Could Stuart Little's Bastard Child Be Human?

[livius drusus]

I was reading this Telegraph article (http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2005/03/06/wmouse06.xml&sSheet=/news/2005/03/06/ixnewstop.html) about reasearchers at Stanford creating mice with brains made entirely of human cells and couldn't help but be particularly entranced by this fanciful notion:

Supporters of stem cell research at Stanford University include the actor Michael J Fox, who suffers from Parkinson's disease. Fox provided the voice for Stuart Little, Hollywood's version of the "human mouse'', who talks, has human parents and lives in a New York apartment.

Opponents of Prof Weissman's work accept that his mice are unlikely to show such obvious human traits, but voice concerns that the brain cells would begin to organise themselves in a way that was more human than mouse. There is growing unease over whether human stem cells could migrate to other parts of the animals, creating human sperm or eggs in their reproductive systems.

Should two such "chimera mice" mate, it could lead to the nightmarish scenario of a human embryo trapped in a mouse's womb.

Um... What? Am I wrong to just burst out laughing at the ridiculousness of such a scenario? First the link to Stuart Little via MJF who as a Parkinson's victim supports stem cell research. Then the stem cells migrate on their own into key reproductive areas. Then they do it and there's a human fetus as a result of Stuart's youthful indiscretion.

I get that the Telegraph is being faux tenebrous here, but what does the actual science involved say? Do stem cells in lab conditions migrate? Did the insertion of stem cells in any of the other chimera animals spread past the target organ?

And how exactly would human cells work to make a mouse brain? Are human brain and mouse brain cells the same size? How are the stem cells going to turn into brain cells one they're in the mouse? Do they form a brain all on their own? Is this done to embryonic mice or full-fledged ones? If it's the latter, what happens to the original mouse brain?

Enquiring minds want to know.

[LadyShea]

What? Now that's just silliness.

[Seven of Nine]

Those poor, pregnant mice are going to need Caesarians, aren't they?

[Ymir's blood]

"Bah, what good is science if no one gets hurt?" - Professor Chromedome (from The Tick)

"Research projects that create human-animal chimeras risk disturbing fragile ecosystems, endanger health and affront species integrity.''
So what exactly is 'species integrity' and why do the words make me think of people obsessed with 'miscegenation', 'race mixing' etc...? Ok, there probably isn't a racist angle, but there still seems to be some sort of question begging going on.

[Crumb]

I think it is a common misconception that a species is some immutable category. Humans like to pigeon hole things when attempting to understand them.

[The Lone Ranger]

Um... What? Am I wrong to just burst out laughing at the ridiculousness of such a scenario?
Not really, no.

Do stem cells in lab conditions migrate? Did the insertion of stem cells in any of the other chimera animals spread past the target organ?
Well, injected stem cells do sometimes migrate to unexpected places. In fact, it has been suggested that it may not be necessary in some cases to inject stem cells exactly where they're needed, because they'll get to where they're needed on their own.

And how exactly would human cells work to make a mouse brain? Are human brain and mouse brain cells the same size? How are the stem cells going to turn into brain cells one they're in the mouse?
Mammalian neurons are mammalian neurons. The basic difference between the neurons that make up a mouse's brain and the neurons that make up a human's brain is that there are a lot more of the latter, and they're arranged into a slightly more complex structure.


If you think about it, there isn't nearly enough information in the human (or mouse) genome to specify the exact arrangement of the hundreds of billions of neurons that make up a brain. (For that matter, neither does the genome contain enough information to specify the exact layout of the circulatory system.)

It's a grossly mistaken impression to think of the genome as exactly specifying how a body is built. The genome is not a blueprint, as most people seem to imagine; it's a recipe. That is, it's a set of fairly vague instructions that go something like: "Put a whole bunch of neurons here in this general arrangement." For this reason, no two animals (not even identical twins) will have identical neural wirings (nor identical circulatory systems). That's why neurosurgery (and vascular surgery) more closely approximate artforms than sciences in many ways.

