My father, a practicing pediatric neurologist, was also a scientist. As a child, I remember my father peering at hundreds of micrographs of neuronal connections. Billions of these small connections form between neurons in the developing brain. Over the years he counted many, many synapses in post-mortem brain samples. A US immigrant who grew up in wartime Germany, he quietly shouldered his own childhood experiences. And he gained lasting fame – among neuroscientists and others – by discovering something fundamental. Brain synaptic connections increase dramatically during early human development, as anyone might expect. But Peter – Dad – Dr. Huttenlocher – discovered that, by the millions, these connections are also selectively removed as we learn and develop. This process, now referred to as synaptic pruning, is the process of refinement that mediates our skills, our abilities and our memories [1].

Peter’s father, Richard Huttenlocher, was born in 1900 in Alte Weinsteige, in the hilly vineyards near Stuttgart. Richard’s father, Johann Huttenlocher, was a policeman in Stuttgart. Richard’s mother, Elisabethe, “Oma” Huttenlocher (family name Gaupp), was a doting mother and ran a traditional home, with a knack for German baking that she shared with her grandson Peter. Both Richard and his older brother Friedrich (Uncle Fritz) studied the sciences in the Gymnasium (high school), but their studies were interrupted by the First World War. Fritz was stationed at the western front from 1914 to 1918, where he was wounded and was recognized with an Iron Cross from the Prussian government. Richard had only a brief stint as a young soldier, toward the end of the war. After the war, they both returned to live at the family home. Richard studied chemistry at the University of Stuttgart and Fritz studied geography/geology at the University of Tübingen. They both married young. Fritz married his wife Hannah, a traditional woman, in 1920, and continued to work at the University of Tübingen as a lecturer and then professor.

Peter Huttenlocher was unendingly interested. Interested in music. In baking. In medicine. In people and their ways of thinking. In his patients. In the science of the human brain. “Peter is a great dreamer,” said Hanne, Peter’s paternal grandmother, in 1948. Although he delved deeply into philosophy in college, Peter decided early after arriving in the United States that he wanted to become a physician. He wanted to take care of people. So, he immersed himself in human medicine.  He memorized. He took part in the multi-year training process for doctors that “knocks every ounce of originality out of you” [1].

As his former National Institutes of Health (NIH) colleague Irwin Feinberg put it, Peter’s research “took a 180-degree turn” after his move to the University of Chicago in 1974. Instead of focusing on the brains of patients with neurological deficits, he started to study the “gridwork” of healthy brains. As Peter said, “the findings in the normal population were more interesting than the abnormal population.” His landmark 1979 study published in Brain Research was unexpected [1]. The accepted thinking at that time was that brains actually get more connections as we learn and develop, but he found the opposite to be true. After a burst of new synapses form in the first year of life, unneeded connections are removed, or pruned. All scientific discoveries are incremental and build on the work of other scientists. But rarely, a scientific discovery can also present an entirely new way of thinking about a problem – and is truly a breakthrough. In a conversation in May 2022, Feinberg said about Peter’s work: “the idea of brain connections was not in the thinking in the 1980s. The skeptics were many.”

In 1937, the Spanish neuroscientist and artist Ramón y Cajal commented on an apparent trial and error period of chaotic dendritic and axonic growth, with most of the resulting connections destined to disappear. But over subsequent decades the prevailing concept among neurobiologists and behavioral biologists was that synaptic connections increase with learning. Peter then rigorously showed in 1979 that after birth and an initial burst of growth in synapse numbers in human infants, there is a regression. He and his collaborators went on to show that these connections disappear at different times, with different kinetics, in distinct regions of the brain. The physical housekeeping task of this process is not small – selecting and eliminating billions of inactive synapses in the developing brain. In some regions of the brain, such as the visual system, the clearance mechanism seems to be relatively rapid over weeks or months. In other regions of the brain, for example in areas of higher cognitive function like the frontal cortex, this process of elimination is apparently more prolonged. What process or system has the intrinsic ability to identify and clear unused synapses? What has the ability to do this in a refined way, by targeting the correct contact sites, and without leaving dead cells and debris behind?

Peering at thousands of neurons under an electron microscope in the 1970s, Peter sought to understand how the structures through which neurons communicate, known as “synapses,” change during development of the human brain. How are these billions of synapses formed and refined? How do these circuits change, and allow us to remember, and to learn? What happens when these connections go awry and what is their relationship to human disease?

In the summer 2012, Peter said to me: “I have become an expert on Parkinson’s dementia.” He paused with a smile, his quiet humor intact after more than two decades of Parkinson’s disease. His next sentence came out after a bit of effort. “It is all about the synapses and abnormal pruning.”

