Erin Schuman: Making memories- Deciphering the mystery of brain cell communication

Text: Linda Geddes

The US American neuroscientist Erin Schuman is a pioneer in brain cell biology. Schuman’s ideas and the techniques she has developed have helped to revolutionise our understanding of how the billions of neurons inside the human brain synthesise the proteins needed to communicate, regulate brain function, and consolidate memories. Building on these discoveries, the Körber Prize winner now plans to investigate disease-related changes occurring at individual sites of communication between neurons called synapses. Doing so could yield new ways of treating brain diseases and disorders such as Fragile X syndrome and Huntington’s disease.

Most biologists study what Erin Schuman calls “little round cells”. Compared to the excitable neurons that transmit information in the brain, she considers them to be relatively simple. Although neurons also have a soccer ball-shaped body, where their chromosomes and various organelles reside, this accounts for only ten to 20 per cent of their volume. The rest of it stretches out into vast and elaborate branches, which form connections with around 10,000 other neurons. At each of these connection points, or synapses, the information that flows between them allows us to think, feel, move, and comprehend the world around us. “It truly is an awesome feat that this individual cell can process a thousand or more different streams of information independently,” says Schuman, who is a director at the Max Plank Institute for Brain Research in Frankfurt, Germany, and the winner of this year’s Körber Prize. And this flow of information is entirely dependent on proteins.

Images:

(1) A method developed by Schuman’s lab visualises the neurons (green) and a newly produced ribosomal protein (red). The nuclei in the cell body are shown in blue.

(2) The microscope image shows a microfluidic chamber developed by Schuman’s team filled with neurons. The cell bodies, visible through the white-coloured nuclei, remain in the lower part of the chamber. This makes it possible to analyse individual parts of the neurons – axons (magenta) and dendrites (cyan) – independently of the cell body.

(3) Microscope image of the cerebellum of a mouse. A special staining technique reveals sites ofprotein synthesis (green).

Proteins are the workhorses of our cells, involved in the structure and function of every living process. In the brain, they give rise to the neural networks that underlie perception, action, learning and memory. Not only do they provide the substrate through which the billions of neurons in our brains communicate, but they also enable the connections between them to be enhanced, remodelled and maintained as we live our lives. Brain scientists call this process of adaptation of neural connections “synaptic plasticity”. It underpins our ability to adapt, learn from and remember our experiences. Understanding precisely how this process works could ultimately help us to better understand ourselves.

Schuman has spent the past 30 years trying to figure out how the billions of proteins that are so essential to neuronal activity are manufactured and delivered in precisely the right amounts to precisely the right synapse, at the right time, when the brain’s demand for them is so high. “In a single neuron, every 24 hours, we need at least 300 million new proteins, just to keep that neuron at status quo,” Schuman says.

When she started her career, the dogma was that all of a neuron’s proteins were made in its cell body and then shuttled out to each of its 10,000 synapses via the cable-like axons and dendrites that connect with its neighbours. Yet over the years, through a combination of intricately designed experiments and dogged persistence, Schuman and her colleagues have turned that thinking on its head.

“Schuman’s pioneering work has provided evidence that proteins made locally near or at synapses are sufficient to maintain and modify synaptic communication during memory formation,” says Edvard Moser, Chair of the Körber European Science Prize’s Search Committee for Life Sciences.

“Her work has solved one of the core problems of neuroscience and established local protein synthesis as a fundamental cellular mechanism in the creation of memories. The machinery identified by Schuman explains not only the normal operation of synaptic plasticity but also points to synaptic mechanisms potentially underlying a wide range of diseases – or synaptopathologies – in the brain”.

With the Körber Prize funding, Schuman now plans to use some of the technologies that she and her colleagues have developed to probe what goes wrong at synapses in neurodevelopmental and neurodegenerative diseases, which she hopes could eventually lead to new treatments for them.

An appetite for learning

Schuman has long been interested in how the brain creates memories. Born in San Gabriel, California, in 1963, she was a serial hobbyist, with childhood interests ranging from painting to softball, dancing and reading. “I was a voracious learner at school, and as I grew older, I began to self-reflect on how all of that stuff that I was taking in was being stored and how it could then be made use of,” she says. “This idea of what is the substrate for information storage and memory in the brain fascinated me.”

