Jonathan Wells recently gave a talk in Albuquerque at something called the “Forum on Science, Origins, and Design”, a conference about which I can find absolutely nothing on the web. I wasn’t there, of course, and I don’t get invited to these goofy events anyway, but I did get a copy of Wells’ powerpoint presentation from an attendee. It’s titled “DNA Does Not Control Embryo Development” — shall we look at it together? It’s really a hoot.
Usually, Begley is reasonably good on science, but her latest piece is one big collection of misconceptions. It reflects a poor understanding of the science and of history, in that it confuses long-standing recognition of the importance of environmental factors in gene expression with a sudden reinstatement of Lamarckian inheritance, and it simply isn’t — she’s missed the point of the science and she has caricatured Lamarck.
Some water fleas sport a spiny helmet that deters predators; others, with identical DNA sequences, have bare heads. What differs between the two is not their genes but their mothers’ experiences. If mom had a run-in with predators, her offspring have helmets, an effect one wag called “bite the mother, fight the daughter.” If mom lived her life unthreatened, her offspring have no helmets. Same DNA, different traits. Somehow, the experience of the mother, not only her DNA sequences, has been transmitted to her offspring.
That gives strict Darwinians heart palpitations, for it reeks of the discredited theory of Jean-Baptiste Lamarck (1744-1829). The French naturalist argued that the reason giraffes have long necks, for instance, is that their parents stretched their (shorter) necks to reach the treetops. Offspring, Lamarck said, inherit traits their parents acquired. With the success of Darwin’s theory of random variation and natural selection, Lamarck was left on the ash heap of history. But new discoveries of what looks like the inheritance of traits acquired by parents–lab animals as well as people–are forcing biologists to reconsider Lamarckism.
She’s describing real and interesting phenomena, but it isn’t new and it isn’t revolutionary. These are results of plasticity and epigenetics, and we aren’t having heart palpitations over them (you’re also going to have a difficult time finding any “strict Darwinians” in the science community who are even surprised by this stuff). We load up pregnant women with folate and maternal vitamins and recommendations to eat well, and we tell them not to get drunk or smoke crack for a few months, because it is common sense and common knowledge that extra-genetic factors influence the health and development of the next generation. Genes don’t execute rigid, predetermined programs of development — they are responsive to the environment and can express radically different patterns in different contexts. The same genes build a caterpillar and a butterfly, the difference is in the hormonal environment that selects which genes will be active.
It’s the same story with the water fleas. Stressed and unstressed mothers switch on different genes in their offspring epigenetically, which lead to the expression of different morphology. It’s very cool stuff, but evolutionary biologists are about as shocked by this as they are by the idea that malnourished mothers have underweight babies. That environmental influences can have multi-generational effects, and that developmental programs can cue off of the history of the germ line, is not a new idea, especially among developmental biologists.
This is just wrong on evolution:
Water fleas pop out helmets immediately if mom lived in a world of predators; by Darwin’s lights, a population of helmeted fleas would take many generations to emerge through random variation and natural selection.
It misses the whole point. The population of water fleas have a genetic attribute that allows the formation of spines under one set of conditions, and suppresses them under others. This gene regulatory network did not pop into existence in a single generation! If it did, then Begley would have a big story, evolution would have experienced a serious blow, and we’d all be looking a little more carefully into this ‘intelligent design’ stuff. The pattern of gene regulation was the product of many generations of variation and selection; only the way it was expressed in a phenotype experienced a shift within a single generation.
It’s also not Lamarckism. It’s another of those short and simple-minded myths perpetuated by high-school textbooks that Lamarck and Darwin had competing explanations for the same phenomena. They did not. This story of giraffes stretching their necks is an example of the purported inheritance of acquired characteristics … and here’s some headline news, Darwin proposed exactly the same thing! Darwin did not have a solid theory of heredity, and he himself proposed a mechanism of pangenesis which permitted the inheritance of characters by use and disuse and by injury or malformation. The key difference is that Darwin proposed that these variations could lead to the formation of new species; Lamarck believed in the fixity of species, and thought that a species would merely express a constrained range of forms in differing environments.
