What would the technical problems be of mass genetic editing? Keidran Animal-Human Hybrids

Question

The Setting

I hear you, I'll make this brief. It's been almost 30 years since the Aurea slow cargo ship arrived at Ilus. When they launched the Aurea, almost a century ago, they had the technology to send starships on decade-long missions with hundreds of tonnes of antimatter, and peta-watt lasers. But the vile autocracy that built it all is falling apart... and their tech is stagnating, and as a result, private industry is starting to pick up speed.

In comes the Sequoia Research and Development Alliance, who, with some corporate partners, have built a secret lab on the moon of a gas giant in the Ilus system, for the autocracy. The point is that they have absolutely no ethics and are willing to do anything, regardless of morality and with basically no oversight. Their goal is to create Keidran, a hypothetical soldier for peacekeeping operations in the Terran system. (basically expendable riot control personnel)

This is the level of technology they'd have, and I want to know the problems I need to solve in regards to animal-human chimeric organisms. I'll start here.

The Question

With regard to making this possible, what would the complications I would need to address in order to maintain believability levels above Jurassic park, which is the only example I can think of where the genetic aspect of creating organisms isn't just outright ignored. (cough cough* Im glaring at you, proto-molecule)

Firstly, it's safe to assume that if we are trying to make chimeric organisms, we will need truly epic amounts of computing power, something I know needs to be addressed. If my understand of genetics is correct, simulating proteins and genetic sequencing is something comparable to training an artificial intelligence, a neural net. Think Tesla's Dojo supercomputer.

Secondly, delivery of the replacement code. If we are drastically modifying humans here, then we are dealing with large amounts of raw genetic material that will be replaced, though noting the fact that we share in the vicinity of 85 to 90% of the same DNA with most other mammals.

From my basic understanding of Crispr and Cas-9, we can use Holology-directed repair to cut pieces of the Genome out and splice in its replacement, but at what point is the piece of genetic material too big to be spliced in a single action. It's a concern I will look at in the appropriate stack.

And lastly would be supportive care during and after treatment. Currently I haven't actually taken a good look at the believability of keidran (human-animal chimeras), but the main concern would be waste management and keeping the body from killing itself.

Apart from the immune system making a small fuss over being drastically altered, there would be a massive uptake in electrolytes, vitamins, basic materials for cell repair, and an influx of toxins that would probably cause kidney failure if they're not connected to a futuristic dialysis machine for the entire procedure.

Getting To The Point

What other concerns should I be aware of when trying to create such a radical genetic treatment. The how I fix it is not important, just what are the problems I need to fix.

The point is wether I should apply some phase-gate handwavium or actually explain real genetics in my book.

End Note

There, Miss Tortliena, I speficially remember you asking for the end of this, so here. (Credit to TwoKinds Author Tom Fischbach... if I said that right...)

Answer 1

Just a few pointers as the process would vary in it's nitty-gritty by species/individual and should be investigated for unique issues every-time.

Gene-splicing must be coordinated with the whole organism's transformation down to a molecular level.

I think of it a little like an enormous and complex piece of machinery which must be kept running, all the while rearranging the parts without breaking any of its functions. Like a huge 3D jigsaw of a building which must be re-arranged block-by-block without the occupants dying or the building falling down.

Auto-immune conditions (fatal) during transition.

Tissue compatibility (histocompatibility) issues will lead to the various aspects of the immune system attacking the new cell-types/proteins appearing within the body. This is tough on the host as it eats-up resources fighting the new tissues and surface-proteins of the transforming cells rather than growing. What might help would be the generation of histocompatible animals to splice with.

It's part of the process.

The structural transformations necessary to re-shape the animal require old tissues to be broken-down, removed and replaced - down to the level of cell-membrane proteins and cell and nucleus components. This would need to be done in very specific sequences.

External support would need to be supplied to compensate for failing function. Dialysis is a tiny but important aspect of the whole. The liver and bone-marrow would be working in overdrive to make new cell-types - all the while their own cell-types would be being replaced.

