Copy-and-paste

I'm really interested in research on aging, and I'd like to think that it's not solely because I'm Of A Certain Age myself.  The whole fact of our undergoing age-related system degradation is fascinating -- more so when you realize that other vertebrates age at dramatically different rates.  Mice and rats age out after about a year and a half to two years; dogs (sadly) rarely make it past fifteen (much less in some breeds); and the Galapagos Tortoise can still be hale and hearty at two hundred years of age.

A lot of research has gone into why different organisms age at such different speeds, and (more importantly) how to control it.  The ultimate goal, selfish though it may sound, is extending the healthy human life span.  Imagine if we reached our healthy adult physiology at (say) age twenty-five or so, and then went into stasis with respect to aging for two hundred or three hundred years -- or more?

Heady stuff.  For me, the attraction is not so much avoiding death (although that's nice, too).  I was just chatting with a friend yesterday about the fact that one of my biggest fears is being dependent on others for my care.  The idea of my body and/or mind degrading to the point that I can no longer care for my own needs is profoundly terrifying to me.  And when you add to the normal age-related degradation the specter of diseases such as Alzheimer's and ALS -- well, all I can say is that I agree with my dad, who said that compared with that fate, "I'd rather get run over by a truck."

Leaving that aside, though, a particularly interesting piece of research that has bearing on this field was published last week in the journal Science Advances.  But to understand it, you have to know a little bit about a peculiarity of genetics first.

Several decades ago, a geneticist named Barbara McClintock was working with patterns of seed color inheritance in "Indian corn."  In this variety, one cob can bear seeds with dozens of different colors and patterns.  After much study, she concluded that her data could only be explained by there being "transposable elements" -- genetic sequences that were either clipped out and moved, or else copied and moved -- functions similar to the "cut-and-paste" and "copy-and-paste" commands on your computer. McClintock wrote a paper about it...

... and was immediately ignored.  For one thing, she was a woman in science, and back when she was doing her research -- in the 1960s and 1970s -- that was sufficient reason to discount it.  Her colleagues derisively nicknamed her theory "jumping genes" and laughed it into oblivion.

Except that McClintock wouldn't let it go.  She was convinced she was right, and kept doggedly pursuing more data, data that would render her conclusion incontrovertible.  She found it -- and won the Nobel Prize in Physiology and Medicine in 1983, at the age of 81.

Barbara McClintock in her laboratory at Cold Spring Harbor [Image licensed under the Creative Commons Smithsonian Institution/Science Service; Restored by Adam Cuerden, Barbara McClintock (1902-1992) shown in her laboratory in 1947]

McClintock's "transposable elements" (now called "transposons") have since been found in every vertebrate studied.  They are used to provide additional copies of essential genes, so that if one copy succumbs to a mutation, there's an extra working copy that can take over.  They're also used in gene switching.  Move a gene near an on-switch called a promoter, and it turns on; move it away, and it turns off.

The problem is, like any natural process, it can go awry.  The copy-and-paste function especially seems to have that tendency.  When it malfunctions, it acts like a runaway copy-and-paste would in your word processing software.  Imagine the havoc that would ensue if you had an important document, and the computer went haywire and inserted one phrase over and over again in random points in the text.

This should give you an idea of why it's so important to keep this process under control.

You have a way of taking care of these "rogue transposons" (as they're called).  One such mechanism is methylation, which is a chemical means of tangling up and permanently shutting down genes.  But the paper just released suggests that aging is (at least in part) due to the rogue transposition of one particular sequence getting ahead of methylation, leaving a particular chunk of DNA scattered again and again across the genome.

The current research, out of New York University, looked at a transposon called Long Interspersed Nuclear Element 1 (LINE-1) that has become especially good at this copy-and-paste trick, to the extent that the human genome contains five hundred thousand copies of it -- a full twenty percent of our genetic material.  The researchers found that LINE-1 can only accomplish this self-insertion when a molecule called ORF1p is present in sufficient quantities to assemble into clumps called condensates.  Find a way to block ORF1p, and LINE-1 is effectively disabled -- potentially slowing down age-related genetic malfunction.

