Student biologists blogging some more

You all want to know what is going on in the minds of my students, right? Here you go.

More scenes from the minds of my students

My developmental class is still plugging away with some new entries.

A surprising Nobel

I would never have guessed this one. The Nobel Prize in Medicine has gone to Robert G. Edwards for his pioneering work in in vitro fertilization. It surprises me because it’s almost ancient history — he is being rewarded for work done over 30 years ago. It’s also very applied research — this was not work that greatly advanced our understanding of basic phenomena in biology, because IVF was already being done in animals. This was just the extension of a technique to one peculiar species, ours.

I don’t begrudge him the award, though, because the other special property of his research was that it was extremely controversial. These were procedures that simply burned through scores (or hundreds, if you count the ones with such little viability that they weren’t implanted) of human zygotes in order to work out reliable protocols, and throughout faced serious ethical risks — these were procedures that had a chance of producing the worst possible result, a viable embryo that came to full term, but had serious birth defects. The public opposition to the work was tremendous, funding was tenuous, and even many in the scientific community opposed the work and ostracized Edwards and his colleague, Steptoe (who did not live to see this day, and so did not receive the award).

Nowadays, IVF is practically routine and about 4 million people were ‘test tube babies’. It’s still controversial, though, with extremist anti-abortion groups, such as the Catholic church, still fighting it, and the redundant, unused zygotes from the procedure still being a point of major contention (ever heard of ‘snowflake babies’? That’s what they’re talking about).

I’m reading a couple of messages in this award. One is simply acknowledging a hard-working scientist, but the other is a signal that we should soldier on through all of the opposition to reproductive health technologies, that science will be rewarded and the Luddites will find themselves in the dustbin of history. I can’t help but see this as, in part, the Nobel committee making an unmistakeably rude gesture at the anti-science, anti-choice fanatics of the religious right.

(For those who are unfamilar with the IVF procedure that Edwards and Steptoe developed, here’s a lovely summary diagram from the Nobel Foundation.)

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The class writes

I told you I’ve got my development class blogging, and here’s the update for this week.

Don’t be shy. They’ve been told to welcome comments and to brace themselves for possible criticisms.

We teach developmental biology at UMM

I’m back to teaching developmental biology this term, and one of the things I do in my upper level classes is have students write blog entries on the themes of the course. In the past, I’ve given them space right here to do that, which I’ve found to be a parlous course of action — the commentariat here is savage and brutal, and infested with trollish nitwits who can derail threads spectacularly, so I’m doing it a little differently this time around. I’ve had them create their very own blogs on their own spaces, which has the additional benefit that maybe they can keep them going after they graduate.

So here’s the list of student blogs from my course. Feel free to visit, criticize, comment, etc., but do remember that they’re just now learning, so constructive discussion is far better than our usual ravaging ferocity. They’ve also been warned to be thick-skinned, though, so you don’t have to be too gentle.

Developmental Biology blogs

There isn’t much there yet in most cases, since they’ve just set them up, but I’ll be making weekly links to relevant articles in the future.

While I’m at it, I’ll mention that a former student, Levi Simonson, has a blog from his perspective as an ex-UMM student, now a graduate student at the wonderful University of Oregon. People do leave here to go on to interesting work!

Beehive development

A beekeeper did something simple: he put a bell jar over an opening in his beehive. The bees obliged by building a hive within it, where you could see it, and captured the process in a series of photos.

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I’m fascinated by the fact that the first struts in the framework are regularly spaced vertical bars of wax — how did they do that? I want to see videos of those early stages when the bees are working to initiate the strips. I suspect there are some interesting bee:bee interactions going on as they set them up.

Ray Kurzweil does not understand the brain

There he goes again, making up nonsense and making ridiculous claims that have no relationship to reality. Ray Kurzweil must be able to spin out a good line of bafflegab, because he seems to have the tech media convinced that he’s a genius, when he’s actually just another Deepak Chopra for the computer science cognoscenti.

