Today’s offering is not directly related to aging, but I’m an evolutionary biologist and these ideas about the fundamental mechanisms of evolution are compelling to me. I think a deep shift in the foundations of evolution is imminent. If some of the following is unfamiliar, I hope you’ll find it worth learning about.
I came out of the closet as a Lamarckian two years ago in this space. I believe that experiences and adaptations that occur during an individual’s lifetime can affect the genetic legacy passed on to her offspring. Darwin believed this, but it was excised early from Darwin’s legacy. Though Lamarckism has been heresy for over 100 years, a Lamarckian mechanism would go a long way toward explaining how evolution manages to be as efficient and directed as it is. Just in the last 15 years, Lamarckian epigenetic inheritance has been documented in lab animals and in humans. These are temporary modifications to the chromosome that affect gene expression, but not the genes themselves. Effects can last for multiple generations, but they are not as “permanent” as modifications to the DNA sequence themselves. In addition, James Shapiro has documented full Lamarckian inheritance in bacteria. Yes, bacteria edit their own DNA.
The last step toward full Lamarckian inheritance would be: Do multi-celled organisms also edit their own genomes? Why shouldn’t we be as sophisticated as bacteria in this regard? The problem with this idea has been lack of a plausible mechanism. How can information about adaptations in this lifetime filter back to affect the DNA within sperm and egg cells that carry genetic information into the next generation?
To this question we now have a tentative answer. Last month, Science Magazine featured an extensive and quite technical article on retrotransposons, which suggests a possible mechanism for full Lamarckian inheritance. (The article is not framed this way, and nowhere does it mention Lamarck.)
When you use a muscle, it becomes stronger. When you practice thinking in a particular way, or playing a musical instrument or solving crossword puzzles or writing with pen in your right hand—any of these can lead to specific adaptations that improve your proficiency for that particular task. Conversely, if you don’t practice remembering your dreams or riding a unicycle, then your dreams become increasingly inaccessible and your potential to learn unicycle skills diminishes over time. But, of course, none of these adaptations affect your children. They get a clean slate, a fresh start in life quite independent of anything you did or didn’t do before they were born.
Darwin didn’t think this was a matter “of course”. Though he is most famous for introducing the idea of natural selection as the primary driving force in evolution, he also wrote about what he called “use and disuse” of a trait, contributing to enhancement of that trait not just in an individual but also his offspring and descendants. Late in life, he wrote
In my opinion, the greatest error which I have committed has been not allowing sufficient weight to the direct action of the environments, i.e. food, climate, etc., independently of natural selection. . . . When I wrote the “Origin,” and for some years afterwards, I could find little good evidence of the direct action of the environment; now there is a large body of evidence. [From a letter to Moritz Wagner, 1876]
Twenty years after Darwin, August Weismann cut off the tails of five generations of mice to seee if their descendants would be born with shorter tails. The experiment showed no effect. Though Weismann regarded the test as definitive, we might object that this is hardly a representative example of “use and disuse”. It came to be regarded as Strike one against Lamarckian inheritance in the halls of theoretical biology. Strike two came in the year 1900 when Mendelian inheritance was rediscovered, and biologists learned to distinguish the body, or soma, from a line of cells sequestered and destined for the next generation, the germ line. It was difficult to imagine a mechanism whereby experiences of the soma could feed back to affect the information stored in the germ line. Twenty more years passed, and Trofim Lysenko in the nascent Soviet Union performed his infamously tainted experiments, motivated by Lenin’s ideology to validate Lamarckian inheritance. If Lenin and Lysenko believed it, it can’t be true. Strike three.
So it became part of the evolutionary canon that all mutations are blind, that the experience of an individual is not passed to her offspring, that Lamarck was wrong and that Darwin was wrong to include a Lamarckian element in his theory. This became a widely-held premise of evolutionary genetics, though there was never a fair experimental test of the question.
By the time that Franklin, Crick and Watson found the structure of DNA and elucidated the replication mechanism, it only remained to seal the coffin of Lamarckism with one more nail, a conjecture that Crick called the Central Dogma of Molecular Biology. The Central Dogma says that DNA is an invariant repository of information for the cell. DNA is transcribed into RNA and thence to proteins, and information flow is always in this direction, never backwards from protein to RNA to DNA.
