CRISPR are segments of genetic material that are used as a guide to search for repeats of that identical piece of genes in cells. Once located, CRISPR associated proteins (Cas) will then act like a pair of scissors to cut out that piece of the gene; Cas are also known as endonuclease enzymes. Put simply, the CRISPR/Cas9 system can locate a piece of genetic material inside a cell – or, hypothetically, a body – with a high level of precision and cut that piece out, thus altering the DNA and the fate of new proteins. For example, cutting out a gene could cure a genetically inherited illnesses, such as the HTT gene associated with Huntington’s. A baby whose entire family is brown eyed could be “edited” to have blue eyes, by inserting the gene that produces the proteins needed to affect eye colour.

The idea of changing the expression of genes has been thrown around for a long time, but with the fairly recent advent of CRISPR/Cas9 technology it is now closer to reality. Very recently, scientists primarily at the Genome Institute of Singapore and other affiliations have researched a new method for gene editing utilizing the Cas9 protein, whose activity can be chemically modified. This Cas variant, called iCas (a newly described protein), has nuclease activity that is tightly controlled by a drug called 4-hydroxytamoxifen (4-HT). Tamoxifen has also been used in the fight against breast cancer. Fusing the original Cas9 enzyme with a section of the estrogen receptor where hormones typically bind makes iCas sensitive to 4-HT. When 4-HT is added, along with the guide CRISPR segment of genetic material and the iCas protein, the gene-editing method now has an on-off switch that is reversible, easy to implement and time efficient (when compared to other methods of controlling genome-editing). “We benchmarked iCas against other chemical-inducible methods and found that it had the fastest on rate and that its activity could be toggled on and off repeatedly,” published in a September issue of Nature Chemical Biology this year. The authors of this article go on to say, “Collectively, these results highlight the utility of iCas for rapid and reversible control of genome-editing function.”

Now that the CRISPR/iCas system can be tightly controlled by 4-HT, this technology is one step closer to being used for “fast, reversible, chemical-inducible genome engineering in mammalian cells”. This technology may seem like a miracle cure, but many issues such as safety and ethical concerns have yet to be resolved before this system can even be tested in humans, let alone enter the market as a viable therapeutic. There is already significant controversy surrounding this technology, most stemming from fears of dangerous side effects, and unethical motives.
In March 2015, these fears came true when news broke of scientists administering CRISPR/Cas9 in non-viable human embryos in an attempt to cure a fatal blood disorder caused by the gene – thalassaemia. They hypothesized that if successful, this procedure could eradicate this genetic disease before the child was even born. Interestingly, the authors originally submitted their findings to the very prestigious scientific journals Science and Nature, but were rejected partly due to ethical concerns.

The idea of changing the expression of genes has been thrown around for a long time, but with the fairly recent advent of CRISPR/Cas9 technology it is now closer to reality

Following the experiment, only a small fraction of the embryos tested had the gene successfully deleted and the side effects were virtually impossible to predict due to the complicated nature of embryo development. It is uncertain whether the embryos could have carried out normal development, or whether they would have suffered fatal mutations due to the imprecise editing. This may also unethical because any genetic changes administered in embryos, known as germline modifications, are heritable. These changes could have unpredictable and potentially dangerous effects on future generations, and some argue it is unfair to decide the designer genetic changes we want for our unborn children.

Many have expressed concerns that any gene-editing research on human embryos, even if they are not viable, could lead to increasing accounts of unsafe or unethical uses of the technique. It is generally assumed by some that germline editing carries a certain level of unsafety, as it affects every cell within the body, including the sperm or egg cells, and the actual side effects would not be known, and would in essence be irreversible. In the previously mentioned example of the paper published in March 2015, some scientists critiquing the paper have argued that even though the procedure worked there were many off-target mutations, which could of course lead to unforeseen circumstances, such as the silencing of typically important genes.

Since gene editing can give rise to undesirable side effects, these changes may then become embedded in the germline, and the procedure may do more harm than good. The romanticized ideas of curing diseases from blood disorders to cancer to HIV/AIDs with a procedure as simple as hitting copy and paste on a keyboard is too premature and frankly, a little naïve. Extensive amounts of research and ethical debate must be done to ensure the safety of patients. Currently, gene editing procedures in humans is more science fiction than reality. However, the future is bright. The science community has accepted CRISPR/Cas9 as a “miracle” technology and has applied it to a vast variety of experiments to better understand fields such as cell biology and molecular genetics. Even though we can’t cure cancer just yet, CRISPR is still a powerful tool that can be used to understand the way our genes work. Perhaps we will unlock new knowledge that will provide us with the keys to utilize this technology to its full potential. In the meantime, it is important to understand and participate in what could be the most high-profile scientific debate of our generation. The applications of CRISPR/Cas9 are coming, and soon we may be faced with the decision of whether to allow doctors to use this to treat a disease, or change a child’s eyes to blue and a high IQ. Science fiction could soon become reality.

