h****y
发帖数: 77 | 1 By GINA KOLATA
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 paper, published Monday in Proceedings of the National Academy of
Sciences, helps explain why every one of nearly 150 drugs tested at a huge
expense in patients with sepsis has failed. The drug tests all were based on
studies in mice. And mice, it turns out, can have something that looks like
sepsis in humans, but is very different from the condition in humans.
Medical experts not associated with the study said that the findings should
change the course of research worldwide for a deadly and frustrating
condition. Sepsis, a potentially deadly reaction that occurs as the body
tries to fight an infection, afflicts 750,000 patients a year in the United
States, kills one-fourth to one-half of them, and costs the nation $17
billion a year. It is the leading cause of death in intensive-care units.
“This is a game changer,” said Dr. Mitchell Fink, a sepsis expert at the
University of California, Los Angeles, of the new study.
“It’s amazing,” said Dr. Richard Wenzel, a former chairman at the
department of internal medicine at Virginia Commonwealth University and a
former editor of The New England Journal of Medicine. “They are absolutely
right on.”
Potentially deadly immune responses occur when a person’s immune system
overreacts to what it perceives as danger signals, including toxic molecules
from bacteria, viruses, fungi, or proteins released from cells damaged by
trauma or burns, said Dr. Clifford S. Deutschman, who directs sepsis
research at the University of Pennsylvania and was not part of the study.
The ramped-up immune system releases its own proteins in such overwhelming
amounts that capillaries begin to leak. The leak becomes excessive, and
serum seeps out of the tiny blood vessels. Blood pressure falls, and vital
organs do not get enough blood. Despite efforts, doctors and nurses in an
intensive-care unit or an emergency room may be unable to keep up with the
leaks, stop the infection or halt the tissue damage. Vital organs eventually
fail.
The new study, which took 10 years and involved 39 researchers from across
the country, began by studying white blood cells from hundreds of patients
with severe burns, trauma or sepsis to see what genes were being used by
white blood cells when responding to these danger signals.
The researchers found some interesting patterns and accumulated a large,
rigorously collected data set that should help move the field forward, said
Ronald W. Davis, a genomics expert at Stanford University and a lead author
of the new paper. Some patterns seemed to predict who would survive and who
would end up in intensive care, clinging to life and, often, dying.
The group had tried to publish its findings in several papers. One objection
, Dr. Davis said, was that the researchers had not shown the same gene
response had happened in mice.
“They were so used to doing mouse studies that they thought that was how
you validate things,” he said. “They are so ingrained in trying to cure
mice that they forget we are trying to cure humans.”
“That started us thinking,” he continued. “Is it the same in the mouse or
not?”
The group decided to look, expecting to find some similarities. But when the
data were analyzed, there were none at all.
“We were kind of blown away,” Dr. Davis said.
The drug failures became clear. For example, often in mice, a gene would be
used, while in humans, the comparable gene would be suppressed. A drug that
worked in mice by disabling that gene could make the response even more
deadly in humans.
Even more surprising, Dr. Warren said, was that different conditions in mice
— burns, trauma, sepsis — did not fit the same pattern. Each condition
used different groups of genes. In humans, though, similar genes were used
in all three conditions. That means, Dr. Warren said, that if researchers
can find a drug that works for one of those conditions in people, it might
work for all three.
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.
Some researchers, reading the paper now, say they are as astonished as the
researchers were when they saw the data.
“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.”
Researchers said that if they could figure out why mice were so resistant,
they might be able to use that discovery to find something to make people
resistant.
“This is a very important paper,” said Dr. Richard Hotchkiss, a sepsis
researcher at Washington University who was not involved in the study. “It
argues strongly — go to the patients. Get their cells. Get their tissues
whenever you can. Get cells from airways.”
“To understand sepsis, you have to go to the patients,” he said.
