Are some of us “immune” to genome editing?

Some of us may have characteristics we would like to change. We may want to be taller, skinnier, or smarter. While many traits can be changed during our lifetime, others simply cannot. There are certain ‘fates’ we cannot avoid, such as inherited diseases. For example, if you inherit two copies of a gene called CFTR that has mutations, you are likely to develop Cystic Fibrosis. Although your life choices can help accommodate the disease, there is currently no cure for Cystic Fibrosis and many other genetic disorders. However, with the development of genome editing, the potential to alter the entirety of our genetic information, there is hope in the ability to one day eradicate genetic diseases once and for all.

There are currently several genome editing methods available, but the most popular method is the CRISPR-Cas9 system, which was recently and famously used to edit the germline of babies born in China. Editing the germline means that the changes made to the genome will be inherited throughout following generations. Although this practice is still officially banned around the world, CRISPR-Cas9 was used to change two twins’ genomes. This tool allows us to edit parts of the genome by either removing, adding, or changing a given segment of DNA sequence. It is the go-to editing technique used by scientists because it can generate changes quickly, efficiently, and accurately  at a relatively low cost. There are two major components of this system – Cas9 and a guide RNA (gRNA). Cas9 is an enzyme that acts as ‘molecular scissors’ and cuts both strands of DNA at a specific location, which allows the removal, addition, or change of DNA sequence. The sequence where Cas9 cuts is determined by the gRNA, which, as its name implies, is an RNA molecule that ‘guides’ Cas9 to a specific place in the genome through complementary base pairing.

The CRISPR-Cas9 system was originally discovered in bacteria as a defense mechanism against viral infection. The most commonly used versions of Cas9 for genome editing come from two bacterial species – Staphylococcus aureus and Streptococcus pyogenes. Both species of bacteria frequently live on the body as harmless colonizers, but in some instances, they can cause disease. If you have been infected with either S. aureus or S. pyogenes, you likely developed adaptive immunity to the bacterium in order to protect yourself against future infections. A recent study from Stanford University published in the journal Nature Medicine examined this phenomenon, asking whether healthy humans possessed adaptive immunity against Cas9 from S. aureus and S. pyogenes.

First off, you may be wondering why adaptive immunity to Cas9 would matter at all. When we are exposed to ‘invaders,’ such as bacteria, our body develops adaptive immunity in the form of antibodies and T cells that target specific components (also called antigens) of the invader. For example, if you’ve eaten raw eggs (in cookie dough, let’s say), you may have suffered from an upset stomach caused by infection with Salmonella. If you are then exposed to Salmonella again in your lifetime, both antibodies and T cells that developed in response to the first infection should act quickly to suppress and clear the infection. Similarly, if you were previously infected with S. aureus, your body may negatively respond to receiving modified human cells producing Cas9 originating from S. aureus for the purpose of genome editing but the antibodies and T cells generated during the initial infection may quickly clear these cells. Our own body may think it is protecting us, although in reality it may be thwarting our efforts to make a change in our genome that is intended to have a positive effect. Even worse, this unintentional stimulation of our immune system could lead to an overwhelming response that can lead to organ failure and potentially death. Unfortunately, there is a documented case of a patient death due to an immune response to gene therapy using viruses. It may therefore be necessary to screen each patient before the start of therapy to determine whether they possess immune components that would make this form of therapy inefficient or even deadly.

The Stanford study mentioned above examined this phenomenon by testing for the presence of both antibodies and T cells against Cas9 from S. aureus and S. pyogenes in healthy donors. The authors found that ~75% of donors produced antibodies against Cas9 from S. aureus and ~60% of donors produced antibodies against Cas9 from S. pyogenes. These results come from analyzing blood from more than 125 adult donors. The scientists also used several approaches to examine T cell responses. In this case, 78% and 67% of donors were positive for antigen-specific T cells again Cas9 from S. aureus or S. pyogenes, respectively.

In summary, the authors of this study provide evidence for existing adaptive immunity to Cas9 from S. aureus and S. pyogenes in a large number of healthy adults. Two additional studies examined adaptive immunity against Cas9 with varying results. However, all three studies suggest that pre-existing immunity to Cas9 needs to be carefully considered and addressed before the CRISPR-Cas9 system moves toward clinical trials as a therapy for genetic diseases. In other words, scientists need to address whether the presence of antibodies and/or T cells against Cas9 would lead to destruction of cells carrying Cas9 for the purposes of genome editing. Other potential solutions include using Cas9 derived from bacterial species that do not cause human infections and thus should not trigger an adaptive immune response, or suppressing the immune system while administering CRISPR-Cas9.

CRISPR-Cas9 genome editing has the potential to transform our lives in many ways. While this technology certainly holds promise for the treatment of genetic disease, the Stanford study highlights the need for more research before we can conclude that CRISPR-Cas9 is effective and safe. Optimization of this system may improve its performance in clinical trials and lead to future approval for the treatment of human disease.

Peer edited by Keean Braceros and Isabel Newsome

A glass of wine a day…does not keep the doctor away
Wine glasses with different types of wine in them.