His latest claim is that we’ll be able to reverse engineer the human brain within a decade. By reverse engineer, he means that we’ll be able to write software that simulates all the functions of the human brain. He’s not just speculating optimistically, though: he’s building his case on such awfully bad logic that I’m surprised anyone still pays attention to that kook.

Sejnowski says he agrees with Kurzweil’s assessment that about a million lines of code may be enough to simulate the human brain.

Here’s how that math works, Kurzweil explains: The design of the brain is in the genome. The human genome has three billion base pairs or six billion bits, which is about 800 million bytes before compression, he says. Eliminating redundancies and applying loss-less compression, that information can be compressed into about 50 million bytes, according to Kurzweil.

About half of that is the brain, which comes down to 25 million bytes, or a million lines of code.

I’m very disappointed in Terence Sejnowski for going along with that nonsense.

See that sentence I put in red up there? That’s his fundamental premise, and it is utterly false. Kurzweil knows nothing about how the brain works. It’s design is not encoded in the genome: what’s in the genome is a collection of molecular tools wrapped up in bits of conditional logic, the regulatory part of the genome, that makes cells responsive to interactions with a complex environment. The brain unfolds during development, by means of essential cell:cell interactions, of which we understand only a tiny fraction. The end result is a brain that is much, much more than simply the sum of the nucleotides that encode a few thousand proteins. He has to simulate all of development from his codebase in order to generate a brain simulator, and he isn’t even aware of the magnitude of that problem.

We cannot derive the brain from the protein sequences underlying it; the sequences are insufficient, as well, because the nature of their expression is dependent on the environment and the history of a few hundred billion cells, each plugging along interdependently. We haven’t even solved the sequence-to-protein-folding problem, which is an essential first step to executing Kurzweil’s clueless algorithm. And we have absolutely no way to calculate in principle all the possible interactions and functions of a single protein with the tens of thousands of other proteins in the cell!

Let me give you a few specific examples of just how wrong Kurzweil’s calculations are. Here are a few proteins that I plucked at random from the NIH database; all play a role in the human brain.

First up is RHEB (Ras Homolog Enriched in Brain). It’s a small protein, only 184 amino acids, which Kurzweil pretends can be reduced to about 12 bytes of code in his simulation. Here’s the short description.

MTOR (FRAP1; 601231) integrates protein translation with cellular nutrient status and growth signals through its participation in 2 biochemically and functionally distinct protein complexes, MTORC1 and MTORC2. MTORC1 is sensitive to rapamycin and signals downstream to activate protein translation, whereas MTORC2 is resistant to rapamycin and signals upstream to activate AKT (see 164730). The GTPase RHEB is a proximal activator of MTORC1 and translation initiation. It has the opposite effect on MTORC2, producing inhibition of the upstream AKT pathway (Mavrakis et al., 2008).

Got that? You can’t understand RHEB until you understand how it interacts with three other proteins, and how it fits into a complex regulatory pathway. Is that trivially deducible from the structure of the protein? No. It had to be worked out operationally, by doing experiments to modulate one protein and measure what happened to others. If you read deeper into the description, you discover that the overall effect of RHEB is to modulate cell proliferation in a tightly controlled quantitative way. You aren’t going to be able to simulate a whole brain until you know precisely and in complete detail exactly how this one protein works.

And it’s not just the one. It’s all of the proteins. Here’s another: FABP7 (Fatty Acid Binding Protein 7). This one is only 132 amino acids long, so Kurzweil would compress it to 8 bytes. What does it do?

Anthony et al. (2005) identified a Cbf1 (147183)-binding site in the promoter of the mouse Blbp gene. They found that this binding site was essential for all Blbp transcription in radial glial cells during central nervous system (CNS) development. Blbp expression was also significantly reduced in the forebrains of mice lacking the Notch1 (190198) and Notch3 (600276) receptors. Anthony et al. (2005) concluded that Blbp is a CNS-specific Notch target gene and suggested that Blbp mediates some aspects of Notch signaling in radial glial cells during development.