Although she began her university education at the University of Southern California thinking that she might become a doctor, she found herself increasingly drawn towards the psychology courses that were on offer during her pre-medical degree. Noticing her interest, Schuman’s tutor started giving her scientific papers on memory to read. Traditionally, psychologists considered the brain to be a black box, and preferred to focus on the behavioural aspects of memory. But Schuman instead found herself wanting to know more and more about what goes on inside that black box when we store information.

She finished university with a BA in psychology, having first completed a study on learning and memory in human twins. This involved driving around Southern California and testing young twins in their homes, an experience Schuman describes as “incredibly chaotic and a little bit weird”. “If you wanted to design an experiment to turn people away from human research, this was it,” she says.

By now, she had abandoned her medical school plans, and having been put off further human research, she embarked on a PhD in neuroscience at Princeton University. This involved teaching sea slugs to associate a stimulus that they would usually be attracted to, light, with the unpleasant sensation of being spun on a turntable at high speed. Schuman then studied their brains to try and understand the molecular changes that this learning event had brought about.

Excited by this research, Schuman decided that she wanted to continue her neuroscience career, so she moved to Stanford University to master what was then a state-of-the-art technique for studying brain cells: keeping thin slices of rodent brain tissue alive and inserting tiny electrodes into it to measure changes in the activity of individual neurons as they were exposed to different stimulation patterns. She then began using it to investigate the molecular events occurring at synapses as learning occurred.

Local protein synthesis

By 1993, Schuman had secured an assistant professorship at California Institute of Technology (Caltech) in Pasadena, US, and had begun setting up her own lab. Together with her first graduate student, Hyejin Kang, she began investigating whether some of the same molecules that sculpt neurons and their connections during development, might also be implicated in shaping and strengthening synapses in adults.

A key discovery was that a growth factor known as brain-derived neurotrophic factor (BDNF), which is needed to maintain connections in the developing brain, could also serve as a synapse-enhancing molecule when it was applied to adult brain slices. However, for this circuit strengthening – or plasticity – to occur, surprisingly, the synapses immediately required newly synthesised proteins.

Proteins are manufactured in tiny factories within cells called ribosomes, using molecular photocopies of protein-coding genes called messenger RNAs (mRNA) as templates. These templates are created in the cell nucleus, where the chromosomes are kept, and are usually then shuttled to nearby ribosomes in the cell body for protein production.

Schuman’s discovery was surprising, because the cell bodies of neurons were too far away from the synapses to enable new proteins to be transported there so quickly. “It suggested that the source of protein synthesis was not the cell body, but local, near the synapses,” she says.

Unexpected as the result was, it wasn’t the first time that someone had challenged the dogma that all proteins were made the cell bodies of neurons. In the early 1980s, Oswald Steward and William Levy at the University of Charlottsville in Virginia, US, had published electron micrographs showing ribosomes near the synapses of certain types of neurons.

Although further studies had detected some mRNA molecules near synapses, these observations had failed to get much traction. “Even by the early 1990’s, the concept was that only a few mRNAs were transported into dendrites for local protein synthesis, and that most protein constituents of synapses were synthesised in the cell body and transported,” says Steward, who is now director of the Reeve-Irvine Research Centre in Irvine California.

Yet, there were problems with the idea of proteins being shipped from the cell body to the synapses when they were needed. “If this were true, the neuron would have a major housekeeping issue because new proteins would have to be directed precisely to the to-be-modified synapses, avoiding the many thousands of synapses of the same cell that are not involved in the learning experience,” says Moser. “With hundreds of thousands of proteins generated in a cell per minute, the required sorting and transporting would be at an astronomic scale.”

Schuman’s research played a key role in overturning this dogma. In 1996, she and Kang published a paper in Science, one of the world’s most prestigious research journals. It showed that synaptic plasticity – a process that depends on newly synthesised proteins – could occur even if a synapse was physically separated from its cell body.

The discovery surprised almost everyone. “When I first shared the data, the idea was called ‘crazy’ by more than one of my colleagues,” Schuman says.

