Novel CRISPR

Novel CRISPR snips itself a Nobel

Since the advent of the novel CRISPR technology, the world not only witnessed a cascade of events it has never seen before, but also hoped for what has never been envisioned.

One would point out how the historical events in Genetics are as antiparallel as the DNA molecule. History narrates how in 1962, all laurels land on a duo of men who elucidated the doublehelix structure of the DNA, while the woman with the x-ray crystallography photograph integral to the success stay behind in the shadow. However, 58 years later, it is a true novelty in history for a duo of highly deserving women to earn the 2020 Nobel Prize in chemistry for the development of CRISPR, a novel technology for genome editing, while a man who had his fair share of contributing to the technology remain unrecognized.

Some speculate the message sent by the Royal Swedish Academy of Sciences by awarding University of California, Berkeley’s Jennifer Doudna and Max Planck Institute for Infection Biology’s Emmanuelle Charpentier the Nobel prize over Broad Institute, Massachusetts Institute of Technology’s Feng Zhang, since the award is large enough to have by DANIEL VARIAS (Isochore)

Zhang share the glory with the two women.

Is this a decision to rectify history? In 2016, the Broad Institute’s President and founding director Eric Lander published an inaccurate article entitled “The Heroes of CRISPR” in the Cell journal, which claims that the men are solely responsible for discovering CRISPR/Cas9. The article places Zhang in the pedestal as the man of the hour, while downplaying the contribution of the women. History often narrates how women are often the hidden figures in science, such as the case for Rosalind Franklin of the DNA structure, Katherine Johnson, Dorothy Vaughan, and Mary Jackson of the Space Race, and other women devoid of glory for their contributions. With a groundbreaking decision to award the women over men along with the past records of gender imbalance in accolades, it is no wonder these speculations spring out.

With the conflicting claims of patents between Doudna and Zhang, where Doudna is winning patents in EU while Zhang wins his in the US through Broad, some wonder whether the decision is for the legal system, thus a political one. Some speculate that bioethics affected the decision, since Doudna and Charpentier use CRISPR in solutions while Zhang uses the technology in human samples, thus paving the way for “designer babies” or human genome editing. However, George Church, a Harvard University chemist who also works on CRISPR, believes that the committee prefers to reward discoveries rather than inventions, where Doudna and Charpentier are discoverers, while Zhang is an inventor.

Recognizing and empowering two women in science, particularly in genetics, is a fresh, progressive sight in the year 2020. This shows the long path women have take in the field known to be dominated my men in history, and such feat shall continue to empower women to progress the field. Nevertheless, Doudna, in her unbothered self, modestly receives the award as she abruptly learned about the news post-slumber and currently enjoys the free parking space in UC, Berkeley as one of the perks of her achievement.

Doudna and Charpentier’s achievement and its impacts,

...continued from page 14 however, transcends a free parking space. Clusters of Regularly Interspaced Short Palindromic Repeats or CRISPR genome editing technology exploits the immune system of prokaryotes against phages where the prokaryote slices the viral genetic material from its genome and acquires immunity against the same virus. Doudna and Charpentier’s discovery of CRISPR as a genome editing tool by modifying the Cas9 protein, enabling the system to “cutand-paste” DNA sequences in a genome.

In their works in CRISPR, Doudna and Charpentier complemented one another in terms of skills. Doudna, a biochemist with extensive work in RNA, hit the road with Charpentier whom she met at a meeting in San Juan, Puerto Rico. Charpentier, who was working with CRISPR/Cas9 in the flesh-eating Streptococcus pyogenes, fascinated Doudna with the mechanism of the system. The latter religiously delved into the system the former introduced, and there went her eureka moment—CRISPR/ Cas9 can be converted into a programmable genome editing tool.

Since its discovery, the published articles regarding the use of the CRISPR technology reached beyond 20,000, proving how CRISPR swept the entire scientific community by the possibilities and applications it entails. CRISPR enabled scientists around the world to genetically modify food and livestock organisms to optimize their yield, quality, fitness, desirability to humans, etc., with never-before seen ease. The discovery also brought an upsurge of attempts in utilizing CRISPR in clinical trials to develop drugs and vaccines and correct disorders in humans, such as sickle cell anemia, thalassemia, inherited childhood blindness, and cancer. This phenomenon, according to Doudna, is the democratization of technology.