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Although new reports of Zika mention sexual transmission as a possibility, its rapid spread has been primarily facilitated by mosquitoes of the genus Aedes, common vectors that allow infectious viruses to move from one host to the next. They spread diseases such as Dengue virus, Yellow Fever virus, and West Nile virus. These viruses, along with Zika, are part of the Flaviviridae family of viruses, which generally cause a variety of symptoms, from a mild fever to a potentially deadly encephalitis – acute inflammation in the brain. Only one-fourth of those infected with Zika develop symptoms, with most cases being very mild and short-lived, a rash being the most distinctive symptom.

This recent spike in media attention has also been due to a possible correlation of microcephaly and the Zika virus. Upward of 4,000 babies in Zika-affected communities have been born with microcephaly, and there has been next to no major response until now. Microcephaly is a neurodevelopmental disorder that shrinks the head circumference and size of the brain. This is believed to occur when pregnant people infected with the virus pass the disease to their child, infecting the developing fetus. There are many potential reasons for this abnormality in newborns, as occurrence also spiked following the dropping of atomic bombs in Hiroshima and Nagasaki during World War II. Despite this, the current spike is believed to be caused by the Zika virus: the World Health Organization (WHO) has stated that the evidence is overwhelming, although it could take at least half a year until this correlation can be proven as a true symptom.

However, it is this symptom that is inciting the most worry in people internationally. Officials of the Center for Disease Control (CDC) in the U.S. noticed the link when the virus was found in the tissues of newborn babies that suffer from microcephaly. Officials at the CDC are advising those who are pregnant to avoid travel to Zika-infected areas, and those who already live in those areas to avoid pregnancy. However, this is easier said than done. Unplanned pregnancies and the lack of sex education in many of the places most affected by the virus make it very difficult for people to simply delay pregnancy.

The WHO declared Zika an international public health emergency earlier this month. The Zika virus is now at a pandemic level, the highest possible degree of an infection, characterized by extremely rapid spread at international magnitudes. This is the fourth declaration of emergency in the entire history of the WHO. This sense of urgency has multiple causes: the possible correlation with birth defects; large populations of mosquito carriers; the rapid spread of the disease; and the lack of a vaccine. It is estimated that 4 million people will be affected by the end of the year, with over 1.5 million in Brazil. With the summer Olympic games planned to take place in Brazil, the virus is likely to spread even faster. The virus has also spread to over twenty countries in the Americas alone, and there are reports of infections in some U.S. states, such as Florida, Texas, and California. Although such reports are mostly of travellers who picked up the virus abroad, WHO Director-General Margaret Chan warns that “it is now spreading explosively. The level of alarm is extremely high.”

The Zika virus is now at a pandemic level, the highest possible degree of an infection.

This announcement has spurred the race to stop the spread of the Zika virus into high gear. This includes the urgent mobilization of research toward vaccine development and the cooperation of nations to work toward the common goal of prevention and treatment. Companies and scientists are racing to produce a vaccine as concern for the dangers of the virus spreads worldwide. Selena Sagan, associate professor and a researcher of Flaviviruses at Mcgill, told The Daily, “We currently know too little about the molecular biology and pathogenesis of Zika virus, so it is hard to predict how long it will take to develop a vaccine. Up until recently, Zika was only known to cause a mild fever and rash in those infected. We never thought of it as a threat because we didn’t realize the association with the birth defects now observed in South America.”

Sagan continues, “This has sparked greater interest, so quick action is important to try and mitigate risks and to understand the virus more thoroughly. There is currently a shadow of doubt surrounding Zika, and it should be of foremost importance to establish causation and then work on developing a vaccine to prevent infection and the birth defects that are causing panic.”

To deal with the current emergency, the most organized form of prevention happening right now are soldiers going door-to-door to destroy anything infested by mosquitos. This is similar to the mosquito brigades in Panama during the early 1900s, intended to get rid of mosquitoes that carried the Yellow Fever virus. However, this is not enough: the issue stems from the problem of a lack of funding for important basic research on neglected tropical diseases. There is a belief that such diseases are neglected only because they occur in impoverished countries, but, much of the neglect is also due to a lack of sufficient knowledge of the virus and its possible risks – most of these neglected tropical diseases are deemed harmless or mild with negligible fatality rates, and research is pushed to the side in favour of more imminent diseases. So when a neglected virus causes the development of severe symptoms in an infected individual, chances are low that it would be noticed by the international community because too little is known about its transmission and origins.