Both were wrong. A concept called the Weismann barrier emerged in the late 19th century, which suggested that the only influences that can be transmitted across generations are those that affect the germ line, the cells that give rise to sperm and egg, and that modification of the somatic tissues alone would not propagate. This is correct, and it’s still true: nothing in these reports suggest anything but that when perturbed by environmental stressors, gametes can switch on different genetic programs.
I think epigenetics and plasticity are important and play a role in evolution, certainly, but these kinds of elaborations on how cells interact do not imply in any way that there is a revolution in evolution, or that evolutionary biology has had it all wrong, or that this is heresy in progress. It’s also annoying to see all the vague handwaving about discrediting a “Darwinian model” — what Darwinian model? These discoveries are about mechanisms of genetic inheritance, and Darwin didn’t have a valid mechanism in the first place. In that sense, the only real heresy that counted was Mendel’s.
We have a long history in developmental biology of studying the most amazing freaks of nature — damage to developing organisms can produce astonishingly ghastly results as the embryo tries to regulate and recover, yielding results that are almost normal. There’s even a whole subdiscipline of the field, teratology, dedicated to studying aberrations of embryology. The word is perfect, since it is derived from a Greek root that means both “wonders” and “monsters”.
An unfortunate child in Colorado was the recipient of one of these wonders/monsters. Diagnosed with a brain tumor, when surgeons opened up his skull, they found fragments of a fetus inside: two tiny feet, part of a hand, coils of intestine. The surgery was successful and the child is doing fine now, but this was the most well-organized ‘tumor’ I’ve ever heard of. It’s not clear exactly what it was; there are things called teratomas, where a particular kind of cancer recapitulates a developmental program and builds tissues, things like skin with hair or teeth or chunks of muscle and bone and gland, but those aren’t this well organized. They tend not to produce complete organs, but partially differentiated sheets and lumps. Another possibility is fetus in fetu, where a fragment of the very early embryo is isolated and begins its own independent pattern of normal development, and then is engulfed by the larger and faster growing sibling embryo. Sometimes people late in life will be surprised to learn that there is a partially developed twin imbedded deep in their body. There is no question in any of these cases, however, that the tissue is not an autonomous individual. It is a piece of human-derived tissue that has executed part of the program of cell:cell interactions and induction that these kinds of cells are capable of doing.
Something struck me when I saw the photograph of this particular surgery. Here it is, a photo of a fetal foot flopping out of a bloody baby’s brain (don’t click if you’re squeamish). As I’m sure you’ve noticed, anti-choice people love to parade about with gory photos of aborted fetuses, and they love to dwell on little details like a recognizable hand or face. This picture is exactly like those, yet realize this: there was no human being behind those little baby toes. The existence of these fragments of non-sentient tissue endangered the life of a child, and there was no question that they needed to be extracted.
This is also how we should view abortion. It’s ugly and messy, and there’s something disquietingly resonant of humanity in the pieces of the embryo or fetus, but we shouldn’t be fooled. Those are beautifully patterned collections of differentiated cells, but there is no person there.
Simon Ings has written a wonderful survey of the eye, called A Natural History of Seeing: The Art and Science of Vision(amzn/b&n/abe/pwll), and it’s another of those books you ought to be sticking on your Christmas lists right now. The title give you an idea of its content. It’s a “natural history”, so don’t expect some dry exposition on deep details, but instead look forward to a light and readable exploration of the many facets of vision.
There is a discussion of the evolution of eyes, of course, but the topics are wide-ranging — Ings covers optics, chemistry, physiology, optical illusions, decapitated heads, Edgar Rice Burroughs’ many-legged, compound-eyed apts, pointillisme, cephalopods (how could he not?), scurvy, phacopids, Purkinje shifts…you get the idea. It’s a hodge-podge, a little bit of everything, a fascinating cabinet of curiousities where every door opened reveals some peculiar variant of an eye.