Again, what we know of its function is experimentally determined, not calculated from the sequence. It would be wonderful to be able to take a sequence, plug it into a computer, and have it spit back a quantitative assessment of all of its interactions with other proteins, but we can’t do that, and even if we could, it wouldn’t answer all the questions we’d have about its function, because we’d also need to know the state of all of the proteins in the cell, and the state of all of the proteins in adjacent cells, and the state of global and local signaling proteins in the environment. It’s an insanely complicated situation, and Kurzweil thinks he can reduce it to a triviality.

To simplify it so a computer science guy can get it, Kurzweil has everything completely wrong. The genome is not the program; it’s the data. The program is the ontogeny of the organism, which is an emergent property of interactions between the regulatory components of the genome and the environment, which uses that data to build species-specific properties of the organism. He doesn’t even comprehend the nature of the problem, and here he is pontificating on magic solutions completely free of facts and reason.

I’ll make a prediction, too. We will not be able to plug a single unknown protein sequence into a computer and have it derive a complete description of all of its functions by 2020. Conceivably, we could replace this step with a complete, experimentally derived quantitative summary of all of the functions and interactions of every protein involved in brain development and function, but I guarantee you that won’t happen either. And that’s just the first step in building a simulation of the human brain derived from genomic data. It gets harder from there.

I’ll make one more prediction. The media will not end their infatuation with this pseudo-scientific dingbat, Kurzweil, no matter how uninformed and ridiculous his claims get.

(via Mo Constandi)


I’ve noticed an odd thing. Criticizing Ray Kurzweil brings out swarms of defenders, very few of whom demonstrate much ability to engage in critical thinking.

If you are complaining that I’ve claimed it will be impossible to build a computer with all the capabilities of the human brain, or that I’m arguing for dualism, look again. The brain is a computer of sorts, and I’m in the camp that says there is no problem in principle with replicating it artificially.

What I am saying is this:

Reverse engineering the human brain has complexities that are hugely underestimated by Kurzweil, because he demonstrates little understanding of how the brain works.

His timeline is absurd. I’m a developmental neuroscientist; I have a very good idea of the immensity of what we don’t understand about how the brain works. No one with any knowledge of the field is claiming that we’ll understand how the brain works within 10 years. And if we don’t understand all but a fraction of the functionality of the brain, that makes reverse engineering extremely difficult.

Kurzweil makes extravagant claims from an obviously extremely impoverished understanding of biology. His claim that “The design of the brain is in the genome”? That’s completely wrong. That makes him a walking talking demo of the Dunning-Kruger effect.

Most of the functions of the genome, which Kurzweil himself uses as the starting point for his analysis, are not understood. I don’t expect a brain simulator to slavishly imitate every protein, but you will need to understand how the molecules work if you’re going to reverse engineer the whole.

If you’re an acolyte of Kurzweil, you’ve been bamboozled. He’s a kook.

By the way, this story was picked up by Slashdot and Gizmodo.

Blaschko’s Lines

One of the subjects developmental biologists are interested in is the development of pattern. There are the obvious externally visible patterns — the stripes of a zebra, leopard spots, the ordered ranks of your teeth, etc., etc., etc. — and in fact, just about everything about most multicellular organisms is about pattern. Without it, you’d be an amorphous blob.

But there are also invisible patterns that you don’t normally see that are aspects of the process of assembly, the little seams and welds where disparate pieces of the organism are stitched together during development. The best known ones are compartment boundaries in insects. A fly’s wing, for instance, has a normally undetectable line running across the middle of it, a line that cells respect. A cell born on the front half of the wing will multiply and expand its progeny to cover a patch on the surface, but none of its offspring cells will cross over the invisible line into the back half. Similarly, cells born on the back half will never wander into the front.