Infection:

At any point in the transition there would be the conspicuous absence of a functioning immune-system. Bacteria, viruses and protists would see this as a free-for-all all-you-can-eat buffet in a life-pod.

You can't exclude them, the body caries them at all times. Pumping the subject full of antibiotics won't help - they function in consort with the immune system, insufficient on their own.

Waste-management, nourishment and homeostasis.

Every single biochemical signal would need to be listened to to check for signs of infectious agent - this would be a continuous ongoing process requiring compensation with artificial immunogens and a means of extracting them once they've bound to invading cells.

The same goes for waste-protein bits and pieces left-over from biochemical processes. They'd need to be cleared to avoid toxicity (and clutter).

Homeostasis may seem like an odd word as it's a ridiculously dynamic process with the need for particular proteins/peptides/minerals/oxygen to be carried to individual cells at particular times.

I'd suggest accomplishing this with the assistance of some kind of Nano-tech machinery, little robot chemical messengers who are able to be the courier-service and mechanics of the system. They'd be busy making deliveries of specific nutrients to their targets, knitting together new tissues and breaking down old - both mechanically and with an enzymatic toolkit. They'd also gobble-up the excess tissues from one place, process them to manufacture the requisite needed in another.

It seems to me that you'd need not just the Nano-tech but a whole series of different micro-bots of different sizes and with different functions. A Nano-sized robot will have a great-deal of difficulty swimming any distance inside the body as viscosity dominates at that scale. So - microscopic ones to swim and carry the little ones where they're needed, then collect and re-deploy as appropriate.

Heat.

The body is running a marathon to transform. This is all enormously energy-expensive, it will generate heat, lots of heat. To prevent tissue (and brain) damage via proteins inc. hormones, enzymes and the cell components themselves from de-naturing and getting toxic, a matrix of temperature-regulating tubes should be infiltrated through all affected tissues, connected to a sophisticated "air-conditioning", keeping the heat down to within manageable limits. (Think Wolverine's transformation or even M.A.C.H. 1's recharging cycle for an image of the invasive machinery.)

Coordination for the splicing - biofeedback.

The whole process pointed at above would need to be micro-managed and coordinated on the genetic, cellular and tissue levels. This goes down to the level of sequences of editing for coding individual proteins. There will be thousands (hundreds of thousands?) of those. They will need to be performed according to what the body needs. The Nano-bots would continuously relay detailed reports of osmotic-gradients, protein concentrations, temperature, oxygen, CO₂ etc. to the supercomputer, these would in turn coordinate the genetic transformation.

There may be intermediate steps of development of the transformation - this is true structurally and at every other level. I wouldn't count on a straight-line from human to hybrid, but think rather of the multiple transformations undergone in the womb by an early foetus. From egg to ball-of-cells, to tube, to tube with rudimentary internal structure of cell-types and so-on. Even gill-structures at one point and a tail. This will require not just the new genes, but switching them on and off at specific stages. Don't let any of the lab geeks play Doom whilst they're waiting, the computer needs all it's capacity.

The brain.

One danger seems to be that memory-integrity is delicate, it's both structural and relies on concentration of messenger neurotransmitters which varies over time. Long-term memory may be able to be preserved, but the procedure may precipitate a form of biochemical trauma resulting in loss of recent memories. An acclimatisation process after the transform would be necessary.

Answer 2

Here are the problems that stand out immediately:

1. DNA delivery

The first issue with making animal/human hybrids out of humans would be to deliver the DNA to every cell in the body. It is estimated that the human body has somewhere around 30 trillion cells. Thus, the first problem would be to somehow deliver the modified DNA into such a great number of cells. Let us assume for the sake of argument that you have a virus that contains the entirety of the DNA that needs to be introduced into the target cell, along with the DNA coding for the enzymes needed to introduce it into the cell, and that this does not produce any adverse effects. Even then, it would take an extremely long time to actually infect all of the cells (Or an acceptable amount thereof). For instance, the time it takes for an infection with HIV to progress to AIDS is stated to be around a decade, and there are much less cells involved in this. If your objective is to only modify certain characteristics (Such as increasing muscle mass by disabling myostatin production), you might get away with infecting only certain cells and accepting the issues involved. If your organization is not content with waiting over a decade for enough of the host's cells to be infected by the virus after an injection, you could have part of the transformation process involve the 𝚟̶𝚒̶𝚌̶𝚝̶𝚒̶𝚖̶ patient being hooked up to an IV drip of fluid that contains countless virions.

