AP Biology class blog for discussing current research in Biology

Author: chrisynthesis

Redesigned Cas9 protein provides safer gene editing than ever before!

Gene editing is a group of technologies that give scientists the ability to change an organism’s DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A recent one is known as CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.

One of the challenges that come using CRISPR-based gene editing within humans is that the molecular machinery may sometimes make edits to the wrong section of a host’s genome. This is problematic because it creates the possibility that an attempt to repair a genetic mutation in one location in the genome could accidentally create a dangerous new mutation in another spot. Scientists at The University of Texas at Austin have redesigned a key component of a widely used CRISPR-based gene-editing tool, called Cas9, to be thousands of times less likely to target the wrong stretch of DNA while remaining just as efficient as the original version, making it potentially much safer.

The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short ‘guide’ sequence that binds to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes can also be used. Once the DNA is cut, researchers use the cell’s own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.

Other labs have redesigned Cas9 to reduce off-target interactions, but so far, all these versions improve accuracy by sacrificing speed. SuperFi-Cas9, as this new version has been named, is 4,000 times less likely to cut off-target sites but just as fast as naturally occurring Cas9. Scientists say you can think of the different lab-generated versions of Cas9 as different models of self-driving cars. Most models are really safe, but they have a top speed of 10 miles per hour.

In my opinion, setting aside any and all ethical concerns, genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.

New research further advances the understanding of DNA repair

In a study recently published in Nature Cell Biology, there’s been a discovery that alters our understanding of how the body’s DNA repair process works and may lead to new chemotherapy treatments for cancer and other disorders. Because DNA is the repository of genetic information in each living cell, its integrity and stability are essential to life. DNA, however, is not inert. Rather, it is a chemical entity subject to abuse from the environment and any resulting damage, if not repaired, will lead to mutation and possibly disease.

The fact that DNA can be repaired after it has been damaged is one of the great mysteries of medical science, but pathways involved in the repair process vary during different stages of the cell life cycle. In one of the repair pathways known as base excision repair (BER), the damaged material is removed, and a combination of proteins and enzymes work together to create DNA to fill in and then seal the gaps. In addition to genetic insults caused by the environment, the very process of DNA replication during cell division is prone to error. The rate at which DNA polymerase adds incorrect nucleotides during DNA replication is a major factor in determining the spontaneous mutation rate in an organism.

Researchers discovered that BER has a built-in mechanism to increase its effectiveness, it just needs to be captured at a very precise point in the cell life cycle. In BER, an enzyme called polymerase beta (PolyB) fulfills two functions: It creates DNA, and it initiates a reaction to clean up the leftover chemical waste. Through five years of study, scientists learned that by capturing PolyB when it is naturally cross-linked with DNA, the enzyme will create new genetic material at a speed 17 times faster than when the two are not cross-linked. This suggests that the two functions of PolyB are interlocked, not independent, during BER.

Cancer cells replicate at high speed, and their DNA endures a lot of damage. When a doctor uses certain drugs to attack cancer cells’ DNA, the cancer cells must cope with additional DNA damage. If the cancer cells cannot rapidly fix DNA damage, they will die. Otherwise, the cancer cells survive, and drug resistance appears. This research examined naturally cross-linked PolyB and DNA, unlike previous research that mimicked the process. Prior to this study, researchers had identified the enzymes involved in BER but didn’t fully understand how they work together. This research improves the understanding of cellular genomic stability, drug efficacy, and resistance associated with chemotherapy, which, as previously stated, can lead to new chemotherapy treatments for cancer and other disorders.

Scientists can now ‘supercharge’ cancer-fighting T Cells

Scientists at Yale University have identified a way to “supercharge” tumor-attacking T Cells, a finding that may not only improve the effectiveness of a promising type of cell-based cancer immunotherapy, but also expand the number of cancers it can treat. Most people are familiar with cancer treatments such as surgery, radiation, and chemotherapy. But, a newer option called immunotherapy, is getting well-deserved recognition across the cancer community. These drugs teach the immune system how to recognize and kill cancer cells, equipping it to hone in on diseased cells while leaving healthy cells alone.

First, blood is drawn from the patient and sent to a lab. At the lab, the T cells are separated from the blood and ‘supercharged’ with a gene that generates chimeric antigen receptors (CAR), which allow the T cells to bind to cancer cells and destroy them. Hundreds of millions of these T cells are synthesized in the laboratory to create a personalized, well-armed immune defense. Finally, the patient’s newly modified T cells are returned to the clinic and reinfused into the patient, seeking and destroying cancer cells in the patient’s bloodstream. The discovery can advance CAR-T cell therapy, which harnesses the immune response of T cells to cancers by introducing tumor-detecting molecules into the cells. In the last decade, the U.S. Food and Drug Administration has approved six CAR-T cell therapies to treat B cell lymphomas and multiple myeloma. But despite early successes, the effectiveness of the treatment tends to diminish over time, which has launched a search for ways to boost function of T cells.