Don’t think it’s lacking in science, though, or is entirely superficial. This is a book that asks the good questions: how do we know what we know? Each topic is addressed by digging deep to see how scientists came to their conclusion, and often that means we get an entertaining story from history or philosophy or the lab. Explaining the evolution of our theories of vision, for example, leads to the story of Abu’Ali al-Hasan ibn al-Hasan ibn al-Haythem, who pretended to be mad to avoid the cruelty of a despotic Caliph, and who spent 12 years in a darkened house doing experiments in optics (perhaps calling him “mad” really wasn’t much of a stretch), and emerged at the death of the tyrant with an understanding of refraction and a good theory of optics that involved light, instead of mysterious vision rays emerging from an eye. Ings is also a novelist, and it shows — these are stories that inform and lead to a deeper understanding.
If the book has any shortcoming, though, it is that some subjects are barely touched upon. Signal transduction and molecular evolution are given short shrift, for example, but then, if every sub-discipline were given the depth given to basic optics, this book would be unmanageably immense. Enjoy it for what it is: a literate exploration of the major questions people have asked about eyes and vision for the last few thousand years.
This is a spectacular video of the development of Clypeaster subdepressus, also called a sand dollar or sea biscuit. These are stunningly beautiful creatures (as are we all, of course), and it is so cool to see them changing here. The video starts with a little echinoderm porn — these animals are profligate with their gametes — and then we see early divisions, gastrulation, the formation of the pluteus larva, metamorphosis into Aristotle’s lantern (one of the more charming names for a developmental stage), and into an ungainly spiky juvenile.
This is why some of us are developmental biologists: it’s all about the exotic weirdness and delicate loveliness of transformation.
Surely there can’t be anything objectionable to the Religious Right in a documentary called Animals in the Womb, can there? It sounds like it could be fun, with videos shot using tiny little cameras (and some simulations) of developing embryos in vivo. The only thing I object to is the silly title, since they do have invertebrates and non-mammalian vertebrates on the show, so “womb” is a major misnomer.
It’s going to be on Channel 4 in the UK — I suppose I’ll have to wait for it to be released on DVD.
How can I respond to a story about zebrafish, development, and new imaging and visualization techniques? Total incoherent nerdgasm is how.
Keller et al. are using a technique called digital scanned laser light sheet fluorescence microscopy (DSLM) to do fast, high-resolution, 3-D scans through developing embryos over time; using a GFP-histone fusion protein marker, they localize the nucleus of every single cell in the embryo. Some of the geeky specs:
1500×1500 pixel 2-D resolution
12 bits per pixel dynamic range
Imaging speed of 10 million voxels per second
Complete scan of a 1 cubic millimeter volume in 3µm steps in 90 seconds
Efficient excitation (5600 times less energy than a confocal, one million times less than a two-photon scope) to minimize bleaching and photodamage
Trust me, this is great stuff — as someone who was trying to do crude imaging of fluorescently labeled cells in the 1980s using a standard fluorescence scope and storing stills on VHS tape, this is all very Buck Rogers. Just load your embryo into the machine, start up the scanner, and it sits there collecting gigabytes of data for you for hours and hours.
But wait! That’s not all! They’ve also got sophisticated analysis tools that go through the collected images and put together data projections for you. For instance, it will color code cells by how fast they are migrating, or will count cell divisions. Similar tools have been available for C. elegans for a while now, but they have an advantage: they’re tiny animals where you might have to follow a thousand cells to get the full story. In zebrafish, you need to track tens of thousands of cells to capture all the details of a developmental event. This gadget can do it.
Here, for instance, are a couple of images to show what it looks like. The right half is the raw embryo, where each bright spot is a single cell nucleus; the left is one where the pattern of cell movement is color-coded, making it easier to spot exactly what domains of cells are doing.
