If you have followed this blog for any length of time, you have probably figured out that I came to the science of aging through evolutionary biology, and that I believe evolutionary thinking is a key to understanding what aging is and how it can be addressed. So without further ado, I introduce a column that is central to how evolution works, but peripheral to the science of aging.
You know (or perhaps you take for granted or you’ve never thought much about it) that your body is really good at learning. Whatever it is that you persist in trying to do with your body, day after day over a period of time, your body gets better at it, stronger, more coordinated, more flexible, more skilled and versatile. (And conversely those potential strengths which you do not exercise will atrophy, and you lose them.)
You also know that you can’t pass these strengths and skills on to your children. They have to acquire them anew with their own effort and their own habits. Whatever is innate in your own heritage can be passed along with your genes, but whatever you have acquired or developed must be developed afresh by each new generation.
Wouldn’t it be great if we could get past this limitation? Imagine if you could bust your gut in Pilates class knowing that it wasn’t just your own abs you were strengthening, but a legacy you could pass to future generations? Imagine if your children could pick up where you left off developing their health and their skills and their coordination and reflexes, each generation building on the last to reach for higher and higher goals.
And what a boon for evolution, this would be – if only it were real!
The process I’m describing is Lamarckian inheritance, an attractive hypothesis, a long-discredited mechanism of evolution.
Curiously, some temporary kinds of Lamarckian inheritance have become well-established in recent years. Could it be that permanent, Lamarckian modification of the genome is also a reality?
Here’s how the story is still taught to this day:
In 1809, Jean Baptiste Lamarck’s theory of evolution was that the training and habituation that our bodies undergo when we exercise our muscles, when we endure heat and cold, when we use our brains to solve problems – these abilities acquired in a lifetime affect offspring, so that they are born better able to cope with whatever it is that the parents have coped with during their lives. Thus the environment and an individual’s response to it helps to shape the character of the next generation, and evolution proceeds efficiently in the directions of those qualities that are required in the environment, and those choices which the parents have made during their lifetimes.
Fifty years later, Darwin’s theory was that offsprings differ from their parents in ways that are purely random. The direction of evolution is controlled indirectly, because some of those offspring are better able to survive and to reproduce than others.
The difference is whether genetic variation is random or directed by the environment and life choices of the parents. Darwin said random. Lamarck said directed.
In the 1890s, August Weismann conducted an experiment in which he cut off the tails of rats and then measured the tail lengths of their progeny. He continued, cutting off the tails of 20 generations of rats, and yet each generation was born with tails just as long as the last generation. This was a definitive (?) refutation of Lamarckian inheritance, and scientists everywhere have developed the theory of Darwin, and reserved the story of Lamarck as a morality tale about discredited science.
If Jean-Baptiste had been alive to defend his theory he might have said that developing a trait by using the neural pathways and strengthening the muscles is quite different from hacking off a body part. What Weismann demonstrated had little to do with the heart of Lamarck’s theory.
But it wasn’t Weismann’s experiments alone that gave Lamarckism a bad name. Austrian Paul Kammerrer set out to prove the reality of acquired genetic inheritance, and was caught in scientific fraud. In the 1930s, Trofim Lysenko and the Soviet propaganda machine promoted Lamarckism not so much as a science but a political ideology. Communist social practice was destined to change the core of human nature.
The coffin of Lamarckism was sealed by Francis Crick, who not only discovered DNA as the repository of genetic information, but articulated in 1958 the Central Dogma of Molecular Biology: Information flows from DNA => Messenger RNA => Proteins, always in that direction. In 1958, there were no mechanisms known by which proteins could feed back to modify DNA, and Crick boldly speculated that no such mechanisms existed.
Here are some facts that don’t fit with that story:
Random variation is extremely inefficient. The big problem is that two or three or even dozens of genes needto change before a new trait can be acquired. Suppose that a few mutations appear that are steps in the right direction – how are those mutated genes to be preserved while waiting for other mutations that will complete the set and create something that actually offers some selective advantage? This problem has been called “irreducible complexity” by the Creationists, Christian critics of Darwinian evolution. Evolutionary scientists, under seige from the Creationists, have decided to “take no prisoners”, and so they deny there is any merit to this criticism, and pretend that Darwin’s theory of evolution works just fine as is. But the honest truth is that the Creationists have hit upon the weakest assumption of evolutionary theory as understood by mainstream scientists today. “Creation science” is in fact not a science at all, but a decision to give up on scientific investigation and accept without question that “that’s the way God made it”. This is not a path I find appealing; nevertheless, creationist criticism of the version of evolution based on one-mutation-at-a-time is actually quite well-founded.
