Among the 20th Century's truly great biologists, the pioneering American geneticist Barbara McClintock is still largely unknown to the public -- except, perhaps, for the fact that her views were decidedly different from those of her mainstream colleagues. Among her accomplishments, McClintock was the first person to document genome repair by living cells. But this fundamental discovery does not appear in the introduction to the Wikipedia biography highlighting her major achievements.
Wikipedia reflects the general perception that the work for which McClintock received the 1983 Nobel Prize in Medicine or Physiology -- the discovery of transposable elements in maize (corn) -- arose more or less independently of previous work. Transposable elements are chromosome segments that can change position, or "transpose," in the genome. The results that led her to describe and document transposable elements did come as a complete surprise -- but a surprise for which she was well prepared (McClintock 1984; McClintock 1987).
Transposable elements have revolutionized our understanding of genome change. Unlike the "genes" hypothesized by pre-DNA genetic theory, transposable elements do not occupy a permanent location on a particular chromosome and can be distributed throughout the genome. In fact, they account for between 40 and 65 percent of our own DNA and exceed protein-coding sequences more than 25-fold in abundance (Lander, Linton et al. 2001; de Koning, Gu et al. 2011).
We now recognize that there are several classes of mobile genetic elements that can move from one place in the genome to a new location (Shapiro 1983; Craig 2002; Shapiro 2011). An earlier blog explained how these mobile elements have played key roles in evolutionary innovation.
X-ray mutagenesis involves cell repair functions and chromosome rearrangements, not "gene mutations"
In her Nobel lecture, McClintock took pains to explain her early work on the chromosomal basis of X-ray mutagenesis, discovered in the 1920s. X-rays were the first of many external agents that have been shown to induce mutations, or hereditary changes, in living organisms. McClintock set out in 1931 to analyze the X-ray mutants Louis Stadler had isolated from maize plants at the University of Missouri. She was well qualified for doing this; as a graduate student at Cornell in the 1920s, she had personally developed the microscopic methods that allow scientists to visualize the 10 maize chromosomes.
Based on her understanding of chromosome behavior, she made a hypothesis to explain the behavior of certain so-called "variegating" mutants. These mutants were unstable and changed (or "variegated") in their inherited properties as the organism develops. McClintock proposed that variegating plants carried ring chromosomes formed by the fusion of broken chromosome ends at either end of a previously linear chromosome. Such ring chromosomes would tend to be lost during the process of cell divisions as the plant grows, thus producing the variegated patterns.
Some colleagues scoffed at McClintock's idea, but in 1932 she went on to demonstrate that the predicted ring chromosomes were present in the variegating mutants (McClintock 1932). Other mutants induced by X-ray treatment also carried chromosome rearrangements (deletions, translocations, inversions, duplications). All of these could be explained as the results of breakage of one or more chromosomes at two sites and rejoining of the broken ends to reconstitute novel chromosome structures.
McClintock reasoned that maize cells must have an inherent capacity to join broken chromosome ends when two of them are present in the cell. In the mid 1930s, she devised experimental methods to induce new chromosome breakage events. Using these experimentally generated breaks, she demonstrated conclusively that maize cells have the ability to detect, bring together, and fuse broken chromosome ends (McClintock 1939; McClintock 1942). Because these studies on broken ends were so important to her thinking and later discoveries, she fully described and illustrated them in her Nobel lecture (McClintock 1984).
Sensitivity and responsiveness, not mechanism, were the key subjects of her Nobel lecture.
McClintock realized two things from those highly original studies of the X-ray mutants. The first was that the action of the X-rays was to break chromosomes. Breakage alone, however, was not sufficient to generate a mutant chromosome. Broken chromosomes would be lost. The cell's ability to repair the damage by fusing broken ends was essential. In other words, X-ray mutagenesis required cell action. It was not a passive consequence of the physical damage induced by the radiation.
The second realization was that maize cells have sensory and other capacities needed to identify, locate, and join the broken chromosomes. Repair was an example of action by what McClintock came to call "smart cells."