Yet, in the years that followed, she and others confirmed and elaborated on these findings. Today, the idea of local protein synthesis is widely accepted by neuroscientists. “The 1996 paper opened up an entire new area of investigation into the role of local translation in neural function,” says Christine Holt, Professor Emerita of Developmental Neuroscience at the University of Cambridge, UK. “It was therefore a primary driving force for the massive ensuing exploration of local translation in development and plasticity that has recently occurred.”

Image:

FUNCAT and BONCAT are revolutionary methods developed by Schuman and her team. They use artificial amino acids such as so-called NAA to visualise proteins in neurons.

Seeing is believing

A key step was finding a way to directly visualise protein synthesis happening in the branch-like dendrites of neurons. “I felt with conviction that if we could see new proteins emerge here, we would really convince ourselves and others that proteins can be made locally,” says Schuman.

Existing imaging methods were too slow and labour-intensive to document protein synthesis occurring in real time, and it was also very difficult to identify which proteins had been made. So, Schuman and her colleagues set about devising new ways to identify and visualise newly synthesised proteins.

One of their first experiments involved using the gene for green fluorescent protein – a protein that glows green when exposed to ultraviolet light – and sending its mRNA to the dendrites. This “local synthesis reporter” construct was introduced into rat neurons, so that when the cells started making the protein, its location would immediately be revealed. In doing so, Schuman’s team identified the dendrites as the site of this protein synthesis, close to where it was needed at the synapses.

Schuman and her colleague David Tirrell also developed a completely new technique, called bio-orthogonal non-canonical amino acid tagging (or BONCAT), which allows newly synthesised proteins to be tagged or visualised in neurons, or indeed any cell, tissue or organ. The technique is increasingly finding applications outside neuroscience – including in microbiology where it is being used study the activity of bacteria in soil and other environmental samples.

BONCAT involves adding tiny chemical tags to amino acids, the building blocks of proteins. When these artificial amino acids are introduced to neurons, they become incorporated into newly made proteins, which can then be labelled with a fluorescent dye or another tag.

“I remember reading about Dr Schuman’s new method and thinking to myself that she was a scientist of unusual creativity, and this conclusion has been borne out over the years,” says Michael Greenberg, Professor of Neurobiology at Harvard Medical School in Boston, US.

These methods provided the visual proof that was needed to convince other scientists that protein synthesis routinely occurs near neurons’ synapses, not just in their cell bodies. “Seeing is believing,” says Steward.

Using BONCAT, tagged proteins can also be pulled out of cells and analysed using a technique called mass spectroscopy. “This has opened the door for identifying the newly synthesised proteins, so you can start to ask what are the proteins that are being increased or decreased when animals learn something,” Schuman says.

Deciphering the protein language of neurons

In 2008, Schuman moved to the Max Planck Institute in Frankfurt, Germany, where she launched an effort to identify all the mRNAs that are present in dendrites and find out how many types of protein are being synthesised near the synapses.

Toh do this, her team isolated mRNA molecules from dendrites and axons, and used a technology called RNA sequencing to read these genetic photocopies and discover which proteins they coded for. They also created fluorescent “barcodes” designed to bind to specific mRNA molecules, meaning that each type could be visualised and counted.

“Instead of the 10-20 mRNAs that had been recognised previously, Schuman’s papers revealed that thousands of mRNAs could be detected in dendrites at levels ranging over 3 orders of magnitude,” says Steward. “This was a second revolution in our understanding: Rather than being limited to a few critical proteins, most or perhaps all of the protein components of synapses could be synthesised on site.”

“Together, these data suggest that local translation isn’t only a mechanism for synthesising new proteins during learning, but a more general mechanism for efficiently building synapses,” says Greenberg. “Consistent with this view, in recent work Schuman has shown that each type of synapse has its own repertoire of localised mRNAs. This means that local protein synthesis has evolved to suit the needs of each type of synapse.”

Manufacturing proteins locally makes sense, says Schuman. She likens it to the distributed generation of electricity, which is increasingly being used to build more flexible and resilient energy grids, by stationing technologies such as solar panels, wind turbines and storage systems close to where the electricity is likely to be used. By stationing mRNAs and the protein synthesis machines, the ribosomes, at the business ends of neurons, it enables them to respond to local demand and keep the connections between neurons stable. It also allows for the rapid modification of synapses in response to external events.

