Friday, 24 January 2014 16:34

Human Stem Cell Models Could Open New Era in Basic Biology Research, ASCB Tells NIGMS Council

Written by  ASCB Post Staff
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goldsteinAt its November launch, the chair of the ASCB Stem Cell
Task Force, Lawrence Goldstein, first outlined the
recommendations that he presented to NIGMS on January 24.
ASCB Photo
By creating laboratory systems that can accurately model all kinds of normal and diseased human cells, tissues, and even organs, advances in stem cell culturing techniques could open the way for a "new era of human cell biology," Lawrence Goldstein, chair of the ASCB Stem Cell Task Force, told the National Institute for General Medical Sciences (NIGMS) Advisory Council meeting on the NIH campus in Bethesda, MD, Friday. "There are tremendous opportunities using stem cell technologies... to advance our understanding of basic biological principles," Goldstein of the University of California, San Diego, told the NIGMS council when presenting the task force's recommendations. "There are some programmatic goals we think will help us get there," he said.

The Stem Cell Task Force was organized by ASCB to determine the next scientific steps in the stem cell revolution. The task force's report, posted for comment last November, urged NIGMS and other research funders to accelerate research into basic cell and developmental mechanisms, to integrate findings from both human and non-human model systems, and to teach people how to work with human stem cells in culture. "They are a little cranky, I can tell you from experience," said Goldstein.

"Where [the task force] sees the most important opportunities are in basic stem cell science ultimately translating to humans and human disease," Goldstein told the NIGMS council.

Goldstein likened the stem cells today to plastics in the 1960s and to recombinant DNA in the early 1980s. In the movie, The Graduate, the hero was given career advice to go into plastics, which at the time was very sensible advice, Goldstein said. "We're at the dawn of the era of what I could call biological 'plastics.' Our ability to work with cells gives us the possibility of beginning to design organs and tissues and implant them into humans to rescue [them] from diseases," he said. Moreover it's hard to predict the course of scientific revolutions. Goldstein pointed out that recombinant DNA did revolutionize research biology but "none of us was bright enough to imagine that recombinant DNA would move into courtrooms," he said, and become a basic tool for policemen and lawyers.

Goldstein began his career as a fruit fly geneticist but now is building a cultured human stem cell system using induced pluripotent stem cells (HiPSc) to model human Alzheimer's disease. "Unfortunately animals don't actually develop the disease," he said. "Most of what happens when disease initiates... still isn't understood." By comparing reprogrammed stem cells cultured as neurons from human patients with either familial or sporadic Alzheimer's disease against neuron cells cultured from "wild type" patient controls, his lab is trying to unravel the complex relationships between genes, growth factors, and pathways of the actual human disease.

"We have cured Alzheimer's disease in the mouse many, many times, and frankly, we don't care," Goldstein declared. "But we'd like to develop drugs that actually affect true human situations."

To illustrate, Goldstein described how his lab used reprogrammed stem cells that differentiated into neurons in a dish to conduct a small-scale drug screen. "A number of [proteins called] kinases we didn't expect were involved [in Alzheimer's] showed up in this screen," he said, indicating that there is much more to learn about how the disease works. As genomic screening becomes faster and cheaper, we are finding much more variation in the human genome, Goldstein explained, and stem cell model systems would allow researchers to explore the question of what is the human "wild type" while also honing drug treatments. Goldstein said that his human stem cell model systems have already identified small changes in mutation patterns that yield big increases in the mechanisms that promote or slow Alzheimer's progression. Human stem cell model systems can recreate actual human phenotypes across a range of variations in genomes, thus vastly speeding up the screening of new drugs, he said.

But Goldstein cautioned, "Don't forget about the [non-human] model organisms in the rush to promote the human system. We need both working together." From fly, worm, and mouse, there is still much to learn, he believes. "If [we] develop in a human system the same kinds of tools we've had for many years in model organisms; shared cell lines, methods development, training, and the like, it would be a very powerful system," Goldstein said. With cultured human stem cell model systems, scientists "can develop very strong insights into both basic molecular mechanisms but also... human disease."