Complexity made simply--and reversals, too

A pair of encouraging gene-manipulation stories were reported in the New York Times on Friday (the graphic is from the story).  Essentially, two groups have found ways to de-differentiate specialized cells so that they become able to go down developmental pathways their cellular ancestors did early in the individual's life (or, perhaps, new paths that that cell lineage never took).

Producing various sorts of 'stem' cells is a major goal of modern medicine.  In principle, it will allow the regeneration or even cloning of a patient's damaged organs, with cells from the same individual.  Unlike other therapies, this will not generally lead to tissue rejection (which usually is only of foreign cells), nor will it require removing something, like a ligament, from elsewhere in the patient, to use as a replacement ligament elsewhere in the body.

The problem is that most cells in an adult are fully committed to their current function.  They are functioning stomach, lung, or muscle cells.  As mature differentiated cells they can't do other things, because those require a different set of genes to be activated (or inactivated).  For a muscle cell to be used in lungs its gene expression would have to be that of a cell that lungs use, and that often means of a cell earlier in lung development than the type of cell the therapist needs.

Most vertebrate tissues are made of a series of partly committed stem cells--say, cells in the blood-cell, or lung, or intestinal lineage--that when called upon will differentiate into final functional cells of that organ, known as terminally differentiated cells.  The latter typically can no longer divide.

If organ-specific stem cells can be made more generic, behaving like cells early in the embryonic lineage, or if organ-specific differentiated cells can be made more like that organ's stem cells, then transplanting healthy cells from a patient back into the patient could regenerate healthy tissue to replace damaged tissue.

The studies reported did that in two different contexts.  While still experimental, they're another example of the productive road developmental-genetic research is making possible.  What one group of  investigators did was block the expression of tumor-suppressor genes, which freed the cells to begin to divide.

Finding the right combination of genes to suppress was a critical step in the new research. One of the two tumor suppressor genes is an ancient gene, known as Rb, which is naturally inactivated in newts and fish when they start regenerating tissue. Mammals possess both the Rb gene and a backup, called the Arf gene, which will close down a cancer-prone cell if Rb fails to do so.

The Stanford team found that newts did not have the Arf backup gene, which mammals must have acquired after their lineage diverged from that of amphibians. This suggests that the backup system “evolved at the expense of regeneration,” the Stanford researchers in Friday’s issue of Cell Stem Cell.

The Stanford team shut off both Rb and Arf with a chemical called silencing-RNA and found the mouse muscle cells started dividing. When injected into a mouse’s leg, the cells fused into the existing muscle fibers, just as they are meant to.

The second group of investigators has found a way to transform heart fibroblast cells in a mouse into heart muscle cells, the cells that a heart attack destroys, bypassing the embryonic stem cell stage.

Both of these methods for reprogramming cells reflects something important about life and it was a major topic of the book after which our blog is named.  What it shows is that complex, differentiated tissue is produced by processes of gene expression and response--signaling in generic terms.   Because signaling is a hierarchical process in which response to one signal leads to subsequent signals and response by and between cells, a few changes in signal timing or intensity can lead to complex changes in cell behavior.  Since cells in a tissue communicate to affect their differentiation, simple processes can have what appear to be complex effects:  Complexity made simply.

Understanding this (we think) greatly helps account for the ability of evolution to generate 'complex' traits, the polygenic nature of such traits which might seem antithetical to simplicity, and the  misrepresentation or culpable misunderstanding of the evolution of complexity by the 'Intelligent Design' people.

A few changes in a few processes can make substantial changes in a trait, or evolve some new trait.  Yet many genes are involved in signaling, so that their individual variation can yield trait variation, the kind of small variation GWAS (genomewide association studies) are picking up.  But over long time periods, increasingly complex, integrated traits can arise.

Since signaling interactions are the essence of life, there is every reason to hope that signal manipulation can be a major productive goal of modern medicine, especially regenerative medicine but probably much beyond.  The current articles show steps along that path.

More education investment should be in K-12, not college

Bob Herbert, columnist for the NY Times, writes on Aug 7 some oft-heard views about the downsliding of American education.  The central complaint for this has come to be represented by the percent of the population with a college education.  President Obama waves this figure around often. By that metric, the US is now 12th in the world.   This is said to be evidence of the need for quick remedial action, if not actual panic.

