Notorious B. McC.

RBG, the 85-year-old US Supreme Court justice known for her fearless feminism and daring dissents, has recently become a pop culture icon and movie star.

But wayyyy before RBG, plant biology had its own great dissenter who said what she meant, smashed glass ceilings, and thought years ahead of her time.

That scientist was the OG maize cytologist Barbara McClintock, aka

“Notorious” is not an exaggeration.  Although some scientists accepted her theories, McClintock was excluded from certain conferences and talks.  She was called “kind of mad” and “just an old bag who’d been hanging around Cold Spring Harbor for years”.

Then she won a Nobel Prize.

How did B McC overcome the haters to do some seriously slick science?

The story starts with a girl from Brooklyn named Barbs who loved the outdoors and played street sports with her brother’s friends.  Despite her mother’s worries that she would be “unmarriageable”, she enrolled at Cornell’s College of Agriculture in 1919.

Barbs entered biology at an interesting time.  In the 1920s, it had only recently been found that chromosomes carried the information that passed traits from parents to offspring.  People still had no idea that chromosomes were made of DNA, or how offspring could end up with different combinations of traits.

After finishing college, Barbs McClintock wanted to do research.  The plant breeding department at Cornell didn’t admit women to its PhD program.  So she joined the botany department.  And worked on plant breeding anyway.

Which plant caught B McC’s attention?

Maize.

 

Why?  McClintock realized that maize was a good model system for genetics.

First off, it’s important for food, feed, and fuel, so there’s funding.  (F+F+F=F?)

Also, every single corn kernel represents a different cross between an egg and a sperm.  (For some down n’ dirty plant sex ed, click here.)

But the key thing about maize for B McC was that you could see its chromosomes under a low-power microscope, which was extremely convenient in the first half of the 1900s.

Knowing all this, B McC quickly figured out how to stain maize chromosomes, and identified all ten of them.

 

 

 

McClintock started to mentor a younger graduate student, Harriet Creighton.  The two women hypothesized that new combinations of traits resulted from the actual physical crossing over of information between chromosomes.

Nowadays we know that chromosomal crossover is real.

 

Crossover happens during the first stage of meiosis when chromosomes pair up (right when this video starts).

How did Notorious B McC figure out crossover without genetic sequencing or live microscopy?

B McC noticed that one variety of corn had a weird knob on the same chromosome that carried the genes for kernel color and waxiness.  This variety had colorful, waxy kernels.  McClintock and Creighton crossed it to knob-less corn with colorless, non-waxy kernels.

They looked at the corn kernels that were produced from the cross, both visually and under the microscope.  Most knobbed chromosomes corresponded to colorful, waxy kernels, as in the original plant, but some knobbed chromosomes ended up with non-waxy kernels.  So crossover must have occurred!

 

By comparing observable traits to microscopic images of chromosomes, McClintock and Creighton had shown that crossover was a thing!

McClintock and Creighton published their findings and presented them at the Sixth International Conference of Genetics in 1932.

After that success, McClintock moved to the University of Missouri.  However, she was unhappy there because she had little chance of recognition or promotion.  B McC began to gain ~notoriety~.

Evelyn Fox Keller, her biographer, writes, “Was it, then, that she was perceived as ‘difficult’ because she demanded–and resented the absence of– rights commensurate with her merit?  To some degree, probably yes… She had long ago rejected the restricted role of a ‘lady scientist’… [but] being a woman and a maverick was simply too much”.

McClintock finally found a more permanent position at Cold Spring Harbor, where she worked on a new problem, the one that made her truly infamous: transposons, or “jumping genes”.

McClintock started to find mutant corn plants whose mutations seemed unstable within the lifetime of a single plant.  Plants had streaks or patches of color in otherwise-normal leaves.  Kernels that should have been colorless showed regular spot patterns.

In many of these “unstable” plants, McClintock found highly specific breaks in the chromosome.  B McC hypothesized that there was a systematic process causing chromosomal breakage.

Using many, many maize crosses, McClintock established that two “loci”, or chromosomal positions, were responsible.  One locus she called Ds for “dissociation”, the other she called Ac for “activation”.    Chromosome breaks at Ds required the presence of Ac.  Chromosome breaks at Ac could happen independently.  Shockingly, both Ac and Ds could “jump” between locations on chromosomes.

The more copies of Ac, the more frequently transposons would “jump” in and out of color genes during development, leading to smaller and smaller patches of color.

 

This was absolutely mind-blowing to scientists at the time, who were just starting to figure out the mechanics of genetic transmission.

 

We now know that most of the maize genome (>75%) is composed of active or inactive transposons.

