Four Washington University in St. Louis researchers are being honored as outstanding scientists by the Academy of Science of St. Louis.
Each year, the academy seeks nominations of outstanding women and men in science, engineering and technology who are known worldwide for their scientific contributions to research, industry and quality of life. Those recognized also have a record of excellence in communicating with the public and/or mentoring colleagues.
John E. Heuser, MD, professor of cell biology and physiology at the School of Medicine, will receive the Academy of Science’s Peter H. Raven Lifetime Achievement Award; David Holtzman, MD, the head of the Department of Neurology, will be honored with the Fellows Award; Caitlin Kelleher, PhD, the Hugo F. & Ina Champ Urbauer Career Development Associate Professor, will receive the Innovation Award; and Lihong Wang, PhD, the Gene K. Beare Distinguished Professor of Biomedical Engineering, will be recognized with the James B. Eads Award.
Heuser, MD, emeritus professor of cell biology and biophysics, pioneered a technique for imaging cells and molecules in the electron microscope that he calls the “quick-freeze deep-etch” procedure. The process has allowed him and his colleagues to take highly detailed pictures of rapid events, including the communication that occurs between nerve cells, the uptake and secretion of materials into and out of cells, and the rapid movements of cells ranging from contracting muscle cells to swimming sperm.
He continues to use his approach, in conjunction with other advanced electron microscope techniques, to provide unique and insightful 3-D views, known as “Heusergrams,” of membranes and molecules in a wide variety of biological contexts, including nerves, muscles, glands, blood, skin and bone. Heuser recently patented an update of the original machine.
Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and a professor of developmental biology, specializes in investigating the molecular mechanisms that cause Alzheimer’s disease and developing new treatments. His team played a leading role in showing how dangerous amounts of a protein called amyloid-beta (ABeta) begin to accumulate in the brain many years before symptoms arise.
Holtzman and his colleagues also have made important contributions to the search for markers of pre-symptomatic disease, research that is expected to help clinicians one day start treatment for Alzheimer’s disease prior to dementia. For example, they recently established a strong link between sleep disruption and Alzheimer’s risk.
Together with collaborators at Eli Lilly and Co., Holtzman has identified antibodies that can decrease amyloid plaques over months in mice. One of those antibodies is being tested in clinical trials involving patients with inherited forms of Alzheimer’s disease.
Kelleher will receive the Innovation Award, which recognizes a scientist or engineer, age 40 or younger, who has demonstrated exceptional potential for future accomplishments in science, engineering or technology.
Kelleher’s research centers on “democratizing” computer programming to make it accessible for everyone.
As a graduate student at Carnegie Mellon University, Kelleher created a programming system, called Storytelling Alice, which presented programming as a means to the end of creating animated stories. She found that Storytelling Alice greatly increased interest in programming. But she also found that many children in the United States don’t have access to a computer science class before college.
When she joined the WUSTL faculty in 2007, Kelleher began work on Looking Glass, a programming environment that explores a variety of mechanisms to support kids learning to program without the support of a teacher or classroom setting. Users write programs to create animated stories that they can share through an online community, where they become potential learning aids.
Kelleher and her group also have created a version of Looking Glass that enables physical and occupational therapists to create games for stroke rehabilitation.
Wang will receive the James B. Eads Award, which recognizes a distinguished individual for outstanding achievement in engineering or technology.
Wang and his lab were the founders of a type of medical imaging that gives physicians a new look at the body’s internal organs, publishing the first paper on the technique in 2003. Called functional photoacoustic tomography, the technique relies on light and sound to create detailed, color pictures of tumors deep inside the body and may eventually help doctors diagnose cancer earlier than is now possible and to more precisely monitor the effects of cancer treatment — all without the radiation involved in X-rays and CT scans or the expense of MRIs.
A leading researcher on new methods of cancer imaging, Wang has received more than 30 research grants as the principal investigator with a cumulative budget of more than $40 million. In 2013, Wang received a Transformative Research Award from the National Institutes of Health.
The Academy of Science of St. Louis aims to foster the advancement of science and encouragement of public interest in and understanding of the sciences. The awards will be given April 9 at the Chase Park Plaza Hotel.
Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, and Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology, will be presented with the honor at the Faculty Achievement Awards ceremony Saturday, Dec. 7, in Simon Hall.
Also to be presented at the ceremony are 2013 faculty achievement awards for Richard H. Gelberman, MD, the Fred C. Reynolds Professor and head of the Department of Orthopaedic Surgery, and James V. Wertsch, PhD, vice chancellor for international affairs, director of the McDonnell International Scholars Academy and the Marshall S. Snow Professor in Arts & Sciences.