Researchers are also eyeing CRISPR as a key solution in the lengthy and expensive testing during the COVID-19 pandemic, as the technology also has the potential to detect SARSCoV-2 in five minutes. The current view in this innovation in motion is the synthesis of an RNA complementary to the RNA sequence unique to SARS-CoV-2 and cutting the target RNA. This enables a release of fluorescent particles, which lights up when hit with a laser light. With the stocks on CRISPR biotechnology skyrocketing in the advent of the award, we can expect financial support from investors in ensuring the realization of such feats.

CRISPR, however, has limitations and challenges amid its brilliance. The system poses technical limitations, such as risks of inaccurate and unintentional splicing of regions of the genome, thus modifying the genome off-target, and difficulty in delivering the CRISPR material to mature cells in large quantities. Bioethical concerns are another consequence of the discovery of CRISPR, where the technology is open for abusive and questionable application, such as He Jiankui’s shocking use of CRISPR in editing the genome of human embryos. Nevertheless, Doudna invokes the international response to that incident, where there has been an effort to ensure global transparency and responsible use of the technology.

Though a technology with technical and ethical considerations, the discovery of CRISPR as a novel genome editing technology catalyzed even the most novel of events: the world witnessing both the rapid progression of science and technology through genome editing and the historical and progressive awarding of an allwomen team to hold the credit for such feat.

Genes Protect, Genes Attack: Decoding Immunogenic Responses to Activate Community Defenses

by JONALYN JAME CATEDRILLA (Polyplex)

With the COVID-19 pandemic taking up the world by storm, there is a need to identify genes that play a role in the immunogenic responses of a population, especially the Filipinos, against SARSCoV-2 infection. As GeneSoc conducts this year's Genetics Week, we look through the lenses of immunogenetics in its continuing relevance to the world's current health situation. Thanks to a functional immune system, the body can feel less agony from infections. Different substances from the environment predispose an organism to favorable or unfavorable response, but the body has an efficient mechanism to identify what remains in the body. Environmental or genetic factors can influence this mechanism. Before the age of medicine and epidemiology, ancient people believed that diseases are punishment befallen from the gods. They commended those who did not contract the disease for having "the favors of the gods." In 430 B.C. Thucydides deducted through observations that those who experienced the disease and recovered did not have it a second time. The discussion about human immunity started since then and centuries after, a lot of discoveries led to the elucidation of treatments to different diseases.

Genetic principle of diverse antibodies

Antibodies are proteins encoded by genes that protect the body from pathogens. Preimmune antibody repertoire is a mechanism in which humans produce several varying antibody molecules, even without the simulation of antigen. A specific antibody can interact with a variety of related antigen-binding sites, but have different antigenic determinants. Antibodies produced will interact with antigen-binding sites, even with low affinity. After simultaneous interaction of the antibodies and the antigenbinding site, B cells can further make antibodies with higher affinity to bind to the antigen. We know this process as affinity maturation. Thus, antibodies continuously increase its ability to recognize and eradicate pathogens.

Major Histocompatibility Complex

Major histocompatibility complex (MHC) molecules bind peptide fragments of pathogens and transport them to the cell surface for T cells to recognize it. The activation of macrophages and B cells eradicate pathogens, along with infected cells.. Macrophages kill bacteria in the intracellular environment and B cells produce the antibodies that will neutralize or eliminate pathogens in the extracellular environment. Mutated pathogens unrecognized by the MHC molecule can be detrimental to an organism's health. MHC has two mechanisms which makes it impossible for most pathogens to avoid immune response. MHC is polygenic, meaning there are distinct classes of MHC genes that persist. Each MHC class, MHC Class I and Class II, have a distinct set of MHC molecules that has a specific binding system with different ranges of peptides. MHC is also highly polymorphic. There are several variants of each gene within an entire population, thus it can interact and eradicate a lot of different pathogens.

