In the first comment on my last blog, Philip Rivera posted:
Unfortunately IMHO, your newer articles are still way too complex for the general public to grasp and the problem is that they are far less knowledgeable about evolution.
...
So keep it VERY simple ... [T]here is 100,000 potential average readers who need to learn from you! However, they should not have to be first versed in the Latin and Greek languages and have a science degree in order to grasp your theories!
Dr. Shapiro, you currently have arguably the most powerful message from science to the general public, but it is worthless if it is not understandable. Your detractors know this...
Since Philip's well-intentioned criticism was justified and constructive, I'll revisit the subject of genetic recombination differently so my main point is easier to understand. Readers who want to access experimental details can find appropriate links in the previous blog.
In the pre-DNA era, students were all taught that genetic change is random and accidental. Because the molecular details were inaccessible, this was the default assumption. But once we learned about DNA carrying hereditary information, we could research the details of how changes occur. We no longer needed to assume. We could investigate.
One of the main topics in molecular genetics has been the process of recombination between homologous chromosomes. This process makes it possible to construct genetic maps showing the relative positions of markers along the chromosomes.
Homologous recombination is not accidental. It is a required part of the special cell divisions called "meiosis" that that produce sperm and egg cells with only one copy of each chromosome. Without meiosis, sexual reproduction would not be possible as found today in higher organisms.
During recombination, chromosomes physically swap segments to generate new combinations of genetic loci without changing their order. Examining how frequently different combinations arise is the basis for computing genetic maps.
In the pre-DNA period, recombinational exchange was called "breakage and reunion." This physical swapping means that cells undergoing meiosis have to cut and splice the DNA molecules in their chromosomes. Molecular studies have revealed that at least a dozen proteins acting in sequence carry out such accurate cutting and splicing (one form of natural genetic engineering).
Recombinational exchange starts with breaks in DNA. When this occurs accidentally, it initiates a recombination process that repairs the break. This repair capacity may well be the original adaptive function of this sophisticated biochemical process.
But cells do not leave to chance what happens to their genomes. They use special DNA-cutting enzymes to initiate recombinational exchange. A University of Chicago colleage, Rochelle Esposito, discovered the enzyme used in meiosis. This enzyme prefers certain DNA sequences to cleave and creates so-called "hotspots" where recombination occurs most often. Sequence preference is one source of non-randomness in recombination.
We have recently learned that mouse cells exert control over recombinational hotspots in meiosis. They produce a blocking protein that binds to cleavage sites that coincide with highly evolved combinations of expression signals in the DNA. This inhibition protects those adaptive combinations from disruption by recombinational exchanges. As we often find in cell biology, one specificity leads to another so biochemical processes are tightly controlled against bad outcomes.
Not all recombinational exchanges occur at corresponding positions on homologous chromosomes. As DNA sequencing reveals, genomes are full of repeated segments at many different locations. Our own genomes contain over 40 percent of their DNA as dispersed repeats.
Recombination between repeats at different locations leads to chromosome rearrangements. Because the locations of the repeats determine where the rearrangements occur, this is another non-random feature of recombinational exchange.
Different organisms take advantage of both sources of non-randomness to target recombinational exchange for functional goals. Cells transfer different DNA sequence information from one genomic location to another when the differences are surrounded by homologous repeats. The cells use specific cleavage at a repeat to initiate recombinational exchange.
The generic term for a sequence flanked by homologous repeats is "cassette." Cassette exchange serves a number of different adaptive purposes, illustrating how inherent non-randomness in natural genetic engineering can be used and reused.
In yeasts, cassette exchange functions to switch mating types -- in effect to perform a sex change. This benefits the yeast cells because it allows the progeny of a haploid spore with one copy of the genome to produce cells of opposite mating type, which can fuse to cells of the original mating type to form diploid cells with two copies of the genome. Being diploid is advantageous because it enables the cell to repair accidental DNA breaks by recombination.
