There has been a lot of clamor and hype surrounding stimulus-triggered acquisition of pluripotency (STAP) cells since their introduction to the research community in 2014. Read this post for a short, succinct summary of the scientific controversy surrounding STAP cells.
Defining STAP Cells
In this article:
- What Is It About
- Background of Stapcells
- The Controversy Over STAP Cells
- Production of Human STAP Cells
What Is It About
Stimulus-triggered acquisition of pluripotency (also known as STAP) is a process of creating pluripotent stem cells by sujecting ordinary cells to specific types of stress, such as the application of a bacterial toxin, submersion in a weak acid, or physical squeezing.[1] It is a radically simpler method of stem cell generation than previously researched methods, because it does not require either nuclear transfer or the introduction of transcription factors.[2]
The technique for creating STAP cells in 2014 was discovered by Charles and Martin Vacanti and developed by Haruko Obokata at the Brigham and Women’s Hospital (BWH), and then later performed at the RIKEN Center for Developmental Biology in Japan. [3]
Background of Stapcells
Interestingly, the concept grew out of an earlier discovery. In 2008, while working at Harvard Medical School, Obokata verified at the request of Charles Vacanti, that some of the cultured cells she was working with had shrunk to the size of stem cells after being squeezed through a capillary tube.[4] She tested the outcome from imposing various stimuli on cells. After improving her technique, Obokata shared that she was able to demonstrate that white blood cells from newborn mice could be transformed into cells that behaved similarly to stem cells. She then repeated the process with other cell types, including skin, brain, and muscle cells, and generated the same result.[5]
When her findings were announced in January 2014 in the scientific journal Nature, they created enormous clamor within the scientific community. The technique is novel in that it has the potential to produce cheap, fast, and flexible cells for use in regenerative medicine, medical treatments, and cloning.
However, at this time, Obokata’s findings are both controversial and not validated, despite attempts by multiple researchers. If the technique was able to be reproduced by other teams of scientists, then the discovery of STAP cells could represent the most significant stem cell discovery of 2014. Unfortunately, the situation has not been this simple or straightforward.
The Controversy Over STAP Cells
On February 15, 2014, the RIKEN Center where Obokata conducts her stem cell research announced that an investigation had been opened to look into irregularities allegedly found in her two papers that were published in Nature. The allegations against her questioned the use of what could be duplicated images within her papers. Other allegations cited the failure of other prominent stem cell laboratories to reproduce her results. Shortly thereafter, the journal Nature also announced that they were investigating the research papers.
To address that reproducibility has not been achieved in other laboratories, Obokata published technical ‘tips’ on the protocols on March 5, 2014, while promising that the full procedure will be published in due time.[6] Despite this action, on March 11, 2014, Teruhiko Wakayama, one of the co-authors for the two articles, advised all the researchers involved to withdraw the articles, citing many “questionable points.”[7] However, a United States based co-author of articles on STAP cell research, Charles Vacanti of Harvard Medical School, has publicly stated that he opposes their retraction and has posted information about how to generate STAP cells on his website.[8]
On March 14, 2014, RIKEN released an interim report of their investigation. Among the six items being investigated, the committee concluded that there has been inappropriate handling of data for two of the items, but did not conclude that the mishandling had involved “research misconduct.”[9] As such, the investigation of the remaining four items continues.
In the original research presenting the technique, STAP cells were produced by exposing CD45+ murine spleen cells to acidic medium with a pH of 5.7 for approximately a half-hour.[10] After this treatment, the cells were confirmed to be pluripotent by observing increasing levels of Oct-4, a transcription factor expressed in embryonic stem cells. This was tested over the following week using an Oct4-GFP-transgene. On average, about 25% of cells survived the acid treatment, but over 50% of those that survived converted to Oct4-GFP+CD45– pluripotent cells.
