Like no other organ, the human brain defines our lives. It directs us to draw every breath, tells us what we want for dinner every evening and then conjures dreams as we sleep. It is at the center of who we are, but remains one of the body’s biggest mysteries.
Casper Hoogenraad is driven to understand the workings of this magnificent machine. Even as a child, Casper couldn’t resist tinkering with the things around him — you might say his brain is just wired that way.
“I wanted to dismantle everything,” says Casper, Vice President and Head of Neuroscience Research. “When I was young, I would take apart my bike completely and then put it all back together again. I wanted to see the pieces. And the most fun part was trying to fix it.”
He would spend hours poring over a building set or piecing together intricate circuits and models, studying every detail of how the various pieces fit together. Remember playing with those childhood electronic kits and chemistry sets? Casper does.
“I could spend hours on those. I didn’t even know what a scientist was, I just knew that I loved working with my hands and solving puzzles. It just made sense to me.”
In many ways, that hasn’t changed. Casper still conjures up projects to understand how things work. Only now, those experiments have the potential to produce treatments for diseases that progressively erode the brain.
Mechanical Inclination
During his younger years, Casper thought he wanted to be an engineer. With his love of breaking things down and building them up, it seemed like a natural fit. Then at university, a biochemistry textbook opened his mind to the world of biological science.
“Learning how oxygen binds to hemoglobin and how a single mutation can change the structure of a whole protein — it was almost like engineering in a living person. As soon as I saw it, I knew that’s what I wanted to do.”
After receiving his bachelor’s degree in biochemistry, he focused on molecular and cell biology for his master’s and doctoral studies at Utrecht University and Erasmus University Rotterdam, both in the Netherlands.
For his PhD, Casper joined the Department of Cell Biology, which was headed by Frank Grosveld, because he was fascinated by investigating the function of genes. It was his mentor’s positive outlook on failure that unleashed Casper’s creative freedom and drove him to succeed.
“He would approach the team and say, ‘Look, we have found a new gene and I have a couple of weird ideas. They’re probably going to fail. But you’re a new PhD student, so let’s go for it.’ And I actually loved that.”
Casper embarked on research into the microtubule cytoskeleton, a structural component that gives cells their shape. His work led to the discovery of a new class of microscopic machines called plus-end tracking proteins, which are essential for microtubule dynamics and play a critical role in cell division and motility.
Focus on the Brain
Over time, Casper became more intrigued by neuroscience. Technical advancements, such as molecular approaches that enabled researchers to grow and manipulate neurons in the lab and the emergence of new imaging technologies to study the brain, showed him the potential of the blossoming field.
Casper joined the MIT lab of Morgan Sheng as a postdoc, where he applied the biochemistry and imaging skills he had honed to the study of synapses, specialized structures critical for neuronal communication. Casper had tremendous success teasing apart the proteins that are involved in building connectivity between neurons by removing them one at a time, then observing the result.
He then returned to the Netherlands to head his own lab, first at the Erasmus Medical Center Rotterdam and later at Utrecht University, where he chaired the Department of Cell Biology, Neurobiology and Biophysics. But he couldn’t shake off his need to fix things in the body, and his desire to be part of the discoveries in neuroscience he saw on the horizon.
“At that time, I could sense that there were going to be some important breakthroughs in neuroscience, just like we had in oncology 20 years ago.”
Morgan Sheng had joined Genentech in 2008, and over the years as Casper ran into him at conferences, he noted how much progress his former mentor made in his work. Casper joined Genentech himself in 2017, with the hope of making important scientific discoveries while also making a difference for people confronting diseases of the brain.
Teaming Up
Today, Casper oversees teams that focus on various aspects of neurobiology, including neurodegeneration, a process that plays a role in a wide range of brain diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), and on finding new ways to treat chronic pain. He is especially excited about the progress being made in MS, which causes the immune system to destroy myelin, the protective insulation that coats nerve cells, interfering with their ability to communicate.
“For years, even decades, everyone’s been talking about how to regenerate myelin. It’s not a secret that remyelination is the next big thing to do in MS. The fact is that at Genentech, we’re actually doing it.”
Last year Genentech started a collaboration with Convelo Therapeutics for the discovery and development of novel remyelinating medicines for patients with neurological disorders such as MS. “Neuroscience needs multiple new ideas and much more creativity; partnering up with external scientists is crucial.”
In one of their most creative programs, Casper’s team is identifying genetic mutations that enable extremely rare people to withstand sensations that would normally cause excruciating pain without so much as a wince. The researchers have already discovered some interesting genes linked to sensing pain this way and are now pursuing ways to block the target.
“Studying the human genetics of pain is a fascinating example of 'reverse translation'. By studying patients with inherited pain disorders, you know that the genetic variant will give you a well validated ‘clinical’ target. If you inhibit that particular target with a drug, then people should feel no pain anymore.”
If A, then B. It’s similar to the logic Casper used as a child when he broke his bike down into pieces to figure out how it worked, or when he removed single proteins from neurons to understand how they build connections. Only now, he’s satisfying his curiosity about the world while making a difference for patients as well.
“In addition to this breadth of fantastic science, I guide the most compelling projects through the research pipelines to eventually test the best targets in the clinic. Genentech is all about an academic atmosphere combined with the potential of developing transformative medicine. I think that combination is really something unique.”
Casper Hoogenraad is a Vice President and Head of Neuroscience Research at Genentech. Learn more about his work here.