Standards and reproducibility in stem cell research

by Alexey Bersenev on February 13, 2014 · 0 comments

in open science

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We are on a quest of reproducibility in stem cell research. There are many controversies, surrounding poorly reproducible discoveries (look at MAPC and VSEL stories). A lot of resources, money and time could be wasted if method is not reproducible. In contrast, remarkably reproducible stem cell research could deliver fantastic outcome very rapidly. For example, (1) iPS cells – led to Nobel Prize and first human study in 6 years (!) after discovery or (2) mesenchymal stromal cell culture technique – led to hundreds of clinical trials and first commercial products on a market in three decades. With translational mindset, I have no doubts that reproducibility of research findings is extremely important and necessarily. However, some scientists disagree. In the recent piece in Nature magazine, Mina Bissell wrote:

The push to replicate findings could shelve promising research and unfairly damage the reputations of careful, meticulous scientists…

This piece triggers lively discussions here and here. I especially like a comment by Andrew Gelman:

…the push for replication is so strong that now there’s a backlash against it. Traditionally, leading scientists have been able to simply ignore the push for replication. If they are feeling that the replication movement is strong enough that they need to fight it, that to me is good news.

I have nothing against of science for sake of science (satisfaction of curiosity, unlocking the mystery of human nature…), but once you choose translational path (to the “bed side”), you should be obligated to make your method reproducible. Once you put in your grant application something like: “my research is very important for future of medicine/ treatment of incurable diseases…” – you’re on “reproducibility path”! This is exactly what every stem cell researcher puts in grant application. Once public gives you money to fined a cure, you become responsible for spreading your findings around the world for replication and further translation.

A lot of solutions have been proposed to increase reproducibility in research. Today, I’d like to focus on one of such solutions – standards for life sciences. Leonard Freedman from Global Biological Standard Institute (GBSI), during the recent Stem Cells as Discovery and Research Tools meeting, highlighted a necessity of standards in life sciences. He said that “standards are lagging behind in life science” and that standards can solve a lot of issues, especially irreproducibility. “Without standards research breakthoroughs are invalidated, papers face retraction and opportunities to translate to clinic is lost” – he noted. GBSI proposed a reform to standardize of life sciences research. GBSI’s white paper is a response to the big issue of irreproducibility in life sciences.

Biological standards—more broadly referred to as life science standards—comprise both material standards and written consensus standards. The latter are often prepared by a standards development organization (SDO). Reference materials and reagents are highly characterized and calibrated in units of biological activity.

There are a number of examples where standards could be implemented in stem cell research. Generation of iPS cell lines is the most discussed topic in standardization. It becomes even more important in a light of collaborations and creation of international consortia on research- and clinical-grade iPS cell banks. There is a big demand for standards in reagents for translational stem cell research. Large batches of reagents with consistent quality will be required for scaling up cell culture in pre-clinical studies. In mesenchymal stem cell (MSC) field, standards in nomenclature and cell characterization is also highly discussed. The next application is a methods for detection of genomic instability.

One of the best examples, where lack of standards can hold field back, is cross-contamination of cell cultures. Freedman said that “18-36% of research cultures contained misidentified species of cell types”. Some of you may remember a story with cross-contamination of primary MSCs by cancer cell lines. You can read brief summary here:

…in 2005 Rubio for the first time reported spontaneous human mesenchymal stem cell (MSC) transformation after standard 6-8 weeks expansion ex vivo. Since that, nearly 10 more reports were published confirming spontaneous adult stem cell transformation in long-term cell culture in mouse and human. It was the first big alarm for cell therapies based on transplantation of ex vivo expanded adult stem cells.

As a follow-up of this intriguing story, two international teams recently reported (here and here) that MSC cultures, which were previously described as spontaneously transformed, were actually cross-contaminated by malignant cells from human cancer cell lines. So, human MSC spontaneous transformation is nothing more that cell culture artifact…

So, MSC field was misled for 5 years, the time was wasted.
One of the examples of standards implementation in stem cell research is a PluriTest.

Since necessity of standards was not widely discussed before, there could be some misunderstanding and resistance from scientific community. Freedman said: “Many basic researchers view standards as a threat (it could attenuate creativity).” Unfortunately (as I mentioned above), this is true. GBSI doesn’t want to mandate standards on government level. This is a quest for collaboration!

David Panchision (NIH) has noted in panel discussion about the potential role of standards: “If you run a gel and band doesn’t look like a standard – don’t go further!” He thinks we need something like that in stem cell research. Ultimately standards will help to save time, money, resources and will allow a rapid progress.

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