Evolutionary scientists have always taken it on faith that there is a mechanistic explanation for the origin of every organ, every system, every biological function that we observe. We have hoped and assumed that the more we learn about the workings of the body, the clearer would be the pathway by which it might have evolved one-mutation-at-a-time, with each incremental step offering some selective advantage that would hold it in place while waiting for random mutation to come up with the other steps. But in fact, the more we know, the more puzzling cases we see of “irreducible complexity” which strains our imagination to account for a plausible evolutionary pathway.
Darwin knew this. Even in the first edition of The Origin of Species (1859), he admitted a role for the hfabits of the parents in determining the traits of the offspring. This idea was coded in the words “use and disuse” in the last paragraph of the book:
It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; Inheritance which is almost implied by reproduction; Variability from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms.
Through the development of Darwin’s thought after The Origin, the idea of Lamarckian inheritance gradually gained ground. In 1876 he wrote in a letter (published after his death):
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
Savor the irony that the version of Darwinism that is best accepted today is ultra-orthodox, far more narrow than beliefs and writings of Charles Darwin. If Darwin were submitting his papers to the journal Evolution today, he would receive a patronizing letter of rejection, criticizing his unfocused thinking, and warning him that Lamarckian inheritance is not a credible mechanism, and that he must re-frame his theory in terms of known, validated laws of inheritance.
This kind of censorship in the name of scientific orthodoxy is bad enough when it is well-grounded in empirical science. But in the case of Lamarckian inheritance, it is the mainstream scientists who have missed the boat.
Epigenetic inheritance is now un-controversial, mainstream science
The term “epigenetic” refers to any inheritance mechanism that is not coded directly into DNA. The best-established kind of epigenetic inheritance occurs through decorations and markers that surround the DNA and affect which genes are expressed and which are held in reserve for another time and place. Methylation of the DNA and acetylation of the histones are two of the best-studied markers that affect gene expression.
Methylation and acetylation patterns can change in response to habitual activities and to the envirnoment. These patterns are copied with the DNA – not quite so faithfully as the DNA itself – and can be passed from parent to offspring through multiple generations. This is a kind of temporary Lamarckian inheritance. It is indisuptably Lamarckian, but seems to last four or five generations at most, if it is not re-inforced.
- Children of obese mothers have greater risk of insulin resistance and diabetes [Ref]. (This inheritance is both genetic and epigenetic, and we have to trust that the authors of the studies cited here correctly separated the two with their statistical filter.)
- Traumatized mother mice are affected in their metabolic as well as their psychological responses, and these effects are detectable in the offspring of the traumatized animals out to the fourth generation [Ref]. Just this last week an article was published about male mice that transmit the effect of trauma to their young, and two more generations beyond.
- “One of the most dramatic examples is with diethylstilbestrol, a synthetic nonsteroidal estrogen prescribed in the 1970s to prevent miscarriage in women with prior history. While the drug helped pregnancies to go to term, it induced severe developmental abnormalities and increased the risk for breast cancer and a rare form of adenocarcinoma in girls whose mothers were exposed to the drug during the first trimester of pregnancy. Furthermore, the risk of cancer appeared to be transmitted to the following generation. A clinical study reported that a 15-year-old girl whose maternal grandmother was exposed to diethylstilbestrol during pregnancy was diagnosed with a very rare case of small cell carcinoma in the ovary. Many more of maternal granddaughters than expected also developed ovarian cancer. Although these findings are among the first and need to be confirmed by further transgenerational studies, they suggest that the detrimental effect of a drug can be transmitted across generations. Such transgenerational effect of diethylstilbestrol was also observed in mice. Similar to humans, perinatal exposure to the drug induced abnormalities in uterine development and uterine cancer in first and second generations. These abnormalities were suggested to result from aberrant DNA methylation in a gene that controls uterine development and in uterine cancer genes.” [from Franklin and Mansuy, 2009]
- Here’s an example that’s not really Lamarckian, but that clearly demonstrates epigenetic inheritance. There’s a mutation in a gene called Kit that causes brown mice to have white spots. One copy of the gene is enough to cause the spots. So experimenters crossed a mother mouse with one copy of the gene with an un-mutated father mouse that had no spots. According to standard Mendelian genetics, we would expect that half the offspring of the cross would get the Kit mutant gene from their mother, and half would get the mother’s normal gene. So they expected half the offspring to have spots. The surprise was that all the offspring had spots. With DNA tests, they checked and, as predicted, only half the offspring had the mutated Kit gene. Still, they all had spots. Epigenetics! The experimenters figured out that the mutated gene signals the body to silence the other copy with methylation. So the offspring mice inherited a methylated version of the normal gene from their mothers. The methylation was copied along with the DNA. [Ref]
Here is a Stanford study that isolated the epigenetic component of longevity inheritance in worms.
