James A. Birchler

SCIENTIST ON THE FARM

Jim’s knack for science started at an early age, while he was growing up as an Illinois farm boy. Surrounded by the plant and animal life on the family farm, Jim was overcome with curiosity that inspired some of his first experiments. In one experiment, described by his former student, Jim decided to test the influence of maternal rearing on ducklings versus chicks. He swapped the eggs between duck and chicken nests and then tracked the fate of the hatchlings. Everything seemed to be going okay until the ducklings hatched by a hen learned that they could swim. As the ducklings waddled into the water, their agitated, adoptive mother paced along the water’s edge, going “bock, bock, bock, bock!” While this exciting result never made it into the pages of a peer-reviewed journal, it was sufficient to spur Jim’s continued hypothesis testing on the farm and eventually in the lab.

As a high school student, he devoured his science classes, and upon graduating, went off to Eastern Illinois University, where he continued to consume his biology, chemistry, and physics coursework. Growing up in a small town with two teachers for parents—his mother taught first grade and his father was a high school physics and chemistry teacher—education seemed like the obvious career choice for Jim. Then one day, while Jim was walking down the hall, one of his professors said: “You’re going to graduate school, and I’m going to write you a letter.” Jim recalls thinking, “This college thing is kind of fun, maybe I’ll just stay here.”

WHEN MORE IS LESS—DISCOVERING THE NEGATIVE GENE DOSAGE EFFECT IN PLANTS AND ANIMALS

After majoring in botany with a minor in zoology, Jim moved to Indiana University, where he pursued his PhD in Drew Schwartz’s lab. It was there that he started “playing around with the chromosome arms of maize.” Geneticists observed that organisms would sometimes inherit an extra copy of a chromosome, creating a trisomy event (Blakeslee et al., 1920; summarized in Birchler and Veitia, 2012). As a PhD student, Jim was able to ask how organisms compensate for these changes in chromosome dosage. He performed allozyme assays on maize trisomy lines to look at changes in enzyme expression in response to chromosome dosage. This work led to his discovery of the inverse effect, a counterintuitive phenomenon in which increased chromosomal dosage leads to genome-wide decreases in gene expression (Birchler, 1979, 1981; Birchler and Newton, 1981). Early critics passed off the discovery as a quirk that is only exhibited by maize. Curious to see whether the negative dosage effect held true for other organisms, Jim moved to Oak Ridge National Laboratories for his postdoc, where he worked with Ed Grell, testing the impact of chromosome dosage in Drosophila trisomy lines. He was able to show that, indeed, the negative dosage effect is not just a quirk of maize but a generalizable phenomenon that applies to both the plant and animal kingdoms.

The Birchler lab is still working on the inverse effect, only now, instead of running allozyme gels, they can apply high-throughput sequencing technology to look at genome-wide changes in gene expression. Birchler says, “We’re having a blast with the stoichiometry stuff… The bigger the piece you change, the more likely you are to observe effects across the whole genome. Even though we’ve worked with this for a long time, there’s still a lot that we don’t understand. In this era, we now have the tools to identify what’s happening at the molecular level, [and] eventually at the individual gene level to identify the mechanisms.” Arguably more powerful than the molecular tools is Jim’s ability to leverage two very different model systems. Using flies, the Birchler lab has successfully narrowed down to individual genes those that can recapitulate the dosage effect (Rabinow et al., 1991; Birchler et al., 2001), whereas maize provides the lab with the flexibility to “throw the genome way out of whack, which would kill almost any other organism,” he says. As part of a National Science Foundation-funded project, his lab members are systematically perturbing chromosome dosage in maize, looking at how one, two, and three chromosome copies affect genome-wide expression. For a separate project in Arabidopsis, Birchler together with Marjori and Antonius Matzke (at Academia Sinica) and Jack Cheng at MU were able to show that all five trisomy lines in Arabidopsis cause inverse effects on gene expression across the genome.

Jim is no stranger to balancing multiple model systems. For his second postdoc (he jokes, “I did two postdocs before it was popular”), he moved to Berkeley to work with Kenneth Paigen. Suddenly he was a fly guy working in a mouse genetics lab and growing maize lines from his PhD in Mike Freeling’s fields. Birchler has continued to maintain Drosophila and maize projects in his research for the past 35 years, explaining that “the systems feed off each other.” Gene silencing, for example, was observed in the plant world several years before they described the phenomenon in Drosophila. For a completely unrelated project, the lab was making alcohol dehydrogenase transgenic lines in Drosophila when they observed a gene-silencing effect in flies. When they went to publish their findings, one of the reviewers was unaware of the discovery of cosuppression in plants and wrote that their observations were “like cold fusion!” Their work, which was eventually published in Cell, is the first discovery of cosuppression in the fly world (Pal-Bhadra et al., 1997). In a separate example, Birchler appreciated the ability of fly workers to routinely identify specific chromosomes using polytene chromosome features. Wanting to create a similar resource in maize, he invented chromosome paints, a technology in which each chromosome can be uniquely identified using fluorescent probes (Kato et al., 2004). Birchler’s ability to seamlessly bridge genetic systems between two kingdoms is rare. He recounts a time when someone at the “Fly Meeting” came up to him and asked, “‘Did you know there’s someone with exactly your same name that works on maize?’ They couldn’t imagine that a fly person would work on maize.”

