rule-following in the way of the physical sciences.  Tomorrow we'll offer some general principles, that we think go a long way toward explaining -- and predicting -- the orderliness as well as the slop in life.

Thursday, July 28, 2011

Mendelian Inheritance: Basic Genetics or Basic Mistake? Part IV

So, if we are right that 'Mendelian' inheritance is fundamentally mistaken--or, at best, generally inaccurate and misleading--then what kinds of conclusions can we draw and how can some of the basic attributes of life be accounted for?  We have to assume that life evolved and that to a great extent means genes, broadly defined.  Indeed, we may be worse off than we think if, as we tried to show in an earlier post, even what a gene is, is elusive with current knowledge.

Waterhouse, A Mermaid
In our book after which this blog is eponymously named, we argued that there has been too much attention placed on evolution (and a competition-centered view of life at that), relative to the more ubiquitous properties found at life's other time scales--of development and maintenance of an organism, and of the interaction of factors on the ecological scale.

The idea of Mendelian inheritance, which is widely extended to the vast majority of gene-trait relationships that clearly are not following the monk's principles, is of discrete states one of which dominates in their various combinations.  This was (and is) extended to evolution, with our grossly inadequate 'winner take all', 'survival of the fittest' notion of one best -- fitness-wise dominant -- variant that natural selection favored into success just as surely as a dominant allele was favored ineluctably into manifestation in the organism.

But if you think of the other properties of life, which we center our book around and will briefly name here, you might ask how Mendelian thinking, which only by deep contortions can be related to those principles, could ever have taken hold, unless it's by what amounts to an ideology, a takeover of a certain highly deterministic, simplistic view of the living world--a view that simply, for decades, wrote off into alleged irrelevance the actual way in which organisms work.

Sequestration and modularity
From DNA on up, life is organized as hierarchically nested partially sequestered units.  DNA has functional sequence elements arranged  together along chromosomes, but partially isolated in that they can serve their individual functions.  The units (such as amino acid codons) are repeated many times.  Proteins have partly separated functional units, too.  Cells are packaged units that have many different partially isolated subunits within them, such as organelles like mitochodria, isolated areas like the nucleus, and local differences in what is present in the cell membrane (e.g., a cell may have a front and back end, so to speak).

An organism (or even collections of organisms as in bacterial biofilms) is made of large numbers of cells.  These are repeated units that communicate with each other via combinations of signaling and other molecules, and this is what leads them to express particular, context-dependent sets of genes.  So that they are repeated, but different.  This process occurs hierarchically during development, and in response to environmental changes during life.  An organism is divided into organs and organ systems, like brain, heart and vessels, digestive organs, and so on.

Organs are made of nested, repeated units.  Intestines are segmented along their length, and their surface is littered with repeated structures called 'villi'.  Skeletons are made of repeated, partially different but interaction bones.  Trees are made of leaves and so on.  Plants and animals alike are constructed by repetition and branching.

Yet, importantly, each organism has only the one genome that it inherited from its parents!  So the same genome makes brains and braincases, that are as different from each other as any two things in all of life.

These processes are both qualitative: each leaf or bone is a separate structure; and quantitative: each such structure is somewhat different.  This is the natural variation that is the material on which evolution can work.

If you just think about this, you would have to wonder how it could be brought about by Mendelian inheritance.  How could just two states at a single gene be responsible for such complexity and quantitative internal organization?

It is perhaps easier to see how breaking a gene could cause a major state change, and thus a normal and dead alternative at a gene could be manifest in Mendelian inheritance terms.  Or if the trait is very close to a protein coded by a single gene, two major alleles (variants) at that gene could have big differences (yellow vs green peas, for example).  But as a rule, Mendelian inheritance makes little sense.  Partly that's because, as mentioned in earlier parts of this series, we confuse inheritance of traits with inheritance of genes.  Genes--specific stretches of DNA--are clearly inherited in a Mendelian way (with some exceptions that don't matter in this context here).  But traits generally are not.

The reason for all of this is that the basic principles of life, that include the above descriptions (see our book for detailed discussion in this context), involve cooperation--that is, co-operation or contemporary interaction--among many different elements, each of them variable in a population.  What an individual inherits are sets of genomic variants from its parents.  The traits an individual manifests are the net results of these variants acting in the particular environments in which they find themselves.

Tuesday, May 11, 2010

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-beta, 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.

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.