I grabbed one of their movies and threw it on YouTube for the bandwidth-challenged. It’s not very pretty, but that’s the fault of reducing it and compressing it with YouTube’s standard tools. This is an example with color-coded migration (blue cells are relatively motionless, orange ones are moving fast), and you can at least get the gist of what you can detect. You can see the early scrambling of cells in the blastula, migration during epiboly and blastopore closure, and convergence in the formation of the body axis fairly easily. Well, you can if you’re familiar with fish embryology, anyway.
This crappy little video doesn’t do it justice, however. Take a look at the Zebrafish Digital Embryo movie repository for much higher resolution images that are crisp and sharp and unmarred by compression artifacts. It contains DivX and Quicktime movies that are somewhat large, 10-40M typically, that represent visualizations of databases that are several hundred megabytes in size.
What can you do with it? They describe observations of early symmetry breaking events; patterns of synchrony and symmetry in cell divisions; direct observations of the formation of specific tissues; and comparisons with mutant embryos that reveal differences in cell assortment. It’s fabulous work, and I think I’m going to be wishing for a bank of big computers and lasers and scopes for Christmas—only about $100,000 cheap! Until then, get a fast internet connection and browse through the movies.
Keller PJ, Schmidt AD, Wittbrodt J, Stelzer EHK (2008) Reconstruction of Zebrafish Early Embryonic Development by Scanned Light Sheet Microscopy. Science 2008 Oct 9. [Epub ahead of print].
Wow…so have you heard about this result?
One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells. The induced β-cells are indistinguishable from endogenous islet β-cells in size, shape and ultrastructure. They express genes essential for β-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
This is a big deal, I think, so allow me to translate.
First, a little caveat: this is a recent result published in Nature, and it is basic science, not clinical work. Before you start thinking it’s a new treatment for diabetes, I have to dash a little cold water on you and warn you that this has a long, long way to go before it can be applied to humans…but it does open the door to some future strategies that might be applied.
The pancreas is a fairly complicated organ. It’s made up of a variety of different cells that we can toss into a couple of different classes. There are garden variety support cells — mesenchyme, connective tissue, components of the circulatory system, and the ductwork of the organ — that provide building services for the other cell types. Then there are exocrine cells, cells that produce quantities of important substances that are piped directly into the digestive tract via ducts. Among the most important materials exported by this route are bicarbonate buffers to neutralize stomach acids and enzymes like amylase to digest sugars. Finally, the class of cells that most people are familiar with, because they are the subject of a common disease, are the endocrine cells. These are cells that generate hormonal signals that are secreted into the blood stream, and the most familiar of these are the beta (β) cells, which are organized into clumps called islets and which secrete insulin…and if something goes awry with the β cells, the resulting disease is called diabetes.
What the researchers did was identify a small subset of transcription factors, the genes Ngn3, Pdx1 and Mafa, that are sufficient to switch on the insulin production genes in non-insulin-producing cells of the pancreas. They can turn exocrine cells into β cells, which produce insulin, and these cells reduce the effects of diabetes.
The way they did this was to insert the transcription factors (and a gene that makes a glowing protein, GFP, as a marker) into adenoviruses, and then inject the virus directly into the pancreases of genetically immunodeficient (to reduce immune response complications) adult mice. The viruses infected a subset of the pancreatic cells, preferentially the exocrine cells, and started pumping out the transcription factors. As is common in these kinds of genetic engineering experiments, the use of viral transfection is perhaps the scariest part of the story; viruses aren’t trivial to keep in check. However, they report that they also did later PCR tests of adjacent tissues and found no evidence that the virus spread beyond the target organ; they also found that inducing the expression of the 3 transcription factors in other kinds of cells, like muscle, seems to do nothing. These genes are only potent in pancreatic cells that are already primed to be competent to respond to the signals generated by the transcription factors.
The virus is also not needed for long term maintenance of these cells. The virus in the pancreas, as determined by PCR, is cleared away after about 2 months. It seems that all it takes is a brief jolt of expression of Ngn3, Pdx1 and Mafa to switch susceptible cells into the β cell state, and that the developmental program is then self-sustaining.