DEVELOPING THE FIELD OF “CHROMOSOMEOMICS”

In 1985, after applying to every genetics job on the market, Birchler landed in the Department of Organismic and Evolutionary Biology at Harvard, where he continued to balance his work between fruit fly and maize genetics. It did not take long before Jim was pulled back to his Midwestern roots. The opportunity to work as a professor in the biology department at Mizzou, where Barbara McClintock’s and Lewis Stadler’s microscopes are on display in Curtis Hall and where the cornfields are less than 5 minutes away, was too good for Jim to pass up. At Mizzou, the Birchler lab has made tremendous contributions to the field of “chromosomeomics,” a term that Jim coined and, he jokes,"is probably only used by one other person in the world.”

CHROMOSOME PAINTS

Recently, the Birchler lab in conjunction with Jiming Jiang’s lab at Michigan State developed the first protocol in the plant kingdom for chromosome painting for all chromosomes of a karyotype (Kato et al., 2004). Their method, which can be used to uniquely label the 10 maize chromosomes, relies on the synthesis of labeled oligonucleotides that tile annotated exons across the maize genome. The Birchler lab uses this technique on a daily basis to track chromosomal rearrangements and breakpoints. Going back to material that descended from a nuclear test blast that occurred over 70 years ago, the Birchler lab was able to use DNA paint to track the DNA breaks that led to the formation of a new chromosome pair on April 15, 1948 (Albert et al., 2019). These oligonucleotides can also be used to probe across distantly related grasses, like Sorghum, and test for chromosomal variation across species.

ARTIFICIAL CHROMOSOMES

The Birchler lab showed how to make artificial chromosomes using a technique called telomere-mediated truncation. Telomere sequences can insert at double-strand break sites, essentially acting as a form of molecular scissors that truncate the chromosome at the site of insertion, as shown in two papers published in PNAS (Yu et al., 2006, 2007). Telomere truncation works at very high efficiency and holds tremendous promise, not only for genome engineering in maize but for crop biotechnology in general. Normal “A” chromosomes can be modified, but more intriguingly, it works even better with the essentially inert supernumerary “B” chromosomes in maize. These “mini” chromosomes, in Jim’s words, are “teenie weenie” chromosomes that can be as short as a few megabases, carry little more than a centromere, telomeres, and a replication site, and are a particularly useful by-product of telomere truncation. These mini chromosomes can potentially be loaded and extended with entire biosynthetic pathways and used to reengineer biochemical pathways.

MINI MAIZE: AMERICA’S NEXT TOP (MAIZE) MODEL

More than 20 years ago, Birchler served on a grant panel, and he heard, “If it’s not done in Arabidopsis, then you have to have a really good justification for your model system.” Knowing that there are several fast-flowering varieties of maize, Birchler embarked on a breeding project to develop a line that’s fertile, easy to grow, compact, and has an upright ear. This work resulted in the release of “Fast-Flowering Mini Maize,” a plant that can be taken “seed-to-seed in 60 days” (McCaw et al., 2016), although a postdoc in the Braun lab at Mizzou recently knocked the cycle down to 49 days (which doesn’t have quite the same ring to it). Mini Maize is the clever result of a double-cross hybrid between four fast-flowering varieties, followed by additional selection for flowering time and architecture over 11 generations of inbreeding. Birchler has been handing out packets of Mini Maize at conferences for years, and the line is now one of the top requested seed stocks from the Maize Genetics Cooperative Stock Center. Birchler says, “Maize is maize, whatever you do to Mini Maize, you can transfer it straight to maize.” Among many studies, researchers are using Mini Maize to study mycorrhizal associations with maize roots, to serve as a convenient pollen donor in wheat haploid production, and are now developing genome assemblies and even more rapid transformation tools with this line.

