How do medical researchers obtain lab animals with diseases like specific forms of cancer which arise spontaneously? Do they raise thousands of apes and hope some eventually develop the disease?

Submitted by userbrn1 t3_yt84g7 in askscience

Lots of diseases like cancer arise spontaneously, and I'm not sure you can specifically breed certain animals to be susceptible to very specific genetic mutations. So when they need to test treatments for specific rare diseases like that how do they do it?

Are there facilities that raise thousands of primates and pray that some of them develop triple-negative breast cancer (or whatever specific disease you're testing treatments for)?

I imagine this is especially important when you're designing drugs like monoclonal antibodies that target specific factors and are increasingly designed for more and more specific diseases

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Chiperoni t1_iw2x410 wrote

Almost nobody works with primates anymore and we don’t really do transgenic primates. For lots of animals we do. Mice are the “work horse” for genetic models. Fruit flies, and rats, and zebrafish to some extent too (and yes others). Yes we can breed colonies with specific traits. Then we keep inbreeding them to keep their mutations. That’s like the old school way.

Then came things like the Cre-Lox system. You can use bacteria to make a bunch of DNA with specific sequences that include sites where it can be cut. You can add it to an embryo and have these DNA sequences integrate at specific sites by making the DNA sequence the same as where you want it integrated because every strand of DNA has a complement. You can then cause specific mutations at these sites as an embryo or even in a way you can trigger with chemicals so that the mutation can be triggered at any time at specific tissues. Then you can maintain a colony with inbreeding.

Now the new, new way is to use CRISPR which lets you do this much more consistently with a lot less effort. Then you can inbreed to maintain a colony.

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Allchemyst t1_iw33tqx wrote

To continue on this:

It's not just done genetically. Xenografts are done pretty consistently in cancer studies. You take a small piece of tumor that and implant it; usually, into a mouse that has been inbred to specifically knockout their immune system (or important parts of it anyway). This also gives you the advantage of being able to test against a human tumor in an animal model.

They also inject tumor based cell lines in order to produce a false tumor.

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Chiperoni t1_iw3452f wrote

Very true. And ideally a “mother” stock of the original tumor or cell line can be stored and expanded when needed if you want to reproduce the same tumor.

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scrangos t1_iw3z136 wrote

I've been meaning to ask something about this, isn't cancer prone to further mutations? When you try to expand it, wouldn't it end up changing sometimes?

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Suricata_906 t1_iw4gg08 wrote

Yes, that is true, but it takes some rounds of replication . That’s why for studies you would want to freeze a big batch of tumor tissue or cells, take out a vial for to use once and go back for another vial later. Essentially you are minimizing genetic drift for experimental purposes. Not perfect, but then what is?

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scrangos t1_iw4i78s wrote

Yeah that makes sense. Are those immortal cancer cells that have been used for a long time also been drifting genetically? Has there been a track record of how they've changed over time?

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GoblinGeorge t1_iw4t5vs wrote

HeLa cells have been drifting. There are studies that show cells from different labs have genetic differences, but I don't think it's possible to track all the variations in all the different lines. There are just too many different lines at this point.

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Suricata_906 t1_iw53p66 wrote

No track record as far as I know, but everyone assumes they are not as originally isolated. HeLa cells still have the original HPV induced mutations but unspecified other ones. When was a lab worker, the protocol was to use cells like that for maybe 15-20 population doublings, then discontinue.

The ATCC (American Type Culture Collection) is the motherlode for all kinds of cells, from the fairly normal, to things like HeLa that I like to say would grow on walls!

Fun fact. Most cells cultures isolated from normal human tissues have an expiration date called the Hayflick Limit of 50 or so population doublings before they become senescent and won’t divide. immortalizing mutations of various kinds override that.

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corduroy t1_iw6n9ae wrote

Just to add, there's a lot less genetic drift when passaging in vivo as compared to in vitro.

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ObscureCulturalMeme t1_iw4pkaz wrote

The lesson I'm hearing is that cancer can be raised just like a sourdough starter. Got it.

^(yes there's an /s)

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Veni_Vidi_Legi t1_iw53zdi wrote

There are transmissible cancers too, like with dogs and Tazmanian devils.

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AkioDAccolade t1_iw5bl5o wrote

Isn't it possible that most cancers are transmissible given the right scenario?

I vaguely remember reading an article about a medical professional who died of skin cancer despite never having skin cancer, but she did experience an accident where she accidentally sliced herself with a scalpel that was being used to excise a cancerous growth in an elderly patient?

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15MinuteUpload t1_iw5nowu wrote

In immunocompetent individuals it's unbelievably rare for a traditionally non-infectious cancer (i.e. all of them except the dog and Tasmanian devil ones) to be able to establish itself in another host, even if the cancer is directly implanted into the host. Part of the reason a natural/endogenous cancer can be so hard for the body to take care of is because it's composed of the host's own cells, which are obviously recognized as "self" and therefore less likely to come under attack by the immune system. Foreign cancers of course do not have this innate defense and so will almost always be very quickly killed off by the host's immune system.

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wulfoftheorderofbio t1_iw66eoy wrote

I was gonna say, seem to recall learning through immunology that the immune system does a pretty decent job fighting off most cancers that try to grow since the body considers them "foreign?" I need to brush up on immunology. It has been 8 years and my memory isn't what it used to be.

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Veni_Vidi_Legi t1_iw5qbzo wrote

> Isn't it possible that most cancers are transmissible given the right scenario?

Such a cancer would have to be able to survive exposure during the transmission process while also being in the right place and condition to transfer to a susceptible host site.

Once there, the immune system would almost certainly kill the more foreign looking cancer, as it almost always does for the more similar looking native cancers that arise in the host. But if it can evade the immune system, or if the immune system were missing, then it would have to find a suitable site and then maybe it can take hold.

