Dr. Phillip Chance and the Neurogenetics Laboratory: Perseverance in Progress

Dr. Phillip Chance
Dr. Phillip Chance

Featured in interaction June 2007 (PDF 2.8MB)

Dr. Phillip Chance is the director of Seattle Children’s Hospital Research Institute’s Research Center for Genetics and Development. His office, sandwiched in the back corner of a bustling laboratory located in the RR Wing of the University of Washington Medical Center, is as warm and welcoming as the Researcher’s smile who works there. “We don’t get visitors back here that often,” he said, motioning toward a chair and then stating with a twinkle in his eye, “You know, my first career choice was to be a professional clarinet player."

It is a good thing for genetic research that Dr. Chance followed his secondary interest in biology and went to medical school. In the fall of 1977, Phillip Chance worked as a student with the late Dr. David W. Smith, professor of Pediatrics at the University of Washington. Dr. Smith, who first described “Fetal Alcohol Syndrome” in the US, authored the well-known and widely-used text, Recognizable Patterns of Human Malformation. “Dr. Smith didn’t have big-time grants or fancy laboratories. He was so well versed in human genetics and embryology that he could immediately bring it into clinical application. He trained an entire generation of geneticists that are now leaders in the field. He inspired me to go into what I am doing today,” said Dr. Chance.

Today, Dr. Chance’s research focuses on neurodegenerative and neurodevelopmental disorders. His laboratory, known as the Neurogenetics Laboratory, grew from three people (himself and two others) to a group that now includes six faculty, three post-doctoral researchers, six research scientists and a genetics counselor. His research is funded by several NIH grants, including three K awards, and is also supported by the Allen & Phyllis Treuer Endowed Chair and the March of Dimes Endowment for Healthier Babies at Children’s Hospital.

The research conducted by Dr. Chance and his colleagues in the Neurogenetics Laboratory focuses on four principal areas:

  • Charcot-Marie-Tooth Neuropathy – a common inherited group of peripheral nerve diseases that lead to physical disabilities in children and adults;
  • Hereditary Neuralgic Amyotrophy (familial brachial plexus neuritis) – a rare disorder that causes episodic bouts of severe arm and shoulder pain and limb paralysis;
  • Familial Juvenile Onset Amyotrophic Lateral Sclerosis (ALS: juvenile Lou Gehrig’s Disease) – a progressive, childhood-onset neurodegenerative disorder that leads to extreme muscle wasting and disability in adulthood; and
  • Joubert Syndrome – a hereditary group of disorders that cause developmental brain abnormalities in children.

Each focus area has a dedicated team of scientists led by a junior or mid-level faculty member. These researchers scour the genetic landscape for markers and mutations with clues to causes, cures or the development of potential therapies and genetic tests for each condition.

Dr. Chance explains, “Our laboratory functions as a companion to the clinical part of the division. Each disorder under study was prompted by my having seen a particular patient in clinic. I lead a dual role – I am division chief of genetics and developmental medicine, and I delegate responsibility among the research programs in the Neurogenetics Laboratory.” With this dual role, Dr. Chance has the opportunity to contribute something to all of the projects being undertaken in the laboratory.

Each project is different, and progress within genetic research sometimes has benchmarks as small as the material under study. When asked specifics about the research being undertaken within his lab, Dr. Chance suggested that interaction speak with each team individually to hear in their own words about the work being undertaken.

Joubert Syndrome

This team consists of Researchers Drs. Ian Glass, Dan Doherty, Melissa Parisi, and Craig Bennett, Research Scientist Nick “Captain Excel” Gorden, Genetic Counselor Dana Knutsen and Lab Manager Jon Adkins. While sitting with five of these team members at a conference room table, interaction received a short but in-depth lesson in the gene identification process.

Lesson One: What is a “Microarray,” and What is it Good For? Microarrays are used to identify thousands of genetic markers called SNPs (single nucleotide polymorphisms) across an entire genome. These genetic markers are used to narrow down the regions in which candidate genes might reside. Once this is determined, the real fun begins:identifying the specific gene responsible.

Lesson Two: The Whole Process is Long and Arduous. The identification of a gene is a multiple-year endeavor. Dr. Chance and his colleagues began collecting families in 1991, and the team identified the first gene for Joubert syndrome in 2004. A variety of mundane, and time-consuming, tasks precede the identification of a causative gene:

  • Identifying the families with the syndrome;
  • Confirming the diagnosis as Joubert;
  • Consenting the family for participation in research studies, and;
  • Collection of the actual samples and clinical information from all over the world including Turkey, Saudi Arabia and many European countries. After all of this, detailed lab work begins by
    • Isolating the DNA;
    • Purifying the DNA;
    • Running the microarrays; and
    • Standardizing the microarray data; followed by
    • Identifying candidate regions and finally;
    • The art and science of combining regions across families and deciding exactly how to look for mutations and in which particular genes.

The past five years in Joubert research have seen both increased interest as well as an increased pace of discovery. As a result of recent work, Joubert syndrome has joined a number of other disorders resulting from defective function of the primary cilium, an historically unappreciated cellular organelle. Very recently, in collaboration with the laboratories of Drs. Ronald Roepman and Nine V.A.M. Knoers at the University Medical Center Utrecht, the UW Joubert team is happy to report the discovery of a 5th gene, and their results will appear soon in the journal Nature Genetics.

Hereditary Neuralgic Amyotrophy (HNA)

Dr. Mark Hannibal is the lead on the HNA team and he shared the status of their research. In 2005, mutations in the SEPT9 gene on chromosome 17, which encodes the septin-9 protein, were found in HNA families and published in Nature Genetics. Dr. Chance initiated the genetic search for HNA in the early 1990s and worked with an international collaborative group to identify SEPT9 as the first gene responsible for HNA.

HNA may serve as a model for an inherited pain syndrome, and research into this disorder could bring insights into treating severe pain. An interesting fact about HNA is that those individuals who are genetically predisposed to it actually look somewhat alike, with their eyes more closely set. Some affected individuals are born with a cleft palate. The goal of the current HNA research is to find out how mutations of the gene interfere with the proteins produced as an expression of the gene. The laboratory will also examine where the SEPT9 gene is expressed in early embryogenesis. Coming at this question from the direction of craniofacial development and palate formation is a unique take on the research currently being conducted in the field.

Familial Juvenile Onset Amyotrophic Lateral Sclerosis (ALS – Juvenile Lou Gehrig’s Disease)

This team is comprised of Drs. Craig Bennett, Maria Moreira and Ying Zhang Chen. At the end of 2003, the cause of this rare form of childhood-onset ALS (known as the ALS4 gene) was found to result from mutations in the Senataxin (also called SETX) gene on chromosome 9. Quite unexpectedly, work on SETX has been challenging for several reasons, one being that this gene encodes a particularly large protein at almost 2,700 amino acids in length. Another sticking point is that many of the standard methods normally used to study genes and proteins require over-expression. But human cell lines or even yeast don’t appear to tolerate over-expression of SETX very well.

“Right now we are poised to make some exciting discoveries,” Dr. Bennett shared. The reason: the successful expression of the gene in mice. The key to progress with this research has been collaboration; numerous teams have encountered difficulties working with this gene. Yet, despite all of the trials and tribulations, painstaking progress is being made toward understanding the genetics behind this form of juvenile-onset ALS.

The work being undertaken in the Neurogenetics Laboratory takes patience and perseverance. With the completion of the human genome project, their tasks have become a little easier, but the long-term outlook and appreciation for microscopic victory is embedded in everyone working on the genetic level. The appreciation for such efforts is apparent in the work of Dr. Chance and his colleagues.