SHOW PREVIEW: Stem cell topics among the highlights of SLAS2014

SAN DIEGO—The annual meeting of the Society for Laboratory Automation and Screening (SLAS), which is being held in San Diego from Jan. 18 to 22, has always been a popular show, and it looks like there won’t be any negative change on that front in this third outing, with two new symposia for the January meeting already filled to capacity when SLAS Director of Education Steve Hamilton was interviewed by DDNews in November.

 

One of the symposia, to be held Monday, Jan. 20, will cover innovative technology for the discovery of new medicines, presented by the Genomics Institute of the Novartis Research Foundation (GNF). “It will be a peek behind the scenes at a pharmaceutical company and their technology,” Hamilton summarizes.

 

GNF was founded in 1999 and now has more than 560 employees. It applies integrated state-of-the-art technologies in chemistry, biology, automation and information sciences to identify new biological processes and disease-relevant mechanisms and develop new therapeutics in a variety of areas, including cancer biology, cardiovascular/metabolism, immunology, respiratory disease, neuroscience and infectious disease. These technologies include genomics and proteomics tools, structural genomics and forward/reverse mammalian genetics, high-throughput screening of genomics reagents or compounds, medicinal chemistry, ADME/PK and pharmacology.

 

The kind of technology SLAS2014 attendees will learn about include many systems created by the GNF engineering group, which designs and builds industry-leading, high-throughput automated systems that amplify GNF capabilities and enable GNF to tackle scientific challenges. This includes state-of-the-art, high-throughput screening systems capable of evaluating millions of compounds per day in biochemical or cellular assays, profiling systems that enable testing of thousands of compounds against hundreds of cell-based assays in parallel, automated protein production, purification and crystallography instrumentation that enable high-throughput structural genomics and protein-intensive studies and functional genomics screening systems that facilitate genome-wide cellular assessments of gene function.

 

Another notable program offering at SLAS2014 is a stem cell-focused short course for screening and laboratory research and development. The course is not focused on therapeutics, Hamilton stresses, but rather on techniques for standardizing the manipulation of stem cells to get valid, reproducible results. The course will look at such issues as making deriving, maintaining, characterizing and differentiating human induced pluripotent stem (iPS) cell  lines more easily, faster and more cost-effectively. Starting with the basics and continuing through characterization assays to lineage-specific differentiation protocols for producing physiologically relevant cell lines, the course will provide a deep-dive into the field that’s rapidly changing drug discovery.

 

“People are extremely curious about stem cells,” says Dr. David Kahler, former director of laboratory automation and the Flow Cytometry Services Laboratory at the New York Stem Cell Foundation. “Over the past few years, at SLAS annual meetings and elsewhere, I’ve been asked: ‘How do you work with them?’ ‘Where can we buy them?’ ‘Can we make them ourselves?’ ‘How do we get involved?’ The short course is geared toward answering those and other questions.”

 

Called “Introduction to the Derivation and Maintenance of Human Induced Pluripotent Stem Cells,” the course will be presented by Kahler, Dr. Justin Ichida, an assistant professor of stem cell biology and regenerative medicine at the University of Southern California, and Kelvin Lam, founder and president of Simplex Pharma Advisors and co-founder of the SLAS Stem Cells and 3D Microtissues Special Interest Group.

 

The increasing availability of various stem cell platforms and technologies is paving the way for a “new ‘hybrid’ discipline that involves collaborations between traditional stem cell scientists and traditional high-throughput screening scientists,” notes Lam. Moreover, opportunities for collaboration are surfacing “within the stem cell research community itself, because so many people are specializing in different areas.”

 

Underlying both the desire to learn more and the need for collaboration is a “tremendous excitement,” says Ichida. “With stem cells, we can unlock or greatly expand our knowledge about numerous diseases. Then, hopefully, we’ll be able to develop more effective treatments because we’ll be able to test them on cells that are actually affected by these conditions.”

 

The discovery that embryonic-like stem cells could be created from mature skin cells, first reported in 2006, laid the groundwork for the discipline as we know it today, says Kahler. “Now we can take anybody’s cells and reprogram them. And because we’re using cells from an adult, we can also take that person’s clinical history. That gives us a lot of metadata associated with those cells, and it’s something we wouldn’t have if we were working with embryonic stem cells.”

 

That said, turning back the clock on adult cells to produce stem cells for use in drug discovery or medicine is far from simple; protocols can be costly and time-consuming—generally, a couple of months from obtaining a tissue sample, reprogramming it, selecting clones or colonies of stem cells and characterizing them to ensure quality, Kahler acknowledges. But newer technologies, which will be explored in the short course, are making deriving, maintaining, characterizing and differentiating human iPS lines easier, faster and more cost-effective. “The field is moving very rapidly, and now one of the big goals for the industry is to be able to screen compounds and drugs on physiologically relevant cells—human cardiomyocytes, for example—instead of hamster cells. That’s where we’re heading with stem cells, and why it’s important for people to understand how to work with them.”