The basis of the panicky reaction is that we're not able to compete in the world.  Other countries are outpacing us.  Industry will falter -- geez, we might even produce fewer investment bankers!

But is that the right reaction?  Or is this a misrepresentation of the real problem that we face?

College degrees have progressively become items of status display, and our society more credentialist.  You need a degree to get jobs that pay more than minimum wage, you mention your degrees at parties (and groan at the insistence by which others there make sure you know of theirs).  Actual achievement sometimes takes a back seat to this kind of score-counting.

At the same time, colleges and universities have progressively become industries, advertising and reinforcing these attitudes about how important and necessary their product is, and doing their best to lure customers.  Even online quasiversities are doing a land-office business.

But the real problem is the lack of earlier education, and lack of stress on the importance of training, at young ages, of people for many of the jobs for which there is a real demand.  Not all of them require what we think of as a 'college' degree.  With proper reform of K-12 we would 'need' a lot fewer college degrees.

A college degree is not so obviously what its image, carefully fostered by the university industry, makes it seem.  Many if not most college degrees involve rather minimal formal or rigorous training.  Classes have become increasingly events to entertain student-customers, attendance dropping or not rigorously insisted on, students majoring in the softer or more quick-money based subjects, remedial courses for the unprepared, and the core technical parts of many subjects (perhaps what industry most needs, but harder to learn and teach) have been watered down to suit these poorly K-12'ed students.

If you want properly trained, industrious graduate students, you'd better recruit them from China or India.  Don't bother with Americans, especially black, Hispanic, or Native Americans who've been through our public education system.  They simply aren't up to speed or aren't interested, and they won't help out on your grants nearly as 'productively'.  And, again partly because of our poor investment in K-12, we're not investing nearly enough in those parts of our society at the college level either -- not to mention that as the cost of college continues to increase, its accessibility to the poor continues to decrease.

Of course these are generalizations and there are certainly exceptions to each of these issues.  Every class in every college or university has skilled, interested students.  But what we need are more people with more technical skills, including computer programming, mathematics, electronics, manufacturing technologies and the like -- even repair and maintenance.  Some of these require post-high school training, or even college degrees (if the college insists on rigor, but not all of them do).

The post-WWII boom in US college training occurred in a day when colleges and universities had much higher standards, and had only been enrolling a small fraction of the population.  Perhaps also, and debatably, a broad liberal arts degree prepared you for analytical thinking and hence all sorts of not purely technical employment.  But colleges were not just tuition-mills; they didn't hesitate to flunk out students who didn't measure up.

By the time one was a senior, s/he was at least something of an expert in her major field, and often broadly knowledgeable beyond that.  It wasn't Nirvana, of course, and there's a ton more to learn now, in the case of science particularly.  But the weakening of standards is at least as important as the number of degrees.

In genetics, molecular, developmental, and evolutionary biology various skills are important.  Among them are statistical tools and understanding of probability.  So much is now computational, that mathematics and computer programming should also be part of life-science majors -- and indeed students should learn at least some of this in high school.  But many upper level students even at good universities claim they chose to study biology so they wouldn't need to do any math.  Try teaching them as seniors!

It's even true that standards for getting a PhD or other higher degrees have declined widely if not universally.  Getting, or keeping, a faculty job rests ever more heavily on bean-counting and formal credentials: number of publications, lists of 'research', amount of grant money brought in.  Yet it is trivially easy to show how little most published research is cited by anybody but the authors and their friends. Meanwhile, in many 'research' universities, teaching is given lower status relative to career advancement and, you guessed it, getting grants and paper-counts more.

Higher education is important in the age in which more of our lives hinge on science and technology, on interpreting research data and acting in 'empirical' ways ('evidence based medicine' for example), and on rigorous education, in classes you can actually flunk if you don't do the work well or show up to class.  We do have a real need for higher education, but skill and ability can come along in many forms, and many types of school.

And that means we need to be training teachers in real subjects, not just bulletin board technique and counseling -- and paying them better, so that better students choose to become teachers.  That is a major part of our problem. 

