When science goes wrong, and what we can learn from it

            Cells develop in an embryo in a step wise manner, like children going into school and finally choosing a career. Initially, children may choose whatever career they want and potentially become any kind of person they want to be. As the environment changes over their lifetime, children evolve and eventually become the stubborn and narrow-minded adults they were destined to become. Jokes aside, cells from an embryo are also given signals by the environment to become the cells they were destined to become. Essentially all the cells in our body are made of a specific set of cells in a developing embryo called pluripotent stem cells – master cells capable of becoming any cell type in the body. Most of the cells in our body now are terminally differentiated cells, meaning they have already chosen their path and arrived at them, and will never be able to turn into another type of cell.

The generation of master pluripotent stem from normal cells that have already become specialized has recently sparked a revolution in the biomedical sciences. This technique, called induced pluripotent stem cells, discovered by a Japanese scientist Dr. Shinya Yamanaka and earning him a Nobel prize in 2012, holds incredible promise in the field. One could envision taking skin cells from a patient who needs an organ transplant, changing these skin cells to master pluripotent stem cells, then giving them signals to become cells that make up the organ that the patient needs, growing and transplanting the organ back into the patient – all with minor risk of rejection by the patient’s immune system. During normal transplants, organs from another person are usually rejected by the patient because the immune system can recognize the organ as foreign and attack it, whereas an organ made from cells of the patient will be much less likely to be recognized as foreign. The technique as originally described by Dr. Yamanaka requires the infection of cells by viruses carrying four master genes. Genes are packets of information encoding proteins that ultimately play a function in the cell. Essentially, these four genes, called the Yamanaka factors, drive the cell into an identity crisis, causing them to morph back into their infantile state. This technique, while effective, is difficult, tedious, and expensive. Moreover, the technique has been thought to be dangerous, since it requires infection of cells by old inactive viruses that can lead to other potentially deadly mutations (think malignant cancer) if injected back into a patient. Therefore, many researchers have since been attempting to discover a faster, more efficient, and less dangerous way of driving terminally differentiated cells into an identity crisis, with success stories few and far between.

Enter another group of Japanese scientists, who published a paper in Nature back in January claiming that these master cells can be made simply by putting normal terminal cells into a slightly acidic environment. This paper took the field by storm – people were incredulous that cells could by coaxed into an identity crisis simply by tripping them out with some acid (pun intended). Not surprisingly, slews of researchers in the field tried to reproduce master cells in their labs using this technique. Soon, rumors started spreading that the technique was irreproducible. The murmurs soon became a loud din in the field, and many questioned the legitimacy of the paper in public. Various independent groups with a goal of revealing false data in peer-reviewed journals found that two pictures of cells in the paper that are supposed to represent different cells are in fact identical pictures. Parts of the methods were also found to be plagiarized. The authors quickly apologized for these mistakes, and called them honest mistakes, but enough doubt was casted on the paper that the research center where most of the research was conducted – the Riken center in Japan – began an investigation. The investigation eventually revealed inadequacies in data management, record keeping and oversight. Data described as coming from different lines or strains of mice were in fact found to be from the same strain of mice, and more cases of replication of the same data was found. The lead author of the paper, Haruko Obokata, a young researcher whose career looked so bright a few months before, was charged with misconduct – a death sentence for her scientific career. She quickly lawyered up and vehemently denied any misconduct with intent, and appealed charges of her misconduct, but these charges were later reaffirmed by Riken. The prestigious journal Nature that published the paper found itself in a public relations nightmare, and finally decided to retract the paper earlier this month.

Backlash in the scientific community is widespread. Ironically, earlier in the year, Nature ran a series of articles about how they were taking steps to improve their peer review process. Many scientists believe that the big journals in the field – Nature, Science, and Cell – are so eager to publish the next big thing that they don’t invest enough time, man-power and level of scrutiny needed to truly peer-review and weed out the faulty science. A recent investigation into big landmark papers in the cancer field found that results from only 6 out of 53 papers were actually reproducible (1). Another paper looking at a wider array of studies found that only 20% of papers have results that are precisely reproducible (2). While most researchers believe that cases like the acid-bath stem cells, where researchers clearly falsified results on purpose in order to advance their own careers, are rare, honest mistakes still lead to irreproducible data that confound and waste months of other researchers’ lives, and millions of dollars of the tax-payers and donors’ money.

            So what can we learn from this debacle? A colleague of mine summarizes the problem well: “most of us know that 90% of the papers in Nature, Science, and Cell are bull****, so God help the graduate student who’s the first to reproduce the results of these papers.” While it is easy to say that we should all take responsibility for our work and take pride in producing excellent, reproducible research that will actually contribute to our knowledge of how the world works, real life problems like shrinking funding sources, pressure to advance in one’s career, and maybe just pride can lead one astray. Maybe what we can really learn from this is that pressure may break us all down into another lesser, or infantile state, although sometimes it might just be a bad case of an acid trip. 

If you would like to read more about this, follow this link:
http://www.nature.com/news/stap-retracted-1.15488
http://www.nature.com/news/stem-cell-method-faces-fresh-questions-1.14895

1. http://www.nature.com/nature/journal/v483/n7391/full/483531a.html#t1
2. http://www.nature.com/nrd/journal/v10/n9/full/nrd3439-c1.html