2. DNA Delivery Part Two

Presumably, the means of delivering the modified DNA that is to be introduced into the host, along with DNA coding for the enzymes to do so, would be done by a virus. Assuming that you do intend to modify the human body completely, you would need a virus that is capable of infecting all types of cells (or several viruses, each capable of infecting a particular cell type but all of them still modifying the same genes in the same way, but, in both cases, there is still the issue of immune response). The first thing that is necessary for a virus to enter a host cell is for a receptor on the surface of the virus particle to bind to a receptor on the host cell. Thus, in order to use a virus to deliver the modified DNA, you must either have a virus that can bind a receptor that is found on every type of cell (I don't think such a receptor protein even exists, but I could be and probably am wrong), or use several different viruses, each capable of binding a receptor found on a particular cell type.

3. Viral interference with bodily functions

Another issue that is likely to arise with the use of viruses for DNA modification is the interference of the virions themselves with things in the body that REALLY shouldn't be interfered with. As an example, the spike protein on SARS-CoV-2 has been found to bind to fibrinogen and induce blood clots. If, for instance, the life cycle of the virus used to enact the genetic modification disrupts cell function, or the proteins on the surface of the virus are capable of acting on cell signaling pathways, there is a good chance that the host is going to die.

4. Immune Response

As you are aware, drastically modifying host cells is going to trigger an immune response. One such means of doing that is that MHC molecules on the surface of a cell display fragments of proteins that are produced and degraded by the cell to immune cells. If the antigens on display are something that is not recognized by the immune cells as part of the body, the immune system will attack. Unfortunately, some of the protein fragments that are going to be on display would be parts of viral proteins and will get recognized as foreign. However, this may actually be a solvable problem. There are some studies that investigate transplanting umbilical cord blood stem cells instead of bone marrow cells, since UCB cells are not yet "trained" to recognize which antigens are supposed to be present and which are not, as a means of preventing graft-versus host disease. So, the use of either gene therapy or transplantation of the appropriate cells might be used to solve this issue in the host.

5. Physical Development

This is probably the biggest issue with transforming someone into a human/animal hybrid. For instance, replacing the DNA of a human with that of a dog will not result in that person turning into a dog, even if you could magically keep that person from dying. A lot of things, such as bone structure, are determined during embryonic development. Chemicals known as morphogens are produced by embryonic cells and diffuse throughout the tissues of the developing fetus. The concentrations of these chemicals regulate gene expression and cell differentiation in the embryonic cells, which in turn determines things such as body plan and how the organs are arranged. As a sidenote, this is thought to be why accutane causes birth defects: The accutane molecule resembles one of the morphogens enough to act as a morphogen and disrupt fetal development. Furthermore, post-embryonic development must also be properly regulated. For example, bone growth takes place at a plate of cartilage at the end of a person's bone called a growth plate. To put it simply, some cartilage at the end of a bone gets turned into more bone, but the cartilage cells also divide to produce more cartilage cells. During puberty, the rate at which cartilage is replaced by bone at the growth plates is greater than the rate at which new cartilage is produced, and eventually all the the cartilage is replaced by bone, which is why people stop growing.

Your method of producing animal/human hybrids will have to somehow regulate the development of the new body plan from the human one (For instance, changing the shape of the skull, other bones, muscles, and various organs). If the physical development also involves temporary structures, you must also figure out how to introduce these structures to the host's body and remove them when necessary. I've roughly explained how it's done starting with an embryo. You would have to recreate that sort of biochemical signalling not only to break down the old body plan, but to generate the new one correctly. Development starting with a zygote has the advantage of not having to work with a developed body plan and having plenty of stem cells to turn into cells that are needed. Transforming a full-grown human is going to be much more complicated.

