BIOLOGIE & MEDIZIN_Zur Person

From football player to : Sam Young has had an astonishing career. Photo: O’Donnell Agency – Jennifer Sullivan BIOLOGY & MEDICINE_Personal Portrait

Still Scoring Touchdowns

In college they called him Stump – as in tree stump – because of his physique and his strong will. Today, former football player Samuel Young is a renowned neuroscientist. Using innovative tools and sophisticated techniques, he would like to find out how nerve cells communicate with one another. The head of a junior research group at the Max Planck Florida Institute is the quintes- sential researcher. But his career took an unconventional path.

TEXT HUBERTUS BREUER

amuel Young doesn’t look like and sophisticated surgical techniques someone to be messed with. that allow him to manipulate the gene The man is muscular and built functions of certain brain cells in mice like a tank, and his loud laugh and rats in order to study their neuro- confidently marks out his ter- nal signal transduction. Sritory. Sitting under the palm trees on the campus of Florida Atlantic Univer- RESEARCHING THE BRAIN sity, eating steak and fries, and hearing WITH VIRUSES how he came from a middle-class neighborhood in New Jersey to head The researcher developed these tools a junior research group at the Max himself at such academic centers as Planck Florida Institute, one gets the Princeton University, the University of impression that his physical presence North Carolina in Chapel Hill, the Salk and sheer strength of will were instru- Institute in La Jolla, California, and the mental in his achievements. After all, Max Planck Institute for Biophysical nothing was handed to this young sci- Chemistry in Göttingen. “What I do is entist on a plate. basic research – we want to know what For a little over a year now, 37-year- biophysical and molecular mechanisms old Samuel (Sam) Young has been a re- underlie brain function. Once we under- searcher in Jupiter, on the Atlantic stand these basic mechanisms, we will coast of Florida. He is researching how then be able to understand the causes of neurons communicate with one anoth- brain disease,” he says. er. He tackles his work with an innova- Young’s career could not have been tive arsenal of tools, such as manipulat- foreseen when he embarked on his

xxxxxxxxxxxx ed viruses that insert genes into cells, studies – from party-loving college stu-

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» I had the feeling that nothing could break me.

dent and football player to outstanding commonplace. One day, Young’s father from his meal, “but my father beat us researcher in the fields of molecular bi- was attacked and shot, and took early when we were young. That instilled in ology, virology, and retirement as a result. “My father was a me a certain amount of insecurity. At biophysics. The scientist remembers highly intelligent man, but unfortu- the same time, my father’s beatings something his mentor, cancer research- nately, he didn’t have the same educa- made me tougher and able to with- er Arnold Levine, told him: Young had tional opportunities that he made sure stand physical and mental punish- just graduated from Princeton and his children had.” ment.” Moreover, Sam Young was al- Levine remarked that people like him ways well built and a good athlete. “I didn’t really exist in the sciences. A GOOD EDUCATION FOR had the feeling that nothing could Sam Young grew up in New Jersey, A GOOD START break me. I always thought that I could in a typical American suburban town – survive anything.” Caldwell, about 16 miles from New Young’s father strongly encouraged his Young also excelled at school: “I York. Home was a two-story, colonial- children to get a good education: “You never had to study. Everything came to style house with a driveway and a gar- need to get an education. You don’t me very easily,” he recalls. He discov- den in the back. When Sam was a child, want to have to be doing hard physical ered his affinity for science at an early his mother worked Friday and Saturday work like me to earn a living.” Sam and age, too. One of his favorite books was nights as a waitress and later became a his siblings took his words to heart. His Science Experiments You Can Eat. He full-time housewife. She only returned older brother, Andrew, was the first per- learned how cabbage can detect acid, to work when he was in high school. son in his family to graduate from col- how bacteria make yoghurt and how ght) She finally earned a college degree two lege. He now works in the pharmaceu- sugar turns to caramel. years ago, at the age of 60. His father tical industry. His younger brother has When he went to high school, he was a sales representative for Frito-Lay, a doctorate in chemistry and works as began playing football. Young wasn’t delivering potato chips and snack foods a senior research chemist in the area of the biggest player on the team – 5’10” in neighboring Newark, a city with a green energy technology. (178 cm) in this sport tends to be below notorious reputation – drug-related “It’s hard for me to say this now,” average – but he was strong and fear- crime, gang wars and muggings were says Sam Young as he takes a break less. His reputation as a talented player

In the patch clamp method, a fine glass pipette is placed on the cell membrane of a nerve cell to measure electrical current in the neurons. left Flow of current through a calcium channel in the presynaptic cell (top); flow of current in the postsynaptic part of the synapse (bottom) (nA: nanoamp; ms: millisecond) center Simultaneous measurement at the presynaptic (red arrow) and postsynaptic part (blue arrow) of a calyx of Held synapse. right Sam Young aspirates the cell membrane. The vacuum causes the edges of the pipette to adhere to the membrane.