Eva Jablonka is an Israeli geneticist who realized early the importance of epigenetic inheritance, and has been writing about the subject for 20 years. Here is a review article from 2009 in which she lists hundreds of examples of epigenetic inheritance.
But where did epigenetic inheritance come from?
A question which I have not seen asked in the literature is this: The epigentic inheritance mechanism is itself permantly installed, presumably with a basis in the genome. So how did the mechanism of epigenetic inheritance come to be? Here is a prime example of irreducible complexity! Copying the methylation state requires a whole different set of enzymes from copying the DNA bases. Epigenetic inheritance offers many potential advantages over the long term, but it is not an adaptation that offers fitness benefits in immediate neo-Darwinian terms (survival or fertility).
In addition, it is agreed that mutations increase in response to stress
Epigenetic inheritance is a well-accepted Lamarckian mechanism, but it is temporary, and doesn’t affect the DNA itself. Is there also Lamarckian influence on the DNA?
Normally, DNA is replicated accurately, with negligible errors, but in times of stress something different happens. It was once described as a breakdown of the cell’s proofreading facility under stress. But it has now become a mainstream idea that this is no accident, that the cell flails at random, trying wild cards when it is clear that the standard strategy is not working so well. Jim Shapiro goes further, and describes “conservation in times of successful growth as compared to active restructuring in times of stress.” [my emphasis] Shapiro’s position stands out from the crowd, and he has credentials that suggest we ought to listen. My belief is that he is pointing the way to the future.
For example, it was once thought that UV radiation damages chromosomes, a purely physical effect of high-energy photons. The truth that has emerged is that the cell detects the UV as a stressor, and mutates its own DNA, under metabolic control, as part of an adaptive response. Whether the mutations are random or whether they are part of a directed response to the radiative environment remains controversial. This was discovered already in the 1950s by Swiss microbiologist Jean Weigle.
True Lamarckism in bacteria?
The classical model for investigating this question is the common E. coli bacteria. These bacteria can normally live on two kinds of sugar, glucose or lactose. For the purpose of experiment, a gene is disabled, preventing them from being able to digest lactose.
- If you put the mutated bacteria in a glucose medium, they do fine, and do not re-evolve the gene to digest lactose.
- If you starve them, with neither glucose nor lactose, they go into stress mode, increase their rate of experimental mutations, and re-evolve the gene to digest lactose.
- If you put them in a medium containing lactose but not glucose, it is claimed that they re-evolve the gene for lactose digestion more quickly. The perceived utility of digesting lactose stimulates them to acquire this ability efficiently.
But does this really happen? It has been a controversial claim for a quarter century. The experiments are not so easy to interpret, first because bacteria readily incorporate genes from their environment in the form of DNA loops called plasmids; and second because in the absence of lactose, it is hard to know whether just one bacterium out of many billions might have acquired the ability to digest lactose. [References: Original Nature article by John Cairns, 1988 proposing Lamarckian mutations in E coli; Davis 1989, a suggested mechanism; a quasi-Lamarckian view, 1990; a follow-on experiment 1996; another traditional explanation, 1997; Statemaster Encyclopedia article; a 2010 review of Lamarckism in bacteria; radical Lamarckian view based on quantum information]
From here, Shapiro takes a leap into full-blown Lamarckism
Shapiro has a thin, dense book called Evolution: A View from the 21st Century, in which he makes the case for a radical departure from the notion that evolution takes place by natural selection on random mutations. He cites evidence that the “mutations” that appear under stress are far from random, that in fact the cell is re-arranging its own DNA, and doing so in a way that is much more likely than “random” to produce an adaptive response to the particular stress at hand. “Natural genetic engineering”, he calls it. He has spent much of his career documenting this effect in bacteria, but he claims that animals and plants have far more sophisticated abilities to re-arrange their own DNA – it’s just that these are more difficult to see in the laboratory.
If Shapiro is right, then perhaps we can begin to understand the mystery of how evolution is so miraculously efficient as it seems to be. One way or another, we will have to leave traditional limits of neo-Darwinian evolutionary theory behind, and I believe that Shapiro’s work together with the literature of evolvability, provide the clearest roadmap we have for a new understanding of evolution.