Beyond direct improvements to plants, insects, and animals, including humans, that genetic modification technologies have brought to the world, these techniques have also served as crucial tools for modeling other conditions and creating a better understanding of how to not only improve the overall health of living organisms, but also how to combat a myriad of gene-based disorders. Particularly those that revolve around a single gene mutation or enzyme production insufficiency, as correction of these issues is much more straightforward than complicated regulatory type conditions. Since the scientific community has seen a lot of success in modeling these alterations and have started to bring them into active practice in humans and other species, focus in research has now turned to the next level of difficulty in disease modeling: haploinsufficiency disorders.

Dealing With Insufficiency

The term haploinsufficiency refers to organisms such as mammals that have diploid chromosomes, where there are two inherited copies of a gene, and one copy of that gene has overall mutated to no longer be able to produce enough of a needed protein. The second copy becomes the dominant producing copy of the gene and its counterpart works at a much lower capacity. This then results in developmental and health conditions when the dominant copy is mutated or otherwise knocked out or deleted and then the remaining insufficient copy has the aforementioned issue that prevents it from taking over the functions of its once dominant counterpart. Or is generally not able to produce enough to account for the needed amounts of protein product for that gene. 

Marfan syndrome is one such haploinsufficient disorder that results in irregular body development that causes a number of heart and other organ conditions due to excessive limb and connective tissue growth. This comes about as a result of a damaging loss of function mutation to the FBN1 gene responsible for making the protein fibrillin that is needed for connective tissue formation, A gene mutation that reduces the total amount of fibrillin produced harms the integrity of the connective tissues and thereby creates deformities in the parts of the body that rely on connective tissue for holding them together and controlling how they develop, including the cardiovascular and skeletal systems. 

While there have been some medical advancements over the decades in being able to treat this inheritable disorder from a young age, the mortality rate is still incredibly high and not enough is known about how all of the body’s systems are affected by the loss in sufficient fibrillin. Particularly because how the disorder progresses can vary between individuals and even has been found to have certain phenotypes be carried through specific familial lines of inheritance. So in what ways the disorder is expressed and how strongly in different body tissues is critical for developing treatments and even a possible cure in the future. 

Originally, research on conditions like Marfan syndrome were done using mouse models and they have certainly been helpful for determining general characteristics and impacts from such diseases. But, over time, we’ve found that mice are not the greatest representation or analogue to human outcomes from disease, since their body systems are different enough that a phenotype in mice might not have any correlation to how it appears in humans. Pigs meanwhile have emerged as much better replications of how diseases progress in humans and we’ve even seen a number of organ transplants from pigs to humans with varying degrees of successful outcomes. With recent revelations on the inadequacy of mouse models in certain fields of research, the question remains open on what the best progression options are for scientific disease research and there are still pros and cons to that question even with the downsides that are now known about mice models. 

Finding Pros and Cons

A research team at Meiji University in Japan have decided to tackle this open-ended question and consider it in light of genetic engineering improvements over the past decade and what our current capabilities bring to the table for future animal models of disease. In the past, there were several strains of mouse models made with different loss of function mutations in the FBN1 gene and the physiological outcomes were found to be directly comparable to humans experiencing the same exact mutations. However, the research team found when replicating and working with these mice that the results were not consistent, with there being differing developmental impacts even within the same strain of mouse, though this did help represent the variability found in humans experiencing Marfan syndrome. The penetrance amount or just how severe the effects were of the mutations changed depending on the genetic backgrounds of the mice in question.

The same mutations were introduced into pig embryos and featured the same sort of developmental impacts after negatively affecting the production capabilities of the FBN1 gene. Their mixed breeding were able to create pig models that showcased late onset effects of Marfan syndrome in over 80% of the pigs born from their breeding crosses, having a longer pre-symptomatic period before the onset of the disorder. Being able to ensure the onset of the symptoms consistently is a challenge for scientific testing purposes, but it does allow more study of how variable production amounts of fibrillin relate to when the actual effects start appearing. This will require further research in order to have stricter control over DNA methylation, as it is the activation timing of genes that decides a large part of when symptoms occur.

As the scientists were merely presenting their findings on mouse vs pig models, they did not make a definitive statement on using one model or the other, as that will still depend on what exactly is being studied. They did, however, note that the penetrance variation in mice models will continually have an issue with massive variation in outcomes when using them for clinical trials. This isn’t the case with pigs, but there are still improvements in genetic manipulation techniques that need to be made in order to have more consistent outcomes for modeling diseases involving haploinsufficiency. For now, the pig models don’t have a high enough rate of disease presentation for generalized testing. The researchers suggest that while RNA interference and microRNA usage may be an option, there still needs to be more optimization done in the future. 

Still Far From The Goal

So, that’s where we stand for now. It seems clear that pig models are superior for investigating diseases and disorders like Marfan syndrome as compared to mouse models, since they have more consistent developmental symptom presentation without the high background variation of mice. But, at the same time, pig models are not advanced enough as of yet to be able to be used in such studies without a significant loss of successful expression of the disorders in the sample population. As is so often the case in science, we’ve got a lot more work to get done.

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