GRAND RAPIDS, Mich. (March 28, 2017)—Van Andel Research Institute (VARI) is now home to one of the world’s most powerful microscopes—one that images life’s building blocks in startling clarity and equips VARI’s growing team of scientists to push the limits of discovery in search of new treatments for diseases such as cancer and Parkinson’s.
Cryo-electron microscopy (cryo-EM) is a revolutionary technique that reveals in unprecedented detail the molecular and atomic interactions at the foundation of life, allowing scientists to observe exactly how viruses enter cells, how DNA replicates, how chemical compounds assemble into functional biological components, and much more.
“Our new state-of-the-art cryo-EM facility, which includes significant investments in technology and talent, is part of our unwavering commitment to improve human health through scientific innovation,” says David Van Andel, the Institute’s CEO and chairman. “Not only will it fuel the discovery of life-changing treatments for devastating diseases, but it also will enhance Grand Rapids’ reputation as a destination for outstanding biomedical research.”
Already, cryo-EM has helped uncover the complex structure of Alzheimer’s-related proteins in the brain, overturned long-held assumptions about DNA replication and elucidated the structure of hundreds more molecules implicated in a variety of diseases.
The centerpiece of VARI’s cryo-EM facility is an FEI Titan Krios from Thermo Fisher Scientific, the world’s highest-resolution, commercially available cryo-EM. The Institute’s Krios is only the second in Michigan and one of fewer than 100 in the world. The facility also houses an FEI Talos Artica and an FEI Tecnai Spirit G2 BioTWIN. Overall, VARI invested $10 million in cryo-EM equipment and related construction.
“The resolution available with the Krios, compared to earlier methods, is akin to upgrading from a road atlas to Google Earth,” says Peter Jones, Ph.D., D.Sc., VARI’s chief scientific officer. “It offers exquisite detail of complex systems, which will help us find new therapies so desperately needed for patients around the world.”
Part of the expansion also included hiring three cryo-EM experts: Huilin Li, Ph.D., an established investigator in the field with more than 20 years of experience; Wei Lü, Ph.D., an early career investigator who joined the Institute this month; and Gongpu Zhao, Ph.D., the cryo-EM facility’s manager, who played a key role in the 2013 discovery that revealed the structure of the HIV-1 virus’s outer shell.
Although cryo-EM has been around for decades, recent advances in both techniques and technology have revolutionized the approach, giving researchers powerful new tools to more quickly and more precisely see some of the smallest yet most important biological components in their natural state. These advances led to it being named as the Method of the Year in 2015 by the scientific journal Nature Methods.
“We are very pleased that VARI has chosen the Titan Krios. We have worked hard with leading life science researchers to perfect the capabilities they need to advance their understanding of living systems and disease processes,” says Peter Fruhstorfer, vice president and general manager of Life Sciences, Materials and Structural Analysis, at Thermo Fisher. “The advanced imaging capabilities of the Titan Krios allows scientists to visualize delicate biological structures at the molecular level without damage and in a nearly-natural context, helping them understand the essential relationships between structure and function that are the basis for life itself.”
Before the advances in cryo-EM, a technique called X-ray crystallography was the dominant method of determining molecular structure. However, the approach is very slow and painfully difficult because biological molecules are hard to crystallize. In cryo-EM, the need for crystallization is entirely circumvented. Scientists simply flash freeze molecules or cells in solution. The molecules, now embedded in a transparent thin layer of glassy ice, are then scanned with a powerful electron beam, generating hundreds of thousands of two-dimensional images that are then assembled in a computer into a detailed three-dimensional portrait.
“In a way, biologists are like locksmiths,” says Li. “We use tools such as cryo-EM or X-ray crystallography to see all of the facets of the lock— a normal protein doing its job in a cell or an abnormal protein in cancer, for example—and then use that information to design a key to fit the lock—a drug with the right shape to link up with the protein and alter its function, which may correct the error, ultimately treating the disease.”
Huilin Li, Ph.D.
Cryo-EM Core Director
Professor, Center for Epigenetics
Wei Lü, Ph.D.
Assistant Professor, Center for Cancer and Cell Biology
Gongpu Zhao, Ph.D.
