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Scientists Elusive Goal: Reproducing Study Results.

It appears that laziness and cheating in a drive to get ahead has moved beyond the classroom

Scientists Elusive Goal: Reproducing Study Results.

Two years ago, a group of Boston researchers published a study describing how they had destroyed cancer tumors by targeting a protein called STK33. Scientists at biotechnology firm Amgen Inc. quickly pounced on the idea and assigned two dozen researchers to try to repeat the experiment with a goal of turning the findings into a drug.

It proved to be a waste of time and money. After six months of intensive lab work, Amgen found it couldn't replicate the results and scrapped the project.

"I was disappointed but not surprised," says Glenn Begley, vice president of research at Amgen of Thousand Oaks, Calif. "More often than not, we are unable to reproduce findings" published by researchers in journals.

This is one of medicine's dirty secrets: Most results, including those that appear in top-flight peer-reviewed journals, can't be reproduced.

"It's a very serious and disturbing issue because it obviously misleads people" who implicitly trust findings published in a respected peer-reviewed journal, says Bruce Alberts, editor of Science. On Friday, the U.S. journal is devoting a large chunk of its Dec. 2 issue to the problem of scientific replication.

Reproducibility is the foundation of all modern research, the standard by which scientific claims are evaluated. In the U.S. alone, biomedical research is a $100-billion-year enterprise. So when published medical findings can't be validated by others, there are major consequences.

Drug manufacturers rely heavily on early-stage academic research and can waste millions of dollars on products if the original results are later shown to be unreliable. Patients may enroll in clinical trials based on conflicting data, and sometimes see no benefits or suffer harmful side effects.

There is also a more insidious and pervasive problem: a preference for positive results.

Read the rest here.

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Hey, I'm just an artist but I think it has to do with the fierce competition among scientists for the meager available funding and the science media's appetite for novelty. This juncture prompts for the premature publication of findings.

Adriana would have a more educated opinion, I'm sure.

This is hardly a new phenomenon, scientists are people just like any others, and you will find cheaters and lazy people and also sloppy scientists. But the reason behind the increased number of these episodes is money. This is happening because there is a shortage of research funds, they have been shrinking basically ever since Reagan, in the US at least. And in addition, the pharma industry is hugely profitable and there is a rush to find new drugs even if their effects are minimal.

And part of the reason is also that some journals rush to publish "glamorous results" without really going through the data with a fine-tooth comb.

The behavior of scientists is also very dependent on the behavior of authority figures like chairmen of departments. It is amazing what a great chairperson can do, as well as what a bad chairperson can do. One of the joys of my life as a scientist is that I work in a department where we are all constantly checking and double checking and triple checking our own results before the paper is submitted. It is the culture that was created, and it is embraced by all. But i have also worked in places that were not like that and where there was a rush to publish, in the name of getting more grants, etc. It encouraged sloppiness. I'm not talking about outright cheating or fabrications (I guess I'm very lucky I never came across anyone doing that, personally), but rather about confirmation bias being allowed to run rampant. It is a normal human mechanism of thinking, but we scientists know it exists and that we must avoid it like the pest.

Luckily, because science is not religion, sloppy scientists or people who rush to publish results that cannot be reproduced by anyone else, always become know. As Bill, says, there is transparency and constant questioning within the scientific community and eventually it comes to light.

This is just one more result of humanity's competition for diminishing resources. Scientists are human, after all, and it is publish or perish. Fortunately, at the same time, the world is becoming more transparent. And that transparency discourages this kind of behavior.  

It seems inexcusable to me - especially the part where the evidence isn't provided to substantiate the claims. 

It is inexcusable to me too. Folks like this don't deserve the name of scientist. It would be fitting to see them formally defrocked.

Perhaps peer review 'magazines' have dropped into the realm of Rupert Murdock tabloaids.

In any case, the STK33 story is not quite as described in this WSJ article. The data that were published pointed to this protein's role in a certain cellular context, and those data hold. The paper was not retracted or anything. It was a bad example to pick by the WSJ journalist ion my opinion. That paper showed a new method of ferreting out proteins involved in carcinogenesis, in a specific cellular context, that in their case pointed to STK33 as an important protein, but that can be used to find other determinants of carcinogenesis in other cellular models. It was a basic science project, and it suggested STK33 could be a good target for drug development. I have no idea what the Amgen scientists could or could not reproduce (that should be transparent, too, shouldn't it? but Amgen did not publish that. I spoke too soon, my APOLOGIES, Amgen did publish the results, and they did contradict the initial findings of the Harvard group; however, this is not an indication of cheating on the part of the Harvard or the Amgen group, this happens rather frequently because complex in vitro models and different techniques are used) from the results, but in many cases it turns out that the protein, while important in that cellular context used for the scientific article), is not a good target for drug development for entirely other reasons.