So there would be a lot stacked against most cancers.

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Chemputer t1_iwoiwzh wrote

Not particularly, not in humans, no. It's even one of the misconceptions/myths on cancer.gov not specifically that story you mentioned (I googled my best and couldn't find it), but that cancers are contagious.

If what you remember reading is actually what you read and it's actually true (not a knock on you, just far more likely for your memory to be your brain trying to confabulate a story from something different, possibly vaguely related. Our memory sucks, especially fuzzy ones, and our brain just fills in the gaps), perhaps it was a cancer caused by a virus or bacteria (which is very possible, some decent percentage -- I've read 15-20% but can't find a citation for that exact number -- of cancers are linked to viruses or bacteria) and said pathogen spread, then causing cancer. The cancer itself would not spread in that manner.

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AkioDAccolade t1_iwok10y wrote

So I looked it up when I remembered it but I'm having difficulty finding the case study for a third time, but in the case I was remembering it was indeed a nurse that contracted it, however she was HIV+ (that she acquired during another accident, guess she would have taken the hint) which is the part I was missing. It was sometime in the early 90s

That pretty well makes anything possible.

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LilyMeadow91 t1_iw6ktep wrote

This is actually a quite good comparison, even if it was meant sarcastically 😅

Sourdough starters are just bacterial cell cultures, and concepts for cancer cell culture are the same: you give them jar to live in, the right temperature and appropriate food 😅

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ScienceIsSexy420 t1_iw37e4z wrote

Additionally, these induced tumor cells have the advantage of being isotopically labeled, making tracking the tumor progression much easier to quantify for comparisons.

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Astaro t1_iw46u0v wrote

Why would new cancer cells include the isotope labels of thier parents? Wouldn't the amount of isotope halve with each cell division?

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Chemputer t1_iwok3yc wrote

Of course, but it's very long down the line before it becomes undetectable much less low enough to be baseline.

That is actually useful in determining how many cell divisions have happened.

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Wankeritis t1_iw4z9z3 wrote

This also works with human leukaemia samples. You inject leukaemic bone marrow into mice and they home to the mouse's bone marrow and proliferate so you can harvest more of the sample than you injected.

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Cersad t1_iw31yul wrote

There have been papers out recently showing CRISPR in primates, so I expect gene edited marmosets or macaques could be feasibly studied these days.

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Chiperoni t1_iw32elo wrote

Oh definitely feasible. We already do it on human cells and even have done it on human embryos. As long as we have the genome sequenced. I just meant more and more people are stepping away from primate research due to ethics and practicality.

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triffid_boy t1_iw3qvhw wrote

It's not the technical difficulty, but the ethical difficulty.

Crispr is already in use in patient cells for things such as Car-t therapy. And we are primates.

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Cersad t1_iw3sn6i wrote

Right, but primates are also the only animal model that is appropriate for more complex etiologies. A genetically-defined model marmoset or macaque of neurological disorders would arguably be a better model than any rodent could aspire to.

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FiascoBarbie t1_iw43vel wrote

For some things. Rodents with Parkinson’s like syndromes have most of the same stuff as humans. Linguistic aphasia’s not so much.

What particular neurological disorders do you think are not well modeled in rodents and what would the better alternative be ?

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Welpe t1_iw4td6q wrote

Linguistic aphasia not so much?! So the rodents could speak perfectly? And here I was thinking all rodents had problems communicating linguistically!

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FiascoBarbie t1_iw5j82l wrote

No, obviously rodents don’t have language so they are not a good model for language problems.

That wasn’t clear when I said they weren’t a good model for linguistic aphasia?

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Delta9ine t1_iw6xhcw wrote

Nah. It was very clear to anyone following the thread who has even the most basic reading comprehension skills.

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triffid_boy t1_iw40zwc wrote

I mean sure, but you said could feasibly be studied since those recent papers - they were feasible models for a long time now.

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Cersad t1_iw422d5 wrote

I thought the CRISPR in primates only dated back to 2018-ish, but my memory could be a bit hazy. In the world of NHP research, six years is less than the useful life of the rhesus macaques I've seen in labs.

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gwaydms t1_iw3s5hv wrote

A young man who had spent much of his life in and out of hospitals with sickle-cell anemia is now being observed for a happier reason: he no longer has the disease. Genetic editing enables him to produce normal red cells. And his germ cells were edited as well, so he doesn't need to worry about having children with SCA.

To him and his family, the risk was worth it. He's just another healthy young man, with the prospect of a normal life.

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triffid_boy t1_iw40t17 wrote

Risk is minimal, I didn't say there was a risk concern?

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Chemputer t1_iwol41l wrote

Yes, we are primates. That's why we call non-human primates "non-human primates" when referring to them in a technical capacity, not necessarily when casually discussing something on Reddit, to avoid confusion.

It is, though, due to ethical reasons, much more practically and technically difficult to work with primates than, say, rodents. Getting any procedure approved on primates is going to be infinitely harder, and involve far more precautions, extra steps, difficulty, etc. than a similar procedure with mice, and be far more limited in number of subjects.

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triffid_boy t1_iwp60md wrote

I think you missed the point of my comment. The implication from the comment I replied to was the technical challenge of Crispr in primates was limiting factor, I used the example of current, clinical, use in humans of Crispr as an argument that it's not a technical limitation that prevents more widespread research in primates.

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Chemputer t1_iwwh6gt wrote

No, I understood what you were saying. I agree with you to a large extent.

I'm simply saying that ethical difficulty and technical difficulty are intrinsically linked. When you have to jump through more hoops for ethical reasons, it makes it more technically difficult.