Gelberman will receive the Carl and Gerty Cori Faculty Achievement Award, while Wertsch will receive the Arthur Holly Compton Faculty Achievement Award. Visit here to read an earlier article about their achievements.
The Chancellor’s Award for Innovation and Entrepreneurship is given on an occasional basis to faculty members whose research has led to the successful development of ideas or businesses that have brought great benefit to others.
“For years, David Holtzman and Randall Bateman have been making prominent and pioneering contributions not only to the early diagnosis and treatment of Alzheimer’s disease but also to our basic understanding of the causes of this disorder,” said Chancellor Mark S. Wrighton. “Their work and that of their colleagues at the Knight Alzheimer’s Disease Research Center (ADRC) has given the world new hope of one day slowing or stopping this devastating condition.”
Bateman’s and Holtzman’s accomplishments include the development of stable isotope-linked kinetics (SILK), which involves giving human research participants a slightly altered form of one of the amino acids the body uses to make proteins.
The alteration has no effect on the chemistry of the amino acid, but scientists can detect its presence in samples taken from spinal fluid and blood. Through monitoring of the presence of the amino acid in proteins of interest, scientists can track how quickly these proteins are made in and cleared from the central nervous system. Assessing these rates helps scientists understand what is going wrong and look for changes in these problems during clinical trials of new treatments.
To make SILK available to the research community as well as to the biotechnology and pharmaceutical industries, Holtzman and Bateman co-founded a company called C2N Diagnostics in 2007.
Holtzman is a leading expert in researching the underlying mechanisms that lead to Alzheimer’s disease to improve diagnosis and treatment. His research team works with mouse models of Alzheimer’s and with the Knight ADRC. Based on those insights, his lab has developed new treatments for Alzheimer’s.
Bateman is principal investigator of the Dominantly Inherited Alzheimer’s Network Trials Unit, which recently began treating participants who have inherited forms of the disease prior to the onset of symptoms.
Holtzman has five U.S. patents issued and 10 pending. Bateman has two U.S. patents issued and seven pending.
Both are physicians at Barnes-Jewish Hospital.
Holtzman earned his bachelor’s and medical degrees from Northwestern University. He completed an internship, residency and postdoctoral fellowship at the University of California, San Francisco, before joining the faculty at Washington University in 1994.
Bateman earned bachelor’s degrees from Washington University in biology and electrical engineering. He earned his MD with special emphasis in neuroscience at Case Western Reserve University School of Medicine. He completed a medical internship at Barnes-Jewish Hospital, followed by a neurology residency at Washington University. He became a member of the faculty in 2005.
September 23, 2013
For years, scientists have attempted to understand how Alzheimer’s disease harms the brain before memory loss and dementia are clinically detectable. Most researchers think this preclinical stage, which can last a decade or more before symptoms appear, is the critical phase when the disease might be controlled or stopped, possibly preventing the failure of memory and thinking abilities in the first place.
Important progress in this effort is reported in October in Lancet Neurology. Scientists at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University School of Medicine in St. Louis, working in collaboration with investigators at the University of Maastricht in the Netherlands, helped to validate a proposed new system for identifying and classifying individuals with preclinical Alzheimer’s disease.
Their findings indicate that preclinical Alzheimer’s disease can be detected during a person’s life, is common in cognitively normal elderly people and is associated with future mental decline and mortality. According to the scientists, this suggests that preclinical Alzheimer’s disease could be an important target for therapeutic intervention.
A panel of Alzheimer’s experts, convened by the National Institute on Aging in association with the Alzheimer’s Association, proposed the classification system two years ago. It is based on earlier efforts to define and track biomarker changes during preclinical disease.
According to the Washington University researchers, the new findings offer reason for encouragement, showing, for example, that the system can help predict which cognitively normal individuals will develop symptoms of Alzheimer’s and how rapidly their brain function will decline. But they also highlight additional questions that must be answered before the classification system can be adapted for use in clinical care.
“For new treatments, knowing where individuals are on the path to Alzheimer’s dementia will help us improve the design and assessment of clinical trials,” said senior author Anne Fagan, PhD, research professor of neurology. “There are many steps left before we can apply this system in the clinic, including standardizing how we gather and assess data in individuals, and determining which of our indicators of preclinical disease are the most accurate. But the research data are compelling and very encouraging.”
The classification system divides preclinical Alzheimer’s into three stages:
The researchers applied these criteria to research participants studied from 1998 through 2011 at the Knight Alzheimer Disease Research Center. The center annually collects extensive cognitive, biomarker and other health data on normal and cognitively impaired volunteers for use in Alzheimer’s studies.
The scientists analyzed information on 311 individuals age 65 or older who were cognitively normal when first evaluated. Each participant was evaluated annually at the center at least twice; the participant in this study with the most data had been followed for 15 years.
