Early in his research career, Jeffrey Macklis set out to unite two seemingly disparate fields of neuroscience: neural development and brain repair. At the time, this was an unorthodox idea, and “being a brain repair guy was a little shady,” he says. Still, he thought, “if we figured out how the brain was built, then maybe we could figure out how to rebuild it or fix it, and we might also be able to figure out something about why it breaks.”
Macklis has made strides in understanding the cells and pathways of the brain’s cerebral cortex, the outer layers of tissue critical for voluntary movement, sensation, thinking, memory, language and consciousness. His research has shown that it is possible to rebuild cortical circuits by coaxing new neurons integrated in the adult brain into specific developmental tracks. And Macklis continues to explore the origins of nerve cell diversity, providing insights into autism, neurodegenerative diseases and spinal cord injuries.
Macklis earned bachelor’s degrees in both bioelectrical engineering and literature from the Massachusetts Institute of Technology. During his junior year, his research mentor, mechanical engineering professor Ernie Cravalho, encouraged him to apply for early admission to the Harvard/MIT Health Sciences and Technology (HST) program, which integrates science and engineering with medical training. In an HST neuroscience course, Macklis arrived at an unexpected realization during a neurophysiology lecture by “this curly-haired Swedish guy by the name of Torsten Wiesel” (a 1981 Nobel Laureate and an emeritus member of the Rita Allen Foundation’s Scientific Advisory Committee).
“He showed us amazing experiments on vision in cats, using electrical recordings,” Macklis recalls. “What I saw was the brain as a machine that also thought. That at connected [my interests in] literature, philosophy, intellectual history and biophysics, and all of a sudden my whole world came together and I said, ‘I want to do that.’”
Wiesel graciously invited Macklis to talk neuroscience over tea and cookies, and, based on Macklis’ desire to investigate how the brain is built, suggested he reach out to Harvard’s Richard Sidman. Macklis describes Sidman as “at that time among the world’s leading developmental neurobiologists” who had “pioneered the ideas of genetic underpinnings of neuron- and circuit-specific development and degeneration before molecular manipulation of the nervous system existed.” Macklis conducted both graduate and postdoctoral research in Sidman’s laboratory, where he focused on myelinating glia and their mutations, biophysical approaches for targeted activation of long-distance circuits, and cell type-specific neuronal degeneration to investigate integration of new neurons.
“What I saw was the brain as a machine that also thought. That connected [my interests in] literature, philosophy, intellectual history and biophysics, and all of a sudden my whole world came together and I said, ‘I want to do that.’”
Macklis began his own research program at Harvard Medical School, and in 1991 he was selected as a Rita Allen Foundation Scholar. He recalls that the Foundation’s Scientific Advisory Committee (including Wiesel) was surprisingly receptive to his idea of combining studies of cortical development with neuronal repopulation and regeneration. The award “gave me a mandate and provided some resources to just go after these venturesome combinations of fields,” he says. “That really enriched the lab, and let us take some risks in directions that I otherwise would have been a bit hesitant to go in.”
Using mice as a model for brain development and neuronal repopulation from progenitors, Macklis induced selective degeneration of subtype-specific neurons in the neocortex. He showed that under the right conditions, transplanted embryonic neurons could migrate to new positions, acquire correct neuron subtype identity and begin to restore functional connectivity to long-distance targets. His group’s subsequent work examined the mechanisms behind this regeneration, which contributed to the seminal finding that progenitors already axisting within the adult brain are capable of being manipulated to generate new long-distance cortical "projection" neurons, partially repairing degeneration of circuitry in the neocortex.
Macklis joined the Foundation’s Scientific Advisory Committee in 2007. Today, Macklis and his team have broadened their investigations of the cerebral cortex, working to more deeply understand molecular controls over development and diversity of neuronal subtypes, the subcellular mechanisms guiding the formation of axons and synapses, and how these processes are perturbed in developmental and neurodegenerative diseases.
Here, Macklis recalls his early impressions of science and engineering, and reflects on some of the highlights from his research career.
Find the full interview here.