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wolfgang784 t1_iw3cwvj wrote

There's that Chinese doctor who illegally edited two human babies (twin girls iirc?) with CRISPR in an attempt to make them immune to something, HIV or something along those lines.

Nobody else knew and he lied to the parents about what he was doing, so the study wasn't cut off at an early developmental stage like usual. The news didn't break till after the children were already born, so now they get to enjoy lots of testing and study for the rest of their lives.

So far they seem healthy and like the immunity part indeed worked, but the thing the doctor edited also does/effects more than he knew/expected and it is theorized that the girls may develop/suffer from a different issue (I can't remember what exactly) as a result.

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CrateDane t1_iw3i3q7 wrote

It was a knockout of the gene for CCR5, a coreceptor for (some types of) HIV. That gives resistance to infection. The coreceptor does not seem to be that important, as some people are in fact born without a functional copy of the gene and appear to be normal (aside from resistance to HIV infection).

We just don't really know enough yet to say whether you're better off with or without CCR5, even putting all the ethical issues aside.

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triffid_boy t1_iw3ram7 wrote

CCR5 is useful in cold/flu response and that's a hell of a lot more common than HIV. even in people with close contact with someone with HIV. Hell these days colds and flus are more of a faff than HIV is for those people infected but taking PReP!!

It was such a ludicrously ethically dumb experiment.

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BorneFree t1_iw33ajn wrote

Take a look at Guoping Feng’s Shank3 macaque KO paper

The off target effects make Crispr primates incredibly expensive to make, and an overall inefficient experiment

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Ph0ton t1_iw46mel wrote

Echoing this. CRISPR is a sea change but not a silver bullet. More developments in the vein of CRISPR-Prime will be great for developing models but besides cytotoxicity, currently there is an issue of cell-cycle arrest with most kinds of edits.

This will cause a survivorship bias among edited cells for those that can avoid that checkpoint and/or avoid cell death for critical, off-target effects.

Lots of work is being done though to minimize off-target edits, prevent cell-cycle arrest, and generally make CRISPR safer for therapy. With the millions of tools in nature, it's only a matter of time for us to find and perfect the right one that can make this viable.

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BorneFree t1_iw47e0v wrote

This is interesting I’m actually not well versed in cell cycle arrest in CRISPR editing.

However, regardless of advancements in CRISPR, I don’t think genetically engineered primates will ever become a mainstay of research - the time and expense of generating these animals is exuberant. I have a friend at NIH who occasionally works with primates and the amount of money invested in their primate center is absolutely absurd.

From the time the first embryo is edited, to the F1 generation alone is what, 4-5 years!? It’s just not feasible imo

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Ph0ton t1_iw4949s wrote

That's a good point. Technical limitations are nothing compared to the logistics.

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zebediah49 t1_iw6ci53 wrote

> With the millions of tools in nature, it's only a matter of time for us to find and perfect the right one that can make this viable.

With the millions of tools in nature, our immune systems have acquired methods of defeating a frustratingly large fraction of them.

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NecessarySpare4930 t1_iw3mosj wrote

Primates are still commonly used in preclinical trials before drugs go to market. Generally they are tested in a rodent species (usually mice) and a non-rodent species (usually dogs, pigs or monkeys.

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movingmanders t1_iw4wec8 wrote

Some things cannot be predicted in models, so these animals are often used in the preclinical trials to learn more about the potential side effects in humans. Drug developers want to make sure the drug is safe first, then they'll look into whether or not it works. If a drug makes an animal piss blood or develop seizures it probably won't make it to human trials regardless of if it works.

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Agood10 t1_iw3wvos wrote

I think your statement that “almost nobody works with primates anymore” isn’t really correct. Most of what ive been reading in the past hour suggests NHP use has remained relatively constant or even increased slightly over the past few decades.

This is purely anecdotal, but as a vaccine researcher I haven’t really noticed any significant decline in the use of NHPs in my field over the past decade. Everyone knows that NHP research isn’t ideal from an ethical standpoint but when it comes to testing a vaccine before trying it in humans, there’s really no better alternative.

Edit: source from USDA showing slight increase in NHP use over time in the US

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Chiperoni t1_iw3xl5a wrote

You might be right that their numbers are stable or increased but if you compare researchers that work on NHP to all other animal models or even just mice, they are a drop in the bucket

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Agood10 t1_iw3y633 wrote

Yes, that’s definitely true. I only bring it up because the way you worded your initial comment seemed to imply that NHP use has been on the decline whereas the opposite appears to be true, at least in the US and China. I suspect the low overall use of NHPs compared to other animal models is more so due to the astronomical economic cost of housing NHPs, not so much because of ethical qualms.

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Cosy_Bluebird_130 t1_iw4swbj wrote

It is being more and more discouraged in the EU and UK to use NHPs. In preclinical pharma research in the UK, you now have to provide justification for why you can’t use another non-rodent species in order to use them. Dogs are also starting to go the same way in the UK (you now need to prove you can’t use pigs), in large part due to the recent uptick in protests relating to “camp beagle”.

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FawltyPython t1_iw5m1kc wrote

That use is not really for disease modeling. It's almost all for ADME.

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stage_directions t1_iw7ul6i wrote

Yeah, we’ve found it very difficult to get primates for neuroscience over the past couple of years - they’re all going to vaccine work I suppose.

Be kind to’em!

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bill_lite t1_iw44918 wrote

I work with spontaneous cancers in primates. We just put out an APB to everyone around the US who works with monkeys and tell them that if they think one of their monkeys has cancer we will adopt it. Otherwise the animals are typically euthanized.

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stage_directions t1_iw7u9ia wrote

Ahoy, fellow primate researcher. Neurophysiologist here. Had not received that APB. Does it go out to vets, or PIs as well?