pre lCa 1 nA

EPSC

1 nA

2 ms Graphics: Max Planck Florida Institute; photos: Institute (center), O’Donnell Agency – Jennifer Sullivan (ri

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Sam Young checks to see how an experiment is progressing. Fluorescent nerve cells can be seen on the screen in the background beside the microscope.

helped him in his college applications. strong bond among the football play- When he again turned his attention to Of all places, it was the elite Princeton ers, and Young soon found a home the natural sciences, he decided to ma- University that was grateful to welcome within the football team. jor in molecular biology. When he ap- the football player with excellent grades Young began his first semester with proached the secretary in the depart- in its incoming college class. For Young, an experiment: “Because I always per- ment, she simply looked at him and it was confirmation of his belief that he formed well in the natural sciences, I said: “There are no football players in could do anything. wanted to see what would happen if I our department.” However, one of the attended seminars only in the human- stars in the field of molecular biology, SNOBBERY AND PREJUDICE ities. As it turned out, that wasn’t such cancer researcher Arnold Levine, was a good idea.” All the while, he was par- himself a football fan and took Young Princeton was a culture shock; the ma- tying hard, just like many American under his wing. “If it wasn’t for Arnie jority of his classmates came from college students living away from Levine giving me a chance, I probably wealthy families who had attended pri- home for the first time. Young in- wouldn’t be a scientist today,” says vate schools and had every advantage dulged excessively in the initiation Young. Levine was famous as the co- that such environments offered. All of rites that mark the passage into the discoverer of the protein p53, which them were destined, from the day they world of young adulthood. “I was the suppresses the development of cancer were born, to attend an Ivy League uni- one who always did something crazy in some tumors. He accepted that versity. “Initially, I had major problems at a party. Most of my fellow students Young would be unable to work in the with the elitism on campus.” Class- didn’t even know my real name. To lab during the football season, but he mates made him and other football them I was simply ‘Stump’” – as in tree could count on him twice as much for players feel that they had been accept- stump, the man who is as wide as he the rest of the time. He assigned Dan ed at Princeton merely because of their is tall and doesn’t move for anything Notterman to be Young’s adviser. The

Photo: O’Donnell Agency – Jennifer Sullivan sporting skills. Naturally, that created a or anybody. molecular biologist had worked with

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» I was the one who always did something crazy at a party.

Levine to investigate whether p53 was During his last year in Princeton, the viral gene therapy and co-creator of also instrumental in preventing the for- young scientist heard two lectures that gene therapy vectors, Jude Samulski at mation of cells with abnormal chromo- would have a crucial influence on his the University of North Carolina in some numbers. In 1998, two years after career: one on the potential of gene Chapel Hill, paved the way for his sci- he graduated from college, Young pub- therapy, and another on the study of entific career. lished the results as co-author in the memory in fruit flies. Young’s decision On his own initiative and at his leading cancer journal ONCOGENE. to do his doctorate with a pioneer of own expense, Sam Young began work- ing in Samulski’s lab immediately after he graduated. He soon had his own project: investigating how adeno-asso- ciated viruses (AAV) are integrated in Entrance to auditory the genetic makeup. The advantage of nerve fibers these viruses is that, as far as is known, they don’t cause genetic disorders. When they are inserted into a human cell, they integrate themselves into chromosome 19. VCN In his dissertation, Young examined the specific mechanism by which these viruses install themselves in this partic- Bushy cells ular location in the human genome. To do this, he had to learn new skills: clon- LSO Calyx of LSO ing, developing new cell lines and pro- Held synapse ducing recombinant viruses. During his MNTB MNTB time with Samulski, he also learned how to write a paper and deliver a pre- sentation. “Jude taught me from the 1 mm ground up how to be a scientist.”