Cracks in the Ideological Wall
In th 21st century, the experimental situation has changed drastically, though the genetic dogma has not yet caught up. First, the epigenetic changes that contribute to adaptation during an individual lifetime have been found to be heritable over multiple generations. Second, experiments have confirmed that bacteria are able to edit their own DNA. Third, and the main subject of my story here, is a mechanism by which large, multi-celled critters like us change our DNA routinely during development and through the lifetime.
Subjecting lab animals (or humans) to one form of stress or another produces adaptations that not only persist for the individual’s lifetime, but can be passed down at least several generations in the future. This effect began to be observed in the 1990s. A decade later, DNA methylation was discovered. Methylation of a region of DNA is a signal that suppresses expression of nearby genes. Methylation is programmed by proteins called transcription factors, and is carried out by methyl transferase enzymes. When DNA is copied, often (but not always) the methylation state is copied along with it. This is the best-understood (not the only) mechanism by which epigenetic adaptations are passed from one generation to another.
This is a subject that has been the life work of Eva Jablonka. She has been writing about heritable epigenetics at least since 1989, and she has a 1999 book on the subject, and a broader perspective, updated 2014. Here is Jablonka’s best recent summary of the evidence (2009). She emphasizes that many aspects of the cell carry information, and that epigenetic inheritance is not limited to the programmed modifications of DNA that controls gene expression.
“Genetic engineering” in bacteria
This is the term used by Shapiro to describe diverse mechanisms by which bacteria restructure their own genomes. It was found experimentally in the 1980s that bacteria up their mutation rates in times of stress, but it was assumed that mutations are still random, and the organism is merely motivated to take big changes when it is in danger. But Shapiro shows us that the changes are not random, and that they are far more likely to generate new and useful functions than if the mutations were by chance. All changes to the DNA of bacteria are heritable, because it has only one copy.
Protists are single-celled eukaryotes, much more complex than bacteria, from which all multicelled life is descended. Protists also splice and dice their own DNA.
Do animals and plants edit their own genomes?
We are taught in school that our bodies have developed from a single fertilized egg, and therefore every cell in the body has the same DNA as that egg. The DNA in every cell in our bodies is identical (except for rare, random mutations).
This has been assumed without experimental support until four years ago, when a team of researchers from Yale decided to test it out. They were surprised to find substantial variation from one tissue to another in the DNA of a single individual. They looked in particular for copy number variation, in which segments of the genome typically a few thousand BP long are duplicated. They found examples wherever they looked, and they unconvered evidence that this is not random but functional. For example, genes that are expressed in the pancreas have extra copies in pancreatic cells. Regulatory genes that operate at a high level were more likely to be duplicated than downstream genes or regions of non-coding DNA.
Most of the biological community still believes what they were taught in school, but this finding suggests that the body is capable of editing its own genome for functional purposes. The article says nothing about the mechanism by which it is accomplished, but whatever it is, it is not hard to imagine that that same mechanism is harnessed for a Lamarckian function.
Retrotransposons: A candidate mechanism for Lamarckian Inheritance. .
This brings us to the article from three molecular biologists at University of Rochester that provided my inspiration for writing this page. It’s titled Retrotransposons as regulators of gene expression.
Retrotransposons are regions of DNA that can copy themselves to RNA, which then picks a site in the genome and inserts another copy of itself. “Retro” refers to RNA ⇒ DNA, which is opposite to the normal order of things, which was once called Crick’s “Central Dogma”. Retrotransposons are able to invert the Central Dogma because the particular sequence of RNA includes a binding site for an enzyme that copies RNA backward to DNA, and inserts into a chromosome. “Long” retrotransposons, or LINEs, actually contain a region that codes for the requisite enzyme; “short” retrotransposons, or SINEs, depend on the protein provided by LINEs.
LINEs and SINEs together constitute 30% of human DNA. By far the most common are a kind of short stretch known as Alu elements. There are over 1 million Alu elements, together making up 11% of human DNA.
