Of mice and men.

[classical_hero]

http://www.nytimes.com/2013/02/12/science/testing-of-some-deadly-diseases-on-mice-mislead-report-says.html

For decades, mice have been the species of choice in the study of human diseases. But now, researchers report evidence that the mouse model has been totally misleading for at least three major killers — sepsis, burns and trauma. As a result, years and billions of dollars have been wasted following false leads, they say.

The study’s findings do not mean that mice are useless models for all human diseases. But, its authors said, they do raise troubling questions about diseases like the ones in the study that involve the immune system, including cancer and heart disease.

“Our article raises at least the possibility that a parallel situation may be present,” said Dr. H. Shaw Warren, a sepsis researcher at Massachusetts General Hospital and a lead author of the new study.

...
The study’s investigators tried for more than a year to publish their paper, which showed that there was no relationship between the genetic responses of mice and those of humans. They submitted it to the publications Science and Nature, hoping to reach a wide audience. It was rejected from both.

Science and Nature said it was their policy not to comment on the fate of a rejected paper, or whether it had even been submitted to them. But, Ginger Pinholster of Science said, the journal accepts only about 7 percent of the nearly 13,000 papers submitted each year, so it is not uncommon for a paper to make the rounds.

Still, Dr. Davis said, reviewers did not point out scientific errors. Instead, he said, “the most common response was, ‘It has to be wrong. I don’t know why it is wrong, but it has to be wrong.’ ”

The investigators turned to Proceedings of the National Academy of Sciences. As a member of the academy, Dr. Davis could suggest reviewers for his paper, and he proposed researchers who he thought would give the work a fair hearing. “If they don’t like it, I want to know why,” he said. They recommended publication, and the editorial board of the journal, which independently assesses papers, agreed.

“When I read the paper, I was stunned by just how bad the mouse data are,” Dr. Fink said. “It’s really amazing — no correlation at all. These data are so persuasive and so robust that I think funding agencies are going to take note.” Until now, he said, “to get funding, you had to propose experiments using the mouse model.”

Yet there was always one major clue that mice might not really mimic humans in this regard: it is very hard to kill a mouse with a bacterial infection. Mice need a million times more bacteria in their blood than what would kill a person.

“Mice can eat garbage and food that is lying around and is rotten,” Dr. Davis said. “Humans can’t do that. We are too sensitive.”

An idea that was so ingrained into the thinking of most scientist that it almost stopped this important paper from being released. So strong was this that to get any funding that you had to propose using this model, which we now know is not ass accurate as first thought. It should have been obvious that we were dealing with two different species that react differently to similar situations.

 

[peter grimes]

http://www.nytimes.com/2013/02/12/science/testing-of-some-deadly-diseases-on-mice-mislead-report-says.html

An idea that was so ingrained into the thinking of most scientist that it almost stopped this important paper from being released. So strong was this that to get any funding that you had to propose using this model, which we now know is not ass accurate as first thought. It should have been obvious that we were dealing with two different species that react differently to similar situations.

This is interesting, indeed.

I'll be curious to hear how this develops. But for now it's a stretch to claim that the paper was rejected from publication because of it's content. It may have been, or may not have been.

I also think it's a stretch to claim that is should have been obvious - if it really were obvious, this would have been acknowledged a long time ago. This is the natural process of science improving itself and correcting previous errors and misconceptions.

And for what it's worth, just because two species are different, does not automatically imply that they will have different responses to similar situations. In fact, biochemically, all life is very very similar.

I wonder if this would affect Mark's work at all? I suspect not, since I think he doesn't do pathology, only neuroscience.

 

[uppi]

An idea that was so ingrained into the thinking of most scientist that it almost stopped this important paper from being released.

Being rejected by Science and Nature and then getting published in PNAS is far from almost being stopped from being published.

 

[El_Machinae]

True, one of my life's goals is to get a PNAS publication. When I was a student, I adored many of their articles.

Yeah, mice and people are very different. We use mice mainly because of convenience, honestly. If we need a mammalian system, mice are much cheaper to deal with. With in vitro work, our main options are either rodent cells or transformed human cancer cell lines (where we try to nurture them to become 'similar' to certain real cells). Now, the science of transdifferentiation is getting better and better, and our rigorousness is getting better too. A major problem is that people who're qualified to really characterized transdifferentiated cells cannot publish papers with enough press to inform the thousands of graduate students that are using out-of-date differentiation protocols that are more established in the literature. When I worked with cardiac cells, the latest 50 publications in pubmed using that cell-line used differentiation protocols that were at least 5 years out of date. Once you see that, you cannot unsee it.

In vitro is not in vivo, even with human cell lines. This is something I personally deal with. The drugs that we give to mice are metabolically transformed in ways that I just don't think would occur similarly in people. Deducing the metabolic processes involved seems nigh insurmountable. Ostensibly, there should be a combination of transgenics that would make mouse-metabolism of drugs (all the way through the blood-brain barrier) more predictive of people, but good luck. Conversely, there should be human phenotypes that are 'closer' to mouse metabolism of drugs that the 'normal person'.

This is a problem that's being chipped away at, though. We are getting better at characterization. We're getting better at looking at certain characteristics and knowing what to look for. For example, our lab is currently working with creating dopamingeric cells (the cells that die in Parkinson's disease) and we think we have a better way of differentiating them to be more similar to a real neuron.

We're a million monkeys at a million typewriters sometimes, but there is progress. Currently, the number of mice sacrificed in medical research is significantly less than the life-extension purchased by medical science, so we're doing okay. We should be doing better.