Peter Gorer first described Matching of Histocompatibility and further investigated it by George Snell and his colleagues. The results of the investigation yield a safer and more efficient organ transplant, hence providing a higher chance of survival of the patient. The MHCs in humans are the human leukocyte antigens (HLA), which have a vital role in rejection or acceptance of organs. Mismatched alleles of HLA of donor and recipient can cause the rejection of organ transplant.

Gene for T-cell receptor

T cell receptors eradicate infected cells and pathogens existing inside the body, but tumors are exceptionally a challenge for T cells to recognize. Cancer cells can make themselves invisible wherein they build their own microenvironment that suppress activity, migration, and survival of T cells. Today’s advancement in biotechnology makes it possible to counter this problem. Health researchers may obtain and modify T cells from the patients, particularly the coding genes for receptors that recognize antigens of cancer cells. Additional genes play a role in resisting immunosuppression to prolong survival and facilitate T cells in penetrating in tumors. Genetic modification can make it possible to eradicate persistent cancer cells in the body.

Immunogenetics in Vaccines

Immunogenetics aid in development, and delivery of Vaccine in humans by understanding the genetic variation that influences adaptive and innate response of the immune system towards vaccines. This can provide information initial identification of adverse effects of vaccines in a specific patient. Vaccine developers should develop a vaccine relative to a patient's genomic information and immune phenotype, by also integrating precision medicine in oncology and other fields. In a study in 2014, they observed that haplotypes in the cytokines interleukin (IL)-1 gene complex and IL8 gene play a role in fever that some patients experience after receiving a smallpox vaccine. Presence of haplotype in the IL4 gene shows significant correlation to lower chances of having fever after receiving a vaccine among vaccine naïve individuals. Haplotypes in IL-1 gene complex, IL8 and IL4 can predict if the patient will develop fever after vaccination for smallpox.

GENEWS

The Official Publication of The UPLB Genetics Society

EDITOR IN CHIEF: Daniel Varias (Isochore) MANAGING EDITOR: Danica Nicole Del Rosario (Crypton)

CREATIVE EDITOR: Brian Alfred Mortera (Crypton)

STAFF: John Nicolas Olitin (Isochore) | Maria Ylenna Notorio

(Zisupton) | Hannah Cueto (Polyplex) | Justin Badlis (Crypton) | Sophia Marie Malagday (Allosyndesis) | Jonalyn Jame Catedrilla (Polyplex) | Jae Joseph Russel Rodriguez (Ribozymes) | John Kenneth Tria (Allosyndesis) | John Dane Valdez (Allosyndesis) | Christy Ann Go (Crypton) | Paolo Miguel Anico (Crypton) | Drew Kyla Baysa (Polyplex) | Nikki Matta (Helraiser) | Aimee Montes (Isochore)

Immunogenetics amid Worldwide COVID-19 Outbreak

Applying these concepts in SARS-CoV-2 infection, the current literature on twin studies tells us how a population's susceptibility to infection and outcome once COVID-19 symptoms manifest is heritable. Immunogeneticists also observed a variation in susceptibility of individuals in a population caused by polymorphisms in the human HLA gene, which emerged from the selective pressure caused by infectious diseases. Gene polymorphisms in the tumor necrosis factor (TNF), IL-6, and IL1β, causing a cytokine "storm" in the overproduction of such gene products as a response to the infection, link themselves in a population’s susceptibility on severe deterioration, multiorgan failure, and death caused by SARS-CoV-2 infection. Even though the current understanding of the immunogenetics of humans against SARS-CoV-2 is incomplete, the information we have is invaluable towards vaccine and drug development.

The genes and environmental factors come hand in hand in strengthening or weakening the body’s immune response. Genes produce the needed materials for the immune system to be possible. Other organisms may be more vulnerable than others because of their genetic make-up. Biotechnological advancements today have made it possible to manipulate genes in the body to make it more robust and decrease the mortality rate of humans. Along with the genes, the environment and the lifestyle of the individual also affect the efficiency of the immune system. Even with the existence of a systematic protection from diseases, individuals take care of the overall condition of their well-being.