The authors also made diabetic mice by injecting them with streptozotocin, which kills islet β cells, and then gave them the viral cocktail injection. It did not cure their diabetes, but it did give them significantly greater glucose tolerance, and they did measure increased blood insulin levels. One reason the treatment may not be as effective as it could be is that it simply converts random, scattered exocrine cells into single β cells that are not organized into the islets of the normal pancreas.
A lot of attention has been paid to embryonic stem cell and adult stem cell technologies, and those are both important and provide research and treatment opportunities that must not be neglected, but this is a third way: mastering the developmental control genes of the cell so that we can reprogram mature cells into any cell type we need. While injecting a person’s pancreas with a collection of viruses to rebuild missing cell types might be a little hazardous and crude, there may come a day when we can collect a few cells from an individual by a scraping or biopsy, grow them in a dish to get enough, tickle their transcription factors to cause them to differentiate into the cell, tissue, or organ type we want, and transplant the final, immunocompatible product right back into the patient.
This is the direction developmental medicine can take us — I hope you’re all ready to support it.
Zhou Q, Brown J, Kanarek A, Rajagopa J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature Aug 27. [Epub ahead of print].
Monday morning, PST: time for some science with a side of controversy, Danio-style
There’s a Department of Health and Human Services document circulating that’s got the pro-choice lobby up in arms. Afarensis and The Questionable Authority weighed in on the sociopolitical impact of such a policy last week, but in addition to the significant threat to reproductive rights that it presents, this proposal is yet another example of the complete lack of scientific expertise informing decisions about public health.
At issue is the determination of a time point that marks the beginning of pregnancy. The consensus of the medical community is that an established pregnancy occurs at the point when the blastocyst successfully implants into the uterine wall. This time point makes a lot of sense in considering early events in the reproductive process. Pre-implantation embryos have a vast distance to travel, complex chemical cues to navigate, and a ticking biological clock to contend with within the bounds of the female reproductive cycle. Roughly 40% of all embryos don’t survive the ordeal. These odds are one good reason to hold off on crying ‘pregnant’ until a successful implantation is achieved; another is that implantation signifies the beginning of the physiological impact of a pregnancy on a woman’s body. Developmental events prior to implantation have essentially no impact on maternal tissues, which are just marking time until the beginning of the next menstrual cycle. The massive signaling between embryonic and uterine tissues that occur during implantation, the establishment of maternal and embryonic connections and boundaries, delineating the difference between ‘self’ and ‘not self’, are all medically relevant occurrences in terms of the physiology of the female patient, hence the general accord within the medical community in marking this time point, and none before it, as the point at which a pregnancy is established.
[Read more…]
Every time I mention this developmentally significant molecule, Sonic hedgehog, I get a volley of questions about whether it is really called that, what it does, and why it keeps cropping up in articles about everything from snake fangs to mouse penises to whale fins to worm brains. The time seems appropriate to give a brief introduction to the hedgehog family of signaling molecules.
First, a brief overview of what Sonic hedgehog, or shh, is, which will also give you an idea about why it keeps coming up in these development papers. We often compare the genome to a toolbox — a collection of tools that play various roles in the construction of an organism. If I had to say what tool Sonic hedgehog is most like (keeping in mind that metaphors should not be overstretched), it would be like a tape measure. It’s going to have multiple uses: as a straightedge, as a paperweight to hold down your blueprints, as something to fence with your coworkers on a break, and even to measure distances. It will be pulled out at multiple times during a construction job, and it’s generically useful — you don’t need one tape measure to measure windows, another to measure doors, and yet another to measure countertops. Sonic hedgehog is just like that, getting whipped out multiple times for multiple uses during development, often being used where structures need to be patterned.
Let’s dig into some of the details. I’m using the 2006 review by Ingham and Placzek for most of this summary, so if you really want to get deeper into the literature, I recommend that paper as a starting point.