Cyro-EM Core Manager
Beth Hinshaw Hall
Director of Communications & Marketing
The Cancer Genome Atlas Research Network recommends clinical trials organizers and drug manufacturers focus on newly discovered molecular subtypes
GRAND RAPIDS, Mich. (Jan. 4, 2017) – A comprehensive analysis of 559 esophageal and gastric cancer samples, collected from patients around the world, suggests the two main types of esophageal cancer differ markedly in their molecular characteristics and should be considered separate diseases.
The study, published today in Nature from The Cancer Genome Atlas (TCGA) Research Network, includes two key takeaways. First, upper esophageal cancers more closely resemble cancers of the head and neck, while tumors further down in the esophagus are virtually indistinguishable from a subtype of stomach cancer. Second, cancer clinical trials should group patients according to molecular subtype—in general, grouping lower esophageal tumors with stomach cancers, while evaluating upper esophageal cancers separately.
“These findings add several layers of depth and sophistication to our current understanding of esophageal cancer genomics,” said Adam Bass, M.D., co-leader of TCGA’s esophageal cancer study and physician-scientist at Dana-Farber Cancer Institute. “Our hope is this work settles several long-standing uncertainties in the esophageal cancer field and will serve as the definitive reference manual for researchers and drug developers seeking more effective clinical trials and new treatment approaches.”
Physicians have known for decades that esophageal cancers, when looked at under the microscope, fall into one of two categories—adenocarcinomas, which resemble stomach or colorectal cancers, and squamous cell carcinomas, which are similar to some lung, skin, and head and neck cancers. What remained unknown was the extent to which adenocarcinomas and squamous esophageal cancers differ molecularly and the relationship between esophageal adenocarcinoma and stomach adenocarcinoma.
“We have shown that these clinical subtypes differ profoundly at the molecular level,” said Peter W. Laird, Ph.D., a principal investigator in the international TCGA Research Network and a professor at Van Andel Research Institute. “These findings suggest that whether the tumor originates in the esophagus or the stomach is less relevant than the molecular characteristics of the individual tumors.”
Esophageal cancer represents just 1 percent of new cancer diagnoses in the U.S. However, it kills 4-in-5 patients within five years of diagnosis, and current treatment approaches often fail to help. Additionally, cases of esophageal adenocarcinoma have skyrocketed over the last four decades, increasing seven-fold since the mid-1970s. Within the field, there has been great uncertainty regarding the relationship between this growing burden of esophageal adenocarcinoma and adenocarcinomas that occur in the stomach.
Results from this new report argue against the need to continue to debate the demarcations of esophageal and gastric adenocarcinoma and instead view gastroesophageal adenocarcinoma as a more singular entity, analogous to colorectal cancer. Specifically, this study revealed that esophageal adenocarcinomas have striking molecular similarity to a class of stomach cancers called chromosomally unstable tumors, the hallmark of which are significant structural chromosomal aberrations.
Oncologists say this nuanced view of the disease, including the detailed molecular taxonomy of esophageal adenocarcinomas, will likely change their approach to studies and treatment.
“It is clear from the TCGA data that esophageal squamous and esophageal adenocarcinomas are completely different diseases and should never be included in the same therapeutic trial,” said Yelena Y. Janjigian, M.D., a gastrointestinal oncologist from Memorial Sloan Kettering Cancer Center who contributed samples to the study and served as a co-author. “In esophageal adenocarcinoma, it is likely a combination of pathways and therapeutic strategies that will be successful. The therapeutic significance of these alterations will be explored in follow-up studies.”
Members of the TCGA Research Network team say these studies represent the work of dedicated collaborators, who seek to maximize results in search of new ways to battle cancer.
“Studies from TCGA transcend the work of any one institution or individual,” said Ilya Shmulevich, Ph.D., a principal investigator in the international TCGA Research Network and a professor at the Institute for Systems Biology. “These are massive undertakings that are possible only through contributions from hundreds of specialists and scientists around the world—people dedicate years of their lives to these projects in the hope of finding new treatments for people who are very sick.”
Peter W. Laird, Ph.D.