The biggest waste of money in companies like Amgen is the money they spend in marketing drugs, not the money they spend on 6 months of bench work trying to find out if something is a viable target for future drug discovery and development.

Being that this is a WSJ journal, it is sympathetic to the pharmaceutical industry and biotech companies, rather than to the scientists. While what happens most of the time is that scientists make the discoveries with public money, NIH grants, for example, and then the industry ends up making tons of money from a successful drug that was discovered thanks to our tax dollars and basic science.

For those who want to see the science from up close, here is the abstract of the Amgen paper:


Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine/threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In the present study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors.

The Amgen scientist did reproduce the initial results of the original article (I highlighted it) but when they investigated further, with two additional methodologies, and with additional cell lines, and it turned out that inhibiting the STK33 protein was not a viable target, because it could be inhibited but the cancer cells still survived. There is no suggestion of cheating or even of non-reproducibility; simply that a further investigation showed that STK33 was not a worthy target for killing KRAS-mutant tumors.

The original paper can be found here. I do not think the Harvard scientists purposely led anyone astray with the publication of their results. Although it would have perhaps been better if they had added the qualifier "potential", as in a "potential good target" and not simply "identify as a target", which can make it sound like a "done deal."

  • Summary

  • An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations.

Anyway, now a group in Germany has been able to reproduce the Harvard results with STK33. Granted, the German scientist who reproduced the results in Germany was at Harvard and is an author of the original paper. I have seen this many times; in most cases, the discrepancy in results is due to different methods or reagents used. This is really pretty common and is not an indication of sloppiness. We will probably need to wait and see if STK33 turns out to be important or not for future cancer therapeutics. I think these discrepancies are an unfortunate side effect of the complexity of the newest methodologies. From the same WSJ and article:

What could account for the irreproducibility of the results?

“In our opinion there were methodological issues” in Amgen’s approach that could have led to the different findings, says Claudia Scholl, one of the lead authors of the original Cell paper.

Dr. Scholl points out, for example, that Amgen used a different reagent to suppress STK33 than the one reported in Cell.  Yet, she acknowledges that even when slightly different reagents are used, “you should be able to reproduce the results.”

Now a cancer researcher at the University Hospital of Ulm in Germany, Dr. Scholl says her team has reproduced the original Cell results multiple times, and continues to have faith in STK33 as a cancer target.

Amgen, however, killed its STK33 program. In September, two dozen of the firm’s scientists published a paper in the journal Cancer Research describing their failure to reproduce the main Cell findings.

I couldn't read the WSJ in completion (I don't subscribe to it), but here is a link to the same article where it can be read for free, from the Office for Medical and Scientific Justice. In my opinion, the article is not entirely fair to academic scientists. The industry also pushes statistics to the limit to get drugs approved, and then they end up with disasters like with the COX2 inhibitors.Although the article does mention that the industry also pushes results:

Drugmakers also have a penchant for positive results. A 2008 study published in the journal PLoS Medicine by researchers at the University of California San Francisco looked at data from 33 new drug applications submitted between 2001 and 2002 to the U.S. Food and Drug Administration. The agency requires drug companies to provide all data from clinical trials. However, the authors found that a quarter of the trial data—most of it unfavorable—never got published because the companies never submitted it to journals.

The upshot: doctors who end up prescribing the FDA-approved drugs often don’t get to see the unfavorable data.

“I would say that selectively publishing data is unethical because there are human subjects involved,” says Lisa Bero of UCSF and co-author of the PLoS Medicine study.

I agree with what Bruce Alberts (editor of Science) says here:

When it comes to results that can’t be replicated, Dr. Alberts says the increasing intricacy of experiments may be largely to blame.

“It has to do with the complexity of biology and the fact that methods [used in labs] are getting more sophisticated,” he says.

Sometimes the methodologies used are so complicated, it is hard for even someone in the field to follow exactly what has been done to obtain the results; one way to avoid this is to collaborate between different groups, this should be fostered. It is always so much better when research is done in a collaborative way. Competition over resources makes collaboration difficult, but it depends on the scientists' personalities, too; some scientists manage to be super successful while being very open and very collaborative. These are the scientists I admire the most.


thanks for opening a little window for us on how science works! See, it is self correcting :). Show me a religion that can do that, and I will be amazed! 

Well, religions never self-correct by definition, because they are about self-preservation. And whenever religion appears to self-correct, like in the case of Christian churches who now accept gays, it is because they were forced to cherry-pick their teachings due to a change in societal mores. But the changes themselves come from secular institutions in the first place.

I hope I wasn't too confusing with my "deconstruction" of the WSJ article.


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