January 29, 2015

Core facilities key driver of VUMC research gains

During the past five years, Vanderbilt University Medical Center has become a leader in “personalized medicine,” the use of genomic information to individualize patient care.

James Crowe Jr., M.D., left, briefs U.S. Sen. Lamar Alexander, R-Tenn., last fall on his lab’s effort to develop a potential treatment for Ebola. Vanderbilt’s cores help make such research possible, Crowe says. (photo by Anne Rayner)

by Stephen Doster and Bill Snyder

During the past five years, Vanderbilt University Medical Center has become a leader in “personalized medicine,” the use of genomic information to individualize patient care.

Its research cores, facilities and shared resources have played a significant role, in part by bringing new technology, like next-generation sequencing, on board.

“One of the real strengths of Vanderbilt is the breadth and strength of our core facilities,” said Mark Magnuson, M.D., the Louise B. McGavock Professor and director of the Vanderbilt Center for Stem Cell Biology.

“By making a strategic investment in next generation sequencing technology we will, without question, accelerate discoveries in both the basic and clinical sciences,” Magnuson predicted in 2011. “This is something that is especially important for our personalized medicine initiative.”

Next-generation sequencing can help scientists identify disease-relevant changes in the genome, quantitatively determine patterns of gene expression, and understand how chromosomes are organized and regulated. It is much faster and less expensive than previous methods.

At Vanderbilt, this technology is provided through VANTAGE (Vanderbilt Technologies for Advanced Genomics), a consolidated shared resource in Medical Center North that offers sequencing, genotyping, bio-banking and flow cytometry services.

VANTAGE also is playing an important role in the development of new antibody therapies to combat the Ebola virus.

VANTAGE scientific director James Crowe Jr., M.D., and his colleagues are using a high-efficiency method they developed to isolate and quickly generate large quantities of human antibodies from the blood of people who survived Ebola infections and are now healthy.

The specific, “monoclonal” antibodies are generated by clones of a type of white blood cell that have been fused to myeloma (cancer) cells to form fast-growing “hybridomas.”

“We’re the only lab in the world that has a high-efficiency human hybridoma technique for isolating human monoclonal antibodies,” said Crowe, Ann Scott Carrell Professor and director of the Vanderbilt Vaccine Center.

No live virus is used in the research here, and the antibodies are not vaccines, which stimulate the body’s own immune defenses against infectious diseases.

One of the techniques offered by the Cell Imaging Shared Resource is super-resolution imaging (using Structured Illumination Microscopy or SIM). In this image, tubules (stained green) and vesicles (stained red and blue) in a single cell are revealed in remarkable detail.

Rather, they are potential treatments that, like heat-seeking missiles, seek out and destroy their targets, in this case, the Ebola virus. The goal is to develop safe, injectable antibody therapies that can provide short-term protection to health care workers and others at risk of exposure.

Here’s how it’s done: “When we make an antibody cell line in the Flow Cytometry Shared Resource (which can physically sort cells), we get the clone,” Crowe said. “Then we sequence it in VANTAGE, and do some structural work using electron microscopy or crystallography by the Center for Structural Biology.

“We put the antibodies on cells that have virus or antigen in them, and we need to take pictures using microscopes, which are in the high end Imaging Core (Cell Imaging Shared Resource).

“We may want to use the antibodies and figure out what parts of a protein they interact with. So we go to the Proteomics Lab (in) the Mass Spectrometry Research Center, and so on …

“You can almost do an entire project in cores without having anyone in your lab,” Crowe said. “You could do 50 different techniques at a world-class level just paying at-cost fees.”

That’s the key. “The people running the cores aren’t just managing them,” he continued. “They are going to meetings, reviewing articles and learning about cutting-edge science as it’s being developed. They are driving the vision for new technologies.”

One of those new technologies is called CRISPR, the acronym for a new genome editing technique that, by many accounts, is accelerating the study of genes and disease.

A common way to study a mutation thought to cause human disease is to mutate the normal gene in an animal model, like the mouse, and see what happens. Conventional gene mutation methods in mice can take 18 months and cost up to $20,000.

“Now we can basically squirt this stuff into mouse embryos and three weeks later mice are born that have the mutation … at a cost of $3,000 or less,” said Douglas Mortlock, Ph.D., scientific co-director of the Vanderbilt Transgenic Mouse/Embryonic Stem Cell Shared Resource, which offers the technique. “It’s stunning.”


Cores give investigators fiscal flexibility

The research cores at Vanderbilt University Medical Center are not supposed to make a profit, and they must be open to all Vanderbilt scientists.

That’s because they support research funded to a great extent by the federal government. As a result, their fees are a fraction of what the corporate sector charges.

“Using our services, Vanderbilt investigators save about one-third to half the costs of using a commercial vendor, and our turn-around time is faster,” said Mark Magnuson, M.D., senior scientific co-director of the Transgenic Mouse/Embryonic Stem Cell Shared Resource.

Nevertheless, last year the cores generated $43 million in revenue, compared to a research enterprise at Vanderbilt that pulled in more than $600 million in grants and other support.

A 384-channel liquid handler in the Mass Spectrometry Research Center spots samples for analysis by an imaging mass spectrometry technique developed at Vanderbilt. (photo by Susan Urmy)

To ensure services are available to Vanderbilt investigators at cost, the cores are tied together by a unique information technology network called CORES — the Core Ordering and Reporting Enterprise System. It offers business models, provides institutional funding and sets best practices.

A dozen years ago, CORES application software was developed to track tens of thousands of lines of transactions generated each year. It is “valuable in overseeing the financial health of each core,” said Susan Meyn, director of research resources and planning in the Office of Research.

“We started off with three cores and very limited functionality, and now we’re up to about 100 cores here and another 16 or 17 outside institutions that use the software,” added Keith Dance, director of systems development in the Office of Research.

In part because of the high volume of requests from core managers to enhance the functionality of the software, CORES is being merged with a core facility management software vendor in Boston, iLab Solutions, one of the leading systems in the industry, Dance said.

The Institutional Shared Resource Oversight Committee provides another level of scientific and strategic review. Composed of 12 faculty members, the committee provides internal pilot project grants of up to $15,000, and conducts internal review of shared equipment grants.

Just as the cores are data-driven, so are the services they provide their customers.

“Most of us were trained extensively in the pipetting aspects of science, when resulting data sets were small,” said James Crowe Jr., M.D., scientific director of the VANTAGE advanced genomics cores.

“Now we’re challenged to find the project isn’t over when we have pipetted and generated Big Data with newer techniques,” Crowe said. “Finishing projects with analysis of these massive data sets requires substantial expertise and resources.”

“That’s the currency of research,” agreed Sam Wells, Ph.D., who directs the Cell Imaging Shared Resource. “We strive to help people acquire the best quality, highest impact data so that they can ultimately be successful with their publications, grant applications, and scientific progress.”