I loved this book, and now PBS is making a miniseries with Neil Shubin. I can’t wait.
A long time ago, right after I read it, I put up a series of posts on a forum detailing the wonderful things I had learned from it. After a while, the threads were hijacked by people who just didn’t get it – or didn’t want to get it – and they disappeared into obscurity. But I stand by what I wrote, and now that this book is back in public view, I want to share these thoughts again. This is a long read, over 4,000 words, and it’s taken from a forum thread, so there are parts that don’t flow entirely well, but I don’t want to edit or rewrite it because it captures the wonder and excitement I felt when I first read the book and I don’t want to change that.
So settle down with a nice cup of tea if you’re ready to go below the fold.
This week, I finished reading “Your Inner Fish,” by Neil Shubin, and I am so excited about all the new thoughts and ideas and questions it has produced in me. I was going to carefully plot out some themed essays to post here, full of quotes and linky goodness, but realized that I might never actually do anything if I made that my goal.
Anyway, Shubin is the paleontologist whose team discovered the fossil Tiktaalik, which is the first creature that clearly shows evidence of the transition from fish to land-dweller. In a very engaging fashion, he explains a number of concepts about embryologic development, evolution, and the evolution of DNA and how it changes in speciation, that made me realize that a lot of the speculation we’ve engaged in here about the possible origins and causes of ADD may have been far too simplistic to be valid.
Regardless of whether a member here is arguing in favor of heritability or environment, we’ve always focused on the origin as a development exclusive to hominids. I’m trying really, really hard to keep myself from diving into the ideas that come after this, so let me know if this seems to be too convoluted. . .
OK, we know that every living thing starts off with all the coding in its DNA that it’s ever going to have. For creatures that reproduce sexually, that DNA is created by the combination produced by the egg and sperm cells of the parents. For creatures that reproduce asexually, it is a duplicate of its single parent’s DNA. Follow me here. . .from the time a living thing is a single cell, whether it stays unicellular or becomes multicellular, its DNA is complete, with all the genetic information that it will have to the end of its life. So, the very first life ever on earth, the very first single-celled living organisms, passed their DNA to their offspring, some of whom eventually became us.
The genetic information that created each individual human being has a history that precedes human life by hundreds of millions of years. As species evolved, all that genetic code remained. It’s still there, but depending on the species, pieces of it may be active or inactive, dominant or rare, and with the potential to be put to use later if it’s useful to a successive species.
I’m going to put more information in the next post, with some quotes, because Shubin’s example will make this one too long to read.
OK, so the idea here is that genes will turn on or off depending on their usefulness to a species. In 1991, Linda Buck and Richard Axel discovered the family of genes that give us a sense of smell. Shubin outlines the hypotheses that allowed them to discover these, and one of them was that there is a one to one match between smells and smell receptors, meaning that there would be an enormous number of genes devoted to sensing odors. They eventually discovered that a full three percent of our genome is devoted to genes for producing odor receptors.
This information allowed other researchers to look for olfactory genes in other species, which led to the discovery that there were two kinds of them – one for detecting scent in water, and one for detecting scent in the air. Shubin also notes that this specialization occurred after the evolution of primitive lungfish, the precursors to the separation of creatures into water-dwelling and land-dwelling. In addition, the number of these genes for smelling increased over time, with the largest number appearing in mammals. The increase came from duplication of the less numerous genes in primitive species.
Then Shubin explains, “Humans devote about 3 percent of our genome to odor genes, just like every other mammal. When geneticists looked at the structure of the human genes in more detail, they found a big surprise: fully three hundred of these thousand genes are rendered completely functionless by mutations that have altered their structure beyond repair. (Other mammals do use these genes.) Why have so many odor genes if so many of them are entirely useless?” He explains that dolphins and whales, who are water-dwelling mammals provided the clues. They don’t use their nasal passages to smell, only to breathe. But they have all of these genes in their DNA, they’ve just been rendered non-functional.
If a mutation occurs in these genes, there will be no functional change in the animal, but that mutation will now exist in the species’ genome, able to be passed along to future generations. If the mutation exists in that gene, and a new species descends with that mutation, it might be expressed if the affected gene is reactivated.
What this means is that if there is an actual gene for ADD, it came about long before there were humans. Human selection advantages or disadvantages would have no impact whatever on the presence or absence of ADD (although I’d wager it would have a lot more impact on species that have brains than on those that don’t. . .) The social structure that would make an ADD individual more or less likely to succeed and reproduce would have no impact on whether or not the gene was present in the population, because it would have existed long before that social structure, or even hominids, ever existed.
I’m going to stop here and let this percolate. This isn’t the end.