"There must be numerous homeostatic adjustments required of cells. The sensing devices and the signals that initiate these adjustments are beyond our present ability to fathom. A goal for the future would be to determine the extent of knowledge the cell has of itself and how it utilizes this knowledge in a "thoughtful" manner when challenged" (McClintock 1984).
This kind of thinking was indeed far outside the mainstream. It is the reason that the neurobiologist and bacterial behavior researcher, Dennis Bray, comments in his 2009 book, Wetware: A Computer in Every Living Cell (Bray 2009), that McClintock was the first biologist to ask what a cell knows about itself.
McClintock's studies of chromosome breakage and repair led directly to the experiment that resulted in the discovery of transposable elements. In 1944, she applied a technique to introduce broken chromosome ends in the pollen grains and egg cells that fused to generate zygotes. McClintock's original idea was to use this method to generate a series of deletions from a specific chromosome region. But, as she wrote:
Although all of this was known before the 1944 experiment was conducted, the extent of trauma perceived by cells whose nuclei receive a single newly ruptured end of a chromosome that the cell cannot repair, and the speed with which this trauma is registered, was not appreciated until the winter of 1944-45.
In addition to the predicted deletions, McClintock obtained a large number of variegating plants. Some of the variegation patterns involved chromosome breaks, which she documented by microscopic photography of cell nuclei (McClintock 1952). Over the years 1944-1947, she demonstrated that the genetic instabilities she observed were the results of activity by what she called "controlling elements" -- genomic factors that could move to new locations, alter the expression of genetic loci where they inserted, and generate a variety of chromosome structural changes.
By 1947 it was learned that the bizarre variegated phenotypes that segregated in many of the self-pollinated progenies grown on the seedling bench in the fall and winter of 1944-45, were due to the action of transposable elements.
Rather than explain how she demonstrated transposition, the process recognized by the Nobel Prize, McClintock chose instead to relate later experiments that confirmed that the "shock" from receiving a single broken chromosome end had the extraordinary effect of awakening previously latent transposable elements in the genome:
It seemed clear that these elements must have been present in the genome, and in a silent state previous to an event that activated one or another of them. To my knowledge, no progenies derived from self-pollination of plants of the same strain, or related strains, had ever been reported to have produced so many distinctly different variegated expressions of different genes as had appeared in the progenies of these closely related plants grown in the summer of 1944. It was concluded that some traumatic event was responsible for these activations.
Most of the remainder of McClintock's lecture provided "further examples of response of genomes to stress." She wished to emphasize the generality of her observations across the living world, taking examples from both plants and animals. With respect to evolutionary change, she emphasized the "shock" of interspecific hybridization, a process that leads to whole genome doubling, widespread genome reorganization, and formation of novel species. For McClintock, genome change was not accidental. Change was a response to life history challenges.
McClintock saw the future agenda for biology as part of an unending scientific revolution
Why did McClintock focus so much attention on cell sensing and not on research that provided molecular evidence in support of her previously heretical views (Shapiro 1983)? From the way she ends her lecture, we can conclude that McClintock had her perspective directed towards the years ahead rather than those behind:
In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome. We know about the components of genomes that could be made available for such restructuring. We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.(McClintock 1984)
McClintock apparently wanted to draw special attention to the most challenging problems in biology: cognition and purposeful action by living cells. As she knew well from her long experience with 20th Century genetics and cell biology, whether life has special "vital" properties that separate it from inorganic matter has been among the most fiercely disputed topics in the history of science. In its early days, molecular biology promised to provide us with an explanation of life in terms of physics and chemistry. However, since the 1960s it has succeeded instead in amazing us with the richness and sophistication of intra- and inter-cellular control and communication networks.