Professor, Center for Epigenetics
New data published today shows drug preserves critical brain function in laboratory models of Parkinson’s
GRAND RAPIDS, Mich. (Dec. 7, 2016)—A new investigational drug originally developed for type 2 diabetes is being readied for human clinical trials in search of the world’s first treatment to impede the progression of Parkinson’s disease following publication of research findings today in the journal Science Translational Medicine.
“We hope this will be a watershed moment for millions of people living with Parkinson’s disease,” says Patrik Brundin, M.D., Ph.D., director of Van Andel Research Institute’s Center for Neurodegenerative Science, chairman of The Cure Parkinson’s Trust’s Linked Clinical Trials Committee, and the study’s senior author. “All of our research in Parkinson’s models suggests this drug could potentially slow the disease’s progression in people as well.”
Until now, Parkinson’s treatments have focused on symptom management. If successful in human trials, MSDC-0160 would be the world’s first therapy to treat the underlying disease and slow its progression—potentially improving quality of life and preventing the occurrence of falls and cognitive decline. It may also reduce or delay the need for medications that can have debilitating side effects, says Brundin.
Parkinson’s disease afflicts between 7-10 million people worldwide, including an estimated 1 million Americans, and these numbers are expected to increase dramatically as the average human lifespan increases. There is currently no cure, and first-line treatment has remained relatively unchanged since the introduction of levodopa in the 1960s.
Tom Isaacs, a co-founder of The Cure Parkinson’s Trust who has lived with Parkinson’s for 22 years, says MSDC-0160 represents one of the most promising treatment the Trust’s international consortium has seen to date.
“Our scientific team has evaluated more than 120 potential treatments for Parkinson’s disease, and MSDC-0160 offers the genuine prospect of being a breakthrough that could make a significant and permanent impact on people’s lives in the near future,” says Isaacs. “We are working tirelessly to move this drug into human trials as quickly as possible in our pursuit of a cure.”
MSDC-0160 was developed by Kalamazoo, Michigan-based Metabolic Solutions Development Company (MSDC) to treat type 2 diabetes. In 2012, Brundin recognized it as an exciting drug candidate because of its mode of action, proven safety in people, local availability and the start-up company’s interest in collaborating on drug repurposing initiatives. After four years of work, the effects of the drug in the laboratory exceeded Brundin’s expectations.
The novelty of MSDC-0160 stems from a recently revived revelation that Parkinson’s may originate, at least partially, in the body’s energy metabolism. The new drug appears to regulate mitochondrial function in brain cells and restore the cells’ ability to convert basic nutrients into energy. Consequently, the cells’ ability to handle potentially harmful proteins is normalized, which leads to reduced inflammation and less nerve cell death.
“Parkinson’s disease and diabetes may have vastly different symptoms with unrelated patient outcomes; however, we’re discovering they share many underlying mechanisms at the molecular level and respond similarly to a new class of insulin sensitizers like MSDC-0160,” says Jerry Colca, Ph.D., co-founder, president and chief scientific officer of MSDC.
While Brundin says he is eager to see MSDC-0160 launched into a clinical trial in Parkinson’s disease, he’s equally excited about the possibility of testing the drug in Lewy body dementia and other cognitive decline conditions, such as Alzheimer’s disease.
“This is an immensely promising avenue for drug discovery,” says Brundin. “Whatever the outcome of the upcoming trial for Parkinson’s, we now have a new road to follow in search of better treatments that cut to the root of this and other insidious diseases.”
The Cure Parkinson’s Trust and Van Andel Research Institute are currently working with MSDC to address regulatory issues and obtain funding to organize the clinical trial, which Brundin hopes can begin sometime in 2017.
Funding for the research was provided by Van Andel Research Institute, The Cure Parkinson’s Trust, the Campbell Foundation, and the Spica Foundation.
The paper’s authors include Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N. Hildebrandt, Jennifer A. Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, Martha L. Escobar Galvis, Jeremy M. Van Raamsdonk and Patrik Brundin, all of Van Andel Research Institute; William G. McDonald and Jerry R. Colca, both of Metabolic Solutions Development Company; and Jeffrey H. Kordower, of Rush University Medical Center and Van Andel Research Institute.
Patrik Brundin, M.D., Ph.D.
VARI Associate Director of Research
Professor and Director of the Center for Neurodegenerative Science
Jay Van Andel Endowed Chair in Parkinson’s Research