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bill_lite t1_iw88v2d wrote

We typically work with vets. So far ONPRC is the only institution that has consistently sent us animals. If you have some leads (or are just interested in our program) DM me and I can arrange more formal communication.

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alurkerhere t1_iw3tcc4 wrote

Not only a lot less effort, but way cheaper. CRISPR is an absolutely amazing technology that scaled up experiments that can be done.

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triffid_boy t1_iw3qo3v wrote

Great explanation. Worth touching on this being a reason that a lot of model animal studies don't always scale well to human.

e.g. P53 knockout mice make lots of tumours, give those mice an antioxidant rich diet and they get fewer tumours. P53 is a major component of the antioxidant pathway, so this shows more about p53 pathway than cancer, really.

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amlyo t1_iw45ddf wrote

How little effort? Could a shady lab use CRISPR on human embryos for implantation?

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Ok-Im-Lost t1_iw4ahz7 wrote

A shady guy with a mailing address and less than $1k worth of tools can do it in a homemade isolation tent in the middle of nowhere.

Edit: unless shady guy also has to store the embryos. Liquid nitrogen storage is less cheap than $1k. But still affordable for just about anyone in the west willing to give up the rest of their assets like a unabomber.

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mattc286 t1_iw4d74f wrote

A researcher in China tried it. It didn't work and he ruined his career. It's not as simple as articles in the popular media make it out to be. The technologies are not really "there" yet.

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LogSouth2717 t1_iw5nrhy wrote

I can’t really add much to this response as it pretty well covers it all. I can point you to Jackson Laboratories where you can see the phylogenic tree of how hundreds of different mouse models arose from a handful. It’s a fun rabbit hole if you’re interested in animal research.

It’s not just disease models. You can compare genes associated with physical activity by having C3H/HeJ and C57/LJ mice in cages with wheels. The C57s will run up to 20km a day, compared to 2km. It’s amazing how far we’ve come in research methods; and they’re still improving and evolving.

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bluesquare2543 t1_iw5zc51 wrote

What does that mean? I understand CRISPR is a gene editing technology. Does that mean you inject the mouse with a crispr drug and it changes their genes? What is the process for using crispr in a lab setting like this?

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Chiperoni t1_iw61cb4 wrote

To Crispr edit you need two things. One is an enzyme known as Cas. Cas’ job is to cut DNA. The other is a piece of DNA you manufacture. In the simplest terms, one piece of the dna binds Cas and the other binds the DNA of the target. When you combine both parts you create a little homing missile that binds the target so that Cas can make a cut. Now there’s a whole bunch of neat tricks you can do but the simplest are either to make a mutation or add DNA.

Just by having Cas at the target, the DNA will keep getting cut and the cell will repair it. Until it doesn’t because it makes an error. Then because your manufactured DNA doesn’t match the target perfectly it dissociates and Cas stops cutting. Now you have a missense, silent, frameshift, deletion, or nonsense mutation.

Alternatively, while Cas cuts you can also add more DNA that matches the DNA around the target with the hope that when the cell repairs the DNA and that this new DNA sneaks in. Now you have an insertion.

Again lots of little tricks you can do. For example let’s say you want to mutate a protein important in heart muscle. You can literally use CRISPR to insert an artificial gene that is only expressed in the heart by sticking close to a gene sequence that is only expressed in heart. Then you can actually CRISPR in the Cas protein but in a way that it’s only turned on when exposed to a chemical like the chemo drug tamoxifen. So you can grow normal mice and then at whatever point you like expose them to tamoxifen which turns on Cas. This Cas will then only have an effect on your original gene target only in the heart because the artificial DNA sequence you added is only expressed there. Really the possibilities are endless.

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turquoise_amethyst t1_iw3o3ym wrote

How is a colony maintained if the specific mutation causes infertility? Do they have to start from scratch every time?

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ChemicalBliss t1_iw3s79v wrote

If it’s recessive, they can breed 2 mice that are heterozygous for the mutation and screen the pups for having 2 copies of the mutation.

Edit: if it’s dominant they can use a conditional system where the gene only gets turned on in the presence of a drug (such as tetracycline), or the gene is turned on in a tissue specific manner.

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mattc286 t1_iw4c359 wrote

To further expound, it depends on what "kind" of infertility. If the dams can produce fertile eggs but the embryos can't implant or there's a placental defect, you can harvest the eggs, do IVF, and implant in another dam. If the males make sperm but have vascular issues that make them impotent, you can treat with drugs (like Viagra) or harvest sperm for insemination/IVF. If the mice can't produce gametes, you can use "conditional knockout" like the Cre/LoxP system so the gene is present and working until you're ready to make the test animals, and then either knockout the gene in the whole animal or in the specific tissue you want. I've also seen temporary "rescue" of a knocked out gene with injecting mRNA at the time of fertility defect to overcome the issue long enough to get viable pups.

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brutal_one t1_iw4axyl wrote

Wow that sounds so much like "Brave New World".

Is there a market in genetic testing for creating these lab test subjects and selling them or is everyone creating these in house?

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Chiperoni t1_iw4rij6 wrote

A very niche market but yeah. Check out jax.org. (This is in no way a sponsorship)

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Wave_Existence t1_iw5s9qq wrote

Oh yeah Jackson labs is huge for providing mice tailored to your specifications. This sort of service is very useful because it keeps different labs results more consistent. So you can refer to the specific lineage of mice you are using and everyone in the scientific community knows what you are talking about and where to get some. But it is also very common to create your own mice in house. Microinjections can be tricky tho.

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TyhmensAndSaperstein t1_iw4eguo wrote

Yeah, but does doing it this way - since it's so unnatural - give you a truly "real" result of how something like cancer arises?