In conversation, McClintock expressed the conviction that computers and information science would help open our eyes to a more inclusive and realistic picture of the genome and its place in the living cell. Near the beginning of her lecture, she predicted an ongoing series of conceptual upheavals:
Because I became actively involved in the subject of genetics only twenty-one years after the rediscovery, in 1900, of Mendel's principles of heredity, and at a stage when acceptance of these principles was not general among biologists, I have had the pleasure of witnessing and experiencing the excitement created by revolutionary changes in genetic concepts that have occurred over the past sixty-odd years. I believe we are again experiencing such a revolution. It is altering our concepts of the genome: its component parts, their organizations, mobilities, and their modes of operation. Also, we are now better able to integrate activities of nuclear genomes with those of other components of a cell. Unquestionably, we will emerge from this revolutionary period with modified views of components of cells and how they operate, but only, however, to await the emergence of the next revolutionary phase that again will bring startling changes in concepts.(McClintock 1984)
Let us hope that her expectations are fulfilled in the 21st Century with all the "pleasure" and "excitement" this extraordinary scientist experienced for much of the 20th Century.
References:
Bray, D. (2009). Wetware: A Computer in Every Living Cell New Haven, CT, Yale University Press. ISBN 978-0300141733.
Craig, N., Craigie, R, Gellert, M, Lambowitz, AM (2002). Mobile DNA II Washington, American Society for Microbiology Press. ISBN 978-1555812096.
de Koning, A. P., W. Gu, et al. (2011). "Repetitive elements may comprise over two-thirds of the human genome." PLoS Genet 7(12): e1002384. http://www.ncbi.nlm.nih.gov/pubmed/22144907.
Lander, E. S., L. M. Linton, et al. (2001). "Initial sequencing and analysis of the human genome." Nature 409(6822): 860-921. http://www.ncbi.nlm.nih.gov/pubmed/11237011.
McClintock, B. (1932). "A Correlation of Ring-Shaped Chromosomes with Variegation in Zea Mays." Proc Natl Acad Sci U S A 18(12): 677-681. http://www.ncbi.nlm.nih.gov/pubmed/16577496.
McClintock, B. (1939). "The Behavior in Successive Nuclear Divisions of a Chromosome Broken at Meiosis." Proc Nat Acad Sci USA 25(8): 405-416. http://www.ncbi.nlm.nih.gov/pubmed/16577924.
McClintock, B. (1942). "The Fusion of Broken Ends of Chromosomes Following Nuclear Fusion." Proc Nat Acad Sci USA 28(11): 458-463. http://www.ncbi.nlm.nih.gov/pubmed/16578057.
McClintock, B. (1952). "Controlling elements and the gene." Cold Spring Harb Symp Quant Biol 21: 197-216. http://www.ncbi.nlm.nih.gov/pubmed/13433592.
McClintock, B. (1984). "The significance of responses of the genome to challenge." Science 226(4676): 792-801. http://www.ncbi.nlm.nih.gov/pubmed/15739260.
McClintock, B. (1987). Discovery And Characterization of Transposable Elements: The Collected Papers of Barbara McClintock New York, Garland. ISBN 978-0824013912.
Shapiro, J. A. (1983). Mobile Genetic Elements. New York, Academic Press. ISBN 978-0126386806.
Shapiro, J. A. (2011). Evolution: A View from the 21st Century. Upper Saddle River, NJ, FT Press Science. ISBN 978-0132780933.
I count another eight comments from you in the ten hours since I last commented on your previous 40 interventions. Please relax and let other people chime in without having to address your repetitive complaints.
You say you wish empirical evidence. My book contains over 1100 references, and I made a couple thousand additional citations available online by clicking the links at http://shapiro.bsd.uchicago.edu/evolution21.shtml.
I have explained in the book and in other HuffPost blogs the many ways that molecular genetics and genome sequences provide us with a radically different picture of how, when and where genome change occurs during evolution than does conventional neo-Darwinian theory. Cells have sensitive, regulated, non-random biochemical systems that change DNA in an episodic way that reflects the kinds of life history events that McClintock was the first to document. This and many other features of real-world genome innovation are incompatible with the neo-Darwinian Modern Synthesis.
Read the book and/or the blogs and challenge, if you wish, specific arguments made there. Then we can all have a far more enlightening conversation.
It does, indeed, seem though, as if cell repair is becoming "The New Flagellum" for some Huffpo commenters. Which, indeed, cements my argument why it is not a good idea to introduce animistic terms into scientific language. Some people will actually take them literally and run with them, no matter how removed these ideas are from the original content that sparked them.
