An Olfaction Odyssey

Thanks to a book, a war, and a big green caterpillar, John Hildebrand found himself mapping the exquisite and surprising wiring of the insect olfactory system.

By | October 1, 2013

Regents Professor
Department of Neuroscience
University of Arizona
Tucson, Arizona
It began with a fateful encounter with a praying mantis. In 1965, a young John Hildebrand, then a biochemistry PhD student at Rockefeller University in New York City, spent his evenings in the university library catching up on the latest publications (“You know—before there was an Internet,” he says).

One night, long after the sun had set and only a few people still milled around the library, Hildebrand was perusing the New Books shelf and noticed a slim volume with a vivid color photograph of a praying mantis on the cover. “I really liked praying mantises—as a kid I used to keep them as pets—so I picked up the book,” says Hildebrand. He settled into a large easy chair and read the book from cover to cover.

“If I hadn’t liked praying mantises, I wouldn’t have picked up the book, and I don’t know that I would ever have found what I’ve loved doing ever since then.”

“When I put it back on the shelf, the little voice in my head said, ‘That’s it. You’ve just found what you want to do,’ ” says Hildebrand. The book was Nerve Cells and Insect Behavior by Kenneth Roeder. Hildebrand hunted down all of Roeder’s papers, then those of other researchers referenced in the book. Using that network of papers and scientists as a foundation, he identified prospective universities where he might study insect neurobiology. “If I hadn’t liked praying mantises, I wouldn’t have picked up the book, and I don’t know that I would ever have found what I’ve loved doing ever since then.”

What Hildebrand has loved doing—and has built a successful career around—is investigating the insect olfactory system. He pioneered the use of the giant sphinx moth Manduca sexta as a model laboratory species for neurobiological research, and has shown how the insect detects various odors and processes them in the brain.

Here, Hildebrand harkens back to how the Vietnam War dictated his early career, why he refused to give up music for science, and how he was tricked into moving from New York to Arizona.

Hildebrand on the Hunt

Beantown. “I grew up in Boston and got into science very early thanks to my father, who was an engineer with a background in chemistry. As a young student, I worked in the fledgling Museum of Science in Boston as a volunteer in the live animal room for several years. But though I especially liked biology, starting at the age of four I was a fanatical musician. I came to the point of choosing going to college or going to a conservatory or becoming a performer. One way or another, I was going to be a musician. The short of it is that I ended up going to Harvard because it was the nearest university to where I lived. Nobody believes it, but that was the reason. It was only 3 miles from my house. I had this rationale in my mind that since I was already active in the music scene in Boston, if I went to Harvard I could keep doing all the things I was doing. And that proved to be true.” But Hildebrand had overlooked one major problem.

When one door closes . . . “I got to Harvard, intending to be a music major, then realized that I’d made a big mistake. You can study music history, composition, or theory at Harvard, but you can’t major in applied music. About the time I started to realize I was in the wrong place, I took a general education science course, called ‘The Nature of Living Things,’ taught by George Wald (who later won a Nobel Prize). It was supposed to be a biology course, but we started with the physical properties of the universe, and he built the story of where life came from. I thought it was the most fantastic thing ever. By the end of that year, I wasn’t going to be a music major anymore. I was co-opted into science.”

Learning the game. As a sophomore, Hildebrand began doing research in a lab. “I was lucky I got to do that. That wasn’t so common back then in the 1960s. I was secondarily lucky that I stumbled into a wonderful young faculty member, John Law, who welcomed me as a research student in his lab. He was only about 10 years older than I, and he had a wonderful philosophy that young students should get to know the whole game. So I learned all about how to get grants and how to publish.” With Law, Hildebrand wrote and published his first paper, on bacterial phospholipids, in Biochemistry.

In times of war. Hildebrand went from Harvard straight to graduate school at Rockefeller, but not of his own volition. “If I had my choice, I would have taken a year off, taken a breather and explored the world a little bit. But it was the Vietnam War, and I was subject to the whim of the draft board. They made it clear to me that if I took a day off, ever, then I would go to Vietnam. So I went to graduate school literally the day after I graduated from college.”

Hands-on lesson. At Rockefeller, Hildebrand joined the research group of Belgian cell biologist Christian de Duve, who would later go on to win the Nobel Prize for his discoveries of lysosomes and peroxisomes. “Although I loved the ideas and the people in the lab, I did not at all like what I was doing. Without going into the gory details, I discovered I didn’t like killing animals and ended up quitting his lab in just one year. It was a great life lesson: There is a big difference between the things you find interesting and the things you want to do with your hands and your time.” Next, Hildebrand worked with Leonard Spector, in a research group led by Fritz Lipmann, where he wrote a thesis on the mechanism of the succinyl coenzyme A synthetase reaction. “I was back to where I liked to be, between chemistry and biology. All was well, but it was a time of uncertainty, because I knew the kind of biochemistry I was doing was bounded; it was finite. Pretty soon all these biochemical pathways were going to be known, so I didn’t know what my future was going to be.”

