Google Shows Us Crazy STAP Cell Dichotomy

What the heck?

STAP cell dichotomy

A recent Google search for STAP cells yielded these two adjacent, completely contradictory results sourced from two Obokata mentors (see image above) by the same newspaper less than 1 day apart.

That certainly clears things up on the STAP cell front, huh?

Adult human therapeutic cloning of embryonic stem cells by SCNT

An international team of stem cell scientists has replicated human therapeutic cloning to make embryonic stem cells via somatic cell nuclear transfer (SCNT).

The team was led by Drs. Dong Ryul Lee of CHA Stem Cell Institute in Korea and Robert Lanza of Advanced Cell Technology (ACT) and reported the advance in the Chung, et al. paper today in the journal Cell Stem Cell entitled “Human Somatic Cell Nuclear Transfer Using Adult Cells”. The cells expressed pluripotency markers (see Figure 1A at left) and had normal karyotypes.

Human SCNT

The research has replicated the human therapeutic cloning work reported last year by Mitalipov’s group and has advanced the field’s knowledge further in some ways.

One major important element of the new paper is the successful use of adult and elderly somatic cell nuclear donors (ages 35 and 75). Therefore, this new work indicates that SCNT may become a viable option for production of ES cells from in principle almost any person. Further, the new paper suggests that a slightly longer period of incubation prior to activation following SCNT may yield better results.

Some questions and challenges remain, which is not surprising for such a new technology. For example, why is it still relatively speaking so difficult to make SCNT work to make NT-ESCs in humans compared to other animals? An additional hurdle is that efficiency remains a challenge. In the current paper, 2 lines were made from a total of 77 human oocytes.

Again, it is early days for human SCNT and we can be almost certain that further refinements to the technology will boost efficiency.

For perspective, production of iPS cells is also an inefficient process, but the key difference here is that to make human iPS cells one can easily start with an almost unlimited numbers (easily in the 10s of millions) of say skin cells. In contrast, the low efficiency of human SCNT is much more of a challenge because every attempt involves a unique, difficult to obtain human oocyte. In specific countries and states in the US, oocyte procurement faces complicated regulatory and legal hurdles. In this regard, it is worth noting that Mitalipov’s group has just recently reported in Nature successfully conducted mouse SCNT to make ES cell lines using 2-cell embryo cells generated from fertilized eggs rather than naive oocytes. If this works in the human context, egg procurement may become less of a challenging issue.

As with the Mitalipov group paper, this team also did not mention the broader context whereby human SCNT technology could be misused by rogue scientists to pursue human reproductive cloning. As with many powerful technological advances, dual use ethical issues can arise and that is certainly the case here with therapeutic human cloning.

Some interesting questions that remain open include why this SCNT process is relatively inefficient in humans versus other species and also why certain human donors produce eggs that have the “right stuff” for successful SCNT.

Overall, I think this paper is an exciting, important, and technically convincing. SCNT ES cells may give us another potential tool to help patients via stem cells. Mouse studies hint that SCNT ES cells may have some advantages over iPS cells, but the jury is still out on that.

 

Top 10 lessons from STAP cell fiasco so far

STAP stem cellsThe ultimate fate of the two Nature STAP cell papers remains in troubled limbo.

One of the senior authors, Dr. Sasai, held a news conference yesterday in Japan that included a call for the papers to be retracted.

He was variously quoted as believing in STAP or alternatively as just thinking it was an unproven hypothesis.

Whether STAP cells or STAP stem cells are real or not, overall STAP has been a disastrous situation. Can biomedical science learn anything from this STAP fiasco? Maybe…some thoughts below.

