Today we held our fourth annual symposium marking Rare Disease Day. As keynote speaker William A. Gahl, M.D., Ph.D., noted, “it takes a village” to diagnose, treat, and care for people with rare diseases. By “village,” he meant parents, advocates, doctors, basic scientists, clinical researchers, government officials, and philanthropists—all of whom were represented at the event. Gahl is clinical director of the National Human Genome Research Institute (NHGRI) and director of the NIH Undiagnosed Diseases Program
José Luis Millán, Ph.D. (left) and William A. Gahl, M.D., Ph.D., Rare Disease Day 2013
A mouse model of multiple hereditary exostoses (MHE), a rare bone disorder, exhibits autism-like social deficits. Shown here is a comparison of nest-building abilities—one measure of social behavior—by normal and autistic MHE mice.
Rare bone disorder reveals new insights into autism
Originally published March 12, 2012
Children with multiple hereditary exostoses (MHE), an inherited genetic disease, suffer from multiple growths on their bones that cause pain and disfigurement. But beyond the physical symptoms of this condition, some parents have long observed that their children with MHE also experience autism-like social problems.
Buoyed by the support of these parents, researchers at Sanford-Burnham recently used a mouse model of MHE to investigate cognitive function. They found that mice with a genetic defect that models human MHE show symptoms that meet the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior. The study, published online the week of March 12 in the Proceedings of the National Academy of Sciences, also defines the molecular and physiological basis of this behavior, pinpointing the amygdala as the region of the brain causing autistic symptoms.
“There is growing evidence that many autistic people have related genetic defects, or defects that are exacerbated by this one,” said Yu Yamaguchi, M.D., Ph.D., professor in the Sanford Children’s Health Research Center at Sanford-Burnham. Yamaguchi led this study, along with colleagues Fumitoshi Irie, Ph.D. and Hedieh Badie-Mahdavi, Ph.D.
A therapist works with three-year-old Joey, diagnosed with severe Autism Spectrum Disorder, and his father. (Image courtesy of U.S. Navy)
This month’s issue of The Scientist magazine features research by Sanford-Burnham’s Dr. Yu Yamaguchi. The article explains how Dr. Yamaguchi uncovered a link between a rare bone disorder and autism—with the help of a mother:
On Memorial Day, members of our military—including those who have sacrificed their lives or have returned to us with injuries or illness—will receive much-deserved thanks and recognition. Whether you attend a parade, observe a moment of silence for those lost, or simply shake a soldier’s hand and say, “thank you,” you will find your way of expressing your gratitude. At Sanford-Burnham, we support the U.S. armed services by doing what we do best: science.
Sanford-Burnham’s headquarters in San Diego County place it in the midst of one of the largest active duty military populations in the country and the largest concentration of soldiers wounded in combat. Additionally, both states where Sanford-Burnham has locations, California and Florida, are among those with the largest populations of veterans. So the men and women who defend us are always on our minds. In honor of Memorial Day weekend, we have chosen to highlight some of the ways we strive to defend them in return.
A mouse model of multiple hereditary exostoses (MHE), a rare bone disorder, exhibits autism-like social deficits. Shown here is a comparison of nest-building abilities—one measure of social behavior—by normal and autistic MHE mice.
Children with multiple hereditary exostoses (MHE), an inherited genetic disease, suffer from multiple growths on their bones that cause pain and disfigurement. But beyond the physical symptoms of this condition, some parents have long observed that their children with MHE also experience autism-like social problems.
Buoyed by the support of these parents, researchers at Sanford-Burnham recently used a mouse model of MHE to investigate cognitive function. They found that mice with a genetic defect that models human MHE show symptoms that meet the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior. The study, published online the week of March 12 in the Proceedings of the National Academy of Sciences, also defines the molecular and physiological basis of this behavior, pinpointing the amygdala as the region of the brain causing autistic symptoms.
“There is growing evidence that many autistic people have related genetic defects, or defects that are exacerbated by this one,” said Yu Yamaguchi, M.D., Ph.D., professor in the Sanford Children’s Health Research Center at Sanford-Burnham. Yamaguchi led this study, along with colleagues Fumitoshi Irie, Ph.D. and Hedieh Badie-Mahdavi, Ph.D.
Crystal Structure of Anthrax Lethal Factor complexed with a small molecule inhibitor
As the United States pauses to observe the 10th anniversary of the September 11th terrorist attacks, we reflect on the research advances that contribute to new counterterrorism measures—understanding anthrax, for example—and the health of our soldiers in Iraq and Afghanistan, including under-studied conditions such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Here are a few examples, and these only cover discoveries made at Sanford-Burnham since September 11, 2001. Can you think of more? Please share your thoughts in the comments below.
Kate Fischer with daughter Morgan, who is being treated for HPP.
There was a moment at our recent Rare Disease Symposium when Dr. Michael Whyte, a pediatrician from Shriner’s Hospitals in St. Louis, presented video of a patient who is participating in a clinical trial. The patient, Amy, suffers from hypophosphatasia (HPP), a genetic bone disease similar to rickets. The trial is for an enzyme replacement therapy developed collaboratively by Dr. Whyte, Dr. José Luis Millán and Enobia Pharma to treat HPP. Before treatment, Amy’s bones were so soft she had to be flown to the trial in an insulated box. She was weeks away from dying. In the video, she runs, jumps and kicks a ball. Hard not to be moved.
