You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Settled science update – of mice and men

Just when you think you know everything there is to know about a model you run tests on, out comes some whippersnapper to upset the scientific apple cart. It makes you wonder how this could have gone on for so long, but as the article says, the researchers became “ingrained” to a certain way of doing research, which I think is also a problem with climate science. – Anthony

Tests in Mice Misled Researchers on 3 Diseases, Study Says

By GINA KOLATA, NYT

For decades, mice have been the species of choice in the study of human diseases. But now, researchers report stunning 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 does not mean that mice are useless models for all human diseases. But, its authors said, it does 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 the Proceedings of the National Academy of Sciences, helps explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed. The drug tests all were based on studies in mice. And mice, it turns out, have a disease that looks like sepsis in humans, but is very different from the human disease.

…

“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.

While the types of data and methods differ, there is a parallel with some of the problems detailed at Climate Audit for Mannian studies lacking in statistical significance and/or reproducibility. Plenty of climate science auditors have said about the same as this researcher:

“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.”

This was investigated in great deal by Edith Efron, “The Apocalyptics”, 1984, ISBN 0-671-41743-6.
Before that time Dr Bruce Ames devised a famous series of rodent tests whose results fuelled the theory that there would be a pandemic of cancers caused by man-made chemicals. Edith, the non-medico journalist, was right. There is no such epidemic. Bruce has done a 180 turn. See the 2005 article (and many more similar) http://www.spiked-online.com/index.php/site/article/1514/ that includes:
“About 50 percent of chemicals, both natural and synthetic, that have been tested in standard, high-dose, animal cancer tests are rodent carcinogens. What explains the high percentage? In standard cancer tests, rodents are given a near-toxic dose of the test substance over their lifetime, the maximum tolerated dose (MTD), to maximise the chance of detecting any carcinogenicity. Evidence is accumulating that cell division caused by the high dose itself, rather than the chemical per se, contributes to cancer in these tests.
……………………………………..
“The Apocalyptics’ of 589 pages is a 30 year old prescription of what is now in progress with another topic, global warming. If you, as an interested person, seek ways to hasten the use of proper science with global warming, methods that proved fruitful are to be found in this book. It plays out the end game, first in the book, then in real life and particularly exposes administrators, politicians, poor-quality scientists and spin doctors and being hugely destructive.
…………………………………….
It was written by a skeptic, unfunded by big anything, and is unusual because the many hundreds of references specifically exclude those by industry, especially tobacco.
The references are verbatim and sourced. Those who are hung out to dry meet their fates from their own words.
Keep your old files safe & secure. The accused tend to deny.

From ‘The Apocalyptics’:
“The ‘environmentalists’ and ecologists, whose base was the EPA, demanded control of industry in the name of nature’s innocence, while experts in chemical carcinogenesis and occupational toxicologists, whose base was OSHA, demanded control of industry on the grounds of ‘man’s’ guilt; and ‘public interest’ groups emerged to do battle for both factions.”

” The press was taken in; the public was ignorant; epidemiologists, who knew better, hesitated to publicly attack other scientists…”

“As a result, years and billions of dollars have been wasted following false leads, they say.”
I’m shocked, shocked I tell you………

Many years ago a large multinational computer company (really large, before the current computer companies, their name is abbreviated to three letters starting with “I”) spent lots of money trying to make computer circuits with Josephson junctions (potentially much faster than silicon transistors). After many years (and dollars) somebody finally noticed that these junctions (at that time) did not ALWAYS make a nice clean switch from the OFF to the ON state (metastability).

That does not matter too much UNLESS you plan on using hundreds of thousands of them. Just think of a digital computer with lots of ZERO’S and ONE’S and a few percent “I’M NOT SURE” bits running around.

Nobody makes a Josephson junction computer to this day. Just another dry hole drilled, explored and plugged as a dead end technology.

The problem with cancer studies in mice is that usually the mice get inoculated with some cancer cell line that has been propagated in the lab for a long time, and therefore has changed quite a bit from the actual cancer of origin.
The problem of inadequate mouse models also applies to Alzheimer’s disease. This is due to the confusion caused by someone who thought it was a good idea to extend the originally narrowly defined term – it applied only to presenile dementia, a rare condition of dementia that becomes manifest in middle age and progresses to death in a few years – to garden variety senile dementia. The mouse model resembles the rare presenile condition, but it has little similarity to the much more common senile dementia. Of course, the smell of the latter is what attracted the vultures, err, pharmaceutical companies, and failure was/is predictable.
The next big disappointment will be the mouse models of aging. The problem here is that mice simply haven’t been optimized by evolution for longevity. Why? Because there are too many cats around – the chance of a mouse to actually benefit from a longevity gene is so small that in practice such a gene confers no selective advantage. In contrast, humans are a dominant species with few enemies, and they can turn their longevity genes to account; therefore, they have already been optimized for this trait quite thoroughly.
Improving the life expectancy of a mouse in the lab may be fascinating, but it is about as relevant to humans as optimizing the aerodynamics of a Ford Model T would be to improving the fuel efficiency of modern cars.
All of this is not rocket science, as they say. But then, the myopia of practicing scientists, not only in climate science, can really be quite astounding.

