Why CRISPR May be the Key to Alzheimer’s
There’s no point ignoring it. CRISPR is taking over the biotechnology world and it’s for the better. During the past 20 years in which CRISPR has slowly been gaining popularity, it’s already being experimented with to cure countless diseases. Although there is the whole ethics discussion over CRISPR, we can’t ignore the potential it holds to further medical development. In order to fully understand CRISPR’s potential, you need to first learn how the technology works.
How Does it Work?
In simple words, CRISPR is a gene-editing tool that allows scientists to alter DNA sequences and change the functions of certain genes. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and it comprises of RNA and a Cas protein. The actions of CRISPR are simple.
Cas-9 is an enzyme that scientists can use to cut the DNA at a precise location. But how does it know where to cut the DNA? Well, that’s the job of the guide RNA. Cas-9 carries with it guide RNA, which is a single strand of RNA holding the bases of A, C, G, and U. As the Cas-9 and guide RNA move along the DNA, the guide RNA first looks for the PAM. PAM stands for protospacer adjacent motif and it is a DNA sequence of 3 or more bases. Once it locates the PAM, the guide RNA sequence of about 20 pairs confirms the location. This confirmation means that the Cas-9 nucleus can cut both strands of the DNA 3 to 5 bases upstream of the PAM. Once the DNA is cut, scientists have two options. They can leave the DNA to repair itself and effectively get rid of the DNA sequence that the Cas-9 cut out. They are also able to introduce a strand of DNA to be added to the DNA during the repair process.
However, CRISPR, like any other new technology, still has its flaws. Scientists are constantly trying to find new methods to perform gene-editing in hopes of increasing specificity. If one or two of the bases of the 20 found in the guide RNA differ from the DNA strands, the Cas-9 may still perform the cut. This is a major problem! Off-target cuts with CRISPR can disrupt the function of necessary genes and create harmful mutations. One way scientists are trying to prevent this is by re-engineering the Cas-9 to retain its efficiency while increasing its specificity. Two of these re-engineered Cas-9 proteins take the form of eSpCas9 and HypaCas9.
So now we know the basics of gene-editing is. But why is it such a big deal that every media source has covered it? And the answer to that is simple. It has the potential to cure almost all diseases. To prove this, I want to focus on how CRISPR may be able to cure Alzheimer’s disease, one of the most common yet untreatable diseases for those of old age.
What is Alzheimer’s Disease?
Imagine you are visiting your parents after two years of separation. You are super excited and can’t wait to spend some quality time with the family you grew up with. But as you arrive, you come to the sad realization that your parents can’t even recognize you! That’s the extent to which Alzheimer’s can affect a person’s life!
Alzheimer’s is an age-related disease that causes memory loss. It gets worse over time to the point that you may not be able to hold a normal conversation. Alzheimer’s disease is no joke. It has been declared the 6th leading cause of death in the United States and over 5.7 million people in US suffer from it. In fact, the numbers are increasing as the number of Americans with Alzheimer’s is expected to triple by 2050. Not only is the number of Americans with Alzheimer’s large, but the cost is CRAZY. In 2020, the estimated total for treating Alzheimer’s was $305 billion dollars and this number is only going to grow. And you want to know what the craziest part about it is? We still don’t have cure!
In order to fully understand how gene-editing can cure Alzheimer’s, you first have to understand what causes Alzheimer’s. Although all the causes of Alzheimer’s are not yet known, we have been able to determine the effect of two proteins, APP and tau. The first of the two stands for amyloid precursor protein and it is a protein essential for normal brain development and brain function. Amyloid-beta plaques form from the APP and they are misshapen in the presence of Alzheimer’s. This abnormality in shape can’t be processed by the brain. The build-up of amyloid plaques between neurons is toxic to the brain and results in changes in glucose metabolism and inflammation.
The second of the two proteins, tau, are structural proteins that are found in neurons. The presence of Alzheimer’s changes how these proteins are processed and results in the proteins forming large clumps known as tau tangles. The tau tangles damage the structure of the cells and make it difficult for the neurons to support themselves.
How Gene-Editing Can Cure Alzheimer’s
Since we know that Alzheimer’s is caused partly because of the build-up of amyloids, couldn’t we just limit the production of amyloid-beta with gene-editing? Jogpil Kim and his colleagues with Dongguk University took the first step in this direction in their experiment with mice. The goal of this experiment was to use CRISPR to cut out the BACE 1 gene from the neurons of the brains of the mice. The BACE 1 gene drives the production of the amyloid-beta and removing it should drastically decrease the number of amyloid-beta plaques between neurons, therefore reducing the affects of Alzheimer’s.
However, the experiment was not nearly as easy as it seems. One of the reasons that Alzheimer’s has not been at the forefront of gene-editing discoveries is because of the complexity of the central nervous system and the difficulty of transporting CRISPR into the brain. The largest problem with transporting CRISPR to the brain is the blood–brain barrier, otherwise known as the BBB. The BBB helps isolate and protect the neural tissues and therefore controls the transfer of molecules, restricting the transportation of CRISPR. However, by combining neuroscience and biotechnology, Jogpil Kim was able to deliver CRISPR to the brain via non-viral vectors by creating nano complexes. These nano complexes are comprised of a negatively charged nucleic acid cargo (CRISPR) and positively charged peptides. However, even with nano complexes, the CRISPR cannot easily pass through the BBB so multiple injections are required to properly distribute the nano complexes across the brain.
The results of the experiment were encouraging as the number of amyloid-beta plaques surrounding the neurons decreased dramatically, resulting in more cognitive function. The experiment also showed signs of minimal side effects due to no signs of increasing mutations in non-targeted parts of the genome.
So What Does This Mean?
Although this experiment brings hope towards finding a cure for Alzheimer’s, scientists are still a long way out. Due to the complexity of the brain and the youth of CRISPR technology, scientists still need to make strides towards more specific gene-editing technology to prevent off-target cuts in the brain. The method used by Jogpil is also risky due to being highly invasive and risks of infections.
The use for CRISPR extends far beyond Alzheimer’s and even curing diseases as it has the potential to change pretty much anything about a person. As a community, it is up to us to decide the limits we should put on the technology. But who knows, maybe in forty years the babies are all genetically modified super babies. No matter what happens, CRISPR has opened up a whole world of possibilities that 100 years ago was no less a mystery to us than the existence of aliens.