Enobia’s HPP drug is in Phase II clinical trials and looks quite promising. However, rare diseases present a difficult problem. While relatively few people suffer from any single rare disease, there are thousands of these conditions. Large pharmaceutical and biotech companies have a difficult time addressing them because they have not figured out how to make back their investments. But the issues go even deeper. How do you conduct a robust clinical trial on a new treatment when only a handful of people need to be treated? And how do you balance the regulatory environment to ensure that new, safe treatments can reach patients? In fact, how do you even diagnose a rare disease when so few physicians have any experience with it?
On February 25, 2011, Sanford-Burnham will hold its Second Annual Rare Disease Symposium at the Institute’s La Jolla, California campus. Chaired by Drs. Hudson Freeze and Yu Yamaguchi and sponsored by Enobia Pharma, the symposium will feature researchers and patient advocates from around the world. The symposium coincides with national Rare Disease Day on February 28.
In the U.S., diseases are classified as “rare” when they affect fewer than 200,000 people. But since there are around 7,000 such disorders, a total of 30 million Americans are affected. Because of the rarity of these diseases, patients and their families often struggle to find information, and many have started advocacy groups to raise awareness and reach out to other families who need help. These families can be a great help to researchers, having gained personal Ph.D.s in the intricacies of an uncommon disease. Several of these parent advocates will attend the event.
How can patient advocates help drive basic research?
Last week I attended the Stem Cell Meeting on the Mesa, an annual event organized by CONNECT. The meeting included all the stellar scientific panels I expected and one I didn’t expect: “Patient Advocacy 2.0 – Can they participate?”
The panel discussed opportunities for patient participation and the ethics involved. I was captivated by panel member Dani Grady’s story of surviving breast cancer and her advocacy for increased cancer research funding, education, improved patient care and more patient participation in clinical trials. It was interesting to hear how a patient’s perspective can improve clinical trials and the drug approval process. But as I sat there, I couldn’t help wondering… how can patients participate in basic research – the earliest phase of biomedical discovery, during which the molecular underpinnings of disease are only just beginning to be understood?
So I did a little research of my own.
The immune system is always standing by, ready to fight infection. Immune cells called lymphocytes and dendritic cellshang out in lymph nodes, surveying the environment for signs of invaders and attacking infected cells when necessary.“It’s crucial that lymphocytes meet dendritic cells in the confined space of a lymph node – they’d have a hard time finding one another in the fast-moving bloodstream,” explains Dr. Minoru Fukuda, professor in Sanford-Burnham’s NCI-Designated Cancer Center.
Dr. Fukuda, along with staff scientist Dr. Xingfeng Bao and their colleagues, recently showed that heparan sulfate – a type of long sugar chain – is responsible for recruiting these immune cells to their lymph node meeting places. Normally, lymphocytes flow through the bloodstream until blood vessel cells rope them in. From there, the immune defenders can squeeze out of the blood stream and into the surrounding tissue or lymphatic system.
Editor’s Note: A few months ago, we told you about a study in which a team of Sanford-Burnham scientists led by Dr. Yu Yamaguchi created a mouse model for a rare bone disease called multiple hereditary exostoses (MHE). Over the years, Dr. Yamaguchi has become friends with Sarah Ziegler, a woman whose son has had more than 100 MHE bone tumors and has suffered through 15 surgeries. Sarah co-founded The MHE Research Foundation to advocate for patients and research. Below is a letter she wrote to Dr. Yamaguchi, describing what his research has meant to her and her family.
Dear Dr. Yamaguchi,
Thank you for becoming my champion! You are the world leader in the effort to discover a cure for Multiple Hereditary Exostoses (MHE).
I clearly remember when I first started to read about your research. Even though you were not studying MHE at the time, I knew you were the one person in the world who could research this disease, with its myriad of effects, as a whole, rather than focusing on just one small aspect of it.
By Claire Attwooll
Recently, Sanford-Burnham hosted our inaugural Rare Disease Symposium, using a unique format in which patients and their families were given a voice—and the scientists were there to listen.
“What we hoped to achieve was to open the lines of communication between researchers, patients, families and advocacy groups,” said symposium organizer Dr. Hudson Freeze. “We can learn so much from these families, and then we can give something back.”
Diseases are classified as “rare” when they affect fewer than 200,000 people in the United States. But there are around 7,000 such disorders, and 30 million Americans are affected. Because of these diseases’ rarity, patients and their families often struggle to find information, and many have started advocacy groups to raise awareness and reach out to other families who need help. These families can be a great help to researchers, having gained personal Ph.D.s in the intricacies of an uncommon disease.
Children with multiple hereditary exostoses (MHE), a rare inherited disease, suffer from multiple growths on their bones that cause pain, disfigurement, and stunted growth. At the moment, the only treatment is surgery to remove the growths, which sometimes number in the hundreds.
“MHE is not usually deadly, but it is debilitating,” said Dr. Yu Yamaguchi, professor in the Sanford Children’s Health Research Center at Sanford-Burnham. “And if not removed by surgery, there is a chance these bone growths will become cancerous.”
MHE research has long been hampered by the lack of a good model that would answer questions about the underlying cause and allow scientists to test new treatments. Today in the journal Proceedings of the National Academy of Sciences, Dr. Yamaguchi and his collaborators unveiled a mouse model that does just that.
“This research is profoundly important,” said Sarah Ziegler, vice president of the MHE Research Foundation, which has provided seed funding for Dr. Yamaguchi’s research. “My son had more than a 100 of these tumors and has gone through 15 surgeries. When your child has such a debilitating condition, and you know there’s nothing you can do, it’s petrifying. With this model, researchers can start looking for a cure.”