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Wave_Existence t1_iw5t6vl wrote

Usually human cells accumulate random genetic mutations over time that get passed down to other cells that they divide into. Each cancer is different but there are some mutations that are "the usual suspects" to look for. For instance mutations in the p53 promoter region will disrupt the cells ability to self destruct when it detects mutations. Obviously that contributes to the likelihood that it will become cancerous. This way of doing things is fairly similar to the way in which cancerous mutations would arise naturally in humans, but it is much less random.

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2legittoquit t1_iw4g930 wrote

There is still plenty of rhesus and marmoset research going on. Rhesus has too long a gestation to breed a reliable transgenic strain and marmosets are pretty finicky. Most people still get them from WWP which is garbage and barely keeps track of who they breed with who.

There are some trandgenic marmoset lines, they are just really hard to breed because it’s hard too reliably keep all of the specific marmosets you need alive and healthy.

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Bekah679872 t1_iw4orh9 wrote

With the inbreeding does infertility eventually become an issue?

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Goetre t1_iw6r2by wrote

As an expansion of this,

There are also other species we can use as model organisms outside of bacteria but as a replacement for animal system. For example, in the past I've used an amoeba called Dictyostelium. Its a great little diverse amoeba which can be used to study both protozoan diseases and human. In pharmaceuticals we can use this species (and others) to test novel compounds for specific diseases. This reduces animals needed in research but not completely eliminates it.

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Krazski t1_iw3xn8j wrote

We don't test on apes anymore, we still do a lot of toxicology testing in macaques though.

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BigFaceCoffeeShop t1_iw4oii8 wrote

Sure we do. A lot of neuroscience research is done on larger NHPs. They offer a few important advantages including larger brains (so your probe to tissue ratio is better), more similar behaviour to humans, and higher intelligence.

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kitt_mitt t1_iw4vuno wrote

Depends on the research. My institute uses macaques and marmosets for parkinsons and MS research.

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SemogAziul t1_iw34zr3 wrote

Mice and zebrafish are the most common for disease studies. Researchers have the whole genome for zebrafish mapped, so as someone already explained, they can use knockout zebrafish and implant the cancer cells on the specific tissue or they can alter the DNA and make the fish produce the specific cancer cells needed

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Corogue t1_iw6athk wrote

Genuinely curious. If scientists can alter the DNA of an animal to produce cancer cells, can a similar genetic alteration cause the body's immune system to stop cancer cells from multiplying or attack cancer cells?

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robcal35 t1_iw6b5xc wrote

Immune cells require "training". Genetic alterations may be able to increase the number, but does nothing to affect their training to target cancer cells.

If you're curious, check out CAR-T (chimeric antigen receptor) cell therapy. This is literally where you are reprogramming and training immune cells to go specifically after cancer cells.

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LachoooDaOriginl t1_iw6zw62 wrote

i like to think of the car t thing as a lil terminator hunting cancer… am i the only one?

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robcal35 t1_iw7fvrd wrote

Hahaha just like the Terminator, sometimes there's some collateral damage

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123frogman246 t1_ix0w78z wrote

If you're in the UK, see if you can watch "War in the blood" - goes behind the scenes of CAR T cell therapy in a couple of patients and one of the academic labs behind developing the therapy

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NotDolledUpForYou t1_iw6elet wrote

Ive done a lot of work on CAR T-cells so in that regard technically yes you can alter the bodies immune system to attack cancer cells, but we do it by taking those white blood cells out the body, altering them and then putting them back, not by changing the bodies genetic makeup itself

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Tlaloc_Temporal t1_iw6usyh wrote

The M-RNA vaccines famously used for CoVID-19 were actually developed to fight cancer like this! The downside is you have to sequence the DNA of each case of cancer, but as sequencing labs get cheaper and more common, there might be a broad-spectrum cure!

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[deleted] t1_iw6dt62 wrote

[removed]

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NotDolledUpForYou t1_iw6enyy wrote

CAR T-cells don't work on the next generation they actually die out in the body so I don't know what you're on about there

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Alpacaofvengeance t1_iw6sr11 wrote

CAR-T cells do proliferate but I agree I don't know what elephants means there

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Gremlinintheengine t1_iw5dd0s wrote

How useful are fish in disease studies, really? Their physiology is so different from us.

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budrose13 t1_iw5owob wrote

Their physiology may seem very different from the outside but the genetic and molecular mechanisms are remarkably similar between zebrafish a humans. It's important to note that the vast majority of medical research is not "physiology" in the sense of studying whole organs or systems but rather molecular. So most research focuses on the genes and proteins involved in causing diseases and these are very similar between humans and zebrafish (about 70% shared genes). For example a gene that when mutated in humans causes heart defects may also cause similar defects in zebrafish (even though they have two chambered hearts while we have 4 chabered). If we mutate or remove that gene from the fish and indeed find that it causes heart defects we can use the fish to try to figure out how it causes those defects and potentially treat it.

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Roy4Pris t1_iw6im64 wrote

This is what aggravates me about nongs who don’t believe we’re related to chimps etc. Yes in the macro we look quite different, but at a metabolic and cellular level we are indistinguishable.

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playawhile t1_iw6x5zu wrote

It's almost like this DNA thing has some sort of... intelligent design behind all of it. Crazy.

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jjanczy62 t1_iw36l2q wrote

Non-human primates are only used at the very end of the therapeutic development process. They're used for to look at a drug's safety profile, get an idea of max tolerated dose, and efficacy (though in not sure how NHP cancer studies work).

Almost all preclinical work is done in mice. They're relatively cheap, breed quickly, and we have tons of reagents for them.

There are a number of models for studying cancer in mice. The easy ones are transplant models where we inject tumor cells (cell lines) into the mouse and go from there. There are induced models as well which will more closely mimic the development of cancer in in patients, but these can take a long time.