The concept of synaptic pruning had an impact on mainstream thinking about early education soon after its discovery. The fact that millions of synapses are eliminated between early childhood and adulthood was mind boggling. But conceptually, it made sense that the brain circuitry starts with more connections than are needed, and subsequently can be sculpted based on input. Although it may seem inefficient, the early overabundance of connections enables a process for selective elimination and refinement that occurs over years, as children learn. But how does synaptic pruning relate to childhood learning? Education scholars and advocates had for centuries been alert to the positive impacts of education on child development. In 1979, education initiatives such as the Head Start program in the United States. were already in place. The discovery of synaptic pruning then supplied a new and specific biological basis supporting the benefits of early childhood education.

Peter and Janellen had shared ideas throughout their careers, molding each other’s perspectives on the fields of brain plasticity and development. Their shared interest and distinct approaches were accurately highlighted when they were introduced to their new retirement community in the early 2000s, through the Montgomery Place newsletter.

The Cognitive Revolution was an intellectual movement in the 1950s and 1960s focused on using the scientific method to understand human cognition, otherwise known as the process of learning and memory. This revolution in the field of psychology was happening at the same time that neuroscientists like Hubel and Wiesel were exploring how neurons in the brain are organized to enable behaviors such as visual perception. It was in this environment that both Peter and Janellen developed further as scientists. The connections between their respective fields provided fodder for discussion and debate throughout their careers. Peter focused on cellular events and biological processes in developmental neuroscience, while Janellen probed the mechanisms of human verbal and mathematical learning and memory.

Peter and Dieter traveled to “America” on the Marine Shark, a US cargo ship (Figure 7.1). The trip, as Peter understood it, was to “visit their mother.” Peter had not seen his mother since he was six years old. Intermittent letters and the packages of food and gifts were the only contacts. Peter refused to make the trip without Dieter, whose approval by the US government was delayed because he had helped in the German Airforce. Richard and Charlotte prepared Dieter and Peter for their transit, putting together a photo album for the boys with childhood photos. Dieter and Peter arrived in Ellis Island at the end of 1948, shortly before Peter’s 18th birthday (Figure 7.2).

Any understanding of Peter, and his motivation to figure out how the human brain develops and can go awry in disease, requires delving into his childhood and the lives of his parents. Peter was particularly inspired by his mother, who was guided by the “need to be good” and spoke out against Nazism while most people remained silent. Peter’s mother, Else Lamparter, was born in 1904 in Ohringen, a medieval village in the rolling hills of southwest Germany. As an only child, she was doted on by her parents and her “Uncle” Uhle. Her family ran an expediting business transporting luggage and goods from the local rail station. As a child, Peter visited his grandparents in the summers and helped his soft-spoken grandfather with the horses and carts as they travelled through the hilly cobbled streets of Ohringen. The Lamparter family had large, lively social gatherings with family and friends, which were documented in the many family photographs.

Sometimes in science you experience an “aha” moment. It can happen while sitting in a talk, reading a paper, doing an experiment or doing the evening dishes. And when you have this jump in understanding it is hard to contain the thrill and excitement. Of course, you might be wrong – the next morning may reveal all the holes. But scientists cherish these infrequent moments when they make a new scientific connection that could change the way they – and subsequently others – think about a problem. This is precisely what happened in May 1993 when the young group leader Chris Walsh heard Peter Huttenlocher present at a neurology meeting focused on epilepsy in Venice, Italy.

Following the Second World War, the United States experienced economic prosperity and, at the same time, turned away from its general policy of isolationism to one more focused on international engagement. The letter Peter wrote to his mother in 1948, before emigrating to the United States, was prescient. As noted in Chapter 6, Peter had written about his concerns over a New York Times article implying that America was already preparing and ready to enter another war, and had said “I hope not.” In 1949, the United States rejected its prior policy of having no military alliances in peacetime by forming the North Atlantic Treaty Organization (NATO) in response to the growing tensions between the United States and the Soviet Union. The first post-war US military engagement started shortly after Peter’s US citizenship was confirmed. Else was relieved to have her sons in the US, but the concerns Richard and Else had written about were valid. Peter, as a US citizen, would be drafted into military service in the United States.

In 1946, Peter’s family reunited in Braubach, a village along the Rhine near Koblenz and Oberlahnstein, Peter’s birthplace. Braubach is a medieval village lined with half-timbered buildings that run along narrow winding streets. Nestled in the hills along the Rhine, Braubach is surrounded by vineyards and forest, and was left largely intact after the war. From all points in town including the Marktplatz (marketplace in the town center), the Marksburg castle is visible on the hill above the village. Initially constructed in the 1100s, the castle was badly damaged during the war and was left in ruins for years. During Peter’s teenage years, the castle served as an adventure playground for the youth of Braubach. However, in current times the Marksburg castle has been restored and is now part of the Rhine Gorge UNESCO World Heritage Sites. The family lived in a small apartment near the town center, Rhinestrasse 3. Peter and Dieter shared a room with a window that had a view of the castle.