We can see these invisible lines by taking advantage of mosaicism: generate a fly wing with two genetically distinct cell types, for instance by making one type express a pigment marker and the other not, and the boundaries become apparent. There are many ways we can generate mosaics, but in Drosophila we can use somatic recombination — with low frequency, chromosomes in the fly can undergo crossing over in mitosis, not just meiosis, so sometimes the swapping of chromosome segments will turn a daughter cell that should have been heterozygous for an allele into one that is homozygous, allowing a marker allele to express itself.

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(Click for larger image)

(A) The shapes of marked clones in the Drosophila wing reveal the existence of a compartment boundary. The border of each marked clone is straight where it abuts the boundary. Even when a marked clone has been genetically altered so that it grows more rapidly than the rest of the wing and is therefore very large, it respects the boundary in the same way (drawing on right). Note that the compartment boundary does not coincide with the central wing vein. (B) The pattern of expression of the engrailed gene in the wing. The compartment boundary coincides with the boundary of engrailed gene expression.

It’s like a secret code written in molecules hidden to the eye until you illuminate it in just the right way to expose it. And these lines aren’t just arbitrary, they’re significant. The wing boundary defines the expression of important molecules that define the identity of specific structures. The posterior half of the wing is the domain of expression of a molecule called engrailed, which is part of the machinery that makes the back half a back half. We can also stain a wing for just that gene product, and also expose the hidden lines.

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We can also mutate the pathway of which engrailed is part, and do interesting things to the fly wing, like turn the back half into a mirror image of the front half. So these lines actually matter for the proper development of a fly.

So you might be wondering if we have anything similar in humans…and no, we don’t have strict compartment boundaries like a fly. However, we do have normally invisible lines and stripes of subtle molecular differences running across our bodies, which are occasionally exposed by human mosaicism. These are marks called the lines of Blaschko, after the investigator who first reported a common set of patterns in patients with dermatological disorders in 1901.

Don’t rip off your shirt and start looking for the Blaschko lines — they’re almost always invisible, remember! What happens is that sometimes people with visible dermatological problems — rashes, peculiar pigmentation, swathes of moles, that sort of thing — express the problems in a stereotypically patterned way. On the back, there are V-shaped patterns; on the abdomen and chest, S-shaped swirls; and on the limbs, longitudinal streaks.

Here is the standard arrangement:

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And here are a few examples:

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Note that usually there isn’t a whole-body arrangement of tiger stripes everywhere — there may be a single band of peculiar skin that represents one part of the whole.

Where do these come from? The current hypothesis is that a patch of tissue that follows a Blaschko line represents a clone of cells derived from a single cell in the early embryo. These clones follow stereotypical expansion and migration patterns depending on their position in the embryo; this would suggest that a cell in the middle of the back of a tiny embryo, as it grows larger with the growing embryo, would tend to expand first upwards towards the head and then sweep backwards and around to the front. One way to think of it: imagine taking a piece of yellow clay and sandwiching it between two pieces of green clay into a block, and then pushing and stretching the clay block to make a human figurine. The yellow would make a band somewhere in the middle, all right, but it wouldn’t be a simple rectilinear slice anymore — it would express a more complex border that reflected the overall flow of the medium.

What makes the lines visible in some people? The likeliest example is mosaicism, a difference between two adjacent cells in the early embryo that then appears as a genetic difference in the expanded tissues. There are a couple of ways human beings can be mosaic.

The most common example is X-chromosome inactivation in women. Women have two X-chromosomes, but men only have one; to maintain parity in the regulation of expression of X-linked genes, women completely shut down one X. Which one is shut down is entirely random. That means, of course, that all women are mosaic, with different X-chromosomes shut down in different cells. This normally makes no difference, since equivalent alleles are present on each, but occasionally an X-linked skin disorder can manifest itself in a splotchy pattern. Another familiar example is the calico fur color in female cats, caused by the random expression of a pigment gene on the feline X chromosome.