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GravityReject t1_iw4jveg wrote

It's not just for drug trials, there are definitely still non-human primate (NHP) experiments going on for the purpose better understanding how infectious diseases work. I work near one of the newer NHP research facilities in the US, so I hear about them fairly often from scientists in my area. Here's one example

Another more recent NHP study from that same lab

That lab specifically does tests on pregnant macaques, intentionally infecting them with a dangerous streptococcus strain to learn about how strep can affect a fetus. And the the mother macaques are often "sacrificed" after giving birth because they're too sick from the infection. Every time I pass by the facility it definitely gives me the heebie jeebies to imagine what's going on in here.

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DentalBoiDMD t1_iw6c9oq wrote

do add, alot of mice are genetically clones and have certain immune dysfunctions that make it easier to induce diseases/conditions in mice.

that's how it was for our lab. im sure there are many ways to do it

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Ami992 t1_iw3qdud wrote

In my lab we have few mothods of creating tumors in general and in specific places:

  1. We breed mice that dont have a tumor suppressor genes so they have random cancers in random areas of the body.
  2. Something we inject the tail vain with cancer cells (in my case cells that i suspect are canserus) the cell's usually metastasize in the lungs
  3. we can remove a lobe from the liver and inject cancer cells to the pancreas in order to create liver tumors
  4. we have the cre-lox system that turns off tumer suppressor genes in specific area of the body to induce cancers in hard to reach parts (usually the nervous system)

I never worked with monkeys but i assume the process is largely the same but require harder premmision from Helsinki comeete.

I have lot's of experience in this subject feel free to ask more questions

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userbrn1 OP t1_iw3wnqy wrote

After you turn off the tumor suppressor genes, at that point do you have to wait until you get lucky with the correct mutation you're hoping to study? Or is it relatively quick if you're precise enough with the gene modification

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Ami992 t1_iw41tvj wrote

I breed mouse without a Gene called ATM (a very important tumor suppressor gene) the usually develop cancer's at the age of 3-4 months.

I can also breed mice with only one allele of the ATM gene also known as heterozygous mouse, they develop cancer at 1-1.5 years

If time of onset is of concern to me i can raise regular healthy mice with the ATM gene on a cre lox system, so when i give the mice water containing TAMOXIPEN (a drug) the ATM gene will turn off and the mouse will quickly develop tumor's

I can see that you are interested in the oods and luck based approach, 40 years ago humanity did breed animals and observed random occurrences of deseases and studied them. today we are way past that, we have almost complete control of the mose genome and can create whatever desease modle we want - no luck involved.

The problem with developing cures is not creating a sick mouse, when we find a cure that works on a mouse 90% of the time it would not be affective on humans and that's is what holding science back nowadays

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Sekmet19 t1_iw34gy4 wrote

Jackson labs in the north east US specializes in breeding rats for animal models of disease. Also, Marshall Ferrets breeds for insuloma and cancers which is why the ones they sell as pets are so unhealthy and don't live long.

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exphysed t1_iw31bvb wrote

There are a number of ways to induce various maladies to create animal models of diseases. Some ways are genetic, some environmental, some through selective breeding, some through nutrition, and many other ways. Most animal research however doesn’t use primates (aside from humans). Mice are often the go to for mammalian research. Their genome is well understood and relatively easily modifiable. For instance, we can modify a gene that makes them less sensitive to insulin and thereby they effectively have type II diabetes. Sometimes some animals naturally have genetic abnormalities that make them good animal models for human diseases. Golden retrievers actually experience something very similar to Duchenne Muscular Dystrophy, and through selective breeding, a colony of dystrophic dogs was managed to study the impacts of treatments that might be viable for humans. Sometimes we also find animals in the wild too. There’s a species of monkeys, I think in Central or South America, that are spontaneously hypertensive and they’ve been used to better understand high blood pressure in humans. For most common human diseases though, you can almost guarantee an animal model has been found or developed. Just type in the disease followed by “animal model” in Google and you’ll find fascinating stuff.

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CommonwealthCommando t1_iw4z25u wrote

I work in neuroscience, so I cannot speak as much to what cancer researchers do. I have seen little lab-based primate research save for some small specialty fields in neuroscience like grabbing stuff and chit-chatting fine motor coordination and language acquisition. Even then, the research is on very small primates like macaques. Thinking practically, feeding thousands of giant apes every day just waiting for one to get breast cancer sounds very expensive and very boring.

The typical procedure for cancer research is to either mutate a mouse and breed them or to inject a human tumor seed into the mouse, causing the animal to get cancer. These processes are have been very well-described in other comments. I would like to add that in neuroscience we use a more diverse range of animals in the lab, but also many researchers go out in the field and observe animals in the wild. Studies on things like tool usage and language acquisition are in fact conducted by watching animals (usually dozens not thousands) and seeing what they do. We save money by having them–and sadly, sometimes the researchers–forage for their own food.

I will say that you have pointed out a systematic flaw with biomedical research, which is that researchers have a much easier time studying a disease caused by particular mutation(s) than one with a more complex etiology. It is much simpler (and cheaper) to make a mouse model that has a BRCA1 cancer or some other genetic disease (e.g. Huntington's) than a disease that is complicated and hard-to-measure (e.g. Major Depressive Disorder), so research funding tends to gravitate towards these projects, even if the diseases they study impact many fewer people.

