Taking Giant Steps to Repair the Infant Brain
words by Eve Jacobs / photograph by Andrew Hanenberg
teve Levison is a happy scientist. He bounds down the hallway to his office with a grin on his face and energy brimming. Why not? As he so simply states, “I like what I do. Science is my life.” And it doesn’t hurt that just five months ago he and five fellow collaborators from the U.S. and Europe — calling themselves the Transatlantic Network on Newborn Stroke — were given a major nod of approval with a $6 million grant from a forward-thinking French foundation to pursue their interest in inflammation and the newborn brain.
This research group is onto something important; and the Paris-based Fondation Leducq has demonstrated its confidence in the team’s members, based not only on a formal grant application six inches thick, but also on their well-established track records. Collaboration among researchers in locations as far-flung as Sweden, France, Newark, NJ, and San Francisco, California, is not an impediment, but an enhancement, according to the philosophy of the foundation’s founders, whose mission includes support of scientific cross-fertilization across national borders and even across the big pond.
The Network — composed of three clinician-scientists and three basic scientists — is investigating the premise that inflammation following newborn brain injury is not all bad. “The accepted view is that inflammation exacerbates brain damage,” Levison explains. “That happens — yes, but we think inflammation also promotes repair.”
Levison’s lab in the New Jersey Medical School/University Hospital Cancer Center in Newark is buzzing with intellectual life. A basic scientist-teacher, he believes that bringing along the next generation of researchers is hugely important. He inspires them with the excitement of making discoveries, which is precisely what propelled him into his career. “The great thing about science is being constantly surprised about what you can achieve,” he says. “When I was a graduate student, the idea that the CNS [central nervous system] could regenerate because it has stem cells was just a dream.”
It is that dream — of repairing damage to an infant’s brain rather than buying into the notion that the brain is irreparable — that solidifies Levison’s bonds to the small community of scientists working on infant stroke, which occurs in more than 1 of 4,000 births. Although most of these infants now survive, 80 percent are impaired by cerebral palsy, epilepsy and developmental disorders. The injury does not occur all at one time, explains the researcher, but “continues over a period of days and weeks following the stroke, resulting from cascades of pathological processes in which brain cells are damaged by being over-activated.”
The questions are many and, right now, the answers are few. Levison rattles off some of the questions at the top of their list: “Which inflammatory signals cause damage? Which cells contribute to the damage? How and to what extent does inflammation promote repair? When should suppression of the damaging neuroinflammatory cascades stop so that the self-repair process can begin?
“Most of the focus in stroke has been on neuroprotection,” he states. “Because we’re dealing with infants, this is different from adult stroke. There’s more plasticity. Infants are still growing. Our goal is to enhance repair, regeneration and remodeling.”
The six-member collaborative group is still in its formative stages. Together they have outlined the “big picture,” but now they’re planning which pieces of this project each will work on and how they will proceed together. Levison explains that there are three major cell types with roles in the immune response of the central nervous system. Microglial cells migrate into the brain early and are the resident “sentinels of the brain,” ready to gear up if there is an injury or invasion. Macrophages, which circulate in the blood, move into the brain when chemokines, which are manufactured by the brain, signal an infection or injury. And mast cells — best known for their response to allergy — also appear to be important players in responding to brain injury.
Levison’s lab team will do proteomic studies (looking at the full set of proteins encoded by a particular genome in order to determine how the proteins interact with each other) and genomic studies (looking at chromosomes, genes and their functions) on all three cell types. One of the Foundation’s primary goals is to move the findings from bench to bedside — or, in this case, from “cells to crib-side”— quickly.
That goal is right in line with Levison’s hopes of impacting clinical practice with his lab’s findings within just a few years. The key question in his mind is: If heavy immunosuppression impedes the brain’s repair process, how long is it necessary to use specific drugs to tamp down the inflammation; and are certain drugs problematic and not others?
“If you give an immunosuppressant drug for inflammation, it may suppress stem cells from producing new neurons,” he explains. “Small changes in current treatment practices could have big long-term meaning.”