Are we merely talking the meaning of "cognition" down to the lowest uncommon denominator to be able to apply it to a number of processes by which cells repair and manipulate their own DNA, which have not been contested by molecular genetics in decades (if I can believe a geneticist friend of mine who pointed many of these out to me almost ten years ago when I asked him about details of mutation and recombination)?
Did we just create a storm in the cognitive teacup, so to speak?
And if we have to reduce "cognition" from an active, conscious mental process (the way it is normally used in a number of disciplines) to an unconscious mechanistic one, to make the shoe fit the foot, then why use it, at all?
Then why not just report, without creating false promises in laymen eager to hear that some miraculous "mental process" may have been discovered by science in the smallest of life's units, that Dr. McClintock was way ahead of her time and that she would have greatly enjoyed the plethora of discoveries that have been made by molecular genetics since her Nobel speech?
I would have thoroughly enjoyed that. I am not enjoying the teeth pulling that has ensued about a term that just does not want to fit, no matter how hard we stretch it.
I believe I did point out in the majority of my posts what I expect from a scientific concept. It has to have necessity and it needs to be backed up by evidence.
I believe that the proposed concept lacks both. Now, I did formulate the problem in a number of ways and I was hoping to get rational responses from other participants. So far, as I can tell, I have gotten none.
Your last response suggests that you are using "cognitive" in a way which reduces it to "unconscious stochastic information processing", in which case I fail to see how your approach would actually differ from conventional molecular biology at all, except that is uses a contentious word in the headline.
As for Dr. McClintock's contribution, what is the evidence that the scientific community is actually lagging behind her insights? What is the evidence that she was talking about "smart cells" in anything but a humorous fashion as an afterthought to her actual scientific expression of cell function and her hope that the homeostatic mechanisms (in her own words) behind it would be discovered in detail in the future (which is now)?
I would like to see somebody present scientific evidence as to why cells are showing cognitive behaviour as defined by the usual use of the word "cognition". Below I gave three quotes from frequently used encylopedic sources as to what "cognition" means. I assume that my understanding of the word is the same as used in the article above.
I am simply looking for hard evidence that cells can be characterised as complex information processing agents that go far beyond the limits of stochastic state machines, which, of course, they are. Nobody in modern biology will have any problem with the latter characterisation of cellular function (not even old style Darwinists).
The only question at hand is why these functions should be viewed at the level of processing that is usually reserved for the most complex information processing system known to man... man's brain... especially in light of the fact that the scientific characterisation of "cognition" is far less advanced than the characterisation of cellular cell repair (when viewed relative to the complexity of the problem).
A propos of how I use the term "cognition," here is an exchange from a previous posting (http://www.huffingtonpost.com/james-a-shapiro/what-is-the-key-to-a-real_b_1280685.html).
HUFFPOST SUPER USER
DAE 02/19/2012
I have no problem with the crux of your argumenmt. It's, as others have noted, your choice of words that's in dispute. Why not use “computational” rather than “cognitive?” Computational is not loaded with extraneous meaning like cognitive. Maybe cognitive has a technical meaning in computer jargon but in popular parlance it implies conscious mental action.
HUFFPOST BLOGGER
James A. Shapiro 02/20/2012
DAE,
The Wikipedia definition of cognition is: "The term cognition (Latin: cognoscere, "to know", "to conceptualize" or "to recognize") refers to a faculty for the processing of information, applying knowledge, and changing preferences. Cognition, or cognitive processes, can be natural or artificial, conscious or unconscious." I think this is quite consistent with how I have used the term. I prefer it to "computation" since that does not include all the sensory processes we know cells can carry out. At the risk of being accused of mercenary motives, may I suggest you read the argument at length as I laid it out in my book. The first part of that is devoted to an extended discussion of cell cognition as studied at the molecular level.
"In science, cognition refers to MENTAL processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions."
I find if a stretch to use a term like "mental" for an, albeit complex, molecular process. We can probably safely discount "producing and understanding language" as well as "problem solving" and "decision making" from the molecular repertoire of a cell. If you disagree, I am willing to listen to how you define these terms to fit the situation.
