James Surmeier, professor at Northwestern University, recently visited Lund University where he gave the 2018 Segerfalk Lecture. In this interview, he talks about how technology is helping brain research to advance, about almost giving up research altogether – and the discovery that could slow the progression of Parkinson’s disease.
James Surmeier grew up on a farm in Idaho, studied mathematics, but then switched direction to conduct neurophysiology research. He wanted to understand how the brain works. After getting his doctoral degree, he was close to giving up the life of researcher to study law. An experienced researcher got him to change his mind: was it worth throwing away all the time and energy he had already invested?
“He asked me to go with him to Tennessee, to help to find out what dopamine does in the brain. And he was sure that would rekindle my passion for research again”, says James Surmeier.
Two years later, James Surmeier had “fallen back in love with research”. Since then, he has won many awards, including prizes from the NIH and Michael J. Fox Foundation, for his ground-breaking research on dopamine and basal ganglia.
Advisors in the brain
James Surmeier mainly conducts research on three disorders: Parkinson’s disease, Huntington’s disease and chronic pain. What is the link? The basal ganglia. They are groups of nerve cells under the cerebral cortex and their functions include regulating our movements. Information from the cerebral cortex and thalamus is passed to the basal ganglia about possible courses of action. The basal ganglia help us to carry out the right sort of movement at the right time.
“You can liken the basal ganglia to trusted advisor that helps us choose the right action at the right time. By keeping track of what has worked in the past – and what hasn’t – the basal ganglia help guide rapid, efficient action. This is an ancient part of the brain is found in all vertebrates, dating back 500 million years. Obviously, it has served an evolutionary purpose, enabling us to rapidly escape from danger or to fight when we need to.”
James Surmeier explains in a simplified form how the basal ganglia receive a question from the part of the brain known as the cortex: “Shall we carry out action one, or action two”? The basal ganglia’s job is then to look back in time, to ask what worked previously. They then give a recommendation for the most appropriate action based on the situation at hand.
According to Surmeier, they can generate two different signals: “Take action, do it again” or “No, we need more time to think, as what we did previously did not work”. In simple terms, the dopamine-signalling nerve cells activate or amplify the “Take action” signal. This way of accelerating and braking our movements is affected in different ways by Parkinson’s disease and Huntington’s disease. Parkinson’s disease is a so-called hypokinetic disease, which means that it is difficult to carry out movements (“initiate actions’). In the initial stages of Huntington’s disease, it is the opposite, as patients have unwanted, involuntary movements.
“In Parkinson’s disease, there is a loss of dopamine-producing nerve cells in the basal ganglia. These nerve cells are constantly alert and ready to help the basal ganglia choose action effectively. Because they are so important and need to be able to maintain their activity for a long period of time, they keep their intracellular power stations – mitochondria – generating energy all the time. Although this keeps these neurons from becoming fatigued, it comes at a cost. Reactive oxygen species or intracellular pollutants are produced by the power plants that can cause damage to the power plants themselves and to other intracellular molecules, like DNA. In the short term, the pollutants do not compromise the ability of these neurons to do their job, but with age and declining capacity to recover from the pollutants, these neurons slowly die. If too many of these cells are lost, perhaps because of a predisposition or the exposure to environmental toxins, Parkinson’s disease manifests itself ” he explains.
Strategy for counteracting emissions from the cells’ power station
Is it possible to reduce the pressure on these cellular power station in some way, reduce their stress and enable dopamine neurons to survive longer? Yes, contends James Surmeier. By studying how the power plants were controlled by activity, his group discovered that a specific type of calcium channel in the nerve cell’s membrane was critical to stimulating mitochondria. By reducing the calcium that flowed through these channels, the mitochondrial power plants slowed down and produced less pollution.
“There was a drug that had been previously used to treat high blood pressure and which antagonized these calcium channels and reduced the stress on dopamine neurons. When we suggested it might be beneficial in Parkinson’s disease, epidemiological studies were conducted. These studies showed that use of this drug (to treat hypertension) was associated with roughly a 30% lower incidence of Parkinson’s disease, in contrast to other blood pressure-reducing medicines such as beta blockers”, he says. ‘This was an exciting confirmation of our hypothesis.’
Phase 3 clinical trials are now underway to ascertain whether the drug can be used to slow the progression of Parkinson’s disease. According to James Surmeier, the trial results are expected in late 2018. The drug is no longer protected by a patent, which reduces the cost for each treatment.
What was the atmosphere like in the lab when you realised you were on the right track?
“As a researcher, I am trained to doubt. I am a big doubter. We always carry out experiments to refute our own hypothesis. Although the details have evolved over the last decade, our work has consistently supported the core idea we’ve been pursuing. This has led to a growing level of excitement and anticipation about the ongoing clinical trial.”
New technology advances brain research
With a structure as complicated as the brain, it is important that researcher have the tools they need to understand its function.
“Over the last 15 years, our experimental toolchest has grown tremendously and it has increased the pace of scientific discovery. The ability to control key experimental variables is fundamental and necessary for all research. For example, new technologies that enable us to know the type of neuron we are studying or monitoring have been a big step forward for us. These are exciting times for brain researchers”, states James Surmeier.
The basal ganglia are an interconnected group of neurons under the cerebral cortex that work together to help guide action. They are grouped together in clusters. Information sent from the cerebral cortex and thalamus to the basal ganglia, where it is processed. The outcome of this processing is passed back to the rest of the brain to help guide action.
Huntington’s disease and Parkinson’s disease
Dopamine has considerable importance for the brain’s control over body movements and when the nerve cells that release dopamine break down, the capacity to control physical movement diminishes. In Parkinson’s disease, the dopamine-producing nerve cells die in an area of the mesencephalon, resulting in a drastic decrease of dopamine levels in a region of the brain known as the striatum. The striatum also contains the most vulnerable nerve cells of those suffering from Huntington’s disease.
Symptoms: involuntary movements, various muscle symptoms and mental symptoms. Problems with motor skills such as slowness, clumsiness, decreased muscle movement, muscle rigidity and difficulties in starting new movements. Movement relating to speech, swallowing, breathing and eyes can also be affected. Capacity for thought and memory is affected at an early stage of the disease.
Parkinson’s disease causes problems such as slowness, shaking and rigidity. The main symptoms are that movements become slower and it becomes difficult to start a movement. Shaking, trembling, muscle rigidity and impaired balance are also part of the range of symptoms. Age and genetics are the main risk factors for developing the disease.