The lessons for all of us are more or less clear. The two most striking are keep the objective clearly in mind and clearly defined; always, always, always, question what and why never taking anything as a given.

I remember Josephson junctions. Wondered whatever happened to them. Now I know.

Remember bubble memories? Same thing. They could hold their memory without power for many years. Perfect for use by a Voyager satellite. Problem was, a few of the bubbles would get lost. So they couldn’t be used.

A jeweler friend of mine ended up with a boule of the bubble material. It’s called “GGG” [gandolinium-something-garnet]. It makes a really beautiful golden yellow gemstone. Sparkles like a canary diamong, and much more rare than diamonds since it is no longer made. He could sell them as a very rare garnet. But he’s honest, and feels he must tell customers exactly what it is. Most of them lose interest at that point [I don’t know why, I bought one for my wife and she loves it].

Pardon me for saying it once again, but there are no CAGW climate scientists with empirical instincts. The lack of parallel development is powerful evidence. They spent many king’s fortunes on supercomputers and poorly done paleo studies but spent only a pittance on empirical research. They are wedded to their tools come hell or high water. They should shift most of their funding to Willis.

in the late 60’s several brands of diet soda had cyclamates as a sweetener. I could barely tell the difference between diet and regular soda – and no after taste! Then came the big report – “Cyclamates Cause Cancer!” Reading about the report I thought, Of course if you inject an ounce of any chemical into a mouse it will get cancer. Even water! They quickly switched over to a new sweetener, and seems like they try another new one every few years. After that I have never tasted a diet soda that did not leave an after taste. About ten years ago I did read that they had proven those early studies wrong, but no one is going to try cyclamates a second time.

And NIH recently announced it was getting rid of many of its primates claiming they don’t need them for drug testing as you can proceed directly from mice models to humans in testing – of course this was partly under pressure from the animal rights lobby. Wonder if NIH will have second thoughts about that; given its bureaucracy, probably not until some kids are killed with a drug tested only in mice.

Years ago, early 90’s, when citrus solvents were all the rage, I guess they still are to some extent, there was all of a sudden a report that they caused cancer in rats. One of those real life experiments where they apply it to the animals skin just about continuously to see what would happen. You can expect that the animal can eat oranges all the time but how would the rat get hold of a concentrated version of the peel extract and get it on its skin is harder to believe. Fair enough they have to start somewhere to see what it could do to human skin if overexposed.
Yet another facility found that it was apparently helpful in limiting human breast cancer.
So rats are not necessarily much help either.
We are starting to run out of suitable test animals soon.

Yes I do, There was a semiconductor company down in Texas that had a “fire sale” on their remaining stock back in the early 1980’s. I think they were trying to recoup their loses by selling them to the “dupes”, sorry, I meant “creative engineers”. I almost bought some.

(Anecdote)
About 1982 in Los Angeles I attended an American Mathematical Society dinner. The speaker was a pharma statistician discussing lab rat and mice studies for carcinogenic potential of chemicals. The focus of the speaker’s talk was all about how you overdose a couple dozen rodents for their short lifetime and see if and how quickly they develop a cancer. If they do, then there was a model that projected back to “acceptable” exposure for millions of humans over decades. These rodent dose data were extrapolated back toward zero by several orders of magnitude.

The funny thing he didn’t spend any time on control. So in the Q&A, I asked, “What is the chance that a rat in your control group develops cancer?”

The speaker didn’t directly address it. “Well that depends upon the species of rat used in the study. ….” We never got to the reason why different rats were used an the implications of that fact. But as to the control rate, I wasn’t going to be deflected.

“Ok. Take for example one of the species used most often. Do 1 in 10 of the control get cancer? 1 in 50?”

“One in three.”

I remember a collective gasp coming from the audience seated around the room. A 40-ish man on the other side of my table shook his head and muttered sotto voce, “You can’t do anything with that kind of data.”

Why we are lucky to have penicillin.
In 1940 the UK was at war with Germany and its allies. Only essentials were being imported, and guinea pigs were deemed non-essential. Nor were they bred for research purposes, so Florey and Chain were forced to test penicillin in mice – with great success. Had they had access to guinea pigs, they would have all died – penicillin is highly toxic to these rodents – and trials would have ceased. In an ironic way we have to thank Herr Hitler for the life-saving antibiotic that made its way to the front lines his madness created.

This is all in a days work for drug testing. Nearly all drug tests fail. So a model that was thought to be equivalent, turns out not to be. So find another model, move on. Geoff Sherringham is right, cancer toxicology (including radiation carcinogenesis) is another science that has been corrupted and politicised by environmentalism, so that in its current state it is not fit for purpose. Environmental activism itself is TOXIC to normal, honest science.