I've dissected -- and assisted in the dissection of -- hundreds of animals, and the first thing you discover is that the "textbook examples" of the nervous and circulatory systems are only approximations, and that each animal's is unique. For instance, some cats have 2 arteries branching off the Ascending Loop of the Aorta as the textbooks claim, but it's not at all unusual to see 3 arteries branching off it, or occasionally only one. The Common Iliac Arteries are "supposed" to branch off the Descending Aorta in the region of the hips, but last year one of our students had a cat whose Descending Aorta split in 2 right after it left the heart -- bizarre!


In a developing embryo, the heart is one of the first organs to form. Blood vessels develop as the heart pumps blood out -- pressure from the heart causes channels to open and become blood vessels. In other words, it's not so much that the genes program the growth of blood vessels (though they probably play a role in laying down general patterns of growth) as they develop "spontaneously" in response to pressure. That's why no two organisms will have identical circulatory layouts.

The nervous system grows in a vaguely similar manner. Certainly, the genes specify general patterns of growth, but a lot of the details are apparently due to "chance." In fact, one of the most important ways in which the nervous system develops is -- paradoxically -- by "pruning" of "excess" nervous tissue. You have a lot more neural pathways during the first few years of your life than you do later. Neural pathways that happen to work well get strengthened, while those that don't work particularly well get "pruned" as the neurons, lacking sufficient stimulation through use, die. As redundant and poorly-functioning neural pathways are pruned away, your nervous system functions more quickly and efficiently.

A vaguely similar process occurs throughout one's life. It has been shown in mice and rats that animals living in mentally stimulating environments (such as environments in which they're forced to solve puzzles in order to get food) have up to ten times the number of synaptic connections in some portions of their brains as do mice raised in environments where there is no mental stimulation. In other words, the brain works rather a lot like a muscle -- use it or lose it. "Mental exercise" not only strengthens connections between neural cells, but seems to slow down loss of brain tissue through cell death. Some studies have shown convincing evidence that individuals who are mentally active throughout their lives are considerably less prone to develop degenerative brain disorders such as Alzheimer's than are those who are more mentally passive.


Do they form a brain all on their own? Is this done to embryonic mice or full-fledged ones? If it's the latter, what happens to the original mouse brain?
I presume they’re injecting human stem cells into embryonic mice, before their brains have begun to form to any degree. “Stem cells” can develop into any specific type of cell, when triggered by the proper chemical environment, so in this case, human stem cells injected into an embryonic mouse’s head should develop into brain cells.

(Again, since every cell in our body has the same genetic makeup – barring sex cells and some of the blood cells, anyway – it’s clear that it’s not the genetic makeup that determines whether a given cell becomes a liver cell, say, or a brain cell, but the local environment.)

I see no particular reason to expect that these mice would have brains that would be distinguishable from the brains of ordinary mice in any important way, except that the cells would be genetically human. So, in practice, it might mean that healthy human cells that just happen to have been grown in mice could be transferred into humans to treat disorders like Parkinson’s.



From the Telegraph:
Should two such "chimera mice" mate, it could lead to the nightmarish scenario of a human embryo trapped in a mouse's womb.
Phooey. For this to happen, the stem cells would have to migrate in such a way as to produce a human ovary or testis inside a mouse, since only a genetically human ovary is going to produce genetically human ova, and only a genetically human testis is going to produce genetically human sperm. If our hypothetical mice have human gonads, I should think this would be rather obvious to even the most unobservant of investigators.

So what exactly is 'species integrity' and why do the words make me think of people obsessed with 'miscegenation', 'race mixing' etc...? Ok, there probably isn't a racist angle, but there still seems to be some sort of question begging going on.
The concern here is that if we introduce genes from species ‘A’ into species ‘B’, and some of these transgenic animals somehow escape into the wild, they’ll thereby introduce genes into wild populations that would never have made it into the gene pools otherwise. This could conceivably be very bad for the wild populations.


Cheers,

Michael

[JoeP]

liv: :rofl:

Lone Ranger: as ever, a fascinating and thorough background. Thanks.

Prof Greely: "If the mouse shows human-like behaviours, like improved memory or problem-solving, it's time to stop." - Could we apply the same principle to the US government? :innocent2:

[livius drusus]

Thank you, Michael, for yet another brilliant and approachable exposition of how science actually works. I realized reading the article that I know very little about stem cell research, that most of what I've read about it has been polemical rather than explanatory.

