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| Pam and her mother Linda (family photo) |
By Pamela-Foye Needle
My name is Pamela Foye-Needle, and I am at risk for Huntington’s disease (HD). On the evening of January 18, 1999 I joined a sad association of HD-stricken families: HD took my mother Linda Jean, robbing my brother and me of her love and presence. It is a night that will remain with me always, a lingering reminder of a disease that must be cured to stop its horrific impact on its victims and their families.
Still, oddly enough, the disease, provided something positive in my life and resulted in a relationship that today offers the promise of understanding and a cure. More on that in a minute.
My mother developed the disease at the age of 30, and as long as I can recall, I remember family members suffering from the horrors of HD, both those with the disease (including one uncle that the disease also claimed a few years ago) and fellow family members affected by the heartbreak, loss and disruption that HD leaves in its dark wake.
Witnessing so much pain and suffering, I developed a keen interest in learning more about HD, and that, in turn, developed into a visceral, driving need to be part of the solution. With a growing interest in genetics and neuroscience, I elected to change my collegiate major from structural engineering to biomedical engineering, and after earning my undergraduate degree from UCSD in 1990, I began a Ph.D. program in genetics at the University of Te
xas Medical School. I realized the enormous healing potential of genetic research and more than anything else wanted to have a hand in bringing HD to an end.
After one year in graduate school, however, my mother began the all-too-familiar downward spiral as her HD progressed into its final, tragic stage. I left school after much soul-searching, realizing that being with my mom was more important to me.
Before I left, however, I attended an HD presentation by Dr. Allan Tobin of UCLA. His dedication and insight left me with a renewed commitment to continue my quest. After the presentation, I spoke with Dr. Tobin and told him my story. Back in
California, I contacted him again, and at his recommendation applied for a position with The Scripps Research Institute in Dr. J. Gregor Sutcliffe’s molecular neurobiology laboratory. Over the ne
xt decade his recommendation would prove life-changing.
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| Dr. Beth Thomas |
Introducing Dr. Elizabeth Thomas
Scripps is a collective of some of humanity’s brightest minds. I was fortunate indeed to meet and associate with so many special people, yet one person in particular forged such a lasting interpersonal bond that together we worked diligently to further the body of scientific knowledge about HD. It’s a bond that continues today, even though I no longer work at Scripps, and this person continues her personal quest to find a cure as a tribute to our friendship.
Dr. Elizabeth Thomas came to Scripps in 1995 as a post-doctoral fellow after receiving her undergraduate degree from UC Berkeley and her Ph.D. in pharmacology at UC Irvine. With similar interests and hobbies, we quickly became good friends.
Dr. Thomas (Beth) attended a number of presentations that I gave on HD while also learning molecular biology laboratory techniques from me. She eventually developed her own keen, intense interest in the disease. Her original academic discipline involved schizophrenia — a dysfunction of a region of the brain called the striatum — and she quickly realized the link: HD also manifests itself in the striatum.
Beth’s growing interest in HD from an academic standpoint increasingly became a personal interest and quest to help me, an at-risk friend whose mother and uncle were dying. Her quest now took on a singular sense of urgency.
I cannot imagine a greater gift.
“Stumbling” on a key discovery
During one particular study on the striatum (please refer to the Glossary by clicking here), Beth stumbled on the gene that encodes a protein involving a disorder called Dentatorubral pallidoluysian atrophy (DRPLA). DRPLA is a neurodegenerative disease that results from the e
xpansion of an unstable CAG repeat, ironically just like HD. The protein which contains the CAG repeat in DRPLA is called atrophin-1. Beth found the gene that encodes insulin receptor substrate protein p53 (IRSp53), which binds atrophin-1.
The importance of this discovery is based on geography. Put simply, in DRPLA atrophin-1 encodes a protein that is e
xpressed throughout the brain; however, the disease only manifests itself in one location. IRSp53 is only e
xpressed in regions of the brain affected by neurodegeneration – another striking similarity with HD.
Accordingly, Beth developed a theory that the neurodegeneration seen in DRPLA is not based on where the atrophin-1 protein is e
xpressed, but rather where it binds with IRSp53. This was highly significant because it foretold profound implications in terms of the chemistry of neurodegeneration.
Together we shared the discovery with the rest of the scientific community in an article titled “Insulin receptor substrate protein P53 localization in rats suggests mechanism for specific polyglutamine neurodegeneration,” Thomas EA, Foye PE Alvarez CE, Usui H, Sutcliffe JG, Neuroscience Letters (2001 AUG 31): 309(3): 145-8.
The meaning of the discovery
So, what does this mean? Essentially, the DRPLA gene encodes a protein e
xpressed all over the brain of the disease’s victim, yet the disease only affects certain, specific regions of the brain. Similarly, in HD, the gene is e
xpressed everywhere, but only certain regions of the brain die, specifically the striatum. Beth and I began to suspect that this phenomenon could be the same in all CAG repeat diseases.
Beth’s interest continued to grow, and she eventually received a grant from the National Institutes of Health to study gene e
xpression in the striatum of HD transgenic mice (more on that in a bit). In her words, her endeavors are ultimately motivated by friendship.