Billions of dollars spent to make very effective drugs for the health of mice seems to be some what misplaced in the greater scheme of things. With that sort of money some better method could surely be developed. Good Grief

Biogerontologists are already aware of the problems inherent in mouse models of ageing (at least all my colleagues are). This is why there have been attempts to generate other animal models that more resemble humans (sheep and dog come to mind). One of the key problems with mouse models is that their cells appear to be immortal in culture (under the right conditions), whereas human cells have a limited lifespan.

It’s a bit too early to ridicule the use of mice as hosts for human disease (or common mammalian diseases, to be precise). The mice are not going anywhere from the lab research; their reputation will not suffer from this debacle, not in the least. They are way too good. And like a few of us have observed upthread, there are no tenable parallels between mouse research and climate modelling, except that both can be screwed up by stupid humans.

In this particular case — I don’t know the exact details, but I am making an educated guess — the whole idea of a drug against sepsis was a misguided one. It probably started a long time ago, before we knew better, and continued to crawl to the end despite more effective alternatives popping up in the meantime, and if this had to be the end of it, so be it.

Sepsis, as nearly always as we can tell, is a gut-derived condition (and that has been aptly demonstrated in mice). It had long been linked to trauma and wounds, but because wounds were an obvious suspect, the research into its real causes was not given a high priority. The cases of sepsis in the absence of open wounds were dismissed as freak irregularities. But as we progressed away from the more violent modes of existence (global wars, unprotected workspaces, poor traffic safety), more and more cases of sepsis could no longer be blamed on septic wounds. All that remained was trauma of some sort, or more generally, an intense shock of pretty much any nature. That is, if you only looked at patients already presenting sepsis on arrival. But there was also a steady stream of sepsis cases arising within hours or days after a surgical intervention of some sort. Sepsis became the #1 cause of post-op mortality. Again, the presence of wounds muddied the picture, and so did the use of antibiotics.

I won’t bore you with details; in the end, surgeons have found ways to prevent it, rather that treat it (and again, mice played a huge role in their research). Surgical patients no longer die from sepsis. If you are really interested in the details, a good place to start is John Alverdy’s home page at UfC:

There is a system in this madness, namely genocentric vision of species evolution, also known as Neo-Darwinism. All mammals are very much alike in their genetic makeup, and so people who see no difference between mice and men because this alikeness, tend to forget about epigenetics: pattern of gene expression which produce all the difference. That is how we differ from mice: the same genes are used in different regulatory schemes. In some traits this is quite important, while in others it is not. But as long as people will see genes as actors in individual development, not as reference texts to be read and interpretated by emergent individ, such blunders will happen. Recognition of this reality is ideologically impossible because it would retire Darwinsm to dust bin of history, and we can not allow it, can we?

We are looking at a phenomena that concerns all fields of science and it has name that perfectly describes it: indoctrination. Couple this with the vested interests on a personal level in form of years of academic work invested in a specific academic school of thinking and topple it with the modern politically defined research financing programs and the problems ahead of us are unavoidable.

We are looking at a phenomenon that concerns all fields of science and it has name that perfectly describes it: indoctrination. Couple this with the vested interests on a personal level in form of years of academic work invested in a specific academic school of thinking and topple it with the modern politically defined research financing programs and the problems ahead of us are unavoidable.

I am sure climate research is the same. All models have CO2 as a cause of heating, GHG theory, and are used as proof that CO2 causes warming. Pure sophistry.
The GHG theory was thought up to make up for a lack of enough solar heat to get the average 15C. There is more than enough solar heat. We are able to measure 1000W/m2 of insolation in the solar zenith position but the GHG theory assumes about 240W/m2 which is not true as actual measurement shows. It is the low 240W/m2 used to calculate the -18C giving 33C to find. !000W/m2, the actual figure, gives a temperature equivalent of 88C. More than enough, the surplus heat warms the below surface soil and the atmosphere which convects the heat eventually to space.

– you cant transport conclusions from the US to Europe etc. without checking
– you cant transport conclusions from caucasians to africans and vice-versa without checking
– models are not reality
– people forget everything that is not convenient to their aims, such has producing papers.
– mice are cheap, considering
– Science, Nature, Scientific American and New Scientist are primarily not scientific, but about science

We use lots of animals as human models, nematodes, mice, rats, dogs and primates. However, we ARE aware that a mouse is not a human. This article is yet another ‘we recognized that mice aren’t human’ feature, based on a university press release.
We know.
Honest we know that mice are not people. However, they are cheap, we can generate gene knock-outs and knock-ins, and most importantly we can do things to a mouse that we can’t do to a human.
As to the billions spent on Sepsis/trauma and burns; I wish.
This is a review of NIH spending by disease

http://report.nih.gov/categorical_spending.aspx
Almost all trauma funding is on brain and spine injuries, not hemorrhagic shock
Septicemia gets 98 million a year, only about 1/3 will involve animal models. Burns do not meet the $500,000 threshold.

So bottom line. We know mice aren’t human. We use them as a mammalian model. For somethings they are fantastic, for other things less so. You don’t need to tattoo ‘Mice aren’t people’ to our foreheads, as it is etched on our souls*.

One possibility now is that we have a closetful of previously rejected chemicals which might actually work on some human ailments. The challenge is to devise a non-mouse screening test panel to determine where some of these my be developed to their potential.

