VARI findings provide keys to further research

January 29, 2010
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Van Andel Research Institute findings released in late 2009 could impact issues as diverse as global hunger, colon cancer and bone marrow disease.

VARI is part of the Van Andel Institute in Grand Rapids, a private, nonprofit organization established in 1996 to further medical research and provide opportunities for science education, from elementary to graduate schools. In December, VAI opened its 240,000-square-foot, $178 million Phase II addition, which is expected to eventually house as many as 550 additional scientists, boost number of laboratories from 18 to 50 and bring research funding to $125 million annually.

A study published in the December issue of the journal Nature detailed VARI research that developed over the course of just a few months, but opens the door to another decade of investigation and the potential to allow plants to grow under harsh conditions.

A VARI team in the Laboratory of Structural Biology led by Distinguished Scientific Investigator H. Eric Xu, Ph.D. identified the structure of receptors of a plant hormone known as abscisic acid, or ABA.  ABA keeps seeds dormant until conditions are right for them to grow. Finding and understanding those receptors was a 50-year quest for plant researchers. It will help scientists understand plant response to stress such as extreme temperature or lack of water.

VARI Research Scientist Karsten Melcher, Ph.D, a lead author of the study, said the findings could impact nutrition and crop yields in the face of diminishing sources of fresh water.

“They show how the signaling molecule and its receptor initiate a cascade of events that ultimately affects the expression of genes that are critical for a plant’s survival under harsh conditions.  This work has enormous implications for global food supply,” explained Grand Valley State University Plant Development Biologist Sheila A. Blackman, Ph.D.

Xu’s lab started studying ABA in March in the course of its investigation of receptors of similar proteins in humans. The research led to a different group of proteins, but the findings still have implications for humans, Xu said.

“Proteins with similarities to plant ABA receptors are also found in humans,” said Xu.  “Further studies in this area could reveal important implications for people with stress disorders.”

Plant biology specialists from the National Center for Plant Gene Research in Beijing, China, the Department of Botany and Plant Sciences at the University of California at Riverside, the Center for Plant Stress Genomics and Technology at the King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and the Department of Biochemistry at the Medical College of Wisconsin helped to validate the data from Xu’s lab. 

“A finding of this importance helps demonstrate how discoveries at the molecular level in plants can have profound implications for the diseases of humans,” VARI President and Research Director Dr. Jeffrey Trent said.

“Remarkably Dr. Xu’s findings (made in only a few short months) will open a decade of research on both plants and man. From a key role in the ripening of fruit through increased understanding of how stress affects a myriad of diseases in man – this finding starts a new chapter in plant and animal biology.”

In another VARI lab, Scientific Investigator Jeff MacKeigan is studying resistance to chemotherapy in colon cancer tumors with a $1.38 million, five-year National Institutes of Health grant.

MacKeigan’s laboratory recently identified 13 enzymes that play a role in tumor cells’ sensitivity to chemotherapy.  The lab plans to sort out the influence of each enzyme, with a focus on the MK_STYX enzyme.

“We think MK-STYX is important because when it is missing, the mitochondria, or ‘power plants’ within cells, increase their energy production, allowing cells to survive that are supposed to die,” MacKeigan said. “Although we think that MK-STYX is related to colon cancer progression in particular, it may also be related to specific types of ovarian and breast cancers.”

“Dr. MacKeigan’s study holds great promise for bringing to light new avenues to fight tumors that are resistant to chemotherapy,” Trent added.

A VARI study published in the journal PLoS ONE revealed that the lab of Distinguished Scientific Investigator Art Alberts, Ph.D., has zeroed in on the gene that determines the progression of melodysplastic syndrome (MDS), a bone marrow disease that strikes up to 15,000 people each year in the United States. It sometimes results in acute myeloid leukemia.

“Using our genetic models, we’ve been able to provide a better understanding of underlying molecular defects that drive the malignant progression of MDS,” said VARI Distinguished Scientific Investigator Art Alberts, Ph.D., whose laboratory recently published its findings in the journal PLoS ONE.  “The genes that we’ve focused on in this study might have a role not only in leukemia, but in solid tumors, as well.”

The gene could prove to be a target for drug therapies, Alberts added.

“Our goal is to identify novel therapeutic targets and develop new drugs that affect their activity, but also to find ways to improve upon existing therapeutic strategies that are often associated with deleterious side effects,” he said.

Working with George C. Prendergast, Ph.D., from the Lankenau Institute for Medical Research, Alberts’ lab found that a lack of proteins related to RhoB gene accelerates progression of MDS. The researchers believe examining RhoB levels in samples from patients with advanced MDS could help direct them to better treatment options.

The study was funded in part by the American Cancer Society.

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