One day, science shows that coffee is good for you, but the next day, science finds that coffee is bad for you. One day, chocolate is bad for you, and the next, it is good for you. Studies show that red meat is both good and bad for you. As we read the latest news, science seems to contradict itself every day. With all this confusion about science and nutrition how do we know which foods are good or bad for our health? A recent study has tried to simplify the answer for the link between alcohol and health.

One of the reasons for apparent contradictions in science is due to the nature of science. There is no answer sheet to check for the right answer and no textbook to see if your conclusion is correct. Science is completely new, and each study adds a small piece to our understanding of the world. Because each study is limited in what it investigates, occasionally the conclusions drawn from different studies may be at odds with one another. However, once enough science has been conducted, it is possible to “average out” all the information on a particular topic and come to a consensus. This consensus is often a “yes” or “no” answer to a single question, such as “Does chocolate lower blood pressure?” or “Does coffee increase the risk for cancer?” (Hint: the answers are yes, chocolate lowers blood pressure and no, coffee does not increase the risk for cancer!). One way to do this is by performing what is called a metanalysis.

Metanalyses investigate the research on a specific topic (such as a possible link between processed meats and cancer) and combine it to come to a single conclusion. A recent metanalysis studied the link between alcohol consumption and disease by combining information from 592 studies that investigated the risks and benefits of  alcohol.

The most important finding from the study is that even a single standard drink of alcohol per day increases a person’s risk of health problems, such as cancer, stroke, injuries, and infections. Furthermore, two drinks per day lead to a 7% higher risk of dying from alcohol-related health problems, and five drinks per day lead to a 37% higher risk of dying. Because of the study’s design, it is unclear how long these drinking levels must be sustained to increase the risk for health problems; future research should study this question. Although the metanalysis found that moderate consumption of alcohol (1-3 standard drinks daily) reduces the risk of ischemic heart disease and diabetes moderate alcohol consumption still increases the risk of developing over twenty other health complications and diseases. This increased risk explains the finding in this study that alcohol is the 7th leading risk factor for deaths globally, with alcohol involved in 2.2% of female deaths and 6.8% of male deaths in 2016. The disparity in male vs. female deaths may be due to discrepancies in drinking rates, since in many areas of the world, men drink more alcohol than women.

This metanalysis emphasizes the importance of re-evaluating current public health recommendations. The U.S. Dietary Guidelines recommends no more than 1 drink per day for women and no more than 2 drinks per day for men, and it also suggests that people who do not drink should not start drinking. However, the metanalysis discussed above suggests that we should reconsider these guidelines and avoid recommending alcohol consumption to anyone. This recommendation is unlikely to be a popular opinion, due to the number of people who enjoy consuming alcohol on a regular basis as well as the alcoholic beverage companies who prefer to cite science showing that moderate drinking is healthy. However, the sheer number of deaths caused by alcohol consumption (2.8 million deaths globally in 2016) highlights the importance of a thorough review of alcohol recommendations. Until then, we should individually consider how much and how frequently we consume alcohol, since alcohol does not keep the doctor away.

Peer-edited by Priya Stepp

The Impossibly Ideal Scientist

Image and artwork created by Lindsay Walton

The solving scientist: can this be fixed in time?

Beverly Crusher. Roy Hinkley. Emmett Brown. Samantha Carter. Sheldon Cooper. The Doctor. Abby Sciuto. Temperance Brennan. What do each of these scientists have in common? From creating a Geiger counter out of bamboo, to discovering, identifying, and curing a disease in the nick of time, each of these cinematic scientists has completed impossible tasks. Often works of fiction create all-knowing scientists who can solve any problem posed to them in the nick of time. However, do these depictions affect public expectations and imply that scientists are experts in every scientific field imaginable?

During recent years, many stereotypes about scientists have shifted, allowing researchers to shed the traditional “geeky” scientist persona. Some say that new perceptions of scientists reflect their cinematic portrayal as heroes and experts, “mavericks” who overcome obstacles both cerebral and physical in nature, persevering until they successfully save the day at the last moment possible.

However, how do these changing ideas about scientists translate to public expectations of the average scientist? Do “maverick” scientists portrayed in film cause people to idealize scientists and lead to the expectation that they will have all the knowledge Data, the android in Star Trek, has in his memory banks? In a recent survey, 49% of polled scientists stated that they felt the public has unrealistic expectations about the speed at which scientists should generate solutions to problems. Perhaps scientists feel the pressure of comparing themselves to their science fiction counterparts. The data certainly shows that the public has historically had high expectations for scientists. When polled, most Americans predicted scientists would cure cancer within 50 years, with polling starting as early as 1949. However, cancer still has not been cured, as exhibited by the recent National Cancer Moonshot proposal generated by President Obama, pushing for research funding to improve cancer patient outcomes.

Is it even possible to be the all-knowing scientist? As a lowly graduate student, I know that I will never be as brilliant as Dr. Beverly Crusher, who could probably cure cancer within one single episode. However, I believe that each of these idealized scientists creates a good model of what we should hope to be as scientists — individuals who thrive on the work, constantly learn new things, contribute to current knowledge, and reward the faith and trust that the public places in them.

Peer edited by Kaylee Helfrich. Image by Lindsay Walton.

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