Sadly typical of medical research. It, too, is a hotbed of vested interest, big money, tenure decisions that hang on positive, not negative, results, confirmation bias, data dredging, and political interest (at the same time many of the practitioners are basically good people who genuinely want to do good for the world, paradoxically) — just like Climate Science.

We might see this change the day we see people getting tenure and promotions for null results, which (as Feynman pointed out) are often MORE useful in the search for positive results. They are WAY more useful than bogus positive results, statistically marginal positive results, data dredged results, cherrypicked results, results based on an incorrect inferential model, simulated results, theoretical results, and results that make somebody piles of money (as long as you don’t look at them too closely and notice that they are really null, failing the test of independent verification).

Papers like the one above with its NULL result are good examples of what should lead the way. It is almost as satisfying to shoot down a widespread but incorrect belief as it is to find something positive, and in the long run, our brains work by BOTH building neural connections AND brutally pruning back the ones that don’t work. Without the pruning, you get a teenage adolescent (literally — proliferation has happened but not the pruning) — and as those of us who have raised or been them well know, teenagers have a sort of brilliant and self-destructive madness until that pruning takes place.

There’s some terrible replies to that article (at the NYT). They’re very defensive and ignoring the main criticism which is against the peer review handling. A lot of anxious mouse choppers defending the “rodent model”.

DocMartyn is that really all you gleaned from the article? They made a discovery and couldn’t get published even though the journals couldn’t tell them where they were wrong. It wasn’t all about mice not being people, far from it.

Mice !! How about Rats – the best developed animal in terms of resistance to the widest range of substances, able to survive in the most hostile of climates and the most hostile of environmental loads.

Ever wondered why they are the preferred animal for manufacturers testing the toxicity of chemicals and then extrapolating the results to humans prior to licensing ?? Has always seemed to me that it is precisely because rats are so resistant that they have been so useful as test subjects to ‘big pharma’.

Brilliant responses, DocMartyn and rgb; I just want to add that not only do we realise that “Mice are not people”, but we also know that “People are not people”. For example, some people’s antibodies are broadly cross-reactive against multiple strains of flu, while others are not sufficiently reactive against the virus they have just been infected with. Some of us die from things others have for breakfast.

This article got me thinking about what evolutionary advantage there might be in being sensitive to bacteria? Like, why don’t we have mouse type resistance to bacteria? (“Mice need a million times more bacteria in their blood than what would kill a person”)

> This article got me thinking about what evolutionary advantage there might be in being sensitive to bacteria?

Probably none for us, but for the symbiotic bacteria we carry, the evolutionary advantage is presumably that they can jump ship when they sense that their host is in trouble. It may just be that by killing the host quickly and in a particular way, their chances of being acquired by the next host are better than starving to death with the present host.

> Like, why don’t we have mouse type resistance to bacteria? (“Mice need a million times more bacteria in their blood than what would kill a person”)

I would question whether that’s really true, and for what kind of bacteria. The most common enterobacteria that we and mice share, E. coli and P. aeruginosa, can kill us equally well, and they don’t even need to be in the blood to achieve that; they can simply let the blood out.

[re the question whether or not cell lifespan is the key question of aging: ]
“This is still under debate in the ageing field. The causes of human ageing are not understood at this time.”
—
This is a strange statement.

Of course, with a complex system like a living organism, we never completely understand anything, but we can have some useful, if limited, degree of understanding. Otherwise, there would be no vaccination, no drugs, no vascular surgery.

So, what could a partial understanding of aging look like?

Let us first clarify the concept of “cell lifespan”. The way it was used here relates to a cell’s generational limit — the number of times a cell is permitted to divide; past this limit, the offspring cells will no longer be viable.

Another relevant, more literal interpretion of the term “cell lifespan” relates to the maximum time a cell may survive without dividing. Why is this relevant? Because it applies to most cells in the brain, which are already formed at the time of birth, or shortly thereafter, and then have to last us through our entire lifetime.

It is important to understand that the number of cell divisions that go on in our organs is vastly different. In the brain, there isn’t much going on at all, whereas for example the bone marrow produces about 500 kilograms each of red and white blood cells over our lifetime, and potentially quite a bit more in long-serving blood donors. Nevertheless, most people do not die because they run out of blood cells, or skin cells, or intestinal epithelial cells, which also regenerate at a very fast clip. So, clearly, the cell generational limit does not as such limit life expectancy.

It is also interesting to note that, as biogerontologist states, a generational limit applies in human cells but not in cells from mice. Nevertheless, mice live only something like 2 years or so, even if not eaten by a cat. So there.

Now, if it is not the generational limit that limits life expectancy, what is?

What do people actually die from? Which organs do give out most commonly? It is interesting to note that the brain is much higher on this list than the bone marrow. What limits the life span of a brain cell? Broadly speaking, a lifetime of collecting waste. Sure, there are mechanisms for removing debris, but they work imperfectly, and in an aging brain such as mine, a lot of accumulated debris will always be observable. In a rapidly dividing tissue, intracellular waste will be diluted with each successive cell division; in long-lived cells, such dilution does not occur. Therefore, the tissues with low regeneration rates are the hard ones to optimize for longevity, not the ones with high turnover.