I’m a little reluctant to call it a “gene for ADD” in the context of a scientific discussion. I’m no expert, but from all the reading I’ve done, it’s much more likely that it’s an allele – a string of adjacent DNA proteins – that would be behind it. Because a new life is created by combining the genetics of two other creatures, there are possible combinations that would lead to an explanation of severity and comorbid conditions being triggered by not only a specific allele, but by its size, or its position in a larger allele, or by being adjacent to another allele. . .
The point is, we need to understand that the randomness in evolution and genetics isn’t the same as what we would call “randomness” in conversation. All the genomic information is there in every one of us, and in every other living creature, the randomness comes from which parts are activated and/or expressed in the individual.
In the dolphin/whale example, the genes for scent detection are still there in their DNA, right where they’re supposed to be, right where they’re found in primates, reptiles, amphibians. . .they’re simply not active. With us, the genes for detecting scent in water are all there, but since we don’t have gills, they’re sitting there doing nothing – but they didn’t go away once they were no longer needed.
Randomness in genetics is sort of like the hand you’re dealt from a deck of cards. Whatever is in the deck is what you have to pick from, but you don’t get all of them. What you get, though, is always going to have a number from 2-10, or be an ace or a face card. It’s always going to be a heart, diamond, club, or spade. You’re not going to get a 47 of daisies. The cards that are still in the deck are still there, and if you draw another hand randomly from the deck, it’ll be different, but still follow those rules. You won’t get a 47 of daisies no matter how many times you reshuffle and deal.
When you have that hand, the order of the cards is important. You may have a sequence that works for the game you’re playing right from the start. You might have the right cards for a winning sequence, but out of order (and in cards, unlike life, you can move them around to fix that.) You might have cards that could win you the game if you draw another card, and that same card might be useful to complete more than one winning sequence in the hand you already have. Each time you draw, you know that you’ll get a card from an established set of available suits and numbers – you don’t have to worry about that 47 of daisies.
The idea here is that, if there is a genetic causation, it originates with the formation of DNA, not with the formation of human society, or even the birth of the first hominid. Whether it’s a gene, an allele, or the placement of one of these on the DNA chain, it’s been there for hundreds of millions of years.
I’m afraid I haven’t seen any reputable research verifying genomic changes outside of the ones from mingling different gene pools. It’s something that can be tested and measured, so if it’s going on, there should be some concrete results.
And because our species adapts its environment to improve survival, rather than surviving by adapting to the environment, there’s little reason to suspect that ADD would have any evolutionary advantages, especially at this late stage. If that were the case, we might see genes for monetary wealth or silicone implants.
The increase in numbers comes mostly from improvements in diagnosis, same as with ASD – many new cases are adults who were previously undiagnosed, so we should see a leveling off in both cases within the next 10-15 years. It isn’t an indication that there’s been a genetic explosion of ADD, in response to societal stress or any other factor.
I want to put this out as a separate subject, even though it’s also coming from what I’ve read in “Your Inner Fish.” A lot of this simply pulls together pieces of information I’d already found, but fleshed it out and provided citations, so I have to tell you that this book will give you some great instruction on the impact of genes on embryologic development, too.
As I mentioned in my previous Shubin-inspired post, all the DNA a creature has is there from the point that it’s only a single cell. The genes start their work right away as the cells start multiplying by division, telling each new cell what it’s going to be, where it’s going to end up in the body, how many more of its companion cells are going to be made. . .Shubin explains,
A skin cell is different from a neuron because different genes are active in each cell. When a gene is turned on, it makes a protein that can affect what the cell looks like and how it behaves. Therefore, to understand what makes a cell in the eye different from a cell in the bones of the hand, we need to know about the genetic switches that control the activity of genes in each cell and tissue.
Here’s the important fact: these genetic switches help to assemble us. At conception, we start as a single cell that contains all the DNA needed to build our body. The plan for that entire body unfolds via the instructions contained in this single microscopic cell. To to from this generalized egg cell to a complete human, with trillions of specialized cells organized in the the right way, whole batteries of genes need to be turned on and off at just the right stages of development.
He goes on to explain some examples of how this process was discovered and manipulated so that the action was confirmed, and you should go read the book if you want the specifics. Really, you should go read the book.
Anyway, each piece of the developmental process in the embryo takes place in a particular order, at a particular point in time, triggered by the same pieces of DNA, regardless of species. In fact, genes that triggered development of a particular structure could be switched from species to species and create duplicates of that structure in the recipient that were just like its own, despite having gotten the gene itself from a completely different creature.