Every system has its false fronts, and it's always easy to find real faults because they always exist.  If our national needs could be served by making college mandatory, they might be satisfied if the standards were higher.  But if the standards were higher, we wouldn't need to rely on, much less idolize, formal credentials, like college diplomas.  And we wouldn't think we simply needed more of them.

The university industry might suffer, for example, by having to shrink while tech schools grew and K-12 received more of the nation's education funds.  But every industry can become self-satisfied and bloated, and the college industry is that way these days.  So it's misplaced to simply say we need more college-educated citizens.  Just delete the word 'college' and you're closer to the truth.

Here we've not mentioned any of the over-arching objectives of college education: exposing students to things they'd never think of otherwise and hopefully enabling them to be better citizens or having more richly edifying lives.  Those are lefty political considerations, perhaps.  We happen to believe in them, but they are partly beside the points we want to make in this blog, which is about science.

A remarkable story, and another croc -- of teeth!

Nature reports what appears to be a remarkable find, and this time the remarkableness isn't a crock.  It's a roughly 150 million year old Tanzanian crocodile fossil that has a dentition that is remarkably like modern carnivorous mammals--Lassie and Tabby.

Most reptiles have a row of continuously replaced peg-like teeth.  They may vary in size but as a rule they don't vary much in shape.  This is called a homodont dentition--all the same.  There are no separate sets of adjacent teeth of a given type, like our heterodont incisors, canines, premolars, and molars.

Mammal teeth vary depending on diet and other uses, such as threatening displays and fighting.  Incisors are used and presumably evolved by and for nipping, canines for goring or fighting, molars for grinding.  Mammals that don't fight with their teeth, like grazers, don't have much if anything in the way of fang-like canines.  Dogs and cats have shearing molars rather than the flat, bumpy grinding molars of grazing animals.

But the O'Connor group found that their crocodilian fossil has threatening canines, followed by a set of small grasping teeth, followed by larger, sharp shearing teeth.  This appears to be a clearly heterodont dentition and one associated with carnivorous diet.  If the findings hold up, this is very interesting because on first glance, at least, it shows that complex, highly ordered segmentation can evolve repeatedly in very similar ways and, presumably, in response to similar causes--a predatory diet.

As we point out in Mermaid's Tale, complexity of this kind can be made simply, and not requiring tons of new genes to arise--maybe not any new genes, just changes in gene regulation.  It instead seems to be achieved by altering the parameters of the patterning process, that sets up spots where teeth (or hair, or feathers, or scales, or color spots, or mammary glands) will grow, separated by spots where they won't.  The parameters have to do with the timing and level of expression of genes that serve as signaling factors for cells, in this case along the future tooth rows.  Altering of a small number of genes' expression patterns to set up regions of differential growth and growth rate, regions of different lengths or widths, can do the trick. Whether the same genes that many of us have studied in mammalian teeth (in our case, in mice) are involved, or different genes, remains to be determined.  But our bets would be on it being largely the same genes.

Very interesting and very revealing, yet again, of the nature of evolutionary processes.  Here's one croc that's not a crock.

The evolutionary restaurant: Silliness now, and tomorrow

On our long driving trips during this week's travels, we heard several Hot New Insights on the various radio programs (mainly on the BBC) that we listened to, to pass away the miles.  Among other things, we learned of a few culinary discoveries that merited media attention:

     - First, humans became smart because they cooked their food.

     - Second, we like salt, sugar, and corn syrup because these tastes evolved when we were hunter-gatherers 10,000 years ago (then agriculture was invented), though these foods were hard to get back then.  We now prefer to overdose on junk food because of our hunter gatherer 'supra instincts' -- but we can train ourselves to like leafy greens and other (organic) vegetables within two weeks.

     - Third, breast-feeding is good for infants and should be encouraged in a global campaign, led by a famous model.  It may be a surprise, we guess, that humans evolved doing this!

But for a few details (most of point #2, e.g.), these culinary discoveries may be true.  But they could be just this generation's punditry, taken seriously by hungry not-very-critical journals and media.  How might we know?

One way is to look back at was said in the past.  If you go back a generation or more, and look at what scientists and the media were saying then, it's easy to judge many of our forebears in science to have been childlike in their simple naivety.