The researchers also found that treatment with bacterial toxins or physical stress was conducive to the acquisition of pluripotent markers.[11] Additionally, STAP cells injected into mouse embryos demonstrated pluripotency, growing into a variety of tissues and organs found throughout the body. According to the researchers, the mice appeared “to be healthy, fertile, and normal” after one-to-two years of observation.[12] Additionally, these mice produced healthy offspring, thereby demonstrating germline transmission, which is “a strict criterion for pluripotency, as well as genetic and epigenetic normality.”[13]
One of the reported traits of STAP cells is that they are supposedly able to differentiate into placental cells. This totipotent capacity, the ability to turn into any cell in the body or placenta. Pluripotent stem cells, such as most embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells), can form any cell in an embryo, but not the placenta. On the other hand, totipotent cells can form any cell in an embryo or a placenta, meaning they have the capacity to create life. The only cells known to be naturally totipotent are ESCs derived from embryos that have undergone only the first couple of cell divisions immediately after fertilization.
Production of Human STAP Cells
Furthermore, research has been undertaken to attempt to generate stimulus-triggered acquisition of pluripotency (STAP) cells using human tissue. Specifically, in February 2014 Charles Vacanti and Koji Kojima, Harvard researchers who were originally involved in the discovery and publication of STAP cells, claimed to have preliminary results of STAP cells generated from human fibroblasts. On February 5, 2014, they provided images of the first human “STAP cell” experiments to the New Scientist. However, they also cautioned that these preliminary results require further analysis and validation.[14]
In summary, STAP cells are of interest to the stem cell research community, in that if validated, they could represent an easier, faster, and more flexible method for generating totipotent cells. However, there is currently substantial controversy surrounding the discovery and the ongoing investigation seems to indicate that the technique may not be worthy of research attention. Rather, it may be a case of misrepresented findings. In particular, lack of reproducibility of Obokata’s findings continues to be a major issue.
Footnotes
[1] Cyranoski, D. 2014. Acid bath offers easy path to stem cells. Nature, 505 (7485), p. 596.
[2] Obokata, Haruko; et al. (2014-01-30). “Stimulus-triggered fate conversion of somatic cells into pluripotency”. Nature 505 (7485): 641–647. doi:10.1038/nature12968.PMID 24476887. Retrieved March 17, 2014.
[3] Grens, Kerry (29 January 2014). “New Method for Reprogramming Cells”. The Scientist. Retreived March 19, 2014.
[4] Sample, Ian (29 January 2014). “Simple way to make stem cells in half an hour hailed as major discovery”. The Guardian.
[5] Ibid.
[6] Haruko Obokata, Yoshiki Sasai and Hitoshi Niwa (March 2014). Essential technical tips for STAP cell conversion culture from somatic cells. Nature Protocols Discussion Forum.
[7] “Professor wants STAP findings withdrawn”. The Yomiuri Shimbun. 11 March 2014. Retrieved March 19, 2014.
[8] Charles A Vacanti (2014). Protocol for generating STAP cells from mature somatic cells. Center for Tissue Engineering and Regenerative Medicine. Retreived March 16, 2014.
[9] Press Release (March 14, 2014). “Interim report on the investigation of the Obokata et al. articles”. RIKEN. Retrieved March 20, 2014.
[10] Obokata, Haruko; et al. (2014-01-30). “Stimulus-triggered fate conversion of somatic cells into pluripotency”. Nature 505 (7485): 641–647. doi:10.1038/nature12968.PMID 24476887. Retrieved March 17, 2014.
[11] Sample, Ian (29 January 2014). “Simple way to make stem cells in half an hour hailed as major discovery”. The Guardian.
[12] Ibid.
[13] Obokata, Haruko; et al. (2014-01-30). “Stimulus-triggered fate conversion of somatic cells into pluripotency”. Nature 505 (7485): 641–647. doi:10.1038/nature12968.PMID 24476887. Retrieved March 17, 2014.
[14] Ibid.