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vicariouslyacat t1_iw4ezrx wrote

I work at a large emergency and specialty Animal hospital in the north east. We get owner permission to include their animals in certain studies and collect samples from animals that fit certain criteria. Some oncology studies automatically obtain data/statistics and many breeders submit or are requested to submit trends they see in their litters. Currently, BIO- bank (through Cornell) runs a number of different studies and collects data from single samples. This means that one vial of blood collected and submitted from one animal can be used in a number of different studies. Shelter and owned animals that are volunteered as blood donors are frequently signed up to participate in other studies. Everything from skin tissue, blood, serum, intestinal biopsies, stool, urine, saliva, etc., can be and/or are collected for a variety of tests and studies. Animals that are euthanized in shelters, or strays that pass in hospitals are often donated. One of our dentists had 4 severed heads in our freezer for months that he used to practice skills on. Additionally, there are breeding/animal labs that do breed excessively to generate sample pools but i try not to think about those. These breeding labs use mice, dogs, pig, rabbits, cats, snakes, etc. The numbers are in the hundreds of thousands (millions for rodent and insect studies).
Apes and other primates are less frequent lab animals and but are still bred for study or volunteered from zoo populations. So yes to your primary question: they do raise thousands and generate captive sample pools, however primates are not as frequently bred or used as lab animals any more. Many are trap-and-release populations but that is not that majority.

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Doc_Lewis t1_iw66xxx wrote

I can't speak to cancer specifically, but in other disease areas there are mice bred specifically in to be susceptible to a disease. There are also ways to induce a disease, or a disease like state.

Knockout mice are given something that stops expression of a specific gene which can induce the disease like state.

I've also seen mice getting a kidney removed, which simulates failing kidneys in chronic kidney disease.

To simulate type 1 diabetes, you can treat a mouse with streptozotocin, which kills the islet cells that make insulin.

It can also be as simple as changing diet, to induce obesity and the associated comorbid diseases you can give mice what's know as a fast food diet, which is just their standard chow supplemented with a massive amount of fat.

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rhapsody7099 t1_iw61orn wrote

Originally yes. Not with primates though. When scientists started to realize that mutations in DNA might be responsible for certain diseases they would treat some model organism (often mice as lots of people have said) with different things known to be mutagenic. They would then breed everything that would have some kind of “weirdness” to it, and evaluate the characteristics, then from that look into specifically what was the DNA mutation that caused it. Nowadays there’s so much information and technologies that we can easily say “I want an animal that will develop triple negative breast cancer” and make it (or order it). My understanding is “triple negative” refers to three specific mutations in the genome, so most likely they identified the mutations in humans then replicated it to other systems.

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gingerannie22 t1_iw63lxj wrote

My experience is in cancer research. Our lab does patient derived xenografts (PDX) - basically, we grow the patients' tumors in immunodeficient mice. We can passage the tumor onto subsequent generations of mice as the first animal's tumor burden becomes too large.

Other methods include knockout mice and rats where specific genes are knocked out in an animal (such as TP53, a tumor suppressor gene). Some of the offspring of the animals will also inherit the knocked out gene.

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eg135 t1_iw6mar4 wrote

My company is just running out first mouse trials for a cancer treatment. We are using xenografts. This model involves growing human tumors inside mice. The mice are genetically modified to suppress their immune system, so they won't reject the cancer cells transplanted into them.

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PleasantTumbleweed39 t1_iw3u038 wrote

There's more and more interest in lab grown, tissue or organ-based disease models. Some groups are working at integrating separate tissues into whole systems to mimic disease states.

It's promising and much more scalable but I don't see it replacing animal models in the near future yet.

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questionname t1_iw4xclm wrote

It depends. For a pharmaceutical treatment, they will inject it, adjust dosage for the weight and type of animal, and observe the outcome. If it’s cancer, see how large the tumor is.

If it’s a medical device, a large animal model is used. What animal is very dependent on the part of body you are studying. Cardiovascular tends to be a pig or sheep or dog model. The harder part is giving it a disease, since heart disease tends to develop after decades of life span and poor QoL, so Doctors and researchers try to find a way to restrict blood flow, increase heart rate to induce heart failure, inject chemicals that kills the muscle cells. There’s no perfect way but a lot of money goes into developing a method.

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DrFredCancerRandD t1_iwb7bxb wrote

As a physician-scientist have been involved in preclinical drug discovery and clinical development Phase I-III oncology therapeutics for over 30 years - this is an important question. The field as evolved considerably largely because of deeper understanding of human cancer biology, pharmacology, genomics/gene expression, improved treatments, innovations in medicinal and biological chemistry, and the development of better laboratory testing methods and models. It is clear that the development and use of increasingly correlated and relevant animal models and preclinical testing are essential for advancing new discoveries in cancer therapeutics in immuno-oncology, targeted therapies, cytotoxic therapies, and others (eg., agonists, cytokine modulation, and overcoming drug resistance in various forms).

We don't use or rely on primates for drug discovery very much at all - almost exclusively now only for relevant species (most commonly cynomolgus monkeys; chimpanzees are no longer allowed for many years now) to human PK/PD safety, starting dose/dose-range testing of investigational new drugs in certain settings.

The vast majority of testing and model systems involve patient derived xenografts (PDX) which intrisically have heterogenous tumor cell populations, and human cell-line derived xenograft human tumors (CDX) that are used for in vitro and in vivo testing. Most PDX and CDX testing for antitumor efficacy and PK/PD are conducted in certain strains of immuno-deficient mice, and some cases rodents.

It would be highly impractical to sit, monitor and wait for tumors to spontaneously arise in primates (or in other species) for cancer drug treatment research - one would have to monitor these animals for new tumors all the time (eg., screening, CT/MRI scanning, biomarker testing for months or years) which would take too much time and be very costly to perform. The other problem is that non-human primate tumors, as well as murine/rodent and canine tumors are not genetically and biologically the same as human tumors. So, there is a significant limitation in testing these types of tumors and the results would not transfer well to humans with cancer. The other consideration is that primate studies are very expensive to conduct - so we use them very carefully and on a limited and very focused basis to arrive at safe starting doses, identify the safe dose range, and preliminary PK/PD profile for human studies of investigational cancer therapies.