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| A normal mouse (squares A and C) and a transgenic mouse with HD (squares B and D) (photo courtesy of Beth Thomas) |
Transgenic Mice
HD transgenic mice are remarkably similar to HD patients. The mice, in essence, are tools that are used to measure specific deviations from normal brain behavior, the details of which are rather comple
x. Where there are physical attributes of the disease’s progression in the animals’ behavior, their brains e
xhibit specific markers that Beth studies to e
xtrapolate correlations and links.
Carrying 115 CAG repeat e
xpressions in their genetic coding, the mice develop behavior abnormalities including loss of physical coordination, tremors, hypokinesis and abnormal gait. Also, much like their human counterpart victims of the disease, the mice die prematurely.
The control mice with healthy brains get picked up by the tail and splay out their limbs. HD transgenic mice, however, curl into tight, fetal positions, suggesting the presence of similar spatial orientation problems and neuromuscular control degradations that afflict human victims.
Likewise, in order to e
xamine gait deficiencies, the transgenic mice have their paws painted with non-to
xic paint. The paw prints left by transgenic mice are telling in reference to their random, clumsy patterns as opposed to the healthy control animals. This too provides clues as to how motor response is affected by the disease’s progression.
A Roadmap to the Disease’s Progression
Questions still linger about why the striatum in particular seems so susceptible to neuronal death. In the case of HD, Beth and her two assistants are currently investigating how the mutated HD protein causes specific neurodegeneration within the striatum by identifying which striatum-specific proteins interact with the huntingtin protein.
Over the past ten years Beth has accumulated a pool of appro
ximately 50 genes that are e
xpressed primarily in the striatum. She has come to theorize that when the huntingtin protein associates with another gene product e
xclusively e
xpressed in the striatum, the neurons in the striatum become oddly susceptible to death. Accordingly, the body of evidence is starting to suggest a possibility that the HD gene might not be the sole culprit in cellular death. Rather, it could be based on chemical/genetic associations and interactions that take place within specific parameters, thus e
xplaining the differences in the disease’s various manifestations in afflicted individuals.
Beth has pioneered new methods for determining where the genetic associations are e
xpressed in HD transgenic mice by performing a procedure called in situ hybridization on thin “slices” of brain tissue. In lay terms, these slices can be studied to determine geographic isolation of genetic markers and disease activity through the use of highly specific chemical reactions.
Beth has pioneered another aspect of HD research by identifying several new genes associated with HD. This is important because HD’s trigger mechanisms are still a mystery in many cases, but their associated genetic locations provide the initial “on ramp” to the highway that will eventually lead to their locations, positions and affectations. Beth and her associates are currently forging ahead in this particular field by comparing gene e
xpression differences in HD transgenic mice at presymptomatic and symptomatic stages.
Her final analysis will provide a wealth of valuable information, including classification of each affected gene by name, biological group, and relative “movement” to other affected and disaffected genes.
To date, Beth and her research group have discovered several changing genes in the HD mouse, and they are currently classifying them into functional groups. When they get several hits in a group suggesting disease activity, they pursue it. Still, this process is time-consuming and requires meticulous attention to detail. The main functional biological groups that these genetic e
xpressions fall under involve vital processes in the body: transcriptional regulation, signal transduction, hormone transport, and energy metabolism – the basic functions that allow us to live.
The discipline of bioinformatics (the classification of genetic e
xpression) often results in thousands of hits on any given gene. Technology provides some respite via sophisticated computer classification programs, but the science remains drawn-out and e
xacting, roughly akin to “genetic accounting.” Beth’s task is daunting to say the least, relegating her team and her to endless repeats of e
xperiments before they can announce their finding to the scientific and medical communities with certainty.
Long Term Goals
Now that Beth has certain gene products initially organized into functional groups, there are very specific therapies for each group that she intends to try on HD transgenic mice as the ne
xt phase of her research. Eventually she intends to study the therapy’s interactions with human cells in tissue cultures, seeking genetic responses that could possibly suggest courses of treatment and/or prevention.
Ultimately, Beth is trying to understand the molecular basis of HD in order to delay the onset of the disease at a chemical level. Eventually the hope is to slow or halt the disease’s progression and/or develop new drug treatments that could lead to a cure. While that might still seem like scientific conjecture to some, the rapidly dynamic realities of her (and others’) research suggests that we might be living amidst the final generation of people afflicted with the horror of HD.
In the meantime, Beth is e
xcited about her research. In August, 2004, she presented a condensed synopsis of it to the HDSA-San Diego support group. Future data from her research can be found within the pages of our newsletter Conquest and on this website. For further information, contact me by clicking here or Dr. Beth Thomas by clicking here
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In the story of a disease marked by suffering, pain and death, there is another, subtle result that does not receive enough merit or praise. The love and dedication of those afflicted with HD and those who share their lives paint a different picture, one of compassion, strength and resolve. Our community is united by the determination to end
Huntington’s. It should be no small comfort, then, to learn that others share in that noble effort. I have been fortunate indeed to have shared much with someone like Beth. Her dogged determination to find the cure continues to inspire me as much as our community inspires her.
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