At the initial testing, 41 percent of the participants had no indicators of Alzheimer’s disease (stage 0); 15 percent were in stage 1 of preclinical disease; 12 percent were in stage 2; and 4 percent were in stage 3. The remaining participants were classified as having cognitive impairments caused by conditions other than Alzheimer’s (23 percent) or did not meet any of the proposed criteria (5 percent).
“A total of 31 percent of our participants had preclinical disease,” said Fagan. “This percentage matches findings from autopsy studies of the brains of older individuals, which have shown that about 30 percent of people who were cognitively normal had preclinical Alzheimer’s pathology in their brain.”
Scientists believe the rate of cognitive decline increases as people move through the stages of preclinical Alzheimer’s. The new data support this idea. Five years after their initial evaluation, 11 percent of the stage 1 group, 26 percent of the stage 2 group, and 52 percent of the stage 3 group had been diagnosed with symptomatic Alzheimer’s.
Individuals with preclinical Alzheimer’s disease were six times more likely to die over the next decade than older adults without preclinical Alzheimer’s disease, but researchers don’t know why.
“Risk factors for Alzheimer’s disease might also be associated with other life-threatening illnesses,” Fagan said. “It’s also possible that the presence of Alzheimer’s hampers the diagnosis and treatment of other conditions or contributes to health problems elsewhere in the body. We don’t have enough data yet to say, but it’s an issue we’re continuing to investigate.”
More than a century ago, Alois Alzheimer, a Bavarian physician, first identified the neurodegenerative brain condition that came to be known as Alzheimer’s disease. Finding ways to diagnose and treat this disease has frustrated scientists and clinicians ever since.
Now the long and hard-fought campaign against Alzheimer’s has reached a potentially significant milestone: the launch of the first clinical trials to test whether giving new drug treatments before dementia can prevent Alzheimer’s.
Brent Whitney, 34, who has an inherited form of Alzheimer’s but does not yet have symptoms of the disease, hopes to participate in the study. The lives of his grandmother and 10 of her 13 siblings were cut short by the Alzheimer’s gene mutation, and the mutation continues to affect succeeding generations of the family.
“The start of this trial is a very exciting moment in Alzheimer’s disease research, and it gives me renewed hope for a future without Alzheimer’s,” Whitney said. “I hope my grandchildren someday learn of this condition in history books, like I learned about polio.”
The trial is testing two new drug treatments and is led by principal investigator Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor in Neurology at Washington University School of Medicine in St. Louis and director of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU).
“We believe that the diverse portfolio of drugs and approaches of the DIAN-TU trial will accelerate the discovery of an effective treatment for Alzheimer’s,” Bateman said. “This trial is possible because of the outstanding support of multiple stakeholders, including patients and family members, pharma partners, the Alzheimer’s Association, the National Institutes of Health, academic researchers and highly dedicated trial operations groups.”
The new trial is funded by a unique mix of private and public resources, including:
• A grant from the National Institutes of Health (NIH) for fiscal 2013 in the amount of $1.5 million, awarded Sept. 18, with the total amount of as much as $6 million over the four years of the project;
• The largest Alzheimer’s Association grant given to date, nearly $4.2 million;
• Donation of the treatments used in the trials from the drugs’ manufacturers, Roche and Eli Lilly & Co., which also provided major financial support for the trial;
• Donation of a new agent for imaging brain plaques, Amyvid, by Avid Radiopharmaceuticals Inc., a wholly owned subsidiary of Lilly; and
• Donation by CogState of a computerized set of cognitive skills tests to help assess cognitive function in participants.
John C. Morris, MD, is director of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center and principal investigator of the Dominantly Inherited Alzheimer Network, which laid much of the scientific groundwork that made a DIAN-TU trial of preventive treatments possible.
“Trying to prevent Alzheimer’s symptoms from occurring is a new strategy, but much of what we’ve learned in recent years about Alzheimer’s and the brain has suggested that prevention has a significantly better chance of succeeding than treatment after cognitive impairment,” said Morris, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology. “We are most appreciative of the support we have received to test this new approach.”
For more information on the trial, see www.DIANXR.org.
One of the treatments under study in the new trial is gantenerumab, an antibody made by Roche that binds to all forms of aggregated amyloid beta and helps remove them from the brain.
Another treatment that will be evaluated is a monoclonal antibody known as solanezumab that binds to soluble monomeric forms of amyloid-beta after they are produced, allowing them to be cleared before they clump together to form beta-amyloid plaques.
David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of neurology, is listed on the patent related to the antibody that is co-owned by Washington University in St. Louis and Lilly. Washington University has licensed its patent rights to Lilly. The financial interests of the university and Holtzman in this patent are managed in accordance with applicable conflict-of-interest policies and regulations.