A second way to evaluate what passes for deep evolutionary wisdom in the mediasphere is to think about what is being said for at least, say, a nanosecond.  Point #1 depends on early hominids having control over fire very early in our evolution, for example, and they'd have to have been eating predominantly cooked foods for it to be enough of an evolutionary force. Our brains were already getting bigger before we invented the Weber barbecuer.

The idea that our hunger for McFoods reflects our ancestral dietary history is odd if our deep 'instinctive' cravings really can be changed in two short weeks.  We may have biological hungers for such things 'because' they were not particularly easy to come by in our past, but if they were rare then they must not have been vital to our success.  And hunger for such things predates humans.  The fact that advertisers play on our innate hungers need not have any particular evolutionary importance.  And if new cravings are so easily learned, who's to say that our McFood cravings weren't taught to us in a few short weeks when we were young?

The idea that breast-feeding is beneficial is news to the general public only if it's something that's not been in the media recently, in a society that spurns and forgets about anything that's more than a month or two old.  The same arguments were hyped all over the place by the same pop-culture media only a generation ago (but old books don't make profits for today's authors or professors).  Advocacy by many authors, the La Leche League, the internal campaign against Nestle's, and many others were common and advocated for the same reasons, within memory. 

The rediscovery of breast-feeding may indeed be based on important points about breast-feeding, but it is not comforting to see how comparably confidently these points were advocated as newly deep insights in the not-so-distant past.  

The important point is to be critical judges, especially when evolutionary just-so stories are being told.  This is not only because they're mostly just that, just-so stories that are not confirmable if they even stand up to critical examination.

All precedent suggests that today's punditry is going to look naive and silly a generation from now (except those things that will be breathlessly asserted again, as if they'd never been said before).  And if we can't tell what will look silly, or we can know that most of what we say and believe will look silly, why do we take any of it seriously today?

A more general question is how we can know which things of those that all of us assert today have any depth of truth or sticking power?  Surely some of what we conjecture about the past is true, but almost as surely, we have a devil of a time knowing what it is, and self-interest and gullibility allow us to accept much that we should be more circumspect about.

There are often if not usually aspects of middle-class short-sightedness in these kinds of statements, too.  Fast food may be making people overweight, but it is important to remember that even if this leads to disease later in life, most people didn't live that long in our not-so-idyllic hunter-gatherer ancestry.  We might legitimately wish to live even longer and more healthfully, but junk food is not 'poison' in evolutionary perspective.  It's actually rather nutritious--if we were doing something other than sitting on our duffs watching mindless television all day long.....

Taking the cat out of MCAT

Here's an interesting story from the NY Times that appeared while we were out of town.  It's about an idea that cycles around once a generation or so; medical schools that admit a few students who have not taken organic chemistry or physics, nor even their MCAT qualifying test. A study has found that the humanist med students did as well as the driven pre-med majors did. Perhaps they were even better, more sensitive and less techy docs.

These artsy admittees were good students, not just goof-offs as undergrads, but they were not cookie-cutter students after high GPAs come what may, or walk over whosoever's in the way. If any reader has trained pre-meds, we need say no more.

It's partly the system. The pre-meds know they need the courses, the grades, and the MCATs. Rote over reason is a well-known path to those ends. Universities treat their pre-meds (and other pre-health science students) like soldiers. Standardized interviews with faculty are done, so only one standard evaluation form need be sent out to all the schools the student applies to. To do well in this interview, the student has to have a record of 'service' activities--clearly padded for that purpose in many cases--and talk a good game about why they want to be doctors.

They know the game, and they game it! Of course, there are always the fraction of truly dedicated, devoted, honorable, broadly trained people who you want to help into the best med schools. You hope one of them will be carving on you when you undergo your next surgery.

Can the fraction of those kinds of people be increased? The idea of breaking down the gamed, cookie-cutter system seems like a good one. If students knew that thinking, not just knowing 'the answer', would be rewarded, they might be better students, more worthy of faculty time and effort. And they might be better judges of complex phenomena like health--better able to evaluate complex data and literature, and more likely to understand patients as people.

