Though it might be surprising to hear a scientist say this, it’s important to know that science is an imperfect art. As researchers pick apart questions about the universe and mankind, it’s not that uncommon for disagreements to arise between different scientists about their favorite theories and the validity of results. Sometimes this is because there isn’t enough information available yet to confirm or refute particular ideas – but sometimes this arises because of concerns regarding the techniques and methods used by particular scientists when conducting their research. These arguments are especially important in biomedical research, because the outcomes of scientific studies often directly influence medical treatments. A paper recently published by a large group of scientists in Nature, a prominent scientific journal, emphasizes how serious the impact of these disagreements can be.

Back in 2012, scientists at the University of Virginia were investigating the underlying causes of a disease known as Rett Syndrome. Rett Syndrome, or RTT, is a genetic disorder caused by a mutation in a particular gene, known as MeCP2, resulting in a total lack of MeCP2 protein in the cell.

Because the MeCP2 gene is found on the X chromosome, it affects males and females differently. Males only have one X chromosome, and so one mutant copy of the MeCP2 gene. They are severely affected and usually die within two years of birth. With two copies of the X chromosome, females can have one good copy and one mutant copy of the MeCP2 gene, and are less intensely affected. Instead of early death, females tend to develop seizures, stomach problems, breathing irregularities, limited mobility, and symptoms of severe autism spectrum disorder (ASD), usually with little to no language ability. As a result, parents of children who suffer from RTT are often desperate for any treatment they can access.

Scientists have determined that the lack of MeCP2 protein leads to changes in the connectivity of the brain. Neurons, the cells in the brain that do all of the communicating, have to wire together properly to coordinate signaling for us to walk, talk, and think about the world around us. In RTT, patients have problems with that wiring; their neurons can’t make the proper connections to start with, so the signaling can’t be correctly coordinated. It takes a lot of coordination for those connections to be made in the first place, requiring not only input from the neurons themselves, but also from other cells in the brain. These other brain cells, collectively called “glia”, include subtypes such as astrocytes, oligodendrocytes, and microglia. These cells provide support, nutrition, and protection to your neurons, keeping them functioning and signaling properly, in addition to providing guidance to neurons as they form their connections during development. Dysfunction in these cells can lead to problems for the neurons themselves.

In 2012, a very exciting study by Derecki et. al. was published, showing that a brain cell type called microglia played a role in the improper wiring seen in Rett Syndrome. Microglia are essentially the brain’s immune cells; they help clean up debris and protect against inflammation in the brain. In this study, scientists wanted to know what would happen if they replaced the diseased microglia in a mouse with Rett Syndrome with healthy microglia. To do this, they used two kinds of mice: a mutant mouse that didn’t have the MeCP2 gene, making it a model for Rett Syndrome, and a wild-type mouse that had the normal MeCP2 gene as a healthy control. To replace the microglia, scientists exposed mutant mice to radiation to kill their existing microglia (just like radiation is used to prepare a person’s body for a bone marrow transplant). Then, they took bone marrow from the wild-type mice and injected it into the irradiated mutant mice. Just like a bone marrow transplant in a sick human can help repair their immune system, the bone marrow transplant in the mutant mice resulted in these mice developing new immune cells, including new, healthy microglia.

These mice showed a huge improvement as compared to the mutant mice who didn’t receive healthy bone marrow; the males survived longer than normal, had more normal weights, and showed less severe symptoms of the disease.

Scientists and doctors alike were thrilled to see this. Diseased neurons can’t be replaced to correct the problems with their connections, but radiation and bone marrow transplants could allow doctors to replace the diseased microglia, providing a promising route for treatment. Because RTT is such a severe and debilitating disorder, this study resulted in clinical trials for bone marrow transplants in affected children within just a couple of years. But, it’s important to realize something: bone marrow transplants are super risky! There’s a reason that bone marrow transplants are such a serious procedure and reserved for patients with potentially terminal illnesses. The radiation destroys a person’s immune system; they are left with no protections against bacteria or viruses, so they can be strongly affected by normally minor illnesses. The recovery process after the transplant is long and difficult, and it doesn’t always work – sometimes the sick person’s body rejects the transplant because it’s not compatible with their body, which leads to serious medical problems.

A group of scientists who study RTT became concerned about how quickly doctors began to test the bone marrow transplants in children, and decided that they should do the same experiment to see if they could get the same results. That paper, titled “Wild-type microglia does not arrest pathology in a mouse model of Rett syndrome”, by Wang et. al., was published a couple of months ago in Nature, and directly disagrees with the results of the paper from 2012. Using the same genetic model of RTT, these scientists replaced the mutant bone marrow with wild-type healthy bone marrow, but did not find that it improved the lifespan or symptoms of the male mice.

This was true even when they tried using two other mouse models of Rett Syndrome – none of them showed the improvements that the scientists had seen in 2012. They were not convinced that healthy microglia were enough to save the mutant mice, and to test this, they used genetic tools to create a mouse that did not have any MeCP2 protein anywhere except in the microglia. Essentially, this test does the same thing as giving mutant mice healthy bone marrow, but the mice are born with healthy microglia instead of needing the transplant. Even when the mice always had healthy microglia, the scientists didn’t see a significant improvement in lifespan or the symptoms of the disease. This lead Wang et. al. to conclude that bone marrow transplants are not supported as a treatment for RTT.

So does this disagreement mean that bone marrow transplants don’t work for Rett Syndrome? Not necessarily. Derecki et. al. reviewed the data that Wang et. al. published in their paper, and they believe the results actually do support their original conclusions. Small differences in the genetic backgrounds of mice can affect the results of an experiment dramatically; Derecki et. al. noticed that there were differences in the survival rates and weights of the mutant mice even before the bone marrow transplant, which could explain why they did not see an improvement afterward. And, when you look more closely at the data, there actually was a slight improvement in the symptoms of the mutant mice in the new study.

These conflicting results highlight something important about scientific research: scientists don’t always agree, and different results don’t always mean that someone did the study wrong. A great deal of what we take away from science depends on how the experiments are designed and how we interpret the results. The clinical trials for bone marrow transplants have been canceled since the release of the new study. Studies in animal models are important and helpful for developing new treatments and medications for human patients, but the science doesn’t always translate perfectly. It will take more research to determine if bone marrow transplants are a viable treatment for children with Rett Syndrome, after all.

Citations:

C. Derecki et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012) doi:10.1038/nature10907

Wang, J. et. al. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521, E1–E4 (21 May 2015) doi:10.1038/nature14444