Now, back once more to the question why humans, but not mice, developed a strict generational limit for cell divsion. This generational limit is one of many safeguards against uncontrolled cell growth, aka tumors. A mouse will most likely be eaten, or otherwise die of dementia before it gets a tumor. Man has a generational limit to help him grow old; mouse hasn’t, because its chance of growing old is negligible anyway.

“So bottom line. We know mice aren’t human. We use them as a mammalian model. For somethings they are fantastic, for other things less so. ”

The problem is that they’re being used as a model without trying to verify that they’re a GOOD model prior to proceeding with the research. It’s not that mice are worthless, it’s that scientists got lazy and assumed that the mice would be a good model for what they’re researching rather than putting in the effort to find out before wasting everyone’s time and money.

This article got me thinking about what evolutionary advantage there might be in being sensitive to bacteria? Like, why don’t we have mouse type resistance to bacteria? (“Mice need a million times more bacteria in their blood than what would kill a person”)
—
We actually do have competitive resistance to bacteria. What kills us in septicemia is the very power of our immune system. In most cases, however, the vigilance of our immune system will prevent dangerous numbers of bacteria to accumulate in our system.

The real point to this study is not, as many have said, that “mice are not men” — no one ever thought they were. But they did think that mice acted as valid research proxy for men in many areas. Careers were spent (along with lots of money) using mice as proxies (they call them models, but that will stir up too much confusion here) in sepsis, burn and trauma research.

The use of mice as proxy for this research apparently had not been validated — which is what this study set out to do. It was a negative result — the proxy is NOT valid — results in these areas of mice do not apply to men. They knew this — the drugs developed on mice for sepsis (150 of them!) failed to work in humans. Question: Why wasn’t this study done after the first five or six drugs didn’t work?

This will stir up a lot of trouble in medical research. They should have been validating the use of mice as a proxy for each specific use as a separate study — like validating models and methods in Climate Research…It simply MUST be done or years of work and billions of dollars will be wasted following false leads.

@Kip Hansen: you say, “They should have been validating the use of mice as a proxy for each specific use as a separate study”

They should, no doubt. The problem is in what “they” were, or were not. For drug companies, following false leads is normal business. They call it “screening”. They are using their own funds for that, and they have discovered stuff in the past by random trial and error. They also have the money to do the kind of validation you are talking about, and I bet they do, as a rule.

For researchers working off public grants, validating someone else’s theory or experimental result has become all but impossible.

“Boss, can I spend a couple days validating the results that German lab published in Nature last month?”
“Yes, please do, by all means. We must be sure we’re doing the right thing.”

“Boss, can I send a P.O. for these supplies and equipment and spend 3-4 months validating the results that German lab published in Nature last month?”
“You’re kidding me? My grant officer is not going to authorise it. And these results have been peer-reviewed and double-checked, and cross-validated. We can’t waste our time like that.”

This bring to mind “The Invisible Gorilla” study. This was talked about on NPR just yesterday. A test group was asked to watch a video. It had two teams of children. One group in white t-shirts, the other in black. The observer test subjects were asked to count how many times the team in white t-shirts passed a ball. During the video a gorilla comes out, gestures at the camera, then walks off screen. After the test the observers were asked if they saw the gorilla. 87% did not. They had become so focused on seeing what they expected that the outrageous passed them by completely unnoticed.

Brilliant responses, DocMartyn and rgb; I just want to add that not only do we realise that “Mice are not people”, but we also know that “People are not people”. For example, some people’s antibodies are broadly cross-reactive against multiple strains of flu, while others are not sufficiently reactive against the virus they have just been infected with. Some of us die from things others have for breakfast.

This has always been my concern. The medical trials bring together a group that seems to have been chosen for a political poll – similar lifestyles and occupations. Then they carry out a climatologist level statistical analysis of the effects of diet, of drugs, of natural things such as sunshine. All the while they totally disregard genotypes which they must realize will affect the result. If you trial sunscreens and 75% of the group are dark skinned and 25% are fair skinned red heads it will not be a surprise to have 25% outliers in the trial – but this will be hidden by primitive statistics.
So yes as Gene Selkov says “People are not people” in medical trials.

The problem is that they’re being used as a model without trying to verify that they’re a GOOD model prior to proceeding with the research. It’s not that mice are worthless, it’s that scientists got lazy and assumed that the mice would be a good model for what they’re researching rather than putting in the effort to find out before wasting everyone’s time and money.”

You cannot do work on sepsis in humans: that’s it. If you are a clinical scientist you may be allowed to observe the team who are treating the patient, but you are not going to get any research done.
Same with burns and trauma. Even Ph.D. students who volunteer for everything are not going to have a 20 pound weight dropped 12 inches onto their skull or have a iron on maximum temperature applied to their back for 30 seconds.
I have friends who work on sepsis, most of them use rats. If any of you want to volunteer to have the scientists inject you in you abdominal cavity with excreta, follow progression and then remove you organs, just drop an email address.