In disease-causing microbes, both bacteria and eukaryotes, cassette exchange serves to alter the DNA encoding surface proteins. By regularly changing surface protein structures, these organisms can adapt to new niches in their hosts and evade immune system defenses. The tenacity of illnesses like Lyme disease and sleeping sickness is a direct result of the causative microbes escaping immune surveillance through cassette exchange.
In chickens, the immune system itself uses recombinational cassette exchanges to diversify antibody structure. This diversification is essential to producing antibodies that can recognize an unpredictable variety of invaders.
In this blog, we have seen some functional advantages of non-random natural genetic engineering by homologous recombination. The benefits extend from disease-causing bacteria through sex-changing yeasts to disease-fighting chickens. Uncovering these examples is just one result of the tremendous scientific transition in which we have advanced from treating hereditary mechanisms as a black box to examining DNA-based inheritance in precise molecular terms.
I hope Philip Rivera will let me know if this version of the story satisfactorily responds to his critique.
This looks interesting.
You seem to be suggesting that there's something in the cell machinery that somehow "knows" what's an adaptive combination and what is not. Do you have a reference for this?
I'm slow on the uptake, but have you basically been saying all this time that a cell can recognize a change in their outside environment, and then splice their DNA to a couple of pieces, then rearrange them in a "targeted location" and adjust to their new environment? Wow! Any idea's on how a cell came to know that there was an outside environment? And how did it evolve the capacity to "experiment" until it gets it right while avoiding "Bad outcomes"? And whats the highest number of splicing and rearrangement "experiments" done by a cell to adapt, that has been observed by science? And how can a Darwinist continue to claim that it can all be explained by just Random Mutations and Natural selection? Don't they see the same thing happening under their microscopes?
No wonder why your no longer on Jerry Coyne's Christmas list!
Fascinating stuff Dr. Shapiro!
I hope you notice how careful I try to be in what I say. Cells do have the activation and targeting capabilities I claim. That has been empirically demonstrated. How efficiently they use them in generating adaptive changes remains to be determined.
I know that none of what I have to say is welcome to Jerry Coyne and his allies. But I count on more open-minded people like you to make sure that I continue to distinguish clearly between what has been documented and what we can only project may be possible.
The reason I wrote the two blogs on experimental tests of coordinated naturale genetic engineering (http://www.huffingtonpost.com/james-a-shapiro/network-evolution-genetics_b_1594000.html and http://www.huffingtonpost.com/james-a-shapiro/experimental-evolution-ho_b_1619171.html) is to emphasize what capabilties still need to be documented in real time. I hope there are brave experimentalists out there who will pick up the challenge and do the tests.
The information you are presenting here is interesting and important.
You can go a long way in simplifying the language you use. Examples: preferring words from daily speech over "$2.50 words;" using imagery; and more lively sentence structure. A quick example:
"This diversification is essential to producing antibodies that can recognize an unpredictable variety of invaders." VS. "This makes antibodies with lots of differences between them. Agents that can cause disease are many, and can change suddenly. A diverse population of antibodies is more likely to include some that can destroy a new kind of invader."
I don't know whether this conveys the idea properly, but maybe it gives some flavor of different uses of language. Try reading the two versions out loud.
I understand that once a person gets into the habit of writing (or, God forbid, sometimes even speaking) in academic style, it is so ingrained and automatic that it is very difficult to shake.
Technically intricate ideas can be discussed in straightforward language without "dumbing them down."
Merci pour les commentaires. Thanks for the comments. I assume you use the French for a moniker because that says something about your heritage.
I recognize the problem you point out. The advantage of expensive words is that they say a lot in less space. HuffPost puts a word limit on the posts. So it is a challenge to be both clear and terse.
I'm still on a steep learning curve. I'll appreciate your help in moving closer to the sweet spot where clarity, brevity and accuracy all come together.