[Small, easily ignorable, totally self-serving suggestion]An article from you explaining some of the scientific controversies with desperately low signal-to-noise ratios would be so fabulously wonderful.
[/Small, easily ignorable, totally self-serving suggestion]

Well, injected stem cells do sometimes migrate to unexpected places. In fact, it has been suggested that it may not be necessary in some cases to inject stem cells exactly where they're needed, because they'll get to where they're needed on their own.

So not only does the environment signal what kind of cells they should become, but they stem cells might even move where they need to be? Does that mean that in a sense the entire body is a detectable environment for a stem cell?

Mind you, I'm not entirely sure what you mean by "needed". Would they detect damage, somehow, a need to reconstruct, or anything not full developed, or...?

Mammalian neurons are mammalian neurons. The basic difference between the neurons that make up a mouse's brain and the neurons that make up a human's brain is that there are a lot more of the latter, and they're arranged into a slightly more complex structure.

Thank you. That makes sense. I think I may have known it at some point, but if so, it was a deeply buried nugget of information.

It's a grossly mistaken impression to think of the genome as exactly specifying how a body is built. The genome is not a blueprint, as most people seem to imagine; it's a recipe. That is, it's a set of fairly vague instructions that go something like: "Put a whole bunch of neurons here in this general arrangement." For this reason, no two animals (not even identical twins) will have identical neural wirings (nor identical circulatory systems). That's why neurosurgery (and vascular surgery) more closely approximate artforms than sciences in many ways.

What the genome actually contains or is thought to contain is another veeeery blurry area for me. It wouldn't have occurred to me to think there wasn't enough information to specify exact arrangements. Now that I know, I find the genome and how it works with environment endlessly more interesting when I thought it was a big paint by numbers with some options kit.

For instance, some cats have 2 arteries branching off the Ascending Loop of the Aorta as the textbooks claim, but it's not at all unusual to see 3 arteries branching off it, or occasionally only one. The Common Iliac Arteries are "supposed" to branch off the Descending Aorta in the region of the hips, but last year one of our students had a cat whose Descending Aorta split in 2 right after it left the heart -- bizarre!

Erm yes. Bizarre and a little disturbing, frankly. The deviations were benign? I mean, they weren't the cause of death or disease or anything?

I see no particular reason to expect that these mice would have brains that would be distinguishable from the brains of ordinary mice in any important way, except that the cells would be genetically human. So, in practice, it might mean that healthy human cells that just happen to have been grown in mice could be transferred into humans to treat disorders like Parkinson’s.

That made more sense to me in regards to the sheep with almost human livers and pigs with human blood, only because it seems a very intuitive thing to me: the animals are incubators for transplantable organs and transfusable blood. The brain cells are a bit less clear to me simply because I have no idea what injecting healthy brain cells into a brain with Parkinson's will do.

From the Telegraph:
Should two such "chimera mice" mate, it could lead to the nightmarish scenario of a human embryo trapped in a mouse's womb.
Phooey. For this to happen, the stem cells would have to migrate in such a way as to produce a human ovary or testis inside a mouse, since only a genetically human ovary is going to produce genetically human ova, and only a genetically human testis is going to produce genetically human sperm. If our hypothetical mice have human gonads, I should think this would be rather obvious to even the most unobservant of investigators.

That actually made me laugh out loud. Thank you kindly, Michael. :bow:

[The Lone Ranger]

[Small, easily ignorable, totally self-serving suggestion]An article from you explaining some of the scientific controversies with desperately low signal-to-noise ratios would be so fabulously wonderful.
[/Small, easily ignorable, totally self-serving suggestion]
Aw shucks. That might be fun to write, but I'll have to put it on hold for the immediate future, I'm afraid. I have an insane amount of writing to do in the next two months' time -- something about getting the word "Doctor" in front of my name. Maybe during the Summer I can sit down and do some serious writing on something other than my dissertation. (What a concept!)