Many people misunderstood or dismissed her work, but McClintock pushed ahead, lecturing extensively around the US during the 1950s.

B McC also began to pursue another passion, maize diversity.  She worked with local scientists in Peru, Colombia, and Mexico to catalog the evolutionary and ethnobotanical origins of different varieties of corn.

B McC’s hustling eventually paid off.  In the early 70’s, scientists started to find transposons in bacteria, viruses, and yeast.  McClintock received a flurry of awards: the National Medal of Science, a MacArthur “Genius Grant”, and the 1983 Nobel Prize in Physiology or Medicine.

The standoffish McClintock had become a celebrity and even something of a saint.

Other plant biologists carried on B McC’s transposon work.  Nina Fedoroff isolated the Ac and Ds transposons through molecular cloning, showing that Ac and Ds are identical except for deletions in Ds.  Ds transposons require those missing parts, which they can get from Ac, to “jump”.

McClintock’s work continues to resonate throughout biology.  Her ideas about gene regulation help present-day scientists think about why cells with the same genome can have different characteristics and functions.  B McC also pioneered the concept of mosaicism, which is when single organisms carry mixtures of genetically distinct cells.  McClintock’s interests in ethnobotany and plant diversity are also having a resurgence.

The most remarkable thing about B McC, though, was her ability to maintain her chill.

Forget the haters!  In Notorious B McC’s own words: “If you know you’re right, you don’t care. You know that sooner or later, it will come out in the wash.”

 

Footnote: 

* There are two main types of transposons:

Class I, or retrotransposons, are “copy and paste” transposons.  Their DNA gets transcribed into RNA, the RNA is translated into DNA, then the new copy of DNA is inserted elsewhere in the genome.  With this method, the original copy stays in place, leading to genomes full of “junk”.

 

Class II, or DNA transposons, are mostly “cut and paste” transposons.  They rely on enzymes to cut the DNA out of its original position and relocate it to a new genomic home.

B McC’s Ac and Ds transposons are “cut and paste” DNA transposons.  But more of the maize genome is made of “copy and paste” retrotransposons because of their ability to replicate over and over.  Many sequences actually consist of transposons inside transposons inside transposons…

This process has shaped every organism, including you!  Transposons constitute about 45% of the human genome.

 

Sources & Further Reading: 

Birchler, J.A., Han, F.  2018.  Barbara McClintock’s Unsolved Chromosomal Mysteries: Parallels to Common Rearrangements and Karyotype Evolution.  Plant Cell 30.4: 771-779.

Chuong, E.B., Elde, N.C., Feschotte, C.  2017.  Regulatory activities of transposable elements: from conflicts to benefits.  Nature Reviews Genetics 18: 71-86.

Coe, E., Kass, L.B.  2005.  Proof of physical exchange of genes on the chromosomes.   PNAS 102.19: 6641-6646.  (A perspective on McClintock and Creighton’s work 75 years later).

Creighton, H., McClintock, B.  1931.  A Correlation of Cytological and Genetical Crossing-over in Zea mays.  PNAS 17: 492-497.

Fedoroff, N., Wessler, S., Shure, M.  1983.  Isolation of the Transposable Maize Controlling Elements Ac and Ds.  Cell 35: 235-242.

Halpern, M.E.  2016.  Barbara McClintock on Defining the Unstable Genome.  Genetics 204.1: 3-4.

Jiao, Y. et al.  2017.  Improved maize reference genome with single-molecule technologies.  Nature 546: 524-527.

Keller, Evelyn Fox.  A Feeling for the Organism.  San Francisco: W.H. Freeman and Company, 1983.  Print.

McClintock, B.  1929.  A Cytological and Genetical Study of Triploid Maize.  Genetics 14: 180-222.

McClintock, B.  1929.  Chromosome Morphology in Zea mays.  Science 69: 629.

McClintock, B.  1953.  Induction of Instability at Selected Loci in Maize.  Genetics 38: 579-599.

Schnable, P.S. et al.  2009.  The B73 Maize Genome: Complexity, Diversity, and Dynamics.  Science 326: 1112-1115.

“The Barbara McClintock Papers.”  Profiles in Science.  U.S. National Library of Medicine.  Web.  https://profiles.nlm.nih.gov/LL/

Wallis, Claudia.  “Honoring a Modern Mendel.”  Time.  10/24/1983.

 

Image Sources: 

Young B McC, Crossing over, Mitosis gif, Sixth International Conference on Genetics, McClintock’s colorful corn, Jumping genes cartoon, McClintock in Mexico, Word Art