DocMartyn, I think that you are huffing and puffing a bit here. A point well made further up in the comments is that observation led to the conclusion that sepsis is not simply a by-product of wounds. Observation of non-wound related sepsis does not require people to subject themselves to trauma. People with this kind of sepsis have to be treated, and not all of them will be treated the same way, for all sorts of reasons. Detailed observation of those conditions and treatment outcomes is a perfectly valid way of gathering data.

Indeed, it is almost certainly a better way of gathering data than doing nasty things to meeces.

Why is that a problem for you? In medical research, all sorts of things are out of bounds for double-blind tests for ethical reasons. We just have to rely on observation and analysis. It’s not perfect, but that’s just how it is.

“It is almost as satisfying to shoot down a widespread but incorrect belief as it is to find something positive, and in the long run, our brains work by BOTH building neural connections AND brutally pruning back the ones that don’t work. Without the pruning, you get a teenage adolescent (literally — proliferation has happened but not the pruning) — and as those of us who have raised or been them well know, teenagers have a sort of brilliant and self-destructive madness until that pruning takes place.”

It is more satisfying. Finding something positive involves making a promise to keep working even without reward.

My oh my. How wonderful it would be if every adult recognized that he/she had been a teenager and, even better, raised a teenager.

johanna, OK lets play it your way.
Work out how to organize a double bind trial to treat sepsis in humans, without an animal model. First off you need to recruit hospitals, and so need a lot of clinicians to sign up.
You need written procedures for the ER staff to recognize a patient falling with in you studies parameters, then the fun starts,begin by getting informed consent from patients coming into the ER .

“DocMartyn, I think that you are huffing and puffing a bit here. A point well made further up in the comments is that observation led to the conclusion that sepsis is not simply a by-product of wounds. Observation of non-wound related sepsis does not require people to subject themselves to trauma. People with this kind of sepsis have to be treated, and not all of them will be treated the same way, for all sorts of reasons. Detailed observation of those conditions and treatment outcomes is a perfectly valid way of gathering data.”

We are seeing too many cases of people in intensive care dying from an immune system that has turned against them. Physicians are scratching their heads. Research can and must be done.

Those who are chastising the assorted scientists about using the “murine”
(mouse) model should consider what other avenues these scientists could
use for testing.

Dogs? Cats? Spider or rhesus monkeys? Chimpanzees? All of these
animals get PETA and their ilk riled up more than the poor little rodents.
To use some of these other mammals is simply asking for a nuisance
lawsuit (or three) from an animal-rights group; a raid to ‘free’ the animals–
and destroy hundreds of thousands of dollars of lab equipment; ongoing
pickets and other harassment; ‘hacktivism’ against any of your computers
connected to the Internet; and assorted other unpleasantness.

Computer modeling? Please. We here on this Web site have frequently
derided climate computer models as being inadequate to the task. How
much more complicated is a living organism with multiple feedback
loops devoted to trying to maintain homeostasis!

So how about suggesting an alternative? DocMartyn andrgbatduke put forth disclaimers up-thread stating
that the assorted biomedical researchers & doctors know that the murine
model is flawed–but the most practical game in town. Suggest a better alternative,
bearing in mind the cautions I voice above.

Asking someone to put up an alternative because your system doesn’t work is one of the oldest wheezes of the CAGW crowd. It is not up to me to develop a model for biomedical research. What I said was that observation of existing cases of non-wound related sepsis is a valuable source of data – and given the limitations of mice, quite possibly the best source of data we have.

I detect a defensive note in these querulous comments which we have heard before in other spheres of ‘science.’

Stephen Rasey says:
February 11, 2013 at 10:35 pm
(Anecdote)
About 1982 in Los Angeles I attended an American Mathematical Society dinner. The speaker was a pharma statistician discussing lab rat and mice studies for carcinogenic potential of chemicals. The focus of the speaker’s talk was all about how you overdose a couple dozen rodents for their short lifetime and see if and how quickly they develop a cancer. If they do, then there was a model that projected back to “acceptable” exposure for millions of humans over decades. These rodent dose data were extrapolated back toward zero by several orders of magnitude.

The funny thing he didn’t spend any time on control. So in the Q&A, I asked, “What is the chance that a rat in your control group develops cancer?”

The speaker didn’t directly address it. “Well that depends upon the species of rat used in the study. ….” We never got to the reason why different rats were used an the implications of that fact. But as to the control rate, I wasn’t going to be deflected.

“Ok. Take for example one of the species used most often. Do 1 in 10 of the control get cancer? 1 in 50?”

“One in three.”

I remember a collective gasp coming from the audience seated around the room. A 40-ish man on the other side of my table shook his head and muttered sotto voce, “You can’t do anything with that kind of data.”

