new treatments – BioQuakes

One of the hardest problems in biology is predicting the structure of a protein. Proteins are complicated. There are many interactions between both the side chains and backbones of the proteins, making it very difficult to predict how a protein will fold into its 3D structure solely based on the amino acid sequence (primary structure). In our AP Biology class, we talked extensively about how this 3D (tertiary) structure of the protein is extremely important as it determines the function of the protein. For example, the success of the delta variant of SARS-CoV-2 is largely due to the change in the tertiary structure of it’s spike proteins. Thus, if the 3D structure of a protein is known, it is much easier to predict the function of that protein, and how well it performs the function. However, the methods of determining the tertiary structure of proteins is extremely costly. To determine the structure of a single protein, it can take up to $120,000 and one year.

AlphaFold 2.0 is a breakthrough in this long thought impossible problem. AlphaFold, created by Deepmind, uses deep learning to predict protein’s tertiary structures. In particular, it uses an architecture of transformers, a relatively new and increasingly popular deep learning technique. Using this method AlphaFold is able to achieve remarkably accurate and detailed results, even on an atomic level.

Because of its ability to predict the structure of unknown proteins, AlphaFold can be used to determine how a single nucleotide mutation can affect the structure of a protein. Interestingly, many diseases result from an improperly folded protein, these include: Cystic Fibrosis, Alzheimer’s, and Parkinson’s. While the protein structures themselves do not often lead to the creation of new treatments, they do offer a better understanding of how the protein works. This deeper understanding can then be used to develop new therapies. Thus, AlphaFold has the potential to accelerate new treatments for many untreatable diseases at a much lower cost.

In addition to diseases resulting from misfolded proteins, AlphaFold can be used to predict the effect mutations will have on the folding of the SARS-CoV-2 spike proteins. This can help to quickly determine how a mutation will change the shape (and thus function) of the spike proteins. This makes it much easier to predict how these mutations will affect the spread and severity of the new variants and, using this info, classify the new variants.

However, AlphaFold is not perfect. While most predictions are quite good, a small percentage of the protein structures generated are clearly inaccurate, putting hydrophobic amino acids on the outside of the protein. Knowing this, it is still necessary to analyze any prediction made by the computational model before using it for biological analysis. Nonetheless, AlphaFold is a powerful tool for prediction of protein structure and will revolutionize the field of computational protein structure prediction.

If you want to experiment yourself with AlphaFold, a working notebook can be found here. Any PDB sequence can be queried, and the AlphaFold model will predict the structure to the best of its ability.

Could Messenger RNA Be the Future Chronic Disease Treatment?

By eseffiegus

On January 12, 2019

In Student Post

What is mRNA and what makes it a good treatment option?

Messenger RNA (mRNA) sends signals to the cells to make certain proteins by changing the genetic coding. So mRNA has the potential to treat a variety of diseases because it can induce cells to make therapeutic proteins. This essentially makes the patient’s body cells into a treatment factory which would give patients a less invasive treatment option.

One of the obstacles with this treatment is how to deliver mRNA to the diseased area safely and efficiently. Researchers at MIT have found a new way to provide patients with mRNA. They made an inhalable form of mRNA. The goal would be to administer the mRNA similar to an asthma inhaler where powered mRNA medication would be sprayed into the lungs but as of now, the medication is only available in nebulizer form. However, there needed to be a way to stabilize the mRNA molecules using an aerosol method. So the researchers experimented with positively charged beta-amino esters which are biodegradable and are more easily broken down by the body. The upside to using a biodegradable material is that there would be a minimal accumulation of the substance in the area it was administered. Accumulation would cause unwanted side effects to the patients’ health.

To test out their new product MIT scientists put the mRNA molecule and polymers in spheres. Then suspended those spheres in water droplets and distributed a mist through a nebulizer to mice. But the mRNA molecules that they put into the spheres coded for the production of the bioluminescent protein luciferase. Using the code for the bioluminescent luciferase, the researchers would be able to see if the mRNA had effectively made the protein that it coded for if it glowed.

After 24 hours since administering the medication, the mice were producing bioluminescent proteins in their lungs which hints that eventually scientists could inject the code for therapeutic proteins in the mRNA and the cells would respond. But as the mRNA levels dropped so did the protein production. That showed that only with repeated doses of the medication the mice would be able to continuously produce their own proteins. They also found that mRNA was evenly distributed throughout the five lobes of the lungs so the mRNA reached all the areas of the lungs which would be helpful in treating cystic fibrosis. This process could be the future treatments for chronic lung diseases as researchers work to make this product into inhaler form instead of the nebulizer for convenience purposes.

A Breath of Fresh Air: Epigenetic Studies Help Asthmatics

By nicheloss

On March 10, 2015

In Student Post

Asthma and allergies affect many people worldwide. Up until recently, treatments for both asthma and allergies were administered without an appropriate prediction of responses; However, this is about to change. In a recent study conducted by scientists at Imperial College London, “30 new genes that predispose people to allergies and asthma” were found. The discovery of these genes means that new treatments for allergies are possible and more accurate predictions for current treatment responses will be available.

Photo by Author

By observing the epigenetic changes, ones that influence gene activity- not genetic code, the scientists were able to identify genes which are linked to triggering allergic responses. Such genes regulate specific antibodies. Genes become inactive through methylation: the attachment of methyl molecules to DNA. The scientists studied white blood cells of families with asthma to see if methylation levels in specific genomic locations were associated with levels of an antibody in the blood. Immunoglobin E (IgE) is the antibody studied in the case. The antibody IgE was known prior to this study, but the genes which activities it regulates were not. After monitoring the IgE levels in the blood, researchers saw a strong correlation between IgE and low methylation at 36 places in 34 genes. These genes are overstimulated in asthmatics, thus the production of IgE is increased, contributing to asthma symptoms. In expanding the investigation, researchers came to believe that IgE-involved genes may activate eosinophils, a type of white blood cell which in asthmatics promotes airway inflammation by gathering and releasing chemicals in airways/lungs. Researchers believed that these genes, and their ability to activate eosinophils, then cause the most damage. In order to test this, researchers isolated eosinophils from the blood of subjects and demonstrated that all 34 genes have high activity levels in asthmatics with high IgE levels. Thanks to the findings of new activation signals, patients can avoid high costs and ineffective “treatment-trials” because we’ll be able to predict responses to treatments with more accuracy. Professors Cookson and Moffatt, the leaders of the investigation, give credit to epigenetics for allowing them to make a breakthrough in discovering new potential drug targets for allergies and asthma and sharpening the accuracy of treatment-response predictions. Professor Cookson explained that, “the genetic code that can influence disease and DNA sequencing can only take you so far. Our study shows that modifications on top of the DNA that control how genes are read may be even more important.”

As someone who suffers from allergic asthma, I find it intriguing how the disease-triggering genes aren’t inactive, thus leading to poor lung function, but rather they are overstimulated. Our genes’ ability to regulate disease-triggering antibody activity is amazing. With new studies like this one, we can see that the solution to proper activity regulation is in epigenetic changes, rather than the broad expectations of “our genes”. This just goes to show that epigenetics is helping us make strides in the ever-changing world of medicine. It should be interesting to see how epigenetic medical-solutions, the current gold mine of Biological research, evolve in the near future.

BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: new treatments

Progress Towards Solving a 50-year-old Problem in Biology

Could Messenger RNA Be the Future Chronic Disease Treatment?

A Breath of Fresh Air: Epigenetic Studies Help Asthmatics

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