Most researchers writing about transposable elements (TEs) regard them as random or (worse) “parasitic DNA”, existing just to duplicate themselves and go along for the ride, while persisting in genomes passed from species to species over tens of millions of years. I suspect that evolution is more efficient than this, and that anything lasting tens of millions of years has a purpose, whether or not we are yet able to divine what that is. In the case of Alu elements, the purpose is to affect DNA transcription, not just epigenetically but by locating strategically, so as to promote or suppress particular genes. This can happen in the soma, changing gene expression from one tissue to another, or in the germ line, making long-lasting changes to the genetic legacy.
Curiously, the article begins and ends with the assumption that TEs are parasites that have learned to copy themselves, and that organisms have learned to work around them. But in between, the article cites a great deal of evidence that TEs have acquired functions, and have evolved to be essential for life. I think it probable that anything that has survived tens of millions of years of natural selection has an adaptive purpose. I think of mitochondria as an analogy. Mitochondria began as parasites that invaded the first, primitive eukaryotic cells, but over time they became fully integrated into the cell’s energy metabolism, and eventually became essential for the cell’s survival. Perhaps retrotransposons had a parasitic origin once upon a time, but now they are part of the structure of DNA and part of the machinery of evolution.
Alu elements tend to be rich in methylation sites (CpG islands) which are places where the most common, best-understood kind of epigenetic regulation takes place.
Retrotransposons actively copy themselves, thereby restructuring chromosomes, during development. This accounts for some variation in DNA in tissues (documented in the Yale article mentioned above). There is also active copying throughout life within the brain, which makes me wonder if learning might be accompanied by restructuring DNA in the brain.
Carl Zimmer recently featured Job Dekker on a short video that explains the importance of the intricate way that DNA is folded over on itself, helping to determine which regions are transcribed and which remain locked up as heterochromatin. The stretches of TE DNA certainly affect transcription, and they are re-programmable during an organism’s lifetime. We might expect as a matter of course that the number and placement of TEs has been subjected to natural selection, and has become highly adaptive in a way that responds to experience during a lifetime.
We know for a fact that methylation programming extends back to the germ line, and accounts for heritable epigenetics. Now that we have a glimpse of the retrotransposon mechanism, why wouldn’t we expect it also to feed back and restructure the germline DNA?
The Bottom Line
Scientific bias against Lamarckian inheritance is an anachronism. Some modes of Lamarckian evolution have been firmly established. The most general and most permanent form has never been tested competently. The last remaining argument against it was the difficulty of imagining a plausible mechanism. What we have learned about retrotransposons and genetic variation among different tissues of the same body removes that objection.
The time is ripe for a well-planned exploration of Lamarckian inheritance in various circumstances, with a variety of animal and plant species, coordinated over multiple laboratories worldwide. At this point a “surprising” result is to be expected.
Interesting take on TEs. I’m curious about the role in neurons. Thanks for posting.
Here is some information from a few years ago: http://learn.genetics.utah.edu/content/epigenetics/brain/
The problem of course is that true mutation with selection does in fact occur. Shapiro cannot explain the results of the Lenski experiments with E. Coli nor could what you have demonstrated here. Twelve genetically identical samples have diverged with one becoming a new species. With what you have proposed above, this should not happen. The E. coli should “edit their” genome in predictable and consistent ways under identical conditions. We also see non-selective change and genetic drift which would not fit with an epigenetic model. Gene doubling also falls out of this model, and it is essential in explaining the lengthening of simpler proteins into more complex proteins.
What is true is that epigenetics has a role in evolution. However, we cannot swing from one extreme to the other – it simply doesn’t fit with the evidence.
I think there’s plenty of room to explain Lenski’s results if we allow roles for both random mutation and directed restructuring of the genome.
“Shapiro cannot explain the results of the Lenski experiments with E. Coli nor could what you have demonstrated here. Twelve genetically identical samples have diverged with one becoming a new species. With what you have proposed above, this should not happen.”