Of course, even in the best-case scenario, it's unlikely that tweaking one molecule will affect overall aging in any kind of dramatic way.  Even so, the whole thing is tremendously interesting.  On the other hand, I have to say that the idea that we are getting to the point that we can tinker around with fundamental processes like aging is a little frightening.  It opens up practical and ethical issues we've never had to consider before.  How this would affect human population growth?  Who would have access to such genetic modifications if they proved effective and safe?  You can bet the rich would have first dibs (and the last thing we need is Rupert Murdoch living to two hundred years old.)  

Even such things as how we approach the idea of careers and retirement would require significant rethinking.  Imagine if you reached the age of sixty and could expect another fifty or more years of active health.  More staggering still is if the effect on humans was greater -- and the upper bound of human life span was increased to two hundred or three hundred years.  It seems like science fiction, but with the research that is currently happening, it's not outside of the realm of possibility.

Who would want to retire at sixty if you still had the physiology and mental acuity of a twenty-five year old?  At the same point, who would want to stay in the same job for another hundred years or more? 

The whole thing would require a drastic reorganization of our society, a far more pervasive set of changes than any scientific discovery has yet caused.  And lest you think that I'm exaggerating the likelihood of such an eventuality; remember how much progress has happened in biological science in the last century.  Only a hundred years ago, children in industrialized countries were still dying by the thousands of diphtheria and measles.  There were dozens of structures in cells, and a good many organs in humans, about whose function we knew essentially nothing.  We knew that DNA existed, but had no idea that it was the genetic material, much less how it worked.

Makes you wonder what our understanding will be in another hundred years, doesn't it?

And maybe some of the people reading this right now will be around to see it.

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Leaps of knowledge

One of the most amazing and inspirational figures in the history of modern science is the geneticist Barbara McClintock.

McClintock got her Ph.D. in botany back in 1927, in a time when women simply didn't go into science.  There was a huge cultural bias against female scientists -- not only a sense of "that's not something a woman should be interested in," but the presence of a huge, white-male-dominated edifice already in place that was damn near impenetrable for women and minorities.

This wasn't a glass ceiling, it was a solid marble monolith.

But if there was one phrase that describes McClintock's career, it's "dogged determination."  She focused on the genetics of maize during a time when just about everyone was studying fruit flies.  She racked up success after success, doing the first-ever preliminary analysis of the maize genome way back in 1929, and afterward demonstrating how crossing over contributed to variation in offspring.

Barbara McClintock in her lab at Cold Spring Harbor in 1947 [Image is in the Public Domain]

The story becomes even more interesting with her discovery in the 1950s of transposable elements -- gene segments that can move within an organism's genome.  She showed -- beyond any reasonable doubt -- that these transpositions were responsible for features of seed color inheritance in Indian corn, and very likely for a host of genetic inheritance patterns in not only maize, but other species as well.

Well, "beyond any reasonable doubt" is said with 20/20 hindsight.  The members of the aforementioned marble monolith were grudgingly okay with a woman making docile and innocuous additions to the body of scientific knowledge, but not with her overturning a major tenet of genetic dogma.  They derided her discovery as "jumping genes" and, basically, refused to participate in or fund research to elucidate further what McClintock had discovered.

This is where the "dogged determination" part comes in.  Undeniably discouraged but not defeated, McClintock continued to amass more and more information, both supporting her original claim and also showing how it happened and what the effects of genetic transposition were.  It took almost thirty years, but eventually she had enough data to convince even the most negative of the naysayers -- and for her discovery, she won the Nobel Prize in Medicine in 1983.

The topic of McClintock's discovery comes up because of a paper that appears this week in Science Advances.  In the rather intimidatingly-titled "Primate-Restricted KRAB Zinc Finger Proteins and Target Retrotransposons Control Gene Expression in Human Neurons," we find out something extraordinary; McClintock's transposable elements are responsible for the differentiation of neurons in our own brains.

The study, led by Priscilla Turelli of the École Polytechnique Fédérale de Lausanne, looked at a group of proteins called Krüppel-associated box-containing zinc finger proteins, which seemed to regulate the activity of transposable elements very early in fetal development.  What they found was that these "KZFP" genes were active only in certain cells in the developing brain -- and seemed to be guiding differentiation of brain cells.

More amazing still, the researchers found two KZFP genes that appear to be unique to primates, a tantalizing clue about the evolution of our own large and complex brains.