  • Organize, keep records, and annotate your images. It seems that the STAP papers were plagued by confusion over images and the way image data was handled or changed. More broadly in science, sometimes research projects generate tons of data even if they are not “big data” genomics projects. In fact, it is not unusual for just one line of cell or developmental biology research to generate hundreds of image files. Each one might have a different exposure time or other varying attributes and researchers might legitimately adjust some images that are too faint, etc. It is wise to use a system where lab members catalog images and a naming paradigm that includes the date. Any changes to images must also be documented in writing and original unmodified forms kept as trackable backup files.
  • Don’t always believe your eyes. It seems that some of the STAP authors believe in STAP, but I wonder if “STAP” to them means simply cells glowing green? The reality is that for cells to be STAP they must have functions and pass a whole host of tests, not simply glow green (even if that green is real and not autofluorescence–see next point below) from a Oct4-GFP reporter. Just because you “see the green light” doesn’t mean it is STAP. Human beings including scientists are very visual creatures. Who doesn’t find certain microscopy images captivating? Seriously, a microscopy image can be like a piece of fine art. But sometimes data in the form of a visual image can be deceiving. The more general expression “I see the light!” is about discovery, but usually more about a discovery of beliefs rather than facts.
  • Danger, autofluorescence ahead. And speaking of “seeing the green light”, it was only days into the STAP craziness when a stem cell biologist told me in confidence that s/he believed STAP could be largely a mistake due to misinterpretation of autofluorescence as real signal. I still haven’t seen compelling evidence against the notion that the greenness of STAP is just autofluorescence in certain images and FACS data. Perhaps this STAP mess will make the entire biomedical research community more cognizant of the dangers of misreading cellular autofluorescence and the need to check for it.
  • Cells are not always what you think they are. It seems quite possible that some of the cells involved in the STAP cell research were not what some of the researchers thought they were. Cell line contamination is a common problem at least in part because different kinds of cells are stored and sometimes simultaneously grown in labs. Cells also grow at different rates so contamination of one cell type with even a few different cells can burgeon into a big problem over a surprisingly short period of time.
  • To be a good reviewer, data should always trump big names in importance. One of the problems exemplified by the STAP papers is that big name authors can sometimes sway reviewers inappropriately to be lenient on papers. In the end, as a good reviewer, you have to keep focused on the data, not the reputation of the authors.
  • Weigh the risks, benefits and responsibilities of being an author yourself. If you are possibly going to be an author on any given collaborative paper, use caution. Read the paper carefully, ask to see data if you have concerns, think about what it means for you to be an author of this paper, and if in doubt, at least consider saying ‘no’. In this time when most everyone wants more publications, sometimes paradoxically it is best not to be an author. Of course, sometimes potential co-authors or even corresponding authors don’t know about problems in papers and such problems can be hard to find so the decision as to whether to be an author can be tricky. Finally, take the specifics of those “author contributions” sections seriously as to what you did or did not do for any given paper. I wonder at this time how many of the STAP authors, if they could go back in time, would choose not to be author on those papers?
  • To editors, be extra-cautious about those “sexy” papers. A paper like either of the STAP ones is certainly exciting on first read and could have big impact. You might call them “editor-bait”. Heck, despite the controversy the STAP papers have already been cited many times in just a couple months by other papers. However, these kinds of high-profile papers are high risk for journals and editors too. As with the reviewer caution above, editors should not be swayed by big name authors if the story seems too good to be true and if anything, the more excited an editor is about a paper the more cautious they should be in how they handle it. Paradoxical? Perhaps, but I think it’s true.
  • To journals, give all manuscripts a thorough automated checkup. EMBO now reportedly has an automated screening process for manuscripts for image issues (manipulation, duplication, etc) and EMBO editors have indicated that the STAP papers would not have passed. Did Nature not have such screening in play when the STAP papers were reviewed? Does it now hopefully have such a system? Which journals automatically test for plagiarism of text or images? Clearly this kind of automated manuscript checkup should be standard procedure for all journals.
  • To scientists, don’t fall in love with your hypothesis. STAP almost feels like a fairy tale love story gone bad. I’m not talking about the love of two folks for each other like Cinderella and the Prince in a Disney movie, but rather the way scientists can sometimes fall in love with an idea. Avoiding this trap is naturally easier said than done because ideas can be super exciting.
  • Check the hype. There is nothing wrong with being excited about a paper or its potential impact, but be cautious about crossing the line to outright hype. Not everything is a “breakthrough” and that’s OK. Good, strong science doesn’t have to be a stunning breakthrough to have a positive impact. Scientists, journals, and institutions need to walk a fine line between advocating for our work publicly (which is needed) and overstating its importance, especially to the public or reporters. Many media folks are prone to hyping science as well. I believe that STAP was hugely hyped by many of the parties involved.

Any other things possibly to be learned in a positive way from all the STAP calamity?

As Predicted, Big News For California Stem Cell, Inc.: Purchased by NeoStem

Hans KeirsteadLate last year I was hearing some exciting things about California Stem Cell, Inc. under the leadership of Hans Keirstead.

In fact, I thought a big move for California Stem was in the cards for 2014 and looking into my stem cell crystal ball, I went so far as to make that one of my top 10 stem cell predictions for 2014.

Today, that prediction came true with the purchase of California Stem by stem cell biotech, NeoStem.

The acquisition of California Stem by NeoStem is a sure sign that the company’s scientists are indeed on track for great things. StreetInsider reports:

“As a result of this acquisition, NeoStem plans to initiate a pivotal Phase 3 trial of Melapuldencel-T, an autologous melanoma initiating (stem) cell immune based therapy intended to eliminate the tumor cells capable of causing disease recurrence.”

There’s reason for some cautious optimism on Melapuldencel-T making it eventually to successfully treat actual cancer patients.

I also see this purchase as a good sign for NeoStem.

So far I’m batting a thousand on my 2014 predictions, but I don’t expect they will all come to fruition by year’s end. Still, off to a nice start and this move for California Stem is good news.

After nightmare stem cell week, some good news?

Nightmare

We in the stem cell field should call this past week

A Nightmare on Stem Street.

I can’t think of many weeks that have been worse for the stem cell field than this past one. I’m a new week is starting soon.

It was a real nightmare, although I wish it was just something fictional out of the movies (see movie poster from Wikipedia). What happened?

  • The STAP horror fest kicked it up a notch in providing pain to the stem cell field with a dramatic press conference from Dr. Obokata in Japan that was a toxic stew. More STAP press conferences are apparently coming….
  • Brigham and Women’s Hospital and Harvard Medical School took a stem cell hit with a paper retracted (by request from Harvard) from the outstanding journal Circulation. This paper from cardiologist Dr. Piero Anversa had claimed against all odds/previous data that the heart could quickly repair itself.
  • A second shot to the heart for the stem cell field came again from Brigham and Women’s Hospital and Harvard Medical School, as they face another burgeoning stem cell paper fiasco. The Editors of The Lancet published an expression of concern about another stem cell paper from Anversa.
  • And there was yet another high profile stem cell paper retraction, this time from Cell, was announcedThe compromised paper “Directed Conversion of Alzheimer’s Disease Patient Skin Fibroblasts into Functional Neurons” had reported some interesting direct reprogramming, but one author, Dr. Ryousuke Fujita, has reportedly fessed up to some serious shenanigans on the data. The retraction was at the request of the authors.
  • Finally, NIH CRM is finished. Finally, the chilling cherry on top of the stem cell week from hell was the news that NIH’s stem cell program, the Center for Regenerative Medicine (CRM) was closing up shop after only having funded one grant. Terrible news.

So how about some good stem cell news?

Any other stem cell good news recently?