Researchers have devised an ingenious way to efficiently scan the genome of CD8 T cells for specific genes that might enhance the cells’ ability to attack cancer cells. They developed a new kind of genome-wide gain of function screen to find a molecular enzyme that acts like a foot on a gas pedal to increase metabolic activity in T cells.

They found high levels of activity in several genes, including PRODH2, a gene involved in cell metabolism, stimulate increased CAR-T cell activity in mouse models used to study three different types of cancers, including solid-tumor breast cancer. The findings show it is possible to produce hyper-metabolic CAR-T cells that outperform existing cell therapies. Using these systems and findings, I believe future studies can test the newly identified types of metabolically enhanced CAR-Ts in clinical settings, to identify other T cell super-chargers, and to extend cell-based immunotherapy to different cancer types, especially solid tumors.

New research exposes and demonstrates how damaged cells survive the cell cycle

In recent news, the Center for Cancer Research have recently discovered a previously unknown phenomenon, which allows certain cells to continue through the cell cycle despite experiencing DNA damage. This also includes past natural safety checkpoints within the cell cycle that are designed to stop the problem from occurring. On January 13, 2021 researchers, in Science Advances, suggested that the timing of DNA damage was crucial for determining whether a faulty cell would survive the cycle.

When cells begin to divide and replicate as part of their natural cycle, they transition from their resting state to one called the G1 phase. In this phase, cells have several important checkpoint mechanisms to ensure that the cell is healthy enough to proceed onto the next stage of the cell cycle. If/when these mechanisms fail due to genetic mutations, cells can progress through the G1 phase unobstructed, which can ultimately lead to cancer.

It was previously believed that cells with DNA damage could not pass through these safety checkpoints in the G1 phase and that the cells would either repair the DNA damage or die. However, scientists helped uncover evidence proving that cells with damaged DNA can actually progress past these critical checkpoints. A team of scientists studied individual cells for days at a time, using live cell time-lapse microscopy, single-cell tracking software, and fluorescent biosensors to detect the cell’s safety checkpoint mechanisms. They added a substance to induce DNA damage for cells of different ages in the cell cycle. Strikingly, the majority of cells seemed to ignore the DNA damage because they failed to trigger the checkpoint between G1 and the next phase, and proceeded into the next phase anyway.

Further investigation revealed that the timing of DNA damage during the cell cycle influenced the likelihood that damaged cells would slip past the checkpoints. The researchers found that the cell’s response to DNA damage is relatively slow compared to the speed of the cell cycle. This means if cells were already very close to the next phase of the cell cycle at the time DNA damage happened, they were more likely to continue into that phase. If the cells were still early in the G1 phase, they were more likely to revert back to a resting state. These observations are a form of inertia, where the cell will continue moving towards the next phase regardless of safety checkpoint signals.

It was also discovered that cells which were genetically identical were more likely to share the same cell cycle fate than non-identical cells. This suggests that factors specific to the cells themselves influence their fate during the cycle, rather than random chance. More studies are needed to understand how these findings apply to cancer. Testing is also extremely important in order to fully understand what the long-term consequences of the checkpoint failures are and find out if the cells that entered the next phase despite considerable DNA damage can become cancerous and eventually form a tumor, which, in my opinion and most likely the opinion of others, will be groundbreaking for cancer research.

A New Type of Biochemical That Could Be Found In All Life on Earth.

The wonderful jumble of molecules that make up living things is so complex that biologists have overlooked an entire class of them, until now. This missing piece of biochemistry is neither rare nor difficult to find, it’s just that no one had thought of looking for it before. Researchers at Stanford University have discovered a new kind of biomolecule that could potentially play a significant role in the biology of all living things. This newfound biomolecule, consisting of RNA modified by sugars, could be present in all forms of life and might possibly contribute to autoimmune diseases.

This newly discovered biomolecule is called glycoRNA. It is a small ribbon of ribonucleic acid with sugar molecules, called glycans, dangling from it. Up until this point in time, the only kinds of similarly sugar-decorated biomolecules known to science were lipids and proteins. These glycolipids and glycoproteins appear everywhere in and on animal, plant and microbial cells, contributing to a wide range of processes essential for life.

After documenting the presence of the newly discovered glycoRNA in human cells, Ryan Flynn (the study’s lead author) and colleagues searched for it in other cells. They found glycoRNAs in every cell type they tested which consisted of human, mouse, hamster, and zebrafish. The presence of glycoRNAs in different organisms suggests they perform fundamentally important functions. Furthermore, the RNAs are structurally similar in creatures that evolutionarily diverged hundreds of millions to billions of years ago. This suggests glycoRNAs could have ancient origins and may have had some role in the emergence of life on Earth, The function of glycoRNAs is not yet known, but it requires further research and study as they may be linked to autoimmune diseases that cause the body to attack its own tissues and cells. For example, the immune systems of people suffering from lupus are known to target several of the specific RNAs that can compose glycoRNAs.