"These results reveal how two proteins that appeared only recently in evolution have contributed to shape the human brain by facilitating the co-option of transposable elements, these virus-like entities that have been remodeling our ancestral genome since the dawn of times," said Didier Trono, the study's senior author, in a press release from the École Polytechnique.  "Our findings also suggest possible pathogenic mechanisms for diseases such as amyotrophic lateral sclerosis or other neurodegenerative or neurodevelopmental disorders, providing leads for the prevention or treatment of these problems."

Wouldn't Barbara McClintock be thrilled to see where her discovery has gone?  From an obscure and much-doubted mechanism initially thought to be active only in maize, genetic transposition has been found in every organism studied.  And its effects are far from minor.  The same process that gives Indian corn its bright colors is the one that has given us brains powerful enough to figure it out -- a lovely circularity that I think McClintock would have found fitting.

As she herself said, in her usual understated fashion: "If you know you are on the right track, if you have this inner knowledge, then nobody can turn you off... no matter what they say."

**********************************

This week's Skeptophilia book recommendation of the week should be in everyone's personal library.  It's the parting gift we received from the brilliant astrophysicist Stephen Hawking, who died two years ago after beating the odds against ALS's death sentence for over fifty years.

In Brief Answers to the Big Questions, Hawking looks at our future -- our chances at stopping anthropogenic climate change, preventing nuclear war, curbing overpopulation -- as well as addressing a number of the "big questions" he references in the title.  Does God exist?  Should we colonize space?  What would happen if the aliens came here?  Is it a good idea to develop artificial intelligence?

And finally, what is humanity's chance of surviving?

In a fascinating, engaging, and ultimately optimistic book, Hawking gives us his answers to the questions that occupy the minds of every intelligent human.  Published posthumously -- Hawking died in March of 2018, and Brief Answers hit the bookshelves in October of that year -- it's a final missive from one of the finest brains our species ever produced.  Anyone with more than a passing interest in science or philosophy should put this book on the to-read list.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]

Genetic leapfrog

Barbara McClintock is one of the most inspiring figures in the history of biology.  She received her Ph.D. in Botany from Cornell University in 1927 -- in a time when few women chose to go to college, even fewer pursued a major in the sciences, and almost none made it all the way to doctoral-level work.

In the 1940s and 1950s, she was studying the genetics of maize, especially how genes regulate the expression of seed color in multicolored "Indian corn."  What she found, she said, could only be explained if the genes were moving around within the genome -- altering expression because of shifting position.  When she published preliminary papers on the topic, her discovery was derided as "jumping genes," and no one much paid attention.  This led to her decision to stop seeking publication in 1953.

[Image licensed under the Creative Commons Steve Snodgrass from Shreveport, USA, Indian Corn, CC BY 2.0]

What it didn't do was to slow down her determination to continue her research.  She doggedly pursued her idea -- genetic transposition -- and finally had amassed so much evidence in its favor that the scientific establishment had to pay attention.  "Jumping genes" were a fact -- and in fact, have been found in every species studied -- and the phenomenon of transposition turns out to be a major factor in gene expression across the board.

The discovery, and the body of work that led up to it, earned McClintock the Nobel Prize in Physiology and Medicine in 1983 -- and to this day she is the only woman who has earned an unshared Nobel in that category.

Barbara McClintock died in 1992 at the age of ninety.  So it's unfortunate that she didn't live long enough to learn that not only to genes move around within the genome of an organism...

... they can jump from organism to organism.

Called horizontal transfer, this was initially thought to occur only in bacteria, where it helps them to avoid the bane of asexually-reproducing species, "Muller's Ratchet."  Since in asexual species, the DNA doesn't combine -- i.e., the offspring are clones -- mutations tend to accrue each time the DNA replicates, because replication isn't 100% faithful (it's pretty damn good, but not perfect).  You can think of it as a genetic game of Telephone; each copying process results in errors, and after a few generations, the DNA would be turned into nonsense (it's called a "ratchet" because like the mechanical device, it only goes one way -- in this case, toward converting the DNA into garbage).  But if horizontal transfer occurs, bacteria can pick up extra working copies of genes from their friends, meaning that if Muller's Ratchet knocks out a gene, chances are they have another version of it hanging around somewhere.