Leaves "attention" and "remembering"... which, of course, is part of conventional Darwinian genetics, already. Both can easily be found in much simpler systems (like metals), which can sense temperature and "remember" past stress. Would you call a bi-metal spring a "cognitive system"? Would you call it part of a "cognitive system" if it is part of a temperature regulator?
Additionally, I am still confused as to what kind of scientific insight comes from the application of these terms to cellular function? Does they have additional explanatory power? Can they be used to predict cell behavior? These are merely the usual criteria that are being applied to scientific descriptions of nature.
It seems to me that in your concern regarding the use of terms such as 'cognition' is misplaced. You seem to imply that Shapiro is introducing concepts such as 'vitalism' or 'animism' to account for the behavior of cells. Indeed, if Shapiro were arguing that 'scientific' concepts cannot account for what cells do; that we must introduce something beyond science such as 'vitalism' your concern would be well founded. He obviously is doing no such thing. Shapiro has already clearly explained and justified his use of the term 'cognition' so I'll not bother to repeat it.
The real challenge is not what label should be applied to what cells do, rather it is to understand what cells ARE doing and figure out how they do it. Sophisticated mechanisms are being discovered raising additional challenges regarding how these mechanisms came into existence. The orthodox explanation 'it's all random mutations filtered by natural selection' is becoming less and less convincing as our understanding of the complexity involved increases.
Shapiro is far from the only scientist recognizing the limitations of the neo-Darwinian paradigm. For example Eugene V. Koonin in "The Logic of Chance: The Nature and Origin of Biological Evolution" argues among other things that the translation/replication system, necessary for every form of life, cannot have been produced by 'random mutation filtered by natural selection'. His theory regarding its origin is controversial and I'll not attempt to describe it here..
I am merely relaying what the naive reader will necessarily understand based on encyclopedic definitions of "cognitive behavior". Would you disagree that this is a very poor choice of words?
"Indeed, if Shapiro were arguing that 'scientific' concepts cannot account for what cells do; that we must introduce something beyond science such as 'vitalism' your concern would be well founded. He obviously is doing no such thing."
How will the naive reader know?
"The real challenge is not what label should be applied to what cells do, rather it is to understand what cells ARE doing and figure out how they do it."
As I pointed out, that happens in science labs and the results are being published in peer-reviewed science journals. This here, however, is a public science blog and one has to be a lot more sensitive about the cultural context of the reader. I, for instance, did have laymen asking questions about the science of e.g. Kirlian photography, which they thought was actual science. The problem that people will be looking for animism anywhere they can find it is real.
You will have to find a very old geneticist to even hear that as the default option. I do have several molecular biologists and geneticists in my circle of friends and none of them uses that concept. They will, indeed, tell you in detail about all the different cell mechanisms that are modifying DNA. So the assumption that 19th century Darwinism is the orthodoxy is simply not true. Quite the contrary.
Having said that, there is no discussion about anything other than selection being the driving force towards ADAPTATION. There is, indeed, no belief out there among clinical researchers that I know that cells could somehow "sense" their environment and "intelligently adapt" to it. If anything, cancer cells, which are some of the sturdiest survivors, prove the opposite. They exhibit a complete breakdown of correct cell signaling and they destroy their host organism in the process.
As for Mr. Koonin, if he indeed argues that in his non-peer reviewed book, he better supply supply scientific evidence for his thesis.
Did I just say "scientific evidence", again? And did I use the word "peer-reviewed", again? It's getting old, isn't it? :-)
The discussion has gotten very emotional very quickly and there was no reason for it. I wasn't presenting anything that is NOT standard scientific reasoning. I was asking for evidence, though, which is the first step in science. Without evidence there can be no scientific reasoning.
Is there a mystery here? No, there isn't. At most there is a complex biochemical problem that lacks a few detailed answers. Will these answers come? Yes. Will they require a deviation from standard scientific procedure? No.
Some may believe otherwise. Some may hope otherwise. That's fine. But if they want to make a scientific case, they have to DISCOVER otherwise.