When I worked for Hercules back in the ’80’s I spent some time in the company of one of our toxicologists regarding one of our products. He related how he had become a target of the professional muckraker, Jack Anderson. Seems the good doctor wrote a scathing objection to a negative report on on another of our products based on a mouse study. Jack thought the company was throwing around its ill-gotten weight, hammering at a poor, defenseless three-letter agency. The question was all about the delta on the incidence of a particular cancer in a particulare strain of mice, said agency finding a significant increase (exact figures escape me). Our toxicologist noticed that there was a significant time lapse between sacrificing and necropsy of the control group (earlier) and test group (later). Mortality from cancer for this particular strain of mice was 100%. In time, they would all die of this particular cancer, at a predictible rate. When you graphed the mortality vs time for the control group and test group against the known parameters for the strain, there was no difference!! The agency had “found” a difference by delaying the examination of the test group. Not that Jack bothered asking the good doctor before publishing.

DocMartyn says:
February 12, 2013 at 2:29 pm
johanna, OK lets play it your way.
Work out how to organize a double bind trial to treat sepsis in humans, without an animal model. First off you need to recruit hospitals, and so need a lot of clinicians to sign up.
You need written procedures for the ER staff to recognize a patient falling with in you studies parameters, then the fun starts,begin by getting informed consent from patients coming into the ER .

Now treatment. What you going to do? Come on tell me.

So what, now we know the murine model for sepsis is flat out wrong, let’s continue using it??? Sure, I’ll give you money for that </sarc. Ye gods and little fishes!!

The murine model for sepsis is an adequate one. You can make them sick with Chron’s just like humans; they will haemorrhage like humans; their blood will be infected just like human, with the same kind of stuff; their immune response will be largely similar.

That does not mean it is a good model for drug testing. Drugs are very fiddly.

But, the only efficient “drug” that actually prevents sepsis (PEG lavage) in those situations where it is known to occur with a very high probability has been tested both in mice and in humans, with similar results. A model is only good as long as you understand what it does.

Unfortunately, there are no drugs to treat an ongoing sepsis. But mice are very helpful in learning about its causes.

Performing an intervention on a mouse model of a human disease tells you how the intervention works in that model.
Many of us use strains of mice with a much modified immune system to grow human tumors and to then treat those tumors. Now we know that the tumor growing in the mouse is different than the same tumor growing in a human. We then give chemotherapy and see what happens. Now we then assume that what happens in the mouse is ‘pretty much’ the same as in the human. It isn’t the same, but if the mouse liver turns to mush you know that isn’t going into a person.
What the hell do you people think we can do?
Seriously?
We DO NOT KNOW a better system to guess what is going to happen in people than a combination of tissue culture and animal experiments.
This is the bottom line. Animal experiments give us our best guess.
We are not lying to you, the mice models are not perfect. in some diseases they are damned good, other, suck. Anything to do with aging brain, no models work. Immune system, models can be iffy. Human brains and human immune systems are quite removed from other animals. Makes work hard, slow going and mostly wrong in a strict model=human sense.
So we know all this. I am not lying to you that the models are temperamental. Sometimes fantastic, sometimes completely crap.
We could work on primates instead, but the costs of research would be two orders of magnitude higher and the outcome only slightly improved.
However, i will tell you what will not work. Looking at sick people. Physicians have a duty of care and they have to threat their patients to the best of their ability; under threat of lawsuit. So they treat their patients. Different patients have different doctors and different preexisting conditions and present with a different cocktail of drugs for their hemorrhoids, premature balding, hormone replacement therapy, pain pills for soft tissue injury and copper bracelet.
Patients present at different ages, heights, ethnicity and different drug histories; give me mice that are almost clonal any day.
So don’t shot the pianist’s as they are doing their best.
WE KNOW MICE ARE MODELS; they are bound to be bad in some disease states.
In the case of gerontology and auto-immune diseases mice don’t mimic humans well. We don’t have any good aging models and even chimps have a different immune system to us. Chimps cost a small fortune and have to be looked after in retirement, and as the HIV/AIDS people will tell you, don’t mimic our immune system either.

It’s the way it is joanna. The more centers reporting a disease the less the information is worth. It is the dog shit and ice cream problem; what is the amount of ice cream you need to add to dog crap for it to turn into ice cream.

There is a very good reason for double blind trials. looking at sick people doesn’t work.

I have just spoken to a friend who is a Professor in a large teaching hospital. I read him your comments.

He hopes that you are not practising medicine on real patients, and adds that if you have any suggestions for training medical professionals that do not include “looking at sick people”, he would be very interested to hear about them.

“Good Calories, Bad Calories” by Gary Taubes documents the same types of problems with dietary “science”. In fact, the studies he cites indicate that obesity epademic that we are experiencing today was caused bad science in the 1960s. He also cites several recent studies performed at Stanford and Harvard that have turned yesterdays dietary “science” on it’s ear.

DocMartyn says:
February 12, 2013 at 5:32 pm
” So don’t shot the pianist’s as they are doing their best.
WE KNOW MICE ARE MODELS; they are bound to be bad in some disease states.
In the case of gerontology and auto-immune diseases mice don’t mimic humans well.”

a) You don’t like being criticized, obviously, so excuse me for the following sentence
b) Why did it take 150 failed drug tests to realize that something is wrong with the sepsis model in mice when YOU KNEW THAT MICE CAN BE BAD MODELS.