Lenski: “Each day, 1% of each population is transferred to a flask of fresh growth medium. ”
Repeated dilution might be quite a strong stress factor. Imagine someone did it to you, your family, your community… you make friends and contacts in the morning, and in the evening 99% of your friends are gone! Lamarckian adaptation follows.
For the record, I don’t believe that Lenski’s marathon experiment carries a message one way or the other about Lamarckian inheritance.
Thanks for the concise review on the state of intergenerational epigenetics. We still have a long way to go before we have reasonably accurate human model for heritability. Our book, Biohistory by Jim Penman, outlines a theory for the principles of epigenetic heritability through the study of patterns in history and social change. This allows us to come at the research in this field from a different perspective, to suppliment the work of MJ Meaney, O Rechavi and other leaders in this field. Go here http://www.biohistory.org/biohistory-explained/ see more about our theory of social change.
Multiple people have pointed out that random mutation coupled with natural and sexual selection as the complete engine of evolution appears to be implausible when you consider that the ratio of sense proteins to non-sense proteins that can be assembled by randomly assembling amino acids. To produce a “better” protein based on selection of random mutations will not produce a “more fit” protein frequently enough to drive evolutionary processes in any population of finite size.
Johnjoe Mcfadden and Jim Al-Khailli in their book “Life on the Edge” propose that DNA operates as a quantum computer or quantum computation and strongly biases mutational events towards beneficial mutations.
On the topic of the relevance of epigenetics on aging theory and research, I do think that it is relevant in that it can possibly explain why we see species with the capability to adjust the aging rate of their populations so quickly as the rate of predation changes. Reductions in predation rate on the population can reduce stress on the population causing an epigenetic change to germ cells, resulting in epigenetically determined longer life spans in progeny.
I once felt that the speed with which a species could adjust its rate of aging was a strong indicator that there must be only a few genetic loci that determine rate of aging, otherwise how could rate of aging change so rapidly in a species? However, now in the light of trans-generational epigenetics it seems plausible that aging is governed by a complex set of genetic loci that can only be changed slowly in evolutionary time. However this limitation could be compensated for by the endocrine systems ability to effect epigenetics via stress hormones etc. In essence the endocrine/epigenetic axis affords a population the ability to tweek the rate of aging based on predation rates over a small number of generations. This may be what we are experimentally observing much of the time?
It seems to me that epigenetics may afford us the ability to effect human life span by some percentage but biological immortality will require effecting all the genetic loci that foundationally may be in control of programming death and there could be a large number of such genes since our epigenetic mechanisms might be handling the need to up and down regulate aging rate in response to transient changes in predation rate over short multi-generational time.
I believe transposable elements are directly related to ageing. The general demethylation that occurs with ageing allows increased transcription of transposable elements and it is assumed to have a role in the ageing process. There are plenty of articles for example this one
Josh your thinking is on track. I teach zen- meditation and philosophy, a big part of which is seeing through illusions. We are trapped in our culture with all it’s preconceptions and prejudices. It’s our eccosystem! You have the ability to see through it all and get the big picture. Standard evolution is wary of the word epigenetics – as much as they may see themselves as critical thinkers. I’m off to the gym for a bout of negative stress. But fear not I’ll be biologically younger tomorrow. Keep up the great work, zen- master….
Be patient. They’re still asking themselves how the information survive the great epigenetic erasure event the egg go through right after fertilization, lolz ^_^’
After I wrote this, I came upon the Nobel Lecture of Barbara McClintock, and I realize that she had not only discovered transposable elements, she also realized that they had a major effect on gene expression. Her work was done in the 1940s and 1950s.
McClintock’s work was done in the 40s and 50’s—–!
“Sometimes it’s not so much the discovery of something new as in seeing what’s in front of us with new eyes…”
Interesting stuff. Check it out. Seems to be the the final piece needed for full Lamarckian inheritance. Evidently environmentally-induced Epigenetics leads to mutation. Big stuff. http://www.tandfonline.com/doi/full/10.1080/15592294.2015.1062207#/doi/full/10.1080/15592294.2015.1062207
Yes! This seems to provide the last step of the mechanism I was speculating about.