There are much better methods that have been developed in the last 30+ years for this purpose. The big issue/caveat with any animal testing is that the testing in the lab does not always correlate 1:1 with humans, in fact it's only a highly variable partial correlation in most cases (more than 95% of the time), but in recent years much has been discovered that help to close this gap somewhat further - particularly in the immuno-oncology and targeted therapy fields. There are more sophisticated methods and models that have been developed and are used.

One major factor driving all of this focus on better animal and laboratory models and testing methods in new cancer drug research and development is that survival outcomes for the most common types of cancer has significantly improved in the past 30 years. The cancer death rate for men and women combined fell 32% from its peak incidence in the US in 1991 to 2019. So now, we are working on the harder to treat cancers. Please see Cancer Statistics 2022 from the American Cancer Society and look at the mortality reductions in 1991 to 2019 in the US in the most common cancer types.

Another major factor driving the underlying science and methods for laboratory testing in new cancer drug development is the fact that the evolution of and advances in cancer treatment are very rapid - as well as the understanding of tumor biology is deepening further every day. The lab testing and animal systems we used 5 or 10 years ago would not be capable of identifying new and better drugs today. These areas concommitantly and exponentially have driven the demand for more predictive animal models and testing methods; particularly in the last 8-10 years.

What we do today with relevant animal models and testing systems for generally approaching new cancer drug discovery involves a primary focus on discovering and targeting new biologic/molecular targets that control cancer cell behavior - eg., abnormal proliferation/growth, resistance to drug-mediated apoptosis, resistance to drug treatment (many different types) - especially resistance to immune mediated cell killing, metastatic behavior, reducing cancer drug resistance and driver mutations, etc. At a fundamental level, today we look at gene regulation and expression levels to do all of this, since this information is what gives us a genomic tumor signature to work with as well as a means to prove a new drug modifies, normalizes or kills the abnormal signature cell population. To do this, we start in the lab with human cancer genomic expression information and identify when the correlation between the target's presence in a cancer cell type/disease population is over expressed, and how the target of interest operates mechanistically in terms of regulating the cancer cell population's biology and how it can be targeted in best mode for maximal effect and maximal safety/tolerabiltiy (eg., monoclonal antibody, ADC, small molecule, bispecific antibody, CAR-T, CRISPR/gene editing, other cell therapy, etc.).

The selected mode of therapy (any of the foregoing areas above - antibodies, small molecules, bispecifics, BiTEs, CAR-T, CRISPR, etc. - which govern/control the route and schedule of administration) is tested in the laboratory in vitro and in vivo in relevant (partially or fully humanized) test systems and animal models using human tumor cell lines or human tumors from patients, eg., CDX and PDX models. Some animal models (particularly in mice) involve the use of human "knock-in" (gene insertion) and "knock-out" (eg., target gene or immediate proximity partner gene(s) deletion) to investigate and determine the relevance and precision of a specific target and it's downstream pharmacodynamic effects. CRISPR and CAR-T both involve cellular reprogramming the immune system to recognize and kill tumor cells by either genetic recombination/alteration of the abnormal genome (CRISPR) or by using tumor antigen recognition and T-cell (and in some cases NK reprogramming and stimulation).

These testing methods and systems play an important role in the discovery and development of new innovations in cancer treatment because the older systems would miss the critical newly discovered elements in cancer biology that are oncogenic drivers and/or resistance factors to current treatment. What we can do now in the lab has a huge impact on clinical development to better exploit the science for the benefit of patients.

There are many other factors to consider in the discovery and development of new cancer treatment involving complex biology, chemistry, formulation, drug delivery, safety and tolerability, pharmacology (the sum total time- and dose-dependent behavior of absorbtion, distribution, metabolism and elimination of a drug and its metabolite(s)), optimal dosing, and identifying which patients will benefit the most from such therapy.

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5YOChemist t1_iw3i6x9 wrote

To add to what others have said, there are some rules about it too. So, yes you can make transgenic mice or whatever, you can't give genetic disease to cats and dogs. But, vets can report a mutation and the animal can be bred to maintain the mutation in a new colony. That's where the cat model for ML2 came from. The rules are looser for livestock, so there are some pig models that were made with genetic techniques.

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sleepystaff t1_iw4edcm wrote

There are several research primate centers still around but they are strictly regulated because of the history on animal rights. As for diseases, it depends, if you could not show certain conditions on how to replicate the disease, then obviously you would not be allowed to progress to any sort of animal models until you have proof of concept. I think a good way to read up on this is look into the stages of clinical research and what happens in pre-clinical (basic science research).

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sealettuce23 t1_iw5fk8a wrote

They order them from a company that breeds lab animals without an immune system. I never understood it how it worked. I fixed autoclaves at a university and they had a catalog of research animals to choose from bred specific to what they were researching.

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violette_witch t1_iw3bhma wrote

If you want a mouse to have a certain gene so you can study it, one thing you can do is genetically modify a mouse embryo. Then, when it grows up, it will have the gene that you want.

How does this work? To put it simply, mouse embryo only has like 10 cells (for the sake of this example). You can manually modify 10 cells in like an hour, no problem, and you know you have modified 100% of their cells. Implant your modified embryo into a living lady mouse and she’ll birth it the rest of the way. Now you have the mouse that you want.

You can’t fully modify a fully grown adult mouse. The reason is because they have like 6273829288384828 cells (again, not actual number, for example purposes). It would take a really long time to change all the cells. Even then, can you be sure you changed them all? You see the issue here.

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ziostraccette t1_iw4n34u wrote

They breed rats to be prone to certain tumors and deseases

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