Nobody looked at it until now. You were sure the model was right. For decades. You are idiots.

Chris R. says:
February 12, 2013 at 2:52 pm
“So how about suggesting an alternative? DocMartyn and
rgbatduke put forth disclaimers up-thread stating
that the assorted biomedical researchers & doctors know that the murine
model is flawed–but the most practical game in town. Suggest a better alternative,
bearing in mind the cautions I voice above.”

The “most practical game in town” obviously has lead to no progress at all, so the funding is a complete waste. So as long as the ROI is zero, use 90% of the money for something useful. Like battling infectious diseases. Put 10% of the money into a fund that pays for an X prize challenge to be won by the person who comes up with a better model.

DirkH, I think you miss the point of what the 150 failed drug tests mean. Someone has used pub med or scopus to look up the number of treatment models used in mouse sepsis models. Most of it is going to be simple stuff; non-steroidal antiinflammatories, antioxidants nitric oxide synthase inhibitors, drugs to alter blood pressure e.t.c. These will give one lots of information about the system and be applicable to people. There are not tests on 150 newly synthesized drugs, this is off the shelf stuff.

johanna, you are incapable of understanding. A patient arrives at hospital with life threatening condition is treated. In the case of sepsis the treatment is very invasive. The patient is being treated but a team who interact with a patients symptoms. Other than a case report you get no data.
1. Observation
2. Hypothesis
3. Experimental design
4. Test hypothesis
You are suggesting that we just sit at the first one.
Bottom line, people with acute diseases are in the process of dying and the treatment team is busy treating and not in conducting research. They not only can’t get informed consent, but if they knowingly use a treatment that is ‘experimental’ they can be sued. Patients are lousy models for a host of reason, mostly ethical and legal, and physicians fighting for a patients life make lousy researchers. Not only is this true, it is known to be true.

DocMartyn: You are absolutely correct, but your focus is on the cases of people arriving to the ER with acute inflammation and sepsis. There are as many or more cases of sepsis resulting from planned surgery, where patients entering the OR are in good general health except for the problem they hope to resolve surgically. Bowel and thoracic surgery are good examples of procedures that cause major stress for reasons other than studying sepsis. During these procedures, circulation is cut and patients are typically placed on a ventilator. Many survive, but many enough die, and a great majority of those who die succumb to sepsis. It is during cases like these that you can observe and test hypotheses. These are just the typical cases where post-op mortality from sepsis is significant and expected.

But there is no shortage of more diverse cases where death from sepsis is not anticipated. The one I remember was much discussed at the UofC Hospitals during my time there: a girl in her late teens comes in with a toe trauma classed as open wound (although the extent was minimal); because of that, the emergency physician immediately gives her antibiotics (just in case, you know), fixes the injury and sends her home. Within the next couple days (can’t recall the exact delay), she’s back with an acute inflammation of her entire intestinal tract and dies in the hospital almost as soon as she arrives. This might seem like a co-incidence to a casual observer, but once you’ve seen hundreds of cases like that, you begin to think it was either her reaction to trauma or the antibiotic that did her in. Or both.

An experiment (or a whole lot of them) done by accident can deliver as good or even better information than direct testing.

Gene, my mother died of post-operation sepsis nine months ago and I work in a major hospital.
The problem with episodic events is that you need very good general surveillance techniques to record all patients, and then to be able to compare them to the person who get ‘X’.
Never mind different centers, different teams in a single department do things differently and the medics and nurses will report what they think they are doing and not what they are doing. Most people fail to grasp this point. People are liars, all the time, and not deliberately. You can monitor exactly what they do and then ask them what they have done and find huge differences.
Aristotelian philosophy; observation/thought/conclusion kills.

DocMartyn, man, I am so sorry. It is such a sad way of losing your mother. Post-operation sepsis should be preventable, now that its causes are understood, in the first approximation. Maybe it is knew knowledge that hasn’t yet reached everybody concerned. If you are still interested, please have a look at Alverdy’s works on virulence activation, or even better, get in touch with him. He knows it better than anybody.

Another outstanding and informative piece, Anthony. My thanks to you and <PRESIDIO_ANONYMIZED_PERSON>. Obviously, too many people have taken the “mouse proxy” for granted, thinking that it works as a protocol for all medical research. Hopefully this study will get scientists to correct some fuzzy thinking on their part.

We all insist that industrial sectors such as the food industry, auto industry, drug industry, etc. should utilize lots of quality control in making and developing their products. Why science has been neglectful in the area of quality control is somewhat hard to understand. Continuous quality control in medical and scientific research is just as important as it is in the food or drug industry.

The first question from the FDA is where are your study results on mice? That is why test are done on mice, even though the tests are meaningless. But there are other tests that can be run, on human tissue, or humans. After all, the human innate immune system is significantly different from all other animals, even primates. It is why monkeys don’t get HIV. There is no conspiracy here, it is just bloody stubbornness.