You are getting close Dr Shapiro, but it is still too complex. I would dare say that 99% of the Huff readership did not know what “Genetic Recombination” was and didn’t bother to click on this article! I highly suggest you read and compare your articles to the other scientific articles written in the Huff Post. Those science authors have successfully overcome the challenge of reaching the public. They grab the reader’s attention and keep it! Their easy reads to understand. Now you have a far more compelling message that can and will change the evolution debate forever if you can communicate it in plain language like they did! Try tossing in simple analogies, link the big words to Wiki, ask yourself if the average 17 year old will "Get it!" and want to "Get it!"
Werner Heisenberg stated,
“The physicist may be satisfied when he has the mathematical scheme and knows how to use for the interpretation of the experiments. But he has to speak about his results also to non-physicists who will not be satisfied unless some explanation is given in plain language. Even for the physicist the description in plain language will be the criterion of the degree of understanding that has been reached.”
So, I won’t be completely satisfied until the average person is discussing it, there is a lot at stake!!!
: )
Thanks for the feedback. I need to strike a balance between comprehensibility and accuracy. Oversimplifying analogies won't do the job, but putting the problems of evolutionary engineering into more familiar terms is a good idea.
Now, after reading your book, which led my to Keller's book on McClintock (great reads both), I'm experimenting with writing about TEs for my non-scientists' writing group. It's not easy.
IOW, one might wonder how the differences in stability of elements of DNA are established and maintained..
The conventional explanation is that certain DNA regions are stable because they are essential and any changes would be counter-selected. However, there are some ultraconserved sequences (i.e. virtually no changes over very long evolutionary distances) that seem to be dispensable under laboratory conditions.
Knowing that genetic changes are regulated and targeted provides an alternative explanation for more and less variable parts of the genome. Regions may be shielded from change, for example, by epigenetic modifications or by blocking proteins, as in the mouse example cited in the blog. We can expect to find more cases like that in the future.
However, in your comments here you use words like “targets” and “goals” in order to explain the observed biology. Such words cannot help but indicate directionality (i.e. targets and goals have a direction; they are something sought to be obtained; a course of action taken among other possibilities; the very antithesis of a random walk). Yet you have provided no source of the targets and goals, no mechanism of origination, no capacity of measurement related to either their need or attainment (ala Pattee, von Neumann, etc). It’s as if the goals simply appear because they are useful. But what is induces “what is useful” in the system?
Calling these biological events “natural genetic engineering” seems to only beg the question. It’s certainly a satisfactory answer to say the proximate cause of control is written into the programming of the cell, but that only pushes the question back to a systematic level; it doesn’t explain how measurement and choice contingency (required to ‘obtain a goal’ among possibilities) could become instantiated in the system. And given the cell’s programming itself requires physical representations and physical protocols in order to function, yet another layer of measurement and contingency reveals itself.
You have put your finger on key questions for 21st Century research. How cells make survival and proliferation decisions is a central question. Clearly, we don't have answers yet, but we will before the century is out.
As for goal-setting, that is another area we need to investigate. Something has to lie behind successful innovations, but we are hard pressed to define it, let alone explain it.
As I use the term, targeting is different from goal-setting. Targeting refers to the ability of cells to direct genetic changes to preferred locations in the genome. It is an observable phenomenon, and we have information on the molecular processes involved (e.g. DNA binding specificity, protein-protein interactions).
As I see it, our experimental approach has to be based on the recognition that cells have the capability to selectively activate and target natural genetic engineering functions. It would be surprising for cells to have the tools to engineer their genomes but not use them in an efficient way. We need to devise ways of challenging cells to engineer their genomes creatively (i.e. produce novel functionalities) and then figure out how they do so.
I wish I could give you answers, but you have asked about what we still need to learn. Establishing that teleological questions are critical will itself take a considerable effort because we need to overcome the long-held but purely philosophical (and illogical) assertion that functional creativity can result from random changes.