Of course, medicine is an advanced art, properly technical in many ways. But if the hyper-competitive, hyper-technology drive undergraduate student can be rewarded for thinking more synthetically, we might get better medical care, and they might have more broadly rewarding lives, too.

Darwin's barnacles: The boringest book...with the sexiest story ever told!

Charles Darwin was a prolific author of long books. Other than a few, these are now dusty tomes in the reserve annex of university libraries (they're also now available on line, fortunately).

The Origin of Species and a couple of others are good reading, and show the enormity and thoroughness of Darwin's mind and method. He covered the waterfront, from orchids to earthworms. But less well known and hardly read is the way he covered the waterfront's huge population of barnacles. A fairly recent book, Darwin and the Barnacle (Stott, 2003) is about Darwin's fascination, if not obsession, with barnacles, but if you actually try to read Darwin's four barnacle volumes from scratch you'll find them as dry as an Iraqi sandstorm. Most of Darwin's books are dense compendiums of facts, but the barnacle books are more like telephone books than narratives.

At the same time, they tell an incredibly fascinating story, and Darwin was well aware of it (and his letters show that they were far from boring or dry material to him). In fact, while he deals with many issues including species relationships and anatomy, the most fascinating part of the barnacle story is their bizarre, and highly variable reproduction. It's as near to a natural X-rated story as you could image.

Most barnacles are hermaphrodites, carrying both male and female sex organs. But they can't self-fertilize and must mate with nearby barnacles. For this, males in some species have the longest penises in relation to body size that are found in nature (or they may have multiple penises!). Some barnacle species are only partly hermaphrodites, having degenerated organs of one sex or the other. Yet others, discovered by Darwin to his utter amazement, have males as parasites living within the body of the female, which in some cases only have retained a partly hermaphrodite body! In some, these 'husbands' are so rudimentary that they're little more than sex organs.

Darwin noted that in the countless species of barnacles, every trait in every species was variable. He used the data on variation to determine barnacle phylogeny: their relative relationships and order of evolution. By looking at contemporary species with various stages of sexual reproduction strategy, he inferred that some stages, such as live-in husbands, and degenerate husbands, represented stages along the way to being non-hermaphroditic.

The complexity and variation among species must also be found within species, in order for the traits observed today to have evolved over time -- the trait must have varied within species so that today's form would gradually become the standard for that species.

Darwin was trying to solve the species (or 'transmutation') problem of his day. But his very sexy story also reveals the problem of reconstructing adaptations. Darwin assumed that different stages he saw in different species were traits along the way to some final trait. But that's not necessarily so and it nearly assumes predestination, a total no-no in evolution. Just because a species of barnacle has host-husbands does not imply that it, like some other existing barnacle species, is on the way to having only rudimentary husbands or to losing hermaphroditic structure. Or, at least, such arguments about how predictable evolution is are highly debatable based on what we know today.

Darwin is great reading, as a way to see a great mind at work. His utterly dull but sexy barnacle books show some of the problems we face in reconstructing selective stories from the past, because when so many traits vary at the same time, over so much time, it's hard to know why each stage on the way was favored by selection. This is especially true because we can only tell so much from fossils.

Maybe everything in life, even everything totally boring, eventually boils down to sex. But whether HBO can make an exciting film about barnacle bedroom behavior is unclear.

Free range goats and chickens at Polymeadows Farm

Sunday afternoon--
We are up at Polymeadows Farm for a few days, and taking a couple of days relief from browsing the latest and greatest evolution and genetics news.  Hopefully no major breakthroughs will be missed, and the world will still be more or less as confused as it always is when we get home.

In one afternoon we've moved one goat pen, shooed a bunch of errant goats back into their barns twice, packaged and labeled 40 gallons of yogurt and 15 gallons of milk, and washed down the dairy plant twice.  Melvin has been out mowing and baling hay all afternoon, and Hank and Ashley stacked as many new bales in the hay mow as they could before the chain on the elevator to the hay mow broke.  They are fixing it now.  Jennifer worked in a tour of the farm for a couple of agritourists and we went into town to get chocolate for making chocolate milk tomorrow, and up to the farm store to get corn for dinner.    Dinner and then evening milking yet to do.