This article has been revised to reflect the following correction:
Correction: February 11, 2013
An earlier version of this article misstated the position of Dr. Richard
Wenzel. He is a former chairman of the department of internal medicine at
Virginia Commonwealth University. He is not currently the chairman. | h****y
发帖数: 77 | | a***y
发帖数: 19743 | 3 今天早些时候 看到了原文
感觉对研究trauma， burn和sepsis的影响大一些。
it's not the end of the world.
been
human
【在 h****y 的大作中提到】
: By GINA KOLATA
: 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.
| s******y
发帖数: 28562 | 4 这篇文章在临床医学上的意义应该很重要，但是我不明白的是他们干吗不往临床
杂志或者转化医学杂志上发，而非要和Nature, Science 这种专门发基础研究的
杂志较劲。老鼠和人有很多差别，尤其是免疫方面差别很大。这个貌似领域里一早就知
道了。但是人们喜欢用老鼠是因为容易设计各种验证试验来测试一些理论。而那些事情
在人身上是不能做的。
不过他们的审稿者居然让他们去验证人和老鼠到底是不是一样这个也挺奇怪的。
因为从来都只听说过审稿者让作者去验证老鼠得出的结论是否能适用于人身上，没有听
说过倒过来的。除非那些作者在文章里做了一些关于机理的比较惊人的推论，而审稿者
觉得他们必须在一个可控的模型（比方说老鼠）里面验证一下。
【在 a***y 的大作中提到】
: 今天早些时候 看到了原文
: 感觉对研究trauma， burn和sepsis的影响大一些。
: it's not the end of the world.
:
: been
: human
| a***y
发帖数: 19743 | 5 这个显然不适合发到临床的杂志上去啊
【在 s******y 的大作中提到】
: 这篇文章在临床医学上的意义应该很重要，但是我不明白的是他们干吗不往临床
: 杂志或者转化医学杂志上发，而非要和Nature, Science 这种专门发基础研究的
: 杂志较劲。老鼠和人有很多差别，尤其是免疫方面差别很大。这个貌似领域里一早就知
: 道了。但是人们喜欢用老鼠是因为容易设计各种验证试验来测试一些理论。而那些事情
: 在人身上是不能做的。
: 不过他们的审稿者居然让他们去验证人和老鼠到底是不是一样这个也挺奇怪的。
: 因为从来都只听说过审稿者让作者去验证老鼠得出的结论是否能适用于人身上，没有听
: 说过倒过来的。除非那些作者在文章里做了一些关于机理的比较惊人的推论，而审稿者
: 觉得他们必须在一个可控的模型（比方说老鼠）里面验证一下。
| l**********1
发帖数: 5204 | 6 是啊是啊
莫非是
FAQ 她/他 JJ/GG 发地吧
一发cns 就要引导R01 下一轮 关停 以啮齿类作为model 之人体医疗相关的大部分实
验室的纺锭大门了吧
开大以恒河猴或家猪等作为材料的人体医疗相关的实验室的纺锭进水闸门喽
【在 a***y 的大作中提到】
: 这个显然不适合发到临床的杂志上去啊
| s******y
发帖数: 28562 | 7 哈哈哈哈哈，其实也就是对某一些特定领域的人影响最大而已。有可能那些人
就是审稿者，所以百般阻挠？
不过，这个为什么不能发在医学杂志上？看起来应该很合Nature Medicine,
Science Trans Medicine 这种杂志的口味啊？
【在 l**********1 的大作中提到】
: 是啊是啊
: 莫非是
: FAQ 她/他 JJ/GG 发地吧
: 一发cns 就要引导R01 下一轮 关停 以啮齿类作为model 之人体医疗相关的大部分实
: 验室的纺锭大门了吧
: 开大以恒河猴或家猪等作为材料的人体医疗相关的实验室的纺锭进水闸门喽
:
| l**********1
发帖数: 5204 | 8 莫非就是FAQ 其靠谷哥中文翻译 工具 在此发帖地 一旦中了pnas 就再也不来冒头
complain了 lol
【在 s******y 的大作中提到】
: 哈哈哈哈哈，其实也就是对某一些特定领域的人影响最大而已。有可能那些人
: 就是审稿者，所以百般阻挠？
: 不过，这个为什么不能发在医学杂志上？看起来应该很合Nature Medicine,
: Science Trans Medicine 这种杂志的口味啊？
| t*d
发帖数: 1290 | |
|