A recent example is the 2014 outbreak of the Ebola virus. Compared to the symptoms of Zika, Ebola is much deadlier, as it causes hemorrhagic fever in those infected. There were high amounts of criticism directed toward the WHO for not taking immediate action on the issue, and as a result, Ebola spread worldwide, killing over 11,000 people. A similar panic caused by the correlation between Zika and microcephaly has taken over the media and it has become a household name. Vaccine development and preventative measures have been put into place after the WHO declared Zika a public health emergency of international concern. And although the response toward Zika has been much quicker compared to the Ebola crisis, it shouldn’t be necessary to wait until the disease is at our doorsteps to begin basic research in an earnest search for a vaccine.

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A vaccine is a biological substance that either closely resembles a pathogen or is a weakened, attenuated form of a microbe. This substance is introduced to the body, traditionally with a needle, leading to an attack on the vaccine by the immune system. The reason this works is because memory B cells in the immune system keep a record of this administered “infection.” Should the actual microorganism, be it a bacteria or virus, infect that person, their body is well equipped and ready to deal with the threat. Vaccines that work in this way are called prophylactic vaccines, intended for preventative measures against future infections. A second type of vaccine, called a therapeutic vaccine, is used to treat diseases currently affecting the body. No matter the type, vaccines work in tandem with the immune system to rid the body of dangerous disease-causing pathogens.

That the effects of vaccinations differ between sexes was first discovered in a study at Johns Hopkins University in late 2014. Although sex is assigned at birth based on visible characteristics that are a result of the genetic makeup of a person, there are also immunological, hormonal, and genetic determinants when it comes to the assignment. Immunologically, people who are assigned female at birth, who commonly have two X chromosomes, have a higher number of cytokines – cells that act as the “weapons” of the immune system. Cytokines carry out immunological functions against pathogens and allow the body to recover. Hormonal differences in people also play a role. Estradiol, progesterone, and testosterone are the dominant hormones found in people assigned male at birth, who commonly have XY chromosomes, and negatively affect the function of immune cells. It has been found that testosterone suppresses pro-inflammatory cytokine secretion by macrophages, an important type of immune cell that mediates the elimination of pathogens. In contrast, estrogen is dominant in assigned females and interacts with immune cells through estrogen receptors on cell surfaces to enhance cell function.

Many immune-related genes such as interleukins, cytokines, and receptors are located on the X chromosome, leading to the final point of genetic determinants of vaccine proficiency. Therefore, there are less genes in assigned males that are important for immune responses. This double dosage of the X chromosome explains why vaccinations will have a greater variation of effects for those assigned female at birth, both positively and negatively. The biological characteristics of those with XX chromosomes cause them to have nearly twice the antibody response, and stronger cell-mediated immunity following the vaccination. However, they also experience worse reactions following the injection, such as fever, pain and inflammation, when compared to those with XY chromosomes.

Vaccines are not, in fact, seasonal – they are offered year-round for a plethora of diseases.

The findings of the John Hopkins study suggest that the design of vaccines should be strategically sex-specific to reduce side effects in assigned females and increase immune responses in assigned males by altering dosages to optimize its effects. These findings also raise important questions about the effects of vaccinations on intersex or trans individuals, who may have had surgery and or hormonal treatments. This could raise problems when measuring doses based on sex, when the medically recorded assigned sex of the person may not reflect the hormonal or physical changes after birth. It would be very difficult to predict the optimal dosage of various vaccines to achieve high levels of immunity and low levels of adverse side effects for each case, trans and interex people especially. It is especially tricky to determine the effects of immunological and hormonal differences in these individuals after they have undergone changes to their body. Observational studies of side effects are also as or more difficult to observe for intersex and trans individuals, and pose as another hurdle in optimizing individualized vaccinations. Further studies are essential for the safety of vaccinations and the health of all individuals. In order to be most effective, doctors should take into account an individualized approach for vaccine administration and research.

The standards of administered drugs and vaccinations are rapidly changing for the better, and individualized medicine is becoming a promising field in healthcare and therapeutics. Soon, a quick trip to your local drugstore to get a universal flu shot won’t be so simple.

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