Synaptic dysfunction in disease

Despite the great progress that has been made, there is still much to learn about this system. One question is the degree to which dysregulated protein synthesis might be implicated in various brain diseases and disorders.

“What has become clear in the last 15 to 20 years, is that a lot of diseases end up having synaptic dysfunction as their endpoint,” says Schuman. Either there’s a problem in the circuitry of the brain when it is first wired up, such as in developmental conditions like autism spectrum disorder or Fragile X syndrome (a genetic disorder that affects a person’s behaviour and ability to learn), or in the case of neurodegenerative conditions such as Alzheimer’s disease, the loss of neurons and synapses leads to disrupted brain circuits.

“Numerous lines of evidence indicate that synaptic function becomes compromised in disease and there is good evidence to suggest that the local proteome – the entire set of proteins at each synapse – is affected through dysregulated local protein synthesis,” says Holt.

While previous efforts to understand these events at the molecular level have involved sequencing proteins from homogenised brain tissue, or entire single cells, Schuman plans to use some of her Körber Prize funds to conduct experiments that will analyse which proteins and mRNAs can be found in the synapses of mouse models of Fragile X syndrome, Rett syndrome and Huntington’s disease.

Over the past five years, her team has developed methods to deeply characterise, in isolation, the mRNAs and proteins that are only present at synapses and tell exactly which cell types they are coming from.

“What that allows us to do is to really focus on what’s wrong at the synapse in these different disease states. To not only look for the presence or absence of these mRNA protein modules, but also count them, so that we can begin to understand how they work together, or don’t work together, in disease,” says Schuman. “These data will be of great use to both basic and translational neuroscientists and hopefully also clinicians, providing the basis for molecular interventions, which, if successful, could be followed up by potential treatment strategies for humans.”

Inspiring the next generation of scientists

As well as her numerous contributions to scientific research, Schuman has worked hard to enhance women’s and teenagers’ exposure to science. This has included the development of a summer research program for high school students, and inviting them to attend institute seminars, which are preceded by an introductory lecture to the topic. Schuman plans to use Körber Prize funding to further strengthen these outreach efforts.

One issue she feels passionate about is boosting opportunities for students from under-represented groups, including those from immigrant communities. Existing internships and research experiences tend to attract candidates from socially advantaged schools and families, but these programmes may not be on the radar of promising students from disadvantaged backgrounds. Even if they are aware of them, “many of these kids cannot afford the luxury of summer internships because they are usually unpaid,” says Schuman.

One of her plans is to establish an intensive summer “boot camp”, which will provide top high school students from under-represented groups with hands on research experience – including a stipend to cover their living costs. Successful candidates will also receive mentoring and contact during the school year, followed by guidance on next career steps and university applications, if desired. “I think that reaching out to science teachers in disadvantaged schools and trying to bring in some of those promising kids could be transformational,” Schuman says.

Humbled by complexity

Throughout her career, Schuman has strived to unravel the mysteries of how neurons achieve the incredible feats they do. Although she has helped to solve a key part of the puzzle, it will likely take another generation of neuroscientists, persevering and developing new techniques, to answer further riddles – including how the constellation of proteins at synapses manages to etch lasting memories, when each protein only exists for a few days.

When Schuman looks at an image of a neuron today, with its tree-like branches forking into tinier and tinier projections, connecting with a multitude of equally complex cells, she feels humbled by the achievements of something so small. “When I show this picture of a neuron to other people, I call it my muse,” she says. “It is like looking at a fascinating painting: You see so many things going on, that need to be explained.”

The Prize Winner

Erin Schuman is a neurobiologist and director at the Max Planck Institute for Brain Research in Frankfurt, Germany. Born in 1963 in San Gabriel, California, she is the oldest of three children and was raised by her mother, a Catholic school teacher, and her grandparents.