In addition, once the genetic process was known, scientists could interrupt it or repeat it in the lab. Shubin mentions a couple of experiments in which vitamin A was applied to cells that took charge of finishing the development of limbs, triggered by these DNA instructions, and limb development would stop. These same cells could be transferred to a different place on the same creature, and result in extra mirror copies of the limbs.
So, clearly, there’s something in our DNA that determines the final size, shape, and functionality of every structure in our bodies, so a mutation in our DNA could cause a difference in our brains – since they develop from a single starter cell, just like everything else. However, there’s also the possibility that something that interfered with the proteins carrying the instructions to the developing cells would cause incomplete development of the brain.
OK, time for post number two, in which I speculate. . .
So let’s assume that the correlation between the size of the frontal lobe of the brain and ADD is the significant one. This supposition would apply equally well to the idea that chemical neurotransmission is the cause, since that’s a physical structure as well, but conceptually, it’s a lot easier to understand brain size as a developmental issue.
The DNA would contain all the information needed to make a complete brain, and the genes that turn on to create brain cells would begin doing so early on in development. Just like limbs and internal organs, the development of the brain takes place in a particular order, with a consistent timeline. If we assume that the primary cause of ADD is genetic, and the genes cause the underdevelopment of the frontal lobe, then it means that the protein signals being sent out by the DNA during brain development are doing exactly what they were programmed to do.
However, there is a chance that some environmental factor, similar to the vitamin A that stopped limb development, interfered with these protein messengers. It’s certainly conceivable, but my feeling is that it’s unlikely that this is the primary cause of ADD in most people.
First, there is a limited timeframe during which an environmental factor can affect the growth of a particular segment of the developing brain. Too early, and that part will be significantly smaller, or even missing. Too late, and the difference will be so small that it can’t be measured at all. The environmental factors that are frequently implicated tend not to occur at a single point during fetal development.
The signal action of these genes is binary – off or on. Could an environmental factor affect only a few cells of a particular type, leading to a partial deficiency in formation, and leave adjacent cells unaffected? Well, yes, but this would still show some kind of consistent end result.
Second, the result of an environmental factor is consistent enough to be statistically significant. If it affects the development of a particular structure in an embryonic stage, that will be seen in a high percentage of children exposed to it while they were in the womb. We would see a majority of children whose mothers smoked, or drank, or ate foods tainted with pesticides, exhibiting the same structural deficiency in their brains. It might not be as obvious as the stunted limbs caused by Thalidomide, or the reproductive tract deformities caused by DES, but it would be possible to find a consistent result and trace it back reliably to a shared exposure.
Now, the other thing to keep in mind is that most of the information we’ve learned about DNA and embryonic development comes from animal experiments. The mechanism that’s suspected can be singled out and tested, and a consistent result can be tested further until it’s understood. The Hox genes, which control the development of specific body segments, are well documented as to their assignments and functions. Once they were isolated, it was easy to see if manipulating them produced more or less of one body part or another in the various species that could be tested.
Finding this out in a neurological or psychiatric condition isn’t quite so easy, though. Experimenting on humans is clearly unethical. Experimenting on animals requires a way to determine the presence or absence of the condition being studied. How can you tell if a rat or a fruit fly has ADD?
So right now, it’s a matter of reverse engineering. Find the people who have ADD, collect DNA samples, and look for similarities. If you want to find an environmental factor, that’s a little harder. A pregnant mom is not likely to be keeping a log for just in case.
However, the environmental factors that have been commonly implicated haven’t produced the consistent results that would justify making a correlation. If their impact were significant, exposure to them throughout gestation would result in much greater neurological differences than what has been seen in ADD. Few of them were introduced at the specific stage of development that would result in a small difference in brain structure, and never before or after. And none of them have shown a consistent result in a statistically significant number of exposed individuals.
Obviously, my say-so doesn’t negate the possibility, but the ideas that have been floated around don’t fit with the complexity of embryonic development. We want to be able to point to a cause, affix blame, and give ourselves what we hope is the opportunity to avoid unwanted outcomes. It’s just not ever that simple. If an environmental cause is discovered, I think it’s highly unlikely that it’s going to be some chemical to which we are commonly exposed. What I’m saying, I guess, is that it’s possible that there’s an environmental cause, but we’re wasting our time assuming that it’s smoking or alcohol or pesticides, or any other thing to which millions of people around the world are exposed on an almost daily basis.
I ran across an article that criticized this very study for a number of reasons, one of which being that the CNV was found in the control subjects as well, and not infrequently enough to make its presence in the ADD subjects statistically significant. Of course, I didn’t bookmark it, and of course, I was on such a science tear that I can’t pick it out from all the other URLs in my browser history. . .