What no one realized is that like genetic transposition, horizontal transfer turns out to be ubiquitous.  And in a new paper out of the University of Adelaide, geneticists Atma M. Ivancevic, R. Daniel Kortschak, Terry Bertozzi, and David L. Adelson have shown that horizontal transfer is not only everywhere you look, it also is a major driver for evolution.

They write:

Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations.  TEs can jump between organisms or species when given a vector of transfer, such as a tick or virus, in a process known as horizontal transfer. Here, we propose that LINE-1 (L1) and Bovine-B (BovB), the two most abundant TE families in mammals, were initially introduced as foreign DNA via ancient horizontal transfer events. 

Using analyses of 759 plant, fungal and animal genomes, we identify multiple possible L1 horizontal transfer events in eukaryotic species, primarily involving Tx-like L1s in marine eukaryotes.  We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new parasite vectors of transfer such as bed bug, leech and locust, and BovB occurrences in new lineages such as bat and frog.  Given that these transposable elements have colonised more than half of the genome sequence in today’s mammals, our results support a role for horizontal transfer in causing long-term genomic change in new host organisms.

Which I find simultaneously fascinating and creepy.  That a mosquito bite could not only make me itch, but inject into me the DNA of another species -- which then would colonize my own DNA, like some kind of molecular virus -- is seriously bizarre.

"Jumping genes, properly called retrotransposons, copy and paste themselves around genomes, and in genomes of other species," said project leader David Adelson in a press release from the University of Adelaide.  "How they do this is not yet known although insects like ticks or mosquitoes or possibly viruses may be involved – it’s still a big puzzle...  Think of a jumping gene as a parasite.  What’s in the DNA is not so important – it’s the fact that they introduce themselves into other genomes and cause disruption of genes and how they are regulated...  We think the entry of L1s into the mammalian genome was a key driver of the rapid evolution of mammals over the past 100 million years."

So much of what's in "your" genome probably wasn't originally yours, or necessarily even originally human.  Kind of humbling, isn't it?  But I better go wrap this up, because I've got a mosquito bite that's itching like hell.  I'm just hoping that mosquito hadn't bitten a rabbit previously, because the last thing I need is to have a sudden craving for carrots.  I freakin' hate carrots.

**********************************

The Skeptophilia book-of-the-week for this week is Brian Greene's The Fabric of the Cosmos.  If you've always wondered about such abstruse topics as quantum mechanics and Schrödinger's Cat and the General Theory of Relativity, but have been put off by the difficulty of the topic, this book is for you.  Greene has written an eloquent, lucid, mind-blowing description of some of the most counterintuitive discoveries of modern physics -- and all at a level the average layperson can comprehend.  It's a wild ride -- and a fun read.

Slowing down the copy-and-paste

I'm really interested in research on aging, and I'd like to think that it's not solely because I'm Of A Certain Age myself.  The whole fact of our undergoing age-related system degradation is fascinating -- moreso when you realize that other vertebrates age at dramatically different rates.  Mice and rats age out after about a year and a half to two years; dogs (sadly) rarely make it past fifteen (much less in some breeds); and the Galapagos Tortoise can still be hale and hearty at two hundred years of age.

A lot of research has gone into why different organisms age at such different speeds, and (more importantly) how to control it.  The ultimate goal, selfish though it may sound, is extending the healthy human life span.  Imagine if we reached our healthy adult physiology at (say) age 25 or so, and then went into stasis with respect to aging for two hundred or three hundred years -- or more?

Heady stuff.  For me, the attraction is not so much avoiding death (although that's nice, too).  I was just chatting with a friend yesterday about the fact that one of my biggest fears is being dependent on others for my care.  The idea of my body and/or mind degrading to the point that I can no longer care for my own needs is profoundly terrifying to me.  And when you add to the normal age-related degradation the specter of diseases such as Alzheimer's and ALS -- well, all I can say is that I agree with my dad, who said that compared with that fate, "I'd rather get run over by a truck."

A particularly interesting piece of research in this field that was published last week in the Proceedings of the National Academy of Sciences gives us one more piece of the puzzle.  But to understand it, you have to know a little bit about a peculiarity of genetics first.

