Profile of John G. Hildebrand

Musician’s Life with a Bit of Biology

Hildebrand was born in Boston in 1942 and grew up in the nearby town of Belmont, MA. He began studying violin and piano at an early age, fostering a love of music shared by his family of six. His mother was an English teacher and his father an organic chemist who spent the bulk of his career in electronics and scientific photography. For Hildebrand, his father was the model of an interdisciplinary problem-solver. “An important lesson I learned from him,” he says, “was that you get your degree in a subject, but that doesn’t limit what you can do.”

A Saturday morning children’s program called Science Explorers at Boston’s Museum of Science planted the seeds of his forthcoming career in insect neurobiology. The museum offered presentations, many about animal behavior. And intensive hands-on summer courses there, including one on insects and another on freshwater biology, were key experiences, Hildebrand recalls.

However, as college approached, Hildebrand was conflicted about whether to study music or science. He chose Harvard “because it was the closest university to where I lived” and because he could continue his musical pursuits in the local Boston music scene.

During his first year at Harvard, however, his career path chose him. In the fall of 1960, he enrolled in a freshman general education science course taught by George Wald, who 8 years later won a Nobel Prize. The course was called “Life,” but it started with the big bang and had little to do with biology for the first half of the course. The experience was “galvanizing,” says Hildebrand. The labs were a highlight—notably, he says, experiments using “setups to make recordings from nerve cells and muscle.”

The next pivotal event was finding John Law, a young assistant professor associated with Konrad Bloch in Harvard’s chemistry department. Working with Law on phospholipids in bacteria, Hildebrand fell in love with research, published his first paper, and presented his findings at a scientific congress for the first time.

Discovering His Passion in New York

While many of his peers were on the medical-school track, Hildebrand was hooked on research and decided to pursue graduate studies at the Rockefeller Institute (later Rockefeller University) in New York City. His fascination with bio-organic chemistry and cell biology led him to the laboratory of Fritz Lipmann, who had won a Nobel Prize in 1953 for his discovery of CoA.

Hildebrand’s thesis focused on the citric acid cycle—in particular, the mechanism of the succinyl CoA synthetase reaction. His thesis supervisor, organic chemist Leonard Spector, was “a fine mentor,” says Hildebrand. “I had quite an independent experience as a graduate student, encouraged by a teacher who had my back all the time.”

Fritz Lipmann was also a tremendous role model and friend, Hildebrand says. The two shared a love of music: one night Lipmann caught Hildebrand leaving the lab in a tuxedo armed with a trombone. “He wanted to know what I was doing,” says Hildebrand, “and when I confessed that I was working on the side as a musician, he was very pleased and thereafter treated me very well.”

“I’m very grateful to Lipmann and Spector,” Hildebrand adds. “They really made me the scientist that I became by supporting a rigorous, challenging, and stimulating research environment.”

One evening in 1965 while Hildebrand was browsing in the Rockefeller Institute’s library, he saw a new book that changed his life: Kenneth Roeder’s Nerve Cells and Insect Behavior. The book sported a praying mantis on the cover. Engrossed, Hildebrand read the book cover to cover in one sitting. “It was just one of those experiences you never forget. There was a little voice in my head saying, that’s it, that’s what you’ve been looking for,” he adds. “It was an epiphany.”

After completing his PhD in 1969, he returned to Boston as a postdoctoral fellow at the recently launched Department of Neurobiology at Harvard Medical School—the “Mecca for neurobiology” at the time. He chose to work with a young biochemist, Edward Kravitz, who also proved to be a “magnificent mentor.”

Hildebrand found tremendous inspiration among his colleagues: when he entered the department, David Hubel and Torsten Wiesel were doing the research that earned them their Nobel Prize. “I got to watch them do experiments that are now in every neuroscience textbook—talk about inspiring,” he exclaims.

While in Boston, Hildebrand found his muse. He asked his colleague Fotis Kafatos to suggest a large insect that goes through complete metamorphosis—larva to pupa and then to adult—because he wanted to study nervous-system development. For practical reasons, the insect had to be easy to rear in the lab. Kafatos showed him a huge caterpillar: the tobacco hornworm Manduca sexta, which transforms into the giant sphinx moth. “I had the motivation, I knew the kinds of things I wanted to work on, and now I had a creature to do it in, so the stage was set,” Hildebrand recalls.

Dissecting His Muse

In 1972, after a cross-country job hunt for his first faculty position, Hildebrand received an offer he could not refuse—to stay where he was at Harvard Medical School. This option was the worst in terms of salary and setup support, but it had extraordinary students, postdocs, and faculty, as well as other intangibles that could not be found elsewhere at the time. He progressed from assistant to associate professor and remained there until 1980.

At the time, his lab combined anatomical, biochemical, and surgical approaches to probe the postembryonic development of sensory neurons in the antennae and their growth to targets in the brain. With his first graduate student, Joshua Sanes, Hildebrand studied how the antenna arises from a bulb-shaped population of cells—called the antennal imaginal disk—in the head of a caterpillar. The imaginal disk remains in arrested development until metamorphosis begins, when hormones signal the disk to resume antennal development. In Manduca, the antenna includes more than 300,000 sensory receptor cells that send their axons into the developing antennal lobe in the brain, where they interact with developing, target nerve cells destined to receive and process antennal sensory information (2).

“The sense of smell in insects has no parallel of importance.”

In this early phase of his research program, Hildebrand focused on where the sensory cells come from and how they develop. Not until after Sanes had graduated did Hildebrand seriously begin to wonder what the antenna was doing. And thus began a 35-year fascination with olfaction (3).