The best of times, the worst of times. Enter the praying mantis. After fatefully reading Nerve Cells and Insect Behavior, Hildebrand joined Harvard Medical School’s recently launched Department of Neurobiology as a postdoc, once again not taking time off for fear of the draft board. There, he worked for three years with the young biochemist Edward Kravitz, then stayed on at Harvard as an instructor, despite other offers of a faculty position. “The offer [from Harvard] was by far the worst offer I received. Even though it was a tenure-track assistant professorship, there was no salary, just a license to go out and search for grant money to support me. But it was also my best offer, because from an intellectual point of view, I would be part of this amazing department that was in its early golden years. And I was finally free to do exactly what I wanted—to work on bugs.”

Bugs in the cupboard. But which bugs? As he prepared his lab, Hildebrand turned to a fellow insect-loving friend at Harvard, Fotis Kafatos, to find an insect that would allow Hildebrand to study the nervous system. “I described what I wanted—a big insect that goes through complete metamorphosis and is easy to rear in the laboratory. Fotis got this wonderful grin on his face and handed me a caterpillar the size of a large cigar. It was the larva of a big moth called Manduca sexta, and I started to raise them in a cupboard in my lab in Boston. I’ve worked on Manduca ever since.”

Hildebrand Hits the Jackpot

Smelly start. “Metamorphosis is a great opportunity to look at changes in life cycle, because as this animal goes from a caterpillar to a moth, the whole nervous system gets reorganized, but genetically it’s the same animal. With my first graduate student, Joshua Sanes, I decided to look at the olfactory system.” Hildebrand and Sanes studied two physically separate populations of nerve cells in the moth’s olfactory system: those in the antennae—the insect’s main olfactory organs—and those in the brain receiving signals from the antennae. By manipulating each population of cells, they were able to investigate how much each depended on the other for normal development throughout metamorphosis.

Gender-bending experiment. Following up on those earlier studies, a new graduate student, Anne Schneiderman, accepted the task of testing what influence swapping developing antennal structures had on the development of three male-specific olfactory structures—little knots of neuronal processes called glomeruli—in the Manduca brain. “When you take on a new student, you want to give them an orientation project to get them used to the lab, something that it would be okay if it didn’t work—a crazy idea or something adventurous. The project I gave her, thinking it would never work, was to transplant the precursors of adult antennae in caterpillars, before they became moths, from a male to a female and from a female to a male. And the bloody thing worked the first time!” The transplant had a dramatic effect on behavior: The female moth, which developed male antennae, flew toward female sex pheromone, while the male moth, which developed female antennae, showed a characteristic female flight pattern. The finding, that sensory input makes an important contribution to brain development and sex-specific behavior, led to two papers published in Nature in 1982 and 1986. “In the history of my lab, that was one of the greatest ‘wow, gee-whiz’ discoveries.”

Here comes the sun. In 1980, Hildebrand left Harvard’s medically oriented campus to focus on basic biology at Columbia University in New York City. Once settled, Hildebrand never expected to leave New York, but after only five years, he found himself setting up shop at the University of Arizona. “I was sitting in New York on a dreary, wintry day, looking at the sleet and snow, and I got a phone call out of the blue from the University of Arizona’s vice president for research. He said that they had decided to develop a research group in the field of invertebrate neurobiology, and would I come there as a consultant to advise them? I said sure, because it was crummy weather, and I thought I’d like to visit Arizona.” But the “consulting” gig turned out to be more than promised—Hildebrand met with almost 100 people on campus and was asked to submit a proposal on how he would build a neurobiology research unit. “I was amused, and suspicious,” says Hildebrand with a laugh. A year later the university offered him the chance to build his own department and also offered a faculty position to Hildebrand’s new wife, Gail Burd, a neuroscientist at Rockefeller University. The couple took the bait and moved to Arizona in 1985. Hildebrand started his department, and Burd went on to become an associate dean and later, vice provost of the University.

Ready, set, fire. In January this year, Hildebrand and coworkers published in Science what he describes as the “culmination” of work done in his lab. “Ever since I started focusing on olfaction, we’ve wanted to understand how naturally occurring, complex olfactory stimuli are encoded in the nervous system.” His team discovered that sensory cells in insect antennae deliver odor information to the glomeruli in the brain, whose output neurons then convey patterns of simultaneous neuronal spikes—patterns of action potentials—deeper into the brain to stimulate downstream nerve cells and, through them, elicit a behavioral response. When confronted with a non-natural stimulus, an odor that is not behaviorally significant to the moths, the glomerular output neurons do not fire simultaneously. “Having discovered the phenomenon of coincident firing, we’re now searching madly for coincidence detectors. We haven’t found them yet, but we have phenomena that look like we’re on the right track—cells that are activated under conditions that evoke coincident firing.”

“People think they have to make choices, but you can have an enriched life with two different passions.”