MENDEL IN THE CLASSROOM

While Birchler has made tremendous progress in the lab cracking fundamental questions in plant genetics and genomics, it can be argued that his most impressive contribution is actually in the classroom, where he has addressed one of the most challenging questions of all: “How do you engage a classroom that’s packed with over 350 students?” Jim jokes, “If they fall asleep, they don’t learn anything, so I try to keep them awake.” In classic Birchler style, he addresses this challenge with ingenuity. Gregor Mendel teaches students about Punnett squares (see figure 1), and Julia Childs demonstrates DNA gel blotting. For Halloween, Birchler used to open up his genetics class with a pop quiz, asking his students, “What would you get if you crossed Ben Franklin with Groucho Marx?” and then he would pop on a pair of Groucho glasses. His current students no longer know who Groucho Marx is, so Birchler is challenged to keep up with the times, which, he says, also keeps him young. With his inventive, engaging, and entertaining approach to teaching, it’s not surprising that Jim was named one of five “Teaching Legends” by Mizzou Magazine in 2003, and in 2017 he was named the Southeastern Conference Professor of the Year, an award that recognizes one professor across the entire Southeastern Conference.

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Figure 1.

Jim Birchler, as himself and Gregor Mendel in the classroom.

Jim’s approach to teaching is, in many ways, motivated by his own college experience. Having attended Eastern Illinois University, where the class sizes maxed out at 35 students, Jim wanted a way to capture that student-professor engagement that he benefited from as an undergrad. The way Jim sees it, he’s getting the best of the best of the best students coming through his genetics class. To make sure that he gets a chance to interact with those students, Jim invented the “Sweet Sixteen.” Each lecture, he has 16 students sit at the front of the room, where he can introduce himself to them and they sometime help with demonstrations. This extra effort to turn his class of 350 into an interactive classroom pays off. He keeps in touch with many of his students, several of whom spent time as researchers in the Birchler lab and eventually went on to earn PhDs and establish their own science careers.

IF DANIEL BOONE WERE A SCIENTIST

Birchler describes his research questions with an attitude of unencumbered curiosity. He says, “here’s something we’re playing around with…” and “well, this is kind of fun…” When asked how he maintains a sense of creativity and lightheartedness in the face of scientific competition, Jim answers, “I take a Daniel Boone approach to science. When he saw the smokestack of his neighbors, he would get up and move west. In the topics that we work on, if there are areas where we think we can make a contribution, we’re going to hang in there. But if good people enter a field on which we work, then we move on.” His scientific grandfather espoused a similar philosophy that encouraged pioneering in science. He would say, “If you get in the lab and start working, then you can’t help but discover something.” This approach lends itself to discovering new phenomena and laying down the foundations for new fields, which leads to another challenge. How do you help the community understand and appreciate something new? In Jim’s experience, some things, like fluorescence in situ hybridization, catch on quickly, while other discoveries, like the inverse gene dosage effect, take time, but “if you have data that says something, and it challenges the dogma, then you have to stick up for what the facts are. That’s being a good scientist.

POETIC SCIENTIST

At the end of each semester, Birchler summarizes his Genetics class with a poem. During graduate recruiting, each professor gets 2 minutes to summarize their work, and Birchler uses a poem with a couple of slides to keep himself on time. He even manages to squeeze a few stanzas into his publications (Birchler, 2015). Birchler says it’s “doggerel, I hesitate to call it poetry.” To close out this profile, Birchler’s former student Jacob Washburn has composed a piece of “doggerel.”

From humble beginnings on a farm in the mid-west;

Jim’s intellect and prowess made him soar above the rest.

A natural born scientist with a curious disposition;

He put duck eggs under chickens just to test their intuition.

Following the footsteps of Stadler, McClintock, and others;

Jim studied aneuploidy, and dosage balance he discovered.

One and two make three, or so most of us would guess;

But with dosage compensation the answer is far less.

Using models from two kingdoms has made Birchler very wise;

As he’s proven his hypotheses in maize and in fruit flies.

In the field and in the laboratory Jim makes dosage lines and trisomics;

All for use in studies of what he calls chromosomeomics.

In chromosomeomics Jim has truly paved the way;

He paints chromosomes for tracking and makes it look like play.

Visualizing breakpoints, rearrangements, and centromeres;

The paints work in other species, but are used most on maize ears.

From maize B chromosomes and telomere-mediated truncation;

Jim’s developed mini chromosomes for use in transformation.

On these tiny little chromosomes, one loads cassettes of genes;

They are inherited together and make transformation clean.

Why use maize as a model system? The generation time is too slow;

To that Jim gave us Mini Maize and boy how it can grow.

From seed to seed in two months flat—a perfect caryopsis;

This little plant is fast enough to rival Arabidopsis.

With fruit fly geneticists, Jim has made his name;

And in the maize community he has also gained great fame.

But the place where Jim is known by every Ashley, Anne, and Wendell;

Is when teaching in the classroom while dressed up as Gregor Mendel.