However, PZ Meyers has an excellent explanation of evolution that has a couple of pieces that are relevant here. (If you visit, be forewarned that the site itself addresses a number of controversial issues.) Mutations are the root of biological variation, of course, but we often have a naive view of their consequences. Most mutations are neutral. Even advantageous mutations are subject to laws of chance in their propagation, and a positive selection coefficient does not mean there will be an inexorable march to fixation, where every individual has the allele. This is also true of deleterious mutations: chance often dominates, and unless it is a strongly negative allele, like an embryonic lethal mutation, there’s also a chance it can spread through the population.
Stop thinking of mutations as unitary events that either get swiftly culled, because they’re deleterious, or get swiftly hauled into prominence by the uplifting crane of natural selection. Mutations are usually negligible changes that get tossed into the stewpot of the gene pool, where they simmer mostly unnoticed and invisible to selection. Look at human faces, for instance: they’re all different, and unless you’re looking at the extremes of beauty or ugliness, the variations simply don’t make much difference. Yet all those different faces really are the result of subtly different combinations of mutant forms of genes.
“Combinations” is the magic word. A single mutation rarely has a significant effect on a feature, but the combination of multiple mutations may have a detectable or even novel effect that can be seen by natural selection. And that’s what’s going on all the time: the population is a huge reservoir of genetic variation, and what we do when we reproduce is sort and mix and generate new combinations that are then tested in the environment.
He continues with a description of an experiment with fruit flies that tested for heritability of a mutated trait:
We know that this recombination is essential to the rapid acquisition of new phenotypes. Here are some results from a classic experiment by Waddington. Waddington noted that fruit flies expressed the odd trait of developing four wings (the bithorax phenotype) instead of two if they were exposed to ether early in development. This is not a mutation! This is called a phenocopy, where an environmental factor induces an effect similar to a genetic mutation.
I’ve left out the rest, with charts and explanation, because it’s longer than a post here should be. What I felt was relevant here is that there’s a difference between a mutation that affects selection, and a mutation caused by environment. The mutations caused by environment could be inherited, but this one became prevalent in the fruit fly population only by manipulating the selection in the population. On its own, the phenocopy didn’t produce an evolutionary advantage that was naturally selected for.
Just something else to think about.
Most of what we know about the functions of each structure of the brain came from studying people who had been injured in that part of the brain. That’s great information, but has some shortcomings. Because subjects were injured, there was no information collected about their normal brain function beforehand for comparison. People with injuries to the same areas could be compared to one another so that the effects they all shared would indicate what function that area performed, but the overall effect on cognition was impossible to see, because the injured people were not able to understand and/or communicate the changes. V.S Ramachandran has written some amazing books on brain injuries and what we have learned from them, and I highly recommend all of them.
We also have the ability to measure activity in the brain to some extent, and have ways of stimulating the brain to measure results or response, but those also leave a lot of questions unanswered.
In that ADD is assumed to be caused at least in part to a deficiency in the frontal lobes where executive function is seated, then it’s reasonable to assume that a factor that inhibited development there or an injury to that specific area might cause a number of symptoms similar to ADD in the affected people. However, what the symptoms don’t show is the overall effect on cognition, which, again, is a drawback of studying the effect of injury.
If, in addition, there’s a difference in the way neurotransmission occurs, that’s an even more difficult thing to assess. The only way to study a brain to see how it’s processing a neurotransmitter is by performing experiments that would be unethical on humans, or by checking a brain after it’s been removed from its owner’s head. That’s why medication can be such a hit-or-miss proposition.
DNA, though, is now something that can be examined without harming the individual being studied. Since the heritability of ADD has been shown to be statistically significant, it stands to reason that searching for a shared genetic factor should eventually turn up something. Plus, like the search for commonalities among individuals with identical brain injuries, the search for commonalities among people with identical alleles (or identical alleles among people with certain commonalities) is a promising line of inquiry. If there weren’t some kind of information suggesting an answer could be found, nobody would even be thinking of doing any research on it.
My contention is that ADD arises without any of the suggested environmental factors, and exposure to the suggested environmental factors does not lead to ADD consistently enough to be implicated as its cause. As a person with ADD, I also feel that there are ways that my brain operates outside of the symptom checklist (things that get mentioned frequently among this community, as well) that should be considered as part of the condition – and which might serve to determine whether a person had ADD as an inherited condition or was suffering from ADD symptoms due to a physical or chemical injury.
Regardless, I think that before attributing a cause to one thing or another, we need to understand the scope of possibilities, and the limitations behind various potential causes. That means understanding how genetics and evolution work, and how environment can or cannot affect them.