 

Ideally, stem cell-derivation technologies would produce high yields of high-quality stem cells. The reality is that in many cases, “yields are very small and there’s a lot of partially differentiated cellular trash that comes along with the quality cells,” Kahler says. Various strategies are used to physically separate out the “trash,” including manual picking of clones, magnetic beads, and Kahler’s specialty, flow cytometry and fluorescence-activated cell sorting (FACS). While manual separation can take 20 to 30 days, Kahler notes. With FACS, a week to 10 days after cells are infected with the reprogramming material, “you dissociate them and stain them with fluorescent conjugated antibodies to specific surface markers, and then you sort them out, which cuts two to three weeks off the programming process, and also reduces the amount of expensive cell media and manual labor required to generate stem cell lines because now you are expanding an enriched population of cells expressing a unique molecular signature that identifies them as early reprogrammed induced pluripotent stem cells.”

 

In addition to covering strategies to derive, maintain and characterize healthy stem cell lines, the SLAS2014 short course will include a look at protocols for converting human fibroblasts into disease-affected neural cells. This requires “precise combinations of transcription factors, small molecules and growth factors,” explains Ichida, who will provide specific examples of the approach. “Let’s say we have a patient with Lou Gehrig’s disease [amyotrophic lateral sclerosis or ALS], which is caused by selective destruction of motor neurons in the spinal cord. We can now take a skin sample from a patient with the disease and coax fibroblasts out of that skin biopsy. After a month or so, single cells start growing out of the chunk of tissue. We then insert the genes for four transcription factors and wait another month. Then we take those iPS cells and in effect guide their development back into motor neurons,” he summarizes.

 

Will those motor neurons retain the same disease characteristics as the patient? “That’s the million-dollar question,” Ichida acknowledges. “Nobody can really say for sure, but if they do, it will allow scientists to screen on the actual diseased human cell, rather than the right cell type but from a different animal, like a mouse, or the wrong cell type from humans.”

 

“The power of this stem cell technology is that it allows us to study any disease that is heritable through the genome, but we don’t need to know what the genetic mutations are,” Ichida explains. “For ALS, for example, we can understand mechanistically, downstream of the genes, the effects of the mutations—what is actually going wrong in these neurons—and from there, look at ways to correct them.” Ichida’s lab has completed the first step in the process by showing that they can make bona-fide motor neurons.

 

“Step two, which is not yet published, is that we’re now studying the neurons we’ve produced from patients with ALS and comparing them with neurons from control groups,” says Ichida. “We’re seeing a big difference in the viability of the neurons between the two groups, with most of the motor neurons that come from patient showing a tendency to rapidly degenerate. That in itself suggests that these cells are recapitulating some of the disease processes.”

 

How will gaining a better understanding of stem cell biology, reprogramming techniques and the production of physiologically relevant cell lines for disease modeling affect drug discovery? In Lam’s view, this knowledge will “transform the traditional drug-discovery paradigm, which takes 15 years before you finally have a compound.” When small molecules are used to differentiate iPS cells into specific cell types, whether diseased or healthy, “they’re not hitting a single target. They’re probably modulating various signal transduction pathways, and turning on multiple biomarkers along the way,” Lam explains. “Stem cell screening is not about identifying a single drug target; it allows you to identify several targets or genes involved in key pathways, pinpointing an array of potential targets for interventions.”

 

Stem cell screening also is changing laboratory automation approaches, Lam observes. “Traditional high-throughput screening tends to involve the use of fancy robots with lots of moving parts. For stem cell screening, big robots don’t make sense,” he says. “Traditional screening takes about three days, then you’re done with it. But stem cell assays generally take about 28 days, so you need more of a workstation approach, with a small handheld robot and a tissue culture hood. That allows you to change media, add compounds and so on under sterile conditions, which you can’t do with big robots outside the hood.”

 

In the short course, Lam will compare and contrast conventional screening and stem cell screening, discuss various high content and phenotypic screening platforms for doing the latter and explain the factors—e.g., lab space, needs, budget—that participants should take into consideration when deciding on a stem cell-related technology purchase.

 

SLAS 2014 attendees who work in drug discovery R&D today should understand both stem cell biology and stem cell screening, Lam believes. “Stem cell biology itself is not new; it’s been around for more than 50 years. What’s new is marrying that knowledge to drug discovery to create a hybrid discipline built around a stem cell-differentiating screening paradigm,” he explains. “Like it or not, the drug-discovery field is moving rapidly in this direction on all fronts.”