A more spectacular example is tetragametic chimerism. This rare event is the result of the fusion of two non-identical twins at an early stage of development, producing an embryo that is a kind of salt-and-pepper mix of two individuals. After the fusion, the embryo develops normally as a single individual, but genetic or molecular tests can detect the patches of different genotypes. (No scientific tests can tell whether the individual has two souls, however.)

Another way differences can arise is by somatic mutation. Mutations occur all the time, not just in the germ line; we’re all a mixture of cells with slightly different mitotic histories and some of them contain novel mutations, usually not of a malign sort, or you wouldn’t be reading this right now. But what can happen is that you acquire a mutation in one cell that may predispose its clone of progeny to form moles, or acquire a skin disease, or even tilt it towards going cancerous. It’s a fine thing to undergo genetic screening to find that you may not carry certain alleles associated with cancer, but you aren’t entirely off the hook: you may have patches of tissue in your body that are perfectly normal and functional except that they carry an enabling mutation that occurred when you were an embryo.

One final likely mechanism is epigenetic. Throughout development, genes are switched on and off by epigenetic modification of the DNA. This process can vary: epigenetic silencing doesn’t have to be 0 or 100% absolute, but can differ in degree from cell to cell. It can also vary by chromosome — you’re all diploid, and epigenetic modification may affect one chromosome of a pair to a different degree than the other. Since epigenetic modifications are inherited by the progeny of a cell, that means these differences can be propagated into a clonal patch…that on the skin, will likely follow the lines of Blaschko.

Don’t fret over these lines; they aren’t a disease or a problem or even, in most cases, at all visible. The cool thing about them is that there is a hidden map of your secret history as an individual embedded in silent patterns in your skin — you were not defined as a single, simple, discrete genetic entity at fertilization, but are the product of complicated, subtle changes and errors and shufflings and sortings of cells. We’re all beautiful pointillist masterpieces.

Engineering lungs

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This past weekend, I attended my 35th high school reunion. It’s a strange phenomenon to be meeting people you haven’t seen since you were 18, and further weirdness ensues when we discover that most of them are already grandparents. There have been a lot of life changes in 35 years. Saddest of all, though, is the ritual listing of the deceased…and I learned that one of my former classmates died in her late 40s of emphysema, a progressive and irreversible lung disease that leads to the near complete loss of lung function. The only cure right now is a lung transplant, and patients who’ve been suffering with emphysema for long typically have so many other problems that they’re poor candidates for surgery, not to mention that the waiting list for organs is long, and a transplant means a life-long commitment to anti-rejection drug treatments.

There will come a day, though, when new lungs can be built and replacement surgeries more common. That day is definitely not yet here, though, but there are promising signs on the horizon. One such sign is recent work in tissue engineering to grow lungs in a dish.

We can grow functional rat lungs in a tissue culture chamber now, which show some limited ability to support respiration when transplanted back into another rat. Here’s an overview of the procedure; I’ll go through it step by step.

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Schema for lung tissue engineering. (A) Native adult rat lung is cannulated in the pulmonary artery and trachea for infusion of decellularization solutions. (B) Acellular lung matrix is devoid of cells after 2 to 3 hours of treatment. (C) Acellular matrix is mounted inside a biomimetic bioreactor that allows seeding of vascular endothelium into the pulmonary artery and pulmonary epithelium into the trachea. (D) After 4 to 8 days of culture, the engineered lung is removed from the bioreactor and is suitable for implantation into (E) the syngeneic rat recipient.

The first step is to collect a donor rat lung. The organ is cut out of a living rat, who will quickly become a dead rat; this part of the procedure probably can’t be scaled up to human transplantations, for obvious reasons. However, lungs from dead people or perhaps even lungs from appropriately sized animals will be adequate.

This donor lung is then stripped of all of its living cells. This is done by perfusing it with a detergent solution. Membranes dissolve and rupture in the presence of detergent, so all of the cells in the lung are basically destroyed, their contents, including cytoplasm, nucleus and DNA, and membranes and organelles are washed away.