Thank you for your comments. To have someone of your capacity suggest that teleological questions are critical to the advancement of biology should be warmly received in many quarters. I agree with you that we will someday have the answers to those questions (at least) from the standpoint of the programming and operation of the autonomous cell, or as Pattee referred to it, “the paradox of semiotic control of a physical system”. The 'paradox' was his reference to the material incompatibility that exists between (energy) rate-dependent physical laws, and the rate-independent symbol systems that harness those physical laws. I am of the belief that the origin of semiotic control will continue to elude us for those well-documented reasons.
I think it forces an interesting disciplinary question. We operate from an assumption there is a natural mechanism whereby rate-independent *control* can arise from rate-dependent physical law; even as we discount the “purely philosophical and illogical” notion of random changes in control leading to functional creativity. Von Neumann demonstrated convincingly in the 1950’s that the *capacity* to control cannot arise from the controlled, and now you’ve broken ground that this notion of random changes resulting in creativity is false. At what point (as we go through these next years realizing the *operation* of the system) will it become possible for an investigator to respectfully suggest that “something else is indicated” or "something else may be required" without forfeiting his or her career and academic status?
"This process makes it possible to construct genetic maps showing the relative positions of markers along the chromosomes."
What is a 'genetic map'? What's a 'marker'? The following link provides a nice clear answer.
http://www.genome.gov/10000715
This way, important terms can be clearly defined and explained without going beyond your space limits. By doing this, readers who want/need more information can get it quickly and painlessly.
I generally do include links where the place to look is not obvious. This post was special in that I wanted to KISS, as Philip Rivera suggested, and use as few links as possible (in this case, one).
I assume that readers who encounter a novel term will automatically go to Wikipedia or Google to find out what it means. This greatly simplifies the posting process. I may add a generic alert to use Wikipedia or Google at the start of each blog. Do you think that would help?
Now at least a undergraduate student will understand it. :-)
I guess that educating the general public is very difficult. The most broaden view on general public is society as a whole, but most of the people do not have a clue about genetics and evolution.
So I think this is nicely done when the aim of this post is to improve understanding among the somewhat-knowing general public. For example, I know what homologous recombination is, and understand everything, that is because I am trying to become a geneticist, but most people don't.
What is exactly the goal of this blog? Which readers do you have in mind? Are you trying to convince people like me, who aspire to be scientists? That is not clear from the previous posts and this post. Some are extremely difficult (I like that, but probably I just have to read your book ;-)
Others are more general. But this was for sure the easiest post that I read on this blog for quite a while!
Keep up the good work! Don't mind my critical remarks, just trying to give positive feedback.
First, thanks for the positive remarks on comprehensibility. Having lived with molecular genetics for the last 48 years, it is hard to know what other people may or may not know about the subject.
"What is exactly the goal of this blog? Which readers do you have in mind?"
The goal of the blog is to make all kinds of people - biologists, other scientists, IT specialists, the general public - aware of the tremendous revolution in our understanding of genetics that has taken place in the last six decades. This is necessary because that awareness is missing in important public debates about evolution.
The molecular evidence gives us a totally new way to think about evolution. It contradicts much of the conventional wisdom that so many people rightly find hard to swallow. In addition, it provides potential scientific answers to problems that other people claim need supernatural explanations.
Since our nation's educational system is at stake in the evolution debates, I think the effort is worth making. Both the technical and lay audiences need to learn about the most current science. I and some of my colleagues are struggling to make it comprehensible. Any help that you and other readers can provide through your comments (supportive or critical) will be most welcome.
This endeavor is a worthy one, because the worst thing of all is for someone to listen to extremists on either end of the debate argue with each other... and never realize *neither* side is reporting the real science.
I salute all who are willing to read this with enough care to absorb it; this is worth knowing.
Now that you've read this one, try the previous blog to see if it make any sense to you. If not, let me know what your problems were.
Converting cutting-edge science into understandable explanations for the lay public is never an easy task. Those of us trying to do it need all the help we can get.