As a young child, Schuman recalls loving reading and being “obsessed with learning” at school. She completed a bachelor’s degree in psychology at the University of Southern California, followed by a Ph.D. in neuroscience at Princeton University. In 1990, she moved to Stanford University to conduct postdoctoral research, before being appointed to the Biology Faculty at the California Institute of Technology as an assistant professor in 1993 and as a professor in 2004. She was an Investigator of the Howard Hughes Medical Institute from 1997 to 2009. In 2009, she moved to Frankfurt with her husband Gilles Laurent – also a neuroscientist – and three daughters to establish two new departments at the Max Planck Institute for Brain Research.

Her research has been recognised through numerous awards, including the Körber European Science Prize and world’s largest neuroscience prize, the Brain Prize. Schuman has also been elected to various distinguished academic societies, including the US National Academy of Sciences, the American Academy of Arts and Sciences and the UK’s Royal Society.

Schuman is a passionate advocate for enhancing young people’s exposure to science and advocating for women in science. Soon after moving to Frankfurt, she launched a successful initiative to increase the percentage of female directors in the Max Planck Society’s Biomedical Section to twenty per cent by 2020, and the section is now pushing for thirty per cent by 2030. This advocacy has been recognised by the EMBO Women in Science Award and the FENS-Kavli-ALBA Diversity Prize.

Together with her husband Gilles Laurent and colleague Moritz Helmstaedter, Schuman has also worked to transform openness regarding third Reich era crimes conducted by the Max Planck Institute for Brain Research’s predecessor, the Kaiser Wilhelm Institute for Brain Research. The institute was responsible for the euthanasia of hundreds of human patients in order to study their brains. “This heavy topic had previously been dealt with, but without transparency and without an attempt to recognise the individual victims,” Schuman says. “Our efforts have led to the formation of a commission to uncover and account for all such war-time atrocities in the Max Planck Society, to accord the victims with respect and memory, and to ensure institutional memory so that such crimes may not be repeated.”

Professor Moser, you are chair of the Search Committee Life Sciences and yourself a renowned neurobiologist and Nobel laureate. What makes Erin Schuman’s research so special?

Erin Schuman transformed our understanding of one of the fundamental logistical challenges of neuronal cell biology: how the strength of synaptic transmission is maintained and regulated by ongoing synthesis of proteins.
Schuman’s pioneering work has provided evidence that proteins made locally near or at synapses are sufficient to maintain and modify synaptic communication during memory formation. Over the years, and with cutting-edge methods developed by Schuman and her team, it has become clear that the number of proteins synthesized locally is in the order of tens of thousands. Schuman has identified many thousands of those proteins. Her work has solved one of the core problems of neuroscience and established local protein synthesis as a fundamental cellular mechanism in the creation of memories.

Before you joined the Search Committee, you were awarded the Körber Prize in 2014. What did the prize mean to you personally and professionally?

The prize came during a year when our work was recognized by a number of scientific prizes, including the Nobel prize, which came only a few months later. The dense series of prizes brought attention to neural systems studies of the brain and made it textbook knowledge. The prizes emphasized the importance of basic mechanistically oriented studies in neuroscience, and showed that it is possible to identify the neural building blocks of even our most complex cognitive functions. This recognition was important to me personally as well as the entire field of neuroscience. The Körber Prize deserves a lot of the credit for this. It helped spreading the word through carefully prepared media interviews and press coordination, and the ceremony itself was a joy from beginning to end. I felt that our work was understood and appreciated. Moreover through the research money that came with the prize, it was possible to follow up some of our bravest and riskiest ideas with this kind of funding.

The Körber Prize aims to strengthen Europe as a hub for scientific excellence. What measures do you consider to be particularly effective in promoting the European scientific landscape?

Scientific prizes like the Körber Prize are important in bringing the best of European science to the attention of the general public, those who eventually pay for it. They showcase the results that are achieved by long-term investments in fundamental research and they demonstrate that Europe has research groups at the very highest level. Reminders about this fact are important to justify investments in basic investigator-driven research, the starting point for all other research and all innovation. Yet prizes are of course not sufficient to promote excellence in European science. Such excellence requires steady and stable investment into basic research with a long-term perspective. The major instrument for this support is the European Research Council. Increasing their budget, and keeping it stable and predictable, is among the best investments Europe could make into its future.