If you want your hybrid to be capable of reproduction, the modified genome would also have to be able to govern embryonic development correctly. I have no idea how these goals could possibly be achieved. Furthermore, the transformation process has to be survivable. If, as an example, the transformation gradually compresses the braincase, the patient is going to have a very bad time. Nevertheless, if you insist of transforming a full-grown human, the process would be very hands-on, probably with copious surgical intervention and other treatments. In that case, one has to question whether the cost of time, money, and RnD is really worth it to produce an expendable soldier and what advantages this would offer over alternatives.

6. Gene Expression

The process must ensure not only that the DNA of the host is modified, but that the correct cells express only the correct genes. For instance, you do not want a retinal cell to express genes for the production of insulin. Your method of genetic engineering would have to be capable of properly regulating gene expression in the host. Furthermore, you will likely need a means to disable certain genes at a certain point in time after the modification process.

7. Alternative Splicing

It is possible for one gene to code for multiple proteins. The RNA produced during transcription of a given gene can be spliced in different ways before translation, leading to different proteins with different functions. The overwhelming majority of human genes are thought to give rise to RNA that undergoes alternative splicing. Your process of genetic modification would have to address this if modifying genes which give rise to RNA that undergoes alternative splicing.

In closing:

Other issues with the idea of genetically editing someone to produce human/animal hybrids have been discussed by the other answer, and some you are already aware of. My conclusion is that, as proposed, this is extremely implausible.

However, if your organization has access to the enormous computing power required to design the genome for an animal/human hybrid and simulate its development to ensure that all goes according to plan, you can have the organization create a zygote and grow the hybrid in an artificial womb (Seeing that the technology is being explored today, this is more plausible), as an example. This would mean that you do not have to worry about problems associated with transforming a full-grown human. You can either have the hybrid indoctrinated into serving whatever purpose the organization has for them, or transplant the brain of a willing subject into the hybrid body (And do whatever you want with the hybrid's original brain, you did say your organization has no ethics and no oversight). This path does present its own problems, though, namely that the organization would have to take care of the hybrid somehow until it matures (Or use accelerated aging handwavium) and the problems associated with transplanting a brain, plus the fact that the supply of hybrid would be limited (So, they wouldn't exactly be expendable).

Answer 3

Real chimeras start at the blastocyst stage.

Why would anyone in the real world want a human animal chimera? How about to grow human organs in animal hosts. Then if you are ok with killing animals you could ethically harvest the human organs.

Generation of human organs in pigs via interspecies blastocyst complementation

Much back reading above. In short the way this works

1: Make transgenic animals that do not generate certain organs. Examples given include pancreas and kidney. These are usually lethal alterations.

2: Mix human embryonic stem cells in with transgenic animal blastocyst at early stage (= blastocyst!)

3. Human stem cells can fill the empty niches (for example, for a pancreas) that the transgenic animals cannot fill. All the support structures etc to grow a pancreas are present in the animal fetus. The transgenic animal grows a human organ. The functional human organ can rescue the animal to viability.

Issues 1: need to know genetic modifications that specifically prevent desired organs from arising, so you can hack host and make room for chimeric organs.

2. Need to have a cellular setup similar enough between animal and human that human stem cells understand what organ they are supposed to make (e.g. pancreas) in a given environment in the fetus.

If circumstance 2 is met then animal and human are likely evolutionarily close enough that rejection not an issue - the host will have tolerance to the human cells having coexisted from an early stage.

This approach could also be used with genetically modified cells introduced, with the intention that they do a specific job or correct some deficiency present in the host. A host organism which had a genetic blood disorder could be made chimeric (here in the sense of cells with 2 different genetic lineages fused, not necessarily 2 different species) with stem cells having normal genes at that locus. The idea that the subpopulation of chimeric cells could rescue the deficient phenotype. This is nice in that if your engineered stem cells happen to turn into cancer you will lose the embryo very early, not after it is born.