Several decades ago, a geneticist named Barbara McClintock was working with patterns of seed color inheritance in "Indian corn."  In this variety, one cob can bear seeds with dozens of different colors and patterns.  After much study, she concluded that her data could only be explained by there being "transposable elements" -- genetic sequences that were either clipped out and moved, or else copied and moved -- functions similar to the "cut-and-paste" and "copy-and-paste" commands on your computer.  McClintock wrote a paper about it...

... and was immediately ignored.  For one thing, she was a woman in science, and back when she was doing her research -- in the 1960s and 1970s -- that was sufficient reason to discount it.  Her colleagues derisively nicknamed her theory "jumping genes" and laughed it into oblivion.

Except that McClintock wouldn't let it go.  She was convinced she was right, and kept doggedly pursuing more data, data that would render her conclusion incontrovertible.  She found it -- and won the Nobel Prize in Physiology and Medicine in 1983, at the age of 81.

Barbara McClintock in her laboratory at Cold Spring Harbor [image courtesy of the Wikimedia Commons]

McClintock's "transposable elements" (now called "transposons") have been found in every vertebrate studied.  They are used to provide additional copies of essential genes, so that if one copy succumbs to a mutation, there's an additional working copy that can take over.  They are also used in gene switching.  Move a gene near an on-switch called a promoter, and it turns on; move it away, and it turns off.

The problem is, like any natural process, it can go awry.  The copy-and-paste function especially seems to have that tendency.  When it malfunctions, it can be like a runaway copy-and-paste would be in your word processing software.  Imagine the havoc that would ensue if you had an important document, and the computer was inserting one phrase over and over again in random points in the text.

This should give you an idea of why it's so important to keep this process under control.

You have a way of taking care of these "rogue transposons" (as they're called).  One such mechanism is methylation, which is a chemical means of tangling up and permanently shutting down genes.  But the research just released suggests that aging is (at least in part) due to rogue transposition getting ahead of methylation -- leaving random copied chunks of DNA scattered across the genome.

A study by Jason Wood et al. of Brown University has found that fruit flies near the end of their life have a far greater number of active transposons than young flies do.  In fact, as they age, the number increases exponentially, the result being interference with gene function and a system-wide degradation.  Most interesting is that they found two genes -- Su(var)3-9 and Dicer-2 -- that when enhanced both substantially increase longevity in fruit flies.  Su(var)3-9 seems to be involved in increasing the methylation rate of rogue transposons, and Dicer-2 in suppressing the transposition process itself.  An increase in the activity of these genes raised the average longevity of fruit flies from sixty to eighty days -- an increase of 33%.

Of course, there's no guarantee that even if these genes turn out to have similar effects in humans, that the longevity increase will scale up by the same amount (if it did, it would raise the average human age at death to around 100 years).  But the whole thing is tremendously interesting anyhow.  On the other hand, I have to say that the idea that we are getting to the point that we can tinker around with fundamental processes like aging is a little frightening.  It opens up practical and ethical issues we've never had to consider before; how this would affect human population growth, who would have access to such genetic modifications if they proved effective and safe, even such things as how we approach the idea of careers and retirement.

Imagine if you reached the age of sixty and could expect another thirty or more years of active health.  Imagine if the effect on humans was greater -- and the upper bound of human life span was increased to two hundred or three hundred years.  It seems like science fiction, but with the research that is currently happening, it's not outside of the realm of possibility.

If you had the physiology and mental acuity of a twenty-five year old, who would want to retire at sixty?  At the same point, who would want to stay in the same job for another hundred years?  I love my students, but that definitely falls into the "shoot me now" category.

The whole thing would require a drastic reorganization of our society, a far more pervasive set of changes than any scientific discovery has yet caused.  And lest you think that I'm exaggerating the likelihood of such an eventuality; remember how much progress has happened in biological science in the last century.  Only a hundred years ago, children in industrialized countries were still dying by the thousands of diphtheria and measles.  There were dozens of structures in cells, and a good many organs in humans, about whose function we knew essentially nothing.  We knew that DNA existed, but had no idea that it was the genetic material, much less how it worked.

Makes you wonder what our understanding will be in another hundred years, doesn't it?

And maybe some of the people reading this right now will be around to see it.