SLOW AND STEADY WINS THE RACE

One of the areas that Sam Young inves- tigated was the number of AAV pro- teins expressed in a cell. He initially approached the project in his own

top: Relay in the auditory brainstem system of an 11-day-old mouse (the associated brain areas are outlined in white). Using a virus, the nerve cells were genetically modified in such a way that they form a fluorescent protein and are illuminated in green. Information transmitted through the calyx of Held synapse helps the animal localize sound. (VCN: ventral cochlear nucleus, LSO: lateral superior olive, MNTB: medial nucleus of the trapezoid body). bottom: Calyx of Held synapses, greatly magni- fied. At this stage of development, the synapses are cup-shaped. Photos: Max Planck Florida Institute

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Science also needs teamwork: Sam Young doesn’t analyze American football plays anymore. These days, his focus is on ion flows and changes in potential.

way. With hard work and determina- Young completed his doctorate three researchers told him that his idea was tion, he was looking for a quick and a half years after completing his too ambitious. Nevertheless, neurobiol- “touchdown” – to publish a paper as bachelor’s degree. He discovered that ogist Charles Stevens at the Salk Insti- lead author – in just his second year of the AAV integrated itself on chromo- tute for Biological Studies in San Diego graduate studies. However, in order to some 19 not only because it found suit- was interested. “I will always be grateful quickly finish what he thought was able docking sites there, but because its to Stevens for giving me the opportuni- the final experiment, he accepted proteins also supported chromosome ty to switch fields,” says Young today. sloppiness in trade. “What I tried to do replication during cell division. He had to learn a new research field was garbage science,” he now admits. from scratch. He spent the first six Samulski reacted accordingly and HOW DO LEARNING AND months studying ’s classic threw Young out of his lab. “There are MEMORY WORK? textbook on the neurological principles no shortcuts in science.” of memory and Bertil Hille’s definitive In retrospect, Sam Young sees this as Once he had completed this project, work on ion channels in cell mem- the turning point in his young career. Young began looking around for a post- branes. Steve Heinemann, another ex- When he returned to the lab three weeks doctoral position. He didn’t want to pert in molecular neuroscience at Salk later, he had radically changed his atti- stay in gene therapy, as the issues were Institute, also supported Young in ex- tude. “It was a cathartic moment. And I too applied for him – he was interested ploring what was, for him, unfamiliar always remember Samulski’s advice: in basic research. He remembered his territory. The risk he took in working in ‘Sam, you’ll never have enough time to fascination with the neuronal basics of a new field demonstrates one of Young’s do it right the first time, but you’ll al- memory and wondered whether neu- strengths: he doesn’t shy away from ac- ways have enough time to do it again.’” ronal genes could be manipulated in quiring a new skill, even if it serves to Years later, in recognition and respect for such a way that conclusions could be answer just one scientific question. “I everything Samulski had done for him drawn about their function. never aspired to work across disciplines in and outside the lab, Young named his Brain research, however, had not ex- – it was simply the inevitable result of

Photo: O’Donnell Agency – Jennifer Sullivan first son Jude. actly been waiting for Sam Young. Some my research interests,” he recalls. >

3 | 11 MaxPlanckResearch 71 Sam Young always has his work tools from a previous life at hand: a football on the shelf and a pair of cleats under the desk.

Sam Young also learned the complex cess. He established that they evident- mentor Charles Stevens also ensured patch clamp technique. This is a meth- ly have a strong influence on signal that he had an in-depth knowledge of od that uses fine pipette tips to measure strength. Contrary to what was previ- electrophysiology.” the smallest currents through the indi- ously believed, this is not dependent on However, a small problem soon vidual ion channels of a cell mem- the number of vesicles at the cell mem- arose for Young. A few weeks after his brane. This method was developed by brane. Young worked on the project for meeting with Erwin Neher, he met the biophysicists and Erwin four years and, in 2005, summarized love of his life, Sidney, at a party. For Neher in the 1970s at the Max Planck his findings in a paper published in the two months, he remained silent about Institute for Biophysical Chemistry in prestigious scientific journal PNAS. his impending departure. When he told Göttingen. In 1991, both of them re- her about his plans, the new relation- ceived the in or IN THE NOBEL PRIZE WINNER’S ship threatened to fall apart. However, Medicine for their work. Bert Sakmann LABORATORY after a few dramatic crisis meetings, is the Founding Director at the Max they agreed that she would not only go Planck Florida Institute. Sam Young’s stay in California was fol- with him, but that they would also get The patch clamp technique is used lowed by a second postdoctoral posi- married – which, however, took anoth- to investigate how synaptic contacts, tion in , where he also later er three years. and consequently the efficiency of sig- became an internal group leader – with In addition, Young had never been nal transmission, change. At the syn- Erwin Neher at the Max Planck Insti- to Germany before, or anywhere else in apse, the electrical signal that moves tute for Biophysical Chemistry in Göt- Europe. “I wasn’t aware how far north through the neurons is converted into tingen. Young had met Neher at a con- it is – at least compared to New Jersey, a chemical signal, since it must be sent ference in the summer of 2004, where where I grew up.” As much as the cool- from the transmitter neuron to the re- Neher had suggested collaborating. In er climate surprised him, Young still cipient neuron. This process occurs by reply, Young daringly asked: “How considers Göttingen, and Neher’s de- means of neurotransmitters, which are about if I join your research group?” partment in particular, to be the Shan- packed in membrane-bound sacs (vesi- Neher, who receives hundreds of re- gri-la of science – that legendary para- cles). They must fuse with the cell quests every month, spontaneously an- dise in the Himalayas where people membrane before they reach the syn- swered “Great idea!” The Nobel Prize devote themselves entirely to a spiritu- aptic cleft between the transmitter and winner remembers the conversation al existence. the recipient. So-called SNARE proteins, well. “Sam Young had virology exper- In Neher’s lab, Young began work- which Sam Young studied in greater de- tise, which we needed in the lab at that ing, for the first time, with the synapse