Hildebrand's Hopes and Fears

Berra-isms. “My favorite philosopher of the 20th century is Yogi Berra. One of his greatest statements that has really applied to my life was, ‘If you come to a fork in the road, take it.’ That’s what I did. I kept music going for a very long time, as a professional low brass player for 30 years, freelancing in Boston and New York, while developing a career as a scientist. People think that they have to make choices, but Yogi taught me that you don’t. You can follow both paths from the fork and have an enriched life with two different passions.”

Life transition. “I’m 71, near the end of my career. I’m not going to keep running a lab forever. But I have already started transitioning to being involved in professional organizations, including the National Academies. I think graybeards like me that have been around awhile need to be involved, not only in education and research but also in trying to shape and influence science policy as we go forward.”

Losing the basics. “The federal priorities for science funding are off the rails. Now everything has to be about economic development, national security, or translation. Basic discovery research is imperiled. It’s unlikely that anyone could ever start a career today working on what I’ve done all my career. I think that’s a tragedy.”

Around the world. “I’m active with the International Brain Research Organization to teach students in South America and Southern Europe. These are intensive, one- to three-week courses for students at different levels, in countries where students are hungry for opportunities for intensive science training. The young people in South America are so passionate. I love to serve students who know why they’re there and are motivated and grateful for their opportunities.”

Greatest Hits

• Described the organization of the insect’s antennal olfactory system and its development.

• Showed, for the first time, antennal innervation of the brain has a dramatic effect on sex-specific
  development and behavior.

• Established the giant sphinx moth as a model for studying olfaction and demonstrated similarities
  between mammalian and insect olfactory systems.

• Discovered a neural basis for how a complex sensory stimulus activates a behavioral response.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 440

October 1, 2013

Nutrient-dependent/pheromone-controlled adaptive evolution: a model

Excerpt: An epigenetic continuum of nutrient-dependent / pheromone-controlled adaptive evolution


Differences in the behavior of nematodes are determined by nutrient-dependent rewiring of their primitive nervous system (Bumbarger et al., 2013). Species incompatibilities in nematodes are associated with cysteine-to-alanine substitutions (Wilson et al., 2011), which may alter nutrient-dependent pheromone production.


The honeybee is currently an accepted model organism of nutrient-dependent pheromone-controlled adaptive evolution of the brain and behavior that is consistent with what is known about neurogenic niche construction in nematodes (Bumbarger et al., 2013). In flies, ecological and social niche construction can be linked to molecular-level cause and effect at the cellular and organismal levels via nutrient-dependent changes in mitochondrial tRNA and a nuclear-encoded tRNA synthetase. The enzyme enables attachment of an appropriate amino acid, which facilitates the reaction required for efficient and accurate protein synthesis (Meiklejohn et al., 2013). In wasps, manipulation of the genetics of evolved species-specific pheromones characterized the change in a pre-existing signaling molecule triggered by a glucose-dependent (Yadav, Joshi, & Gurjar, 1987) stereochemical inversion (Niehuis et al., 2013). In Ostrinia moth species, substitution of a critical amino acid is sufficient to create a new pheromone blend (Lassance et al., 2013). In the ‘peppered moth’ example of rapid response to human-induced environmental changes, which were heretofore considered to be driven by selective predation, some evidence now suggests the migration pattern of 2 km per evening is consistent with the male moth’s ability to detect the nutrient-dependent pheromones of the female from 2 km upwind (see for review Cook & Saccheri, 2013).


Current concepts now limit attempts to explain selection for nutrient-dependent changes in coat color and kinked tails in mice via mutations theory, since mutations theory does not address pleiotropy and epistasis (see for review Feinberg & Irizarry, 2010). Until recently, the association of the nutrient choline in humans and its metabolism to trimethylamine odor in different species of mice was the best example of how a change in diet becomes associated with the presence of mammalian conspecifics whose androgen estrogen ratio-associated odor distinguishes them sexually, and also as nutrient-dependent physically fit mates (Stensmyr & Maderspacher, 2013). The mouse model makes it clearer that glucose uptake changes cellular thermodynamic equilibrium and differential pathway regulation that results in adaptively evolved fitness in species from microbes (Kondrashov, 2012) to mammals. Species-specific health and reproductive fitness is associated with nutrient-dependent amino acid substitutions and with pheromone-controlled reproduction. Disease is associated with mutations exemplified in cancer where perturbations of the glucose-dependent thermodynamic/thermoregulatory equilibrium are equally clear (Locasale, 2012).

Avatar of: Roy Niles

Roy Niles

Posts: 108

Replied to a comment from James V. Kohl made on October 1, 2013

October 16, 2013

"The mouse model makes it clearer that glucose uptake changes cellular thermodynamic equilibrium and differential pathway regulation that results in adaptively evolved fitness in species from microbes (Kondrashov, 2012) to mammals."

Baloney.  You have presented absolutely no evidence here or elsewhere to support what you claim to be a model of the evolution of either microbes or mice.

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