What’s left then? Connective tissue and extracellular proteins. All that’s left is a frothy, fragile matrix of fibers like collagen and elastin, and imbedded signaling proteins that will be useful in supporting the growth of new cells. It leaves behind a kind of porous, pale ghost lung, a collection of microscopic struts that just needs to be draped with new cells.

This is the key step. Lungs are complicated, delicate membranous structures, and it would be hard to regrow it entirely from scratch. Starting with an acellular scaffold, though, a kind of skeleton of a lung that sketches out the arrangement of alveoli and blood vessels gives the tissue engineering a head start. It really is amazing how much of the organization of the lung is still left when all of the cells are removed: the photos below show the air spaces left behind (on the left) and the major blood vessels (on the right). There are no cells here! This is just an outline of the structure left by the still extant connective tissue!

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What’s promising about this so far is that almost all of the antigenic components of the lung are removed; if this lacework of proteins were transplanted into another animal, it probably wouldn’t provoke an immune response. Of course, it also wouldn’t work as a lung, because there are no gas exchange surfaces present, and everything is leaky. It’s only a skeleton of a lung, remember…so let’s fix that.

The next step is to suspend the lung framework in a chamber, with tubes attached to the airways and to the blood vessels. Living, isolated lung epithelial cells are then introduced into the airways, and lung endothelial cells (the cells that line blood vessels) are introduced into the pulmonary arteries and veins. These cells stick to the scaffolds and grow. They actually grow better in the lung matrix than they do in a petri dish, probably because of the presence of growth factor proteins lurking in the acellular scaffold.

The new cells use the matrix as a guide and repopulate and rebuild the cellular structure of the lung. During this whole process, the tissue culture medium is pumped through the arteries to mimic the effects of blood pressure, and air is pumped into the airways. It works beautifully. New columnar epithelial cells grow to line alveoli, and endothelial cells line the blood vessels appropriately, and the cells produce the right secreted proteins, like surfactants that reduce surface tension and are important for allow lungs to inflate. It takes about a week for the new lung tissues to form, and they are robust, producing sheets of cells that can tolerate the same pressures as intact, normal lungs.

Now for the real test. The regrown lungs were transplanted into living rats for 45 minutes to two hours. They worked! Everything stitched together nicely, and the engineered tissues pinked up nicely as blood flowed into them. Blood was visibly oxygenated as it passed through the new lung, and measurements of the partial pressure of oxygen and carbon dioxide in the blood showed that the former went up and the latter went down, exactly as it is supposed to do.

This is all very promising, but the transplantation times were very short, and you might be wondering why. These lungs aren’t perfect. There was bleeding from the blood vessels into the airways, and also some blood clotting — for this to work, the barrier membranes have to be essentially perfect, and they aren’t, yet. The poor rats’ lungs would have spluttered and fallen apart with prolonged use, and the blood clots would have led to thrombosis eventually.

Another problem, and one that has to be solved eventually if this is ever to work for human transplantations, is the source of the cellular components. The connective tissue stuff is only weakly antigenic, so isn’t going to provoke a strong immune response, but repopulating it with foreign cells brings the rejection problem roaring right back. What we need next for long term success is to find a source of lung adult stem cells, or a way to induce pluripotent stem cells to make the cell types needed.

That’s right, we need more human stem cell research. If you need a new lung, and we’re going to have to reengineer one for you in a dish, we’ll need a population of autologous cells — cells from you — to reseed an acellular matrix taken from a cadaver or a pig with lung tissue that won’t trigger an immune response.

This is a long way from being useful for humans, with two big problems still facing us, refinement of the tissue-engineering technique to produce more reliable and complete membranes, and the all-important stem cell research to allow us to create sources of immunologically-compatible cells, but the cool thing is that the questions that need to be answered are in crystal-clear focus, and there are strategies to get us the answers. Time and money and a less restrictive regulatory environment for stem cell work is all that is needed.


Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE (2010) Tissue-engineered lungs for in vivo implantation. Science 329(5991):538-41.

No metazoan is an island

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I’m one of those dreadful animal-centric zoologically inclined biologists. Plants? What are those? Fungi? They’re related to metazoans somehow. Lichens? Not even on the radar. The first step in fixing a problem, though, is recognizing that you have one. So I confess to you, O Readers, that my name is PZ, and I am a metazoaphile. But I can get better.

My path to opening up to wider horizons is to focus on what I find most interesting about animals, and that is that they are networks of cells driven by networks of genes that generate patterned responses of expression by cell signaling, or communication. See? I’m already a little weird. Show me a baby bunny, and I don’t just see a cute little furry pal with an adorable twitchy nose, I see an organized and coherent array of differentiated tissues that arose by a temporal sequence of cell-cell interactions, and I just wanna open him up and play with his widdle epithelial sheets and dismantle his pwetty ducts and struts and fibers and fluids, oochy coo. And ultimately, I want to take apart each cell and ask why it has its particular assortment of genes switched off and on, and how its state affects its neighbors and the whole of the organism.

Which means, lately, that I’ve acquired a growing interest in bacteria. If I were 30 years younger, I could probably be seduced into a career in microbiology.

There are a couple of reasons why an animal-centric biologist would be interested in bacteria. One is the principle of it; the mechanisms that animal cells use to build complex arrangements of tissues were all first pioneered in single-celled organisms. We have elaborated and added details to gene- and cell-level phenomena, but it’s a collection of significant quantitative differences, with nothing known that is essentially new in metazoan cells. All the cool stuff was worked out by evolution in the 3-4billion years before the Cambrian, a potential that simply blossomed in the past half-billion years into big conglomerations of cells. Understanding how the building blocks of multicellularity work individually ought to be a prerequisite to understanding how the assemblages work.

But there’s another reason, too, a difference in perspective. It is our conceit to regard ourselves as individuals of Homo sapiens, a body of cells clonally derived from a single human cell. It’s not true. It turns out that each one of us is actually a whole population of species, linked by our evolutionary history and lumbering through the world as a team. Genus Homo is also genera Escherichi and Bacteroidetes and Firmicutes and many others.

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Physiology

Let’s begin with the most widely known factor: we’re mostly bacterial in cell numbers, with about ten times as many bacterial cells as human cells. Most of these are nestled deep in our guts, where they are indispensible. In mammals, they help break down complex polysaccharides which we can then absorb through the wall of the digestive tract — these are compounds that would be simply lost without bacterial assistance. Even more dramatically, termite guts contain colonies of bacteria that produce enzymes to break down cellulose. Another insect, aphids, live in plant saps which have negligible protein components, and they rely on gut bacteria that can synthesize nine essential amino acids. One cool feature is that the bacteria can’t complete the synthesis of leucine; the last step is carried out by aphid enzymes. The synthetic pathway is split acros two different species!

Another weird twist is that gut bacteria can affect morphology (or vice versa; physiology influences which gut bacteria thrive). Mice with a genetic predisposition to obesity were found to have a different distribution of gut bacteria; fat mice are full of Firmicutes, while lean mice are loaded with Bacteroidetes. Something in the genetics of the obese mice seems to favor the proliferation of that one species. Cause and effect is not so easily separated, though, since doing a fecal transplant and inoculating the guts of germ free mice with the bacteria from obese mice vs. lean mice has a surprising effect: the mice given obese mouse fecal enemas subsequently increased their body fat by 60%. The bacteria promoted more fat storage in the host animal.

So what, you may be thinking, it’s mice. However, it turns out that obese humans tend to have reduced amounts of Bacteroidetes species in their guts than lean people, and weight loss is accompanied by an increase in Bacteroidetes. Fecal transplants are not recommended as a weight loss technique…at least not yet.

