Today’s guest post was contributed by Nele Haelterman, assistant professor at Baylor College of Medicine’s Molecular and Human Genetics department, who combines team science, genetics, and neuroscience to study the mechanisms that drive joint pain. Nele is also passionate about science communication and advocacy: she is a freelance writer, edits a blog for early career scientists (ecrLife) and promotes open, reproducible science (reproducibility 4 everyone). You can follow Nele on LinkedIn.

Nowadays, we don’t think twice about running a Q-PCR to check the expression of our favorite gene, or to sequence a genomic region to identify a mutation that causes an interesting phenotype. In contrast, 50 years ago, it could take an entire PhD to accomplish such a task. Molecular genetics has evolved at an exponential pace, and its application to other fields has led to groundbreaking progress in our understanding of many physiological and pathological processes. One of the pioneers of molecular genetics, David Hogness, developed several groundbreaking technologies to identify genes and study how their expression changes in different contexts. By combining technological advancements with developmental biology and Drosophila genetics, the Hogness lab cloned important eukaryotic developmental genes and laid the foundation for genomic analysis in humans and many other species.1-3

Despite using technologies and molecular concepts spearheaded by the Hogness lab on a nearly daily basis, many current grad students and early career researchers in the field don’t know the scientist who initially developed them. To celebrate Hogness’ 100th birthday, and to teach the next generation of researchers the history behind some of the concepts our genetic knowledge is based on, November’s issue of GENETICS contains two back-to-back articles: one based on Hogness’ autobiography,2 and one that explores the significance of an unpublished manuscript on ecdysone-mediated gene regulation that remained tucked away in Hogness’ desk for over 40 years.3

“Hogness was a true visionary and was about 10-15 years ahead of the field for the research questions he pursued. His research changed what was possible in many other fields, not just in Drosophila”, say William Talbot and David Kingsley, co-authors of the current perspective in GENETICS that includes Hogness’ autobiography.2

Take for example chromosomal walking, the positional cloning method developed in the Hogness lab to identify, isolate, and clone genes based on their genetic map locations. At the time (mid 1970s), mutant alleles with interesting phenotypes were available for many different species and the genetic positions were known for some of them, but there was no way for researchers to connect this information to the RNA or protein molecules produced by the gene. To solve this problem, the Hogness lab digested genomic DNA and cloned the resulting fragments into bacterial vectors to generate a “library” of cloned genomic DNA fragments (plasmids, phage vectors, and cloning technology were in their infancy at the time). These clones were then used to produce labeled probes that were hybridized against the fly’s polytene chromosomes to identify the precise genomic location of the clone’s DNA fragment. Starting with a clone in the vicinity of the mutation, the Hogness lab “walked” along the fly’s third chromosome by repeatedly isolating clones that partially overlapped. They used this strategy to identify and isolate clones containing the famous bithorax-complex homeotic genes whose mutations alter the identity of body segments in Drosophila.4 This seminal work marked the molecular identification of the first key developmental genes in eukaryotes, and kickstarted the molecular genetics era.

Kingsley and Talbot, along with many others, were among the early adopters of chromosome walking technology. Convinced by this technology’s transformative power, they incorporated it into their own research programs when starting out their labs and applied the method to different species (zebrafish for Talbot; mouse and stickleback fish for Kingsley).Talbot, a former grad student of the Hogness’ lab, and Kingsley are both faculty at Stanford University’s Developmental Biology department, which Hogness helped establish.They had the honor of going through his office after his passing and discovered a trove of information, including handwritten talks, grant applications, and some unpublished manuscripts. They carefully curated these documents, which are now accessible through the Stanford archives.

Among these documents, they found Hogness’ acceptance essay for Stanford’s inaugural Munzer chair position and they realized that this was the closest thing to an autobiography Hogness had ever written. “Many nice retrospectives and obituaries have been written to highlight Dave’s accomplishments,5-6 but what we felt was missing was Dave’s own perspective,” says Talbot. Talbot and Kingsley decided they wanted to share this autobiography with the broader scientific community, so others can read Dave Hogness’ own interpretation of his work. The team added some context to the document and the resulting perspective is now published in GENETICS.2 

“Hogness was slow to write, but what he wrote was inspirational and aspirational. While it was written decades ago, I found that it could still shape my research today,” Kingsley mentioned. Hogness was widely known for his collaborative, humble nature, his remarkable training record, and his moderate publication rate. The pioneer shared his group’s groundbreaking findings at conferences and seminars, and always made sure to credit any trainees or group members who contributed to the work. He was a strong advocate for his trainees and helped many of them establish their own labs. However, when it came down to writing up his findings and publishing them, the scientist’s perfectionism could get the better of him, and manuscripts could spend months to years on his desk.