So not only does the environment signal what kind of cells they should become, but they stem cells might even move where they need to be? Does that mean that in a sense the entire body is a detectable environment for a stem cell?
There have been some studies that have shown beyond any doubt that injected stem cells can circulate throughout the body, and so wind up in unexpected places. For example, there have been at least four instances in which women who received stem cells in bone marrow transplants from male donors were later found to have brain cells containing "Y" chromosomes -- these cells could only be stem cells from the male donors that migrated into the women's brains and then differentiated into brain cells.

The exact chemicals that stimulate one stem cell to develop into a liver cell, another to develop into a skeletal muscle cell, and so forth aren't known yet, alas. What is clear is that when body tissues are injured, the damaged cells release chemicals that have several effects. For one thing, they attract white blood cells (leukocytes), which help fight off disease organisms. They also stimulate nearby cells to grow and divide, to help repair the damage. What's really interesting, though, is that these damaged cells seem to stimulate any stem cells that may be present to differentiate into cells of their type, which helps to replace damaged tissue.

So, if stem cells are injected into the brain of someone with Parkinson's, say, the damaged cells already present may be releasing chemicals that will cause the stem cells to differentiate into neurons to replace the dead/dying ones. That's the hypothesis, anyway.


Mind you, I'm not entirely sure what you mean by "needed". Would they detect damage, somehow, a need to reconstruct, or anything not full developed, or...?
See above: damaged cells release chemicals that attract leukocytes and stimulate growth of nearby cells to repair the damage. It seems they may also be able to stimulate stem cells to differentiate into the "appropriate" cell type to replace those that are injured/killed. Pretty neat.


This isn't terribly surprising, actually, because cells communicate chemically. Every cell in your body has a distinctive "chemical signature," based upon the unique arrangement of glycoproteins that are found in the cellular membranes. Leukocytes work by "testing" the other cells they bump into; when they encounter a cell with the "wrong" chemicals in its membranes, they attack and attempt to destroy it; they simultaneously release chemicals that attract other leukocytes and stimulate production of antibodies to help fight the infection.

NK ("Natural Killer") cells are specialized leukocytes that are good at detecting the subtle chemical differences between "normal" body cells and cancer cells. They chemically attack and kill cancer cells when they encounter same -- though obviously, not always successfully.


Erm yes. Bizarre and a little disturbing, frankly. The deviations were benign? I mean, they weren't the cause of death or disease or anything?
The cat appeared to have been a perfectly healthy adult. There's truly a good deal more variation in the layouts of the nervous and circulatory systems than most people would ever guess. So long as the necessary nerves and blood vessels get to where they're needed somehow, everything seems to be peachy. That's one reason why bypass surgeries can be performed; there's a considerable degree of plasticity and redundancy in both the nervous and circulatory systems. People have recovered from brain damage that has cost them 10% or more of their brain mass and gone on to lead apparently normal lives after recovery, for instance. Similarly, there are two semi-independent routes of blood delivery to the brain, so if one is blocked, the brain still gets blood.

[Of course, one should be careful about taking this too far. The brain contains lots of highly specialized areas, and damage to one or more of those is likely to have permanent effects. See below.]


That made more sense to me in regards to the sheep with almost human livers and pigs with human blood, only because it seems a very intuitive thing to me: the animals are incubators for transplantable organs and transfusable blood. The brain cells are a bit less clear to me simply because I have no idea what injecting healthy brain cells into a brain with Parkinson's will do.
Parkinson's occurs when neurons in a region of the brain called the substantia nigra die or are damaged. The substantia nigra helps control voluntary movement through production of the neurotransmitter dopamine (this is why dopamine can be used to help treat Parkinson's). With sufficient damage to the substantia nigra and subsequent reduction of dopamine production, smooth, coordinated contraction of skeletal muscles becomes difficult or even impossible, leading to tremors, rigidity, and so forth.

The basic idea is that injection of healthy neurons (or stem cells that will differentiate into healthy neurons) into the brains of Parkinson's sufferers will restore normal dopamine levels.

That actually made me laugh out loud. Thank you kindly, Michael.
Quite an image, isn't it?




Cheers,

Michael