This is exciting and interesting because it means that glycoRNAs can participate directly in cell-to-cell communication. Previously, it was believed that this was prohibited for RNAs that were not believed to play a role on the cell surface. While glycoRNAs functions are still a mystery, this discovery will hopefully lead to many more answers soon, possibly about some people’s troublesome immune systems.

How Killer T Cells Could Increase Immunity Against New COVID Variants.

In recent news, there are concerns about the newly discovered COVID variant named Omicron. Preliminary evidence suggests an increased risk of reinfection with this variant, as compared to other variants of concern. Scientists are hopeful that T cells could provide some immunity to COVID-19, even if antibodies become less effective at fighting the disease.

Along with antibodies, the human body’s immune system produces a plethora of T cells which target viruses. Helper T cell’s stimulate killer T cells, macrophages, and B cells to make immune responses. T cells do not prevent infection because they kick into action only after a virus has infiltrated the body. But, they are important for clearing an infection that has already started. If killer T cell’s are able to kill virus-infected cells before they are able to spread to from the upper respiratory tract, it will affect how you feel and will be the difference between a mild infection and a severe one.

Studies by Sette and his colleagues have shown that people who have been infected with SARS-CoV-2 typically generate T cells that target at least 15–20 different fragments of coronavirus proteins. But, the protein particles that are targeted vary from person to person. This means that a variety of T cells will be generated, making it difficult for the virus to mutate in attempt to escape cell recognition. Research suggests that most T-cell responses to COVID variations or previous infection do not target regions that were mutated in recently discovered variants. If T Cells remain active within your immune system against specific variants, they might protect against severe diseases.

Ultimately, in my opinion, this is extremely important since researchers have been analyzing clinical-trial data for several coronavirus vaccines in attempt to find clues as to whether their effectiveness fades in the face of new emerging COVID variants such as Omicron. As of now, coronavirus vaccine developers are already looking at ways to develop next-generation vaccines that stimulate T cells more effectively. Antibodies only detect proteins outside cells, and many coronavirus vaccines target spike proteins, located on the surface of the virus. Since spike proteins are liable to change, it may be prone to mutating and raising the risk that emerging variants will be able to evade antibody detection. T cells, on the other hand, can target viral proteins located inside infected cells, and some of those proteins are very stable. This raises the possibility of designing vaccines against proteins that mutate less frequently than spike proteins, and incorporating targets from multiple proteins into one vaccine.

Biotechnology firm Gritstone Oncology of Emeryville, California, is designing an experimental vaccine that incorporates the genetic code for fragments of several coronavirus proteins known to elicit T-cell responses, as well as for the full spike protein, to ensure that antibody responses are robust. Clinical trials are due to start in the first quarter of next year. If approved, this vaccine could revolutionize how we approach the creation and experimentation of COVID vaccines in the future.

Are Artificial Chromosomes the Key to Future Medicine?

Our DNA is packaged intricately by proteins in order to make up chromatin. If DNA were like a thread, these proteins are the spools that the DNA thread winds around to keep itself neat, organized, and compact inside of a microscopic cell. If a foreign, naked DNA thread with no spool is introduced into the environment, the cell is armed and ready to supply this new thread with its own self-made spools, allowing this naked DNA thread to be stably maintained in the cellular environment as part of the cell’s new collection. This process is known as artificial chromosome formation.

Prospects for the Use of Artificial Chromosomes include the potential to overcome problems in gene therapy protocols such as immunogenicity, insertional mutagenesis, oncogene activation, or limitations in capacity for transgene expression. One case where artificial chromosomes can be useful is found with someone dealing with Cystic Fibrosis. This fatal chronic lung disease is caused by a mutation in the CFTR gene and is currently a disease without a known cure. Scientists have been studying the use of bacterial and yeast artificial chromosomes as a transmitter to implement the normal functioning CFTR gene and overcome the defective CFTR gene in patient cells.

Almost two trillion cells divide every day in an average human body. This means that two trillion cells have to make a perfect copy of themselves every time. In our class, we’ve gone over the importance of cell division and have discussed the Mitochondria and Chloroplast’s ability to replicate independently within cells. The cost of cell division that comes short of flawlessness is undoubtedly humankind’s worst enemy yet: cancer, in which many are characterized by chromosome instability. One important player in ensuring the inheritance of our chromosomes during cell division is the centromere. The current studies of artificial chromosomes provide novel insights into the chromosomal processes required for de novo centromere formation and chromosome maintenance.

Ultimately, the results of these studies could help advance the synthetic biology field by exploring how some characteristics can be designed to optimize the establishment of an artificial chromosome by improving the efficiency of de novo centromere formation through accurate segregation to improve the applications of artificial chromosomes as large-capacity transmitters for cloning and gene therapies.


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