Mariana Wolfner’s PhD project was central to one of those unfortunate manuscripts. Wolfner, currently professor of Molecular Biology and Genetics at Cornell University, was a graduate student in the Hogness lab, where she worked with several other Hogness lab members to identify and study ecdysone-mediated gene expression changes during the larval to pupal transition. To identify which genes are regulated by ecdysone and study the molecular process underlying metamorphosis, the team developed a differential cDNA hybridization technology, which became a precursor to microarray technology. The scientists isolated salivary gland RNAs from developmentally timed animals and copied them into cDNAs which they cloned into plasmids to generate stage-specific libraries. They next generated grids of individual cDNA clones from these stage-specific libraries and conjugated the clones’ DNA to a set of nitrocellulose membranes. Then, they exposed these membranes to radiolabeled cDNA probes generated from the RNAs from a specific developmental stage to identify the clones of genes expressed at that timepoint. In parallel, they used the radiolabeled cDNAs from these clones to molecularly map the gene onto the chromosomes through in situ hybridization. “We were doing things nobody had ever done before, but there was this general sense of enthusiasm in the lab and everyone was convinced that the experiments would work,” Wolfner remembers.

Combining these methods, Wolfner and colleagues showed how salivary gland RNA populations change during the larval-to-pupal transition, molecularly demonstrating the presence of robust gene regulatory mechanisms during development.3 Additionally, they identified and isolated specific genes whose expression was activated or repressed in response to ecdysone, which helped define the molecular pathways that underlie the developmental timing of this transition.

The team wrote up a paper describing their work, but when Wolfner moved to start her postdoc in the lab of Bruce Baker at UCSD, the final version of the paper remained in the Hogness queue, with copies tucked away in Wolfner’s desk and those of her co-authors. Linda Restifo, now professor of Neurology at the University of Arizona, built on Wolfner’s work during her graduate studies in the lab of Greg Guild, former Hogness postdoc and co-author on the ecdysone manuscript. Restifo recently re-discovered the finalized manuscript. Wanting to do justice to the seminal work and fill in a missing historic piece of the ecdysone puzzle, she reached out to Wolfner. The pair teamed up with the remaining surviving original co-authors and with Mark Garfinkel, a scientific grandchild of Dave Hogness like Restifo, to review the discovery of ecdysone-regulated genes and the ecdysone-signaling cascade. As an additional bonus, they included the unpublished original manuscript as a supplement to their perspective.3

Hogness’ work and findings revealed gene identities and unlocked scientists’ ability to study how gene expression in time and space changes across physiological and pathological contexts. The two papers published in the current issue of GENETICS nicely highlight how transformative Hogness’ work has been for the fields of molecular genetics and developmental biology, and will ensure that the next generation of researchers can re-discover this pioneer’s lifework.

References

  •  1. Pedigree: The Morgan lineage.
    Guil Winchester.
    Current Biology. 1996 Feb; 6(2): 100-101.
    DOI: 10.1016/S0960-9822(02)00428-1

  • 2. Hogness at one hundred.
    David M. Kingsley, and William S. Talbot
    Genetics. 2025 Nov; 213(3);iyaf171
    DOI: 10.1093/genetics/iyaf171

  • 3. Launching the molecular genetic investigation of the ecdysone signaling cascade: a tribute to David S. Hogness (1925-2019).
    Linda L. Restifo, Gregory M. Guild, Mark D. Garfinkel, Marc A.T. Muskavitch, and Mariana F. Wolfner.
    Genetics. 2025 Nov; 231(3)iyaf211
    DOI: 10.1093/genetics/iyaf211

  • 4. Molecular Genetics of the Bithorax Complex in Drosophila melanogaster.
    Welcome Bender W, Michael Akam, Francois Karch, Philip A. Beachy, Mark Pfeifer, Pierre Spierer, E.B. Lewis, and David Hogness.
    Science. 1983 Jul; 221(4605):23-9.
    DOI: 10.1126/science.221.4605.23.

  • 5. The 2003 Thomas Hunt Morgan Medal; David S. Hogness.
    Kenneth C. Burtis, R. Scott Hawley, and Howard D. Lipshitz
    Genetics. 2003 Aug;164(4):1243-45
    DOI: 10.1093/genetics/164.4.1243.

  • 6. David Hogness (1925–2019).
    Michael W. Young.
    Curr Biol. 2020 30(5): R194-96.

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