Max Planck cell biologists have challenged the scientific research community to replace one of the most entrenched tools of preclinical studies-the HeLa cell line-with stem cell lines.1 The latter, they contend, more accurately reflect the underlying molecular complexity of healthy and diseased tissue, but technical and economic considerations may slow stem cells' adoption by the wider research community.

Stem cells have not been widely adopted as basic research tools because they are far more complex to grow and maintain than HeLa and many other cell lines. As a result, much of the translational research with stem cells has focused on their therapeutic applications, not on their use as in vitro screens and models.

HeLa cells were derived from a postmortem cervical cancer biopsy obtained in 1951 at The Johns Hopkins University from a woman named Henrietta Lacks and were the first immortalized human cell line ever created.2

"Unfortunately, it has remained unclear how well, if at all, the HeLa cell actually reflects the cellular diversity we know exists at the tissue level. For that reason we are proposing that new and better in vitro models of cellular diversity are needed for studying healthy and diseased tissue" because tissues are a mosaic of cell types with varying functional machineries and architectures that cannot be adequately modeled by a single cell line, said Kai Simons, a group leader at the Max Planck Institute of Molecular Cell Biology and Genetics.

In a commentary in Nature, Simons and Anthony Hyman, director at the same institute, wrote that HeLa cells and other immortalized cell lines "are completely inadequate for addressing the next big topic in cell biology: cellular diversity in normal tissue."

The authors suggested researchers should either "use embryonic stem [ES] cells derived from mice or other model organisms, or convert differentiated cells into precursors using a cocktail of transcription factors," creating induced pluripotent stem (iPS) cells.

"As the stem cell field moves forward, and our knowledge of stem cell biology improves, it only makes sense that stem cells-ES or iPS cells-would replace immortalized cell lines as the basic cell type biologists rely on in their preclinical research," Hyman told SciBX. "As the fundamental cell underlying biological development, the stem cell should serve as the platform of any in vitro research project investigating cellular processes in health and disease."

Simons and Hyman also proposed that cell and developmental biologists should generate "a large library or panel of stem cell-derived cell lines that better represent the various cell types of the body than immortalized cell lines. Such a panel would be ideal for studying cellular processes unique to each cell type, as well as useful for in vitro disease models and drug screens."

"If developed in combination with a publicly available set of protocols and reagents, it should also be possible to standardize the library across the labs of cell biologists throughout the world," said Hyman.

Hyman said organizations like the NIH need to provide additional funding to academic labs to encourage training in the growth, maintenance and differentiation of stem cell lines, as well as help oversee the development of the stem cell library. He declined to speculate on what would be a suitable sum of money for the endeavor.

How to build a library

"The Nature commentary almost reads like part of our company's original business plan," said Chris Parker, VP and chief commercial officer of Cellular Dynamics International Inc. The company's iCell platform differentiates iPS cells into highly homogenous, functional cell types for screening and optimization of compounds as well as in vitro modeling.

The company markets iCell cardiomyocytes, endothelial cells, neurons and hepatocytes, and has iCell hematopoietic cells in development.

"We produce our own cells on an industrialized scale, which removes perhaps the only remaining advantage of immortalized cells-that they can be produced in massive quantities," said Parker.

"Our small company has commercialized four iPS-derived cell types in about four years. Much time and expense go into confirming that the derived cells have definitive functional and morphological characteristics that separate them from other cell types. Equally important is showing that the cells can be matured into a homogeneous adult phenotype, making them suitable for a drug discovery platform. Considering there are about 200 cell types in the body, you can see that a truly comprehensive library would be quite an undertaking," continued Parker. "Obviously, not every one of those cell types is important to drug developers, so prioritizing helps make the task more manageable."

Another company, iPierian Inc., is developing a platform that generates iPS cells from patient-derived fibroblasts, which ensures that genetic variation unique to the patient will be reflected in the cell types differentiated from the iPS cells.

"The better your preclinical screens and models reflect the different cell types in diseased tissue, the easier you can understand how compounds affect phenotypes and the earlier you can weed out suboptimal compounds, thus increasing the efficiency of your drug development program. That makes an iPS cell-based screen much more powerful than a screen based on HeLa cells," said iPierian president and CEO Nancy Stagliano.

"Our goal is to use those cells to create a disease-in-a-dish model that is a useful drug discovery platform for neurological diseases such as Alzheimer's disease, amyotrophic lateral sclerosis and spinal muscular atrophy," Stagliano told SciBX. "We believe an iPS cell-based platform is essential for incorporating the patient's genetic background, which would otherwise be missing if we used HeLa cells as the basis for our in vitro studies."

New and improved immortality

Stem and IPS cells are not the only candidates for replacing HeLa cells in preclinical research.

"The authors' essential point-that one needs to complement studies using immortal cancer lines with studies examining normal cells-is completely valid. However, they are way too global in their insistence on only using ES or iPS cells," said Woodring Wright.

Wright, a professor of genetics and cell biology at The University of Texas Southwestern Medical Center, has shown that normal human cells, which undergo senescence in culture, can be immortalized by engineering them to express the telomerase protein.3 The resulting cell line shows most of the functional characteristics of the parent cell, making it a much better tool for in vitro research than a HeLa cell line.

In some instances, telomerase-immortalized cell lines are easier to produce than stem cell-derived lines because the immortalization method can be applied to any cell along the developmental pathway and does not require starting from an ES or iPS cell, Wright said.

"For example, if you want to generate bronchial epithelial cells, telomerase-immortalized airway stem cells provide a much better starting point than ES or iPS cells, which have to undergo a complex and poorly understood process coaxing them forward to eventually become bronchial epithelial cells," said Wright.

Parker acknowledged that starting from iPS cells means some cell types are indeed harder to generate than others. "Cell types like cardiomyocytes, which form early in development, are certainly easier to generate than cells like hepatocytes and b cells, which form late in development," he said. "The barrier to development is higher for the latter. Nonetheless, we have shown it is possible."

Fulmer, T. SciBX 5(4); doi:10.1038/scibx.2012.90 Published online Jan. 26, 2012

REFERENCES

1.   Hyman, A.H. & Simons, K. Nature 480, 34 (2011)

2.   Lucey, B.P. et al. Arch. Pathol. Lab. Med. 133, 1463-1467 (2009)

3.   Bodnar, A.G. et al. Science 279, 349-352 (1998)

COMPANIES AND INSTITUTUTIONS MENTIONED

      Cellular Dynamics International Inc., Madison, Wis.

      iPierian Inc., South San Francisco, Calif.

      The Johns Hopkins University, Baltimore, Md.

      Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

      National Institutes of Health, Bethesda, Md.

      The University of Texas Southwestern Medical Center, Dallas, Texas