"Many scientists have been upset because Barbara
McClintock characterized herself as a mystic. But this characterization
was central to her creative genius as a scientist.
To her, the term mystic did not mean someone who mystifies.
Instead, for Barbara McClintock, a mystic was someone with
a deep awareness of the mysteries posed by natural phenomena.
The courage to say, ‘I do not understand,’ and the
courage to investigate the unexplainable were at the heart of
her remarkable success."
A scientist who does NOT MYSTIFY but simply keeps searching for NATURAL explanations of NATURAL PHENOMENA. Wow... sounds like a very different Dr. Shapiro, who actually tries to defend Dr. McClintock against very similar feelings of discomfort that he seems to be attracting today himself.
"There must be numerous homeostatic adjustments required of cells. The sensing devices and the signals that initiate these adjustments are beyond our present ability to fathom. A goal for the future would be to determine the extent of knowledge the cell has of itself and how it utilizes this knowledge in a "thoughtful" manner when challenged" (McClintock 1984).
"extent of Knowledge.... and....utilize this knowledge in a thoughtful manner" Wow, no wonder atheists have their panties in a twist. Brought to its logical conclusion, their way of life is dead!
.
An if I may cite from her obituary:
"Perhaps McClinlock’s most challenging idea is the concept
of ‘smart cells,’ a phrase she slipped in humorously at
the end of her lectures in recent years."
It was written by... James A. Shapiro... in 1992. So even Dr. Shapiro seemed to think 20 years ago that she was speaking in jest... and he does not seem to have taken it nearly as seriously as he does today. One wonders what has changed? Surely not the science? The processes discovered since then are just as thermodynamics as they were when Dr. McClintock made these HUMOROUS comments and Dr. Shapiro didn't take here seriously, either.
Dr. McClintock is therefore very much in tune with the science of the 20th and even late 19th century and is not looking toward animistic descriptions of the 17th century. Maybe Dr. Shapiro might want to look for another "witness" for his personal assertions.
Intelligent designer, much? DNA's code and programming — or, arguably, pre-programming — screams of the presence of intelligence, folks. Take the blinders off and start factoring that into your observations and calculations and see if more puzzle pieces don't start falling into place.
Of course, even then nature doesn't produce organisms that "mimic" their environment perfectly, otherwise all fish would have to look like water and deer would have to look like trees. What nature does is to ADAPT species to their environment. And sometimes that means sticking out like a sore thumb... to tell everybody else that you are not "good eats".
Reality is so much more interesting than people's misconceptions of it. :-)
See... all the good stuff that is contained in a single word like "cognition"?
:-)
Most notable, however, is your repeated ramblings with no relevance to the topic. It's become obvious to everyone reading this particular post OCD is preventing you from offering anything substantive on the topic at hand.
Too bad, too. I'd like to believe accomplished physicists are more than mere technicians...or perhaps that's simply your psychological shortcoming and not necessarily common among all competent physicists.
Bacteria are small but not stupid: cognition, natural genetic engineering and socio-bacteriology
JA Shapiro - Studies in History and Philosophy of Science Part C: …, 2007
A 21st century view of evolution: genome system architecture, repetitive DNA, and natural genetic engineering
JA Shapiro - Gene, 2005
Mobile DNA and evolution in the 21st century
JA Shapiro - Mobile DNA, 2010
Genome system architecture and natural genetic engineering in evolution
JA Shapiro - Annals of the New York Academy of Sciences, 1999
Genome organization and reorganization in evolution
JA Shapiro - Annals of the New York Academy of Sciences, 2002
Revisiting the central dogma in the 21st century
JA Shapiro - Annals of the New York Academy of Sciences, 2009
Genome Evolution in the 21st Century
J Shapiro - Bulletin of the American Physical Society, 2006
A Twenty-First Century View of Evolution: Genome System Architecture, Repetitive DNA, and Natural Genetic Engineering
JA Shapiro - Structural Approaches to Sequence Evolution, 2007
SJ, I suggest you do your homework. Read the references before saying things you cannot support.