Levison submitted a manuscript whose findings refute the long-held belief (now the basis for practice in this specialty) that if you suppress inflammation, it’s good for repair. “We gave immunosuppressive drugs to rodents and found just the opposite. But we were looking at a different part of the brain.” The NJMS group was studying the “brain marrow” — also called the subventricular zone (SVZ) — that houses the stem cells in the neonatal brain, whereas other groups had focused on the precursors in the hippocampus.
In prior research, Levison’s lab demonstrated that brain injury in the infant stimulates the proliferation of the stem cells within the “brain marrow,” resulting in a doubling in their number after just three days, and that these new stem cells can generate new neurons and glia. “Naturally, it would be detrimental to recovery from injury if any clinical intervention interferes with the stimuli that coordinate the expansion of the neural stem cells and their attempts to repair the brain,” he states.
“Therefore, it’s critical to understand the signals that stimulate the proliferation of stem cells and the effects of commonly used anti-inflammatory drugs on the naturally occurring regenerative responses of the stem cells.”
Indomethacin is the anti-inflammatory drug that is most commonly used in hospitals to prevent intraventricular hemorrhage and to treat babies with the congenital heart defect known as patent ductus arteriosus. While this drug reportedly decreases infant mortality, Levison’s lab found that it may also interfere with repair: the researchers surmise that a certain amount of inflammation is needed to stimulate the neural stem cells of the SVZ to begin the process in which the brain starts to heal itself.
Based on these preliminary findings, lab members will focus on more specific questions deemed crucial to treating infant stroke: If you use immunosuppressive therapies [such as Indomethacin], how much should be used? When should you begin this treatment? How long should you continue the therapy? What effect does this have on the production of stem cells?
Levison’s lab is also involved in studying another facet of infant brain repair. There is a large cohort of premature infants who sustain brain damage, he says. “At 28 weeks, you can’t call it a stroke. The brain damage is related to the infant’s prematurity. At the 28 to 32 week period of development, specific cells are very vulnerable to injury. They are precursors of myelin-producing cells and are most fragile during this time,” he explains. These cells are vulnerable to the inflammatory cytokines, excitatory amino acids and to free radical injury.
“When this happens, you do not get proper myelination in the brain. There are many consequences of this,” he says. Like other regenerative neurobiologists Levison is confident that strategies to enhance the development of myelin producing cells can be implemented. “We have high hopes for being really productive in this area.”
Levison is also the principal investigator on a sizable grant from the New Jersey Commission on Brain Injury Research, established in 2004, which collects research monies through legislation adding $1 to motor vehicle or traffic violation fines. His $1,533,130 award underwrites three collaborative projects at UMDNJ and NJIT to devise strategies to enhance regeneration of brain cells and to promote recovery of function after traumatic brain injuries (TBI).
Using rodent models, the group is assessing TBI in both young and adult animals. They are focusing on novel therapies to promote regeneration for those with earlier injuries. Building on recent findings in stem cell research, they are assessing the capacity for resident stem cells, as well as for transplanted stem cells, to heal brain damage. In addition, they are evaluating the roles of support cells in the brain to promote or inhibit regeneration. The overall goal of the research is to identify cells or molecules that can be targeted for treatment.
Levison, whose father was on obstetrician/gynecologist and whose mother was a psychotherapist, chose his life’s work early and stayed with it. He graduated in 1983 from the University of Rochester, one of the few schools that offered a major in neurosciences at the undergraduate level. “I loved biology,” he remembers, “and I was reading Carl Jung and thinking the brain is really really cool. And I was wondering: ‘How do cells give way to our complicated behaviors, fears, thoughts and emotions?’”
“I was in touch really early on with what I felt was really important and interesting — and that is the brain,” he comments.
His interest has never flagged — not during his doctoral studies at the University of North Carolina (UNC) Chapel Hill researching neural development, his post doc at Columbia, his 11 years as a faculty member at Penn State, and his six years to-date at NJMS. He is married to fellow neuroscientist Terri Wood, whose research focus is multiple sclerosis (MS).
“I want to bring what I’m working on in the lab into medical practice — that’s why I’m doing this,” he says. “I want my work to make a difference — to treat people with brain disorders.”
There’s no question that the challenges of repairing brain damage following infant stroke and traumatic brain injury are enormous; but with a mighty push from such researchers as Steve Levison and his collaborators, doctors may soon be able to better assist the damaged brain on its path to recovery.