They have worked for some other problems. Crohn’s disease and ulcerative colitis are diseases that involve intestinal inflammation, and they’re also associated with imbalances in the species distribution of gut bacteria. Some promising treatments have involved collecting feces from healthy individuals, and using a nasogastric tube to inoculate the guts of Crohn’s patients with the stuff. Ick, I know, but it seems to have worked surprisingly well in a small number of patients.

Development

Bacteria are present in the gut from a very early age, and populate the digestive epithelia. There must be interactions going on, and it appears that the bacteria are actually regulating the growth of the gut lining.

Germ-free zebrafish lines have no gut bacteria, and they also have problems. The intestinal lining arrests its development and fails to fully differentiate; the lining also grows much more slowly. They also have difficulty absorbing some nutrients. Add bacteria, though, and growth and differentiation resume. This is a case where the developmental program and the bacterial influences are interdependent, and it makes sense — they’ve co-evolved.

It’s not just fish, either — these are conserved interactions across the vertebrates. Mice exhibit the same dependence on gut flora for development of the intestinal lining.

The very best example of a developmental dependence on bacteria, though, is in squid. The bobtail squid has a light-emitting organ that relies on colonization by a luminescent bacterium, Vibrio fischeri. The animal gleans the bacteria from the water with a special ciliated epithelium and secreted mucus that seems to be just the right flavor for Vibrio, and the bacteria migrate deep into the light-emitting organ. Once colonized, the squid dismantles the harvesting cilia and downregulates the secretion of mucus. If no bacteria of the right species are present, it maintains the cilia. If the bacteria in the organ die, resumes mucus production.

i-71f9c1c36169ef227a4840e26cd5f704-squid_symbionts.jpeg
Bacterial symbionts induce light-organ morphogenesis in squid. A Adult squid (E scolopes). SEM images of epithelial fields before B and after C regression of ciliated appendage. Scale bar, 50 mm. Ciliated appendages are marked by an orange dashed line.

Evolution

If something affects development and physiology, it affects evolution, so evolutionary importance is simply rather unavoidable. However, there’s also one somewhat surprising observation (to me, at least — microbiologists probably expect it): different species of related organisms can have different microbial populations, even when raised in identical conditions. Different Hydra species in the lab under controlled conditions have recognizably different populations of bacteria living on their epithelia, and Hydra of the same species collected in the wild have similar distributions of species. The properties of each Hydra species uniquely favor different distributions of bacteria, and the bacteria are also preferentially colonizing particular species of Hydra.

Hydra are wonderful experimental animals in that one can ablate stem cells for a particular tissue type, and still get an animal that develops and lives; do the same thing to a vertebrate, for instance knocking out the mesodermal lineage in the embryo, and you get an aborted blob. In Hydra, you get a tissue that survives and is colonized by bacteria…but the kinds of bacteria populating it is different from the populations in the intact animal. The animal and the bacteria are swapping molecular signals that specify favored relationships. Again, these are coevolved populations that recognize molecular properties of the host and symbiont.

This is all getting very complicated. I’m used to thinking in terms of networks of genes: there are regulatory interactions between genes in a single cell that establish cell-type specific patterns of gene activity; all express a common core of genes, but different cell types, such as a neuron vs. a cell of the digestive epithelia, will also have their own unique special-purpose genes switched on. I’m also comfortable thinking of networks of cells: cells are in constant negotiations with their neighbors, mainting a common pattern of expression within a tissue, and defining interacting edges with other tissues. Cells are continually sending out messages about their state into the system and responding to local and global signals. All this is part of the normal process of thinking developmentally.

Now, though, there’s another layer: we have to think in terms of networks of species that cooperate in the development and physiology of individual multi-cellular organisms. Purity is compromised. My precious animalia — they’re inconceivable without bringing bacteria into the picture.


Fraune S, Bosch TCG (2010) Why bacteria matter in animal development and evolution. Bioessays 32:571-580.