tail in La Jolla, play a role in this pro- time. His time in the lab of my earlier that would be central to his work right Photos: Max Planck Florida Institute (3)

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» The opportunities the offers, and the ideals for which it stands, were very attractive.

up to the present day: the calyx of Held, membrane, helps position synaptic ves- He is also working with Florida Atlan- a huge synapse in the auditory brain- icles at the active zone and co-facili- tic University to develop a graduate stem of rats and mice, which can mea- tates their simultaneous release. program in neurosciences there, and sure up to 0.02 mm in diameter. Once Before the paper was published, has already organized a neuroscience again, the researcher was entering un- Young once again had to think about symposium at which the graduate pro- charted territory. He had to create new his future and had discussions with sev- gram was launched. “We can establish technology and develop special recom- eral universities in the US. “My home something special here,” he says binant adenoviruses. At the same time, and my family’s home are in the States, cheerfully. This writer is convinced he developed a surgical method that al- so staying in Germany was not an op- that the program will be a success. lowed him to specifically inject the re- tion.” But he was not completely lost Sam Young has the determination to combinant viruses into the calyx of to the country – an opportunity unex- make it one. Held in the auditory brainstem of new- pectedly arose to apply for the position born rats. This meant that he could use to head a junior research group at the the viruses as transport vehicles to in- newly founded Max Planck Florida In- sert new genes into the nerve cells and stitute. “The opportunities that Max thus manipulate molecular processes at Planck offers – without the pressure of the synapse and obtain information having to constantly write research ap- GLOSSARY about how they worked. plications or teach too much – and the ideals for which Max Planck stands, Adenoviruses LAST-MINUTE SUCCESS were very attractive,” says Sam Young. A group of viruses that can infect human “I was already very familiar with the and animal cells. They find their way For the first two years, not one of his Max Planck ecosystem from Göttingen, into the cell interior in membrane- bound sacs. Adenoviruses don’t have a experiments worked. Then, in 2007, at and the new institute gave me the op- viral envelope and are highly resistant. lunch with Erwin Neher one day, Young portunity to continue working within Scientists often use them to insert genes revealed that, if the next experiment the Max Planck family.” into somatic cells. In humans, naturally did not work, the entire project would Using the tools that he developed occurring adenoviruses can cause infections such as respiratory or gastro- be a failure. Meanwhile, his wife was himself, Young embarked on the task of intestinal infections. five months pregnant. As a responsible further unraveling the precision engi- Ion channels family man, Young was anxious to neering of synaptic signal transduction. Channel-shaped proteins in the cell achieve success, which would also se- His viral gene shuttles allow him to ge- membranes through which electrically cure his future career. Everything de- netically manipulate neurons; his inno- charged particles such as sodium, pended on whether the foreign genes vative surgical methods and the patch calcium or chloride ions can flow in or out. Various triggers can change the that he inserted into the calyx synapse clamp technique help him to take pre- physical structure of the protein, with by means of viruses would be activated cise measurements. He wants to use the result that the channel becomes at a level that would disrupt the molec- these methods and tools to examine a permeable or blocked. These include ular processes there. number of other issues in greater detail: electrical and mechanical stress, binding He wanted to conduct the crucial how the vesicles and neurotransmitters partners and light. Ion channels are crucial in determining the electrical experiment before his daughter was become functional, what role selected properties of a cell. born. But just as he was about to take proteins play in this process, and how Viral gene therapy the first electrophysiological measure- the pre-synaptic calcium channels are Viral gene therapy is used to cure ment, the micromanipulator broke. He arranged at the active zone. “We have genetic diseases. The viruses are used as had to wait another few weeks before to perform both quantitative measure- vehicles to insert a functioning version of the defective gene in certain cells. announcing that he had successfully ments and molecular manipulations, as The genetically modified viruses can manipulated the synaptic function. this is the only way we can develop ac- infect cells but cannot multiply further. The scientist discovered that Synapto- curate models of how synapses func- tagmin, a protein localized in the cell tion,” says the researcher.

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