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.