The word neurosurgery conjures images of drills, scalpels, saws and all manner of sharp, invasive instruments. But the tools of neurosurgeons in the future are unlikely to be based in stainless steel, at least according to neurosurgeons from the University of Chicago Medicine.
At a symposium held on March 26, David Frim, MD, Chief of the Section of Neurosurgery, Maciej Lesniak, MD, Director of Neurosurgical Oncology, Peter Warnke, MD, Director of Stereotactic and Functional neurosurgery, and Issam Awad, MD, the John Harper Seeley Professor of Surgery, with distinguished guest Robert Martuza, MD, Chief of the Neurosurgical Service at the Massachusetts General Hospital in Boston, discussed what they hope will be the basis for neurosurgical treatments into and beyond the 21st century: viruses, genes, proteins and molecules.
“The role of the academic neurosurgeon is to put himself out of business,” said Martuza, a pioneer of gene therapy approaches toward treating brain tumors and mentor to many prominent neurosurgeons around the world, including Frim and Lesniak. “The neurosurgery of the future is to exploit the internal anatomy of brain circuits and change what neurons do—strategies of altering the brain in ways that are not thought of traditionally neurosurgical.”
The average adult brain weighs around just three pounds, and is made of cells, fat, proteins and blood vessels. Remarkably, when these components are functioning correctly, they generate senses, memories and thought, and regulate functions critical to life such as movement, breathing and the heartbeat. Encased in the skull and protected by the blood-brain barrier, which keeps harmful toxins and other molecules in the blood from entering, the brain is normally well-defended from harm. However, because of these vital functions and natural defenses, when disease or injury does occur, it can be difficult to treat.
Stem cells and viruses
Take brain tumors, for example. The most common—and most lethal–brain cancer is known as glioblastoma multiforme, which affects thousands in the US every year. Once diagnosed, survival time is measured in months. The need for new treatments to battle this deadly disease is great, and Maciej Lesniak has a vision for addressing this challenge: viruses loaded onto stem cells.
Targeting and killing cancerous cells with genetically engineered viruses is not a new concept to science. But clinical trials have shown that the utility of these viruses as a therapy is limited by their inability to disperse throughout a tumor. For the past seven years, Lesniak and his collaborators have been working on improving a virus that can specifically target cancerous brain cells. To make the virus spread and kill as much of the tumor as possible, they worked with an FDA-approved neural stem cell line that has an innate ability to travel and spread in the brain. When loaded with a tumor-killing virus and injected into the brain, these stem cells have shown remarkable promise in reducing tumor sizes and increasing survival in animal models. Lesniak anticipates a phase I clinical trial soon, and has already submitted the mountain of paperwork necessary to initiate one to the FDA.
Although there is no guarantee this method will cure or eliminate brain tumors, Lesniak quoted the famous Canadian neurosurgeron Wilder Penfield: “Simply to postpone death is very much worthwhile, for life, when we measure it by weeks and months, becomes a very precious thing.”
“I think this is something people forget,” said Lesniak.
Drugs where they need to be
As for why general approaches to treating brain cancers have thus far failed, Peter Warnke addressed the problems he sees as a researcher and surgeon. Brain tumors are a complex mix of different cell types and most treatments are unable to selectively target all these cell types. And though the brain has the highest amount of blood vessels of any organ, most substances have a difficult time crossing the blood-brain barrier. Even when drugs or other therapeutics are injected into the middle of a tumor, pressure gradients inside quickly drive the substances out before they have a chance to destroy cancerous cells.
“Overall approaches do not work in brain tumors,” said Warnke. “It has to be tailored to the individual tumor and individual patient.”
Warnke proposed a potential solution to this issue: a computational model based on physics. Well recognized for his expertise in stereotactic surgery, which involves the real time monitoring of probes and other instruments in the brain in 3D, Warnke believes that this type of tracking can help surgeons make sure drugs go where they are needed. But targeted delivery must be guided by maps of each individual, unique tumor. He described his work on a model which uses physics to calculate how molecules occupy a single capillary. Combined with contrasting agents and CT or MRI scans, the model allows surgeons to estimate how permeable specific areas of tumors are to drugs, and where those drugs might go once injected. With this information, surgeons might be able deliver substances where they have the most effect, or areas which need higher concentrations than others.
“If you don’t know where you smart molecules go and how they go there, all sophistication in the lab is wasted,” Warnke said.
A paradigm disease
Although certainly devastating, cancer is not the only disease that affects the brain. Studying these other disorders is critical, argued Issam Awad.
“The idea of molecular neurosurgery is to move to new research frontiers,” Awad said. “In the process of deconstructing neurosurgical diseases, we learn how to predict disease behavior, refine surgical strategies and design new therapies that could avoid surgery altogether.”
An internationally recognized leader in neurovascular diseases and stroke, which affect blood flow in the brain, Awad spoke on a rare disorder known as cerebral cavernous malformation (CCM). In this disorder, abnormal blood vessels in the brain balloon outwards, forming relatively large, blood-filled cavities. Although CCM only affects less than one percent of people, patients are constantly at risk for bleeding events, seizures, neurological issues and stroke.
Little is known about how these lesions form, how they grow and what causes the bleeding. Therefore, no therapies are available to prevent the progression of the disease. To study this disease, Awad and his team started with the very basics. They defined the structural, anatomical and physiological traits of the disease, such as how the abnormal capillaries leak blood and how cavernous malformations spread. They studied the immune response to these vessels in order to clarify the disease mechanism and dove into the genetics, even creating genetically engineered mice to better understand the genes involved.
After years of arduous work, they found ROCK. Short for rho-associated kinase, ROCK, a protein that affects how cells adhere to each other, appeared to be activated by the mutations that cause CCM. When ROCK is blocked, symptoms of CCM, such as hyper-permeability of the capillaries, are reversed. When given a drug to block ROCK, mice developed fewer mature CCM lesions. Awad and his team are now studying ROCK in humans.
Awad believes that, even though CCM is a rare disease, it can serve as a paradigm for other disorders. CCM can lead to strokes and epilepsy, and its genetics, protein interactions, traits such as abnormal blood vessel formation and permeability across capillaries, can all provide insight into other diseases.
“What we understand about this very special orphan disease is that windows may open in medicine to other diseases, just like we use tools from other diseases to dissect what we learned about this entity,” Awad said.