Hildebrand says that his motivation to study the antennal pathway as an olfactory system was rooted in early childhood experiences with his father, who was a consultant for the flavor and fragrances industry and often introduced his children to new smells and tastes.

From 1975 to the present, Hildebrand’s lab has focused on olfaction: how this sense develops in the moth, what it is doing for the insect, and how the moth uses olfactory information. Today he and his students and postdocs focus mainly on neurophysiology and behavior.

Gender-Bending Experiments

After 11 years at Harvard, Hildebrand felt the need to move away from a medical-school setting to focus on basic biology. In 1980, he accepted an offer from Columbia University to move back to New York City. At Columbia, Hildebrand explored how meaningful odors—including host-plant odors and sex pheromones—are encoded in the moth’s olfactory system and motivate the insect to find food and a mate.

To address some of these questions, Hildebrand asked graduate student Anne Schneiderman to try a couple of gender-bending experiments that involved transplanting the male antennal imaginal disk into the head of a female caterpillar. Because male and female antennae are different and respond to different odors, Hildebrand wondered whether putting male antennae on a female would influence behavior.

“What she did was one of the most fun things that’s ever happened in my lab,” says Hildebrand. The experiment, reported in Nature (4), showed that a normal male antenna develops on the head of an otherwise normal female and innervates that female’s brain, sending in axons of genetically male receptor cells. The transplant had a dramatic impact on behavior. The female moth flew toward the sex pheromone, released by the female to attract male moths. The transplanted antenna had masculinized not only her brain but also her behavior, all of the way from the antennal lobe through the rest of the nervous system.

“It was one of the greatest Eureka moments we’ve ever had,” says Hildebrand joyfully.

In a follow-up to that experiment, Schneiderman and Hildebrand discovered that a female antenna developing on a male innervates and feminizes its target antennal lobe; the male moth then shows a characteristic female flight pattern to certain plant volatiles that are especially attractive to females. These experiments show the powerful controlling effect of the sensory axons as they interact with their targets in the brain, and the behavioral implications for the animal that is receiving that sensory input (5).

Hildebrand and his wife, fellow neuroscientist Gail Burd, expected never to leave New York, but in 1985 they were drawn to Tucson to contribute to a renaissance of life sciences at the University of Arizona. For Hildebrand “it was a once-in-a-lifetime opportunity to build and lead a new research unit, the Division of Neurobiology of the Arizona Research Laboratories.”

Cracking the “Meaningfulness” Code in Manduca

In Arizona, Hildebrand focused on structures in the antennal lobe of the Manduca brain called glomeruli, in which primary processing of olfactory information takes place. He and his coworkers found that the insect has 63 glomeruli—including three that are male-specific and three female-specific—that receive information about different slices of the olfactory world. He hypothesized that there are 63 functional olfactory receptors, each capable of binding a different type or range of odorants. Hildebrand explains it is like having 63 sensory channels to monitor all of the odors that the moth might encounter in its environment. The job of the brain’s olfactory system is to read activity from these channels and recognize different patterns (6).

Since 2000, Hildebrand’s group has focused on how the brain encodes the “behavioral significance” of a natural odor and how the spatiotemporal dynamics of the actual plume of odorant molecules can influence the moth’s behavior (7).

Hildebrand and his colleagues also have studied how Manduca responds to carbon dioxide. Although CO₂ is odorless for humans, they showed that it guides Manduca to nectar-rich flowers (8). CO₂ is also a key odorant that enables mosquitoes to find and bite humans and other hosts. Hildebrand points out that if atmospheric CO₂ levels continue to rise, they could “increasingly confuse the plant-oriented behaviors of insects and ultimately have a negative effect on pollination behavior.”

Hildebrand’s Inaugural Article examines how Manduca find flowers. He and his coworkers, Jeffrey Riffell and Hong Lei, analyzed the fragrances of two desert flowers on which the moths rely for nectar, and identified small mixtures of key odorants, out of more than 60, that are critical for attracting the moths. They also recorded the responses of groups of neurons to see how the brain encodes these meaningful odors. They found that the firing of action potentials in certain neurons in the antennal lobe is synchronized when the moths sense a behaviorally “meaningful” odor mixture—either the full floral scent or the subset of volatiles used to stimulate the antenna.

Understanding how the brain encodes behaviorally significant scents, and then deciphering the neural codes, continues to be Hildebrand’s central line of research (9).

To study such questions has involved some technical wizardry. Hildebrand notes that to identify patterns of brain activity associated with particular scents, his group needs to measure activity from many neurons simultaneously. To do this, his team applied multiunit recording to insects, which allowed the researchers to learn about system-level dynamics (10).

To date, Hildebrand has focused on odors that have innate meaning to Manduca—sex pheromone and host-plant odors. But he knows from other experiments (11) that Manduca is a quick study and rapidly learns to associate an odor with a food reward. He hypothesizes that the moths encode the “meaningfulness” of a rewarded odor using coincident firing of antennal-lobe output neurons. “We think that coincident activity is likely to be a coding mechanism for behavioral significance or salience of odors, either innate or learned. So we’re now on a quest for coincidence detectors downstream from the antennal lobe,” he says.

Hildebrand is most proud of what his studies have revealed about the insect olfactory system and its role in controlling insect behavior, including harmful and beneficial activities. Indeed, insect olfaction guides pollination. Olfaction leads moths and other insects to plants to lay eggs, from which larvae emerge and in turn damage or destroy the plants. And olfaction guides disease-vector insects, such as mosquitoes, to their hosts to take blood meals and thus transmit disease. All of these are olfaction-dependent behaviors. “I can make a pretty strong case,” says Hildebrand, “that the sense of smell in insects has no parallel of importance.”

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John Hildebrand and his wife, fellow neuroscientist Gail Burd.