“By all means," Dawkins replied. "There is nothing wrong with improving lives.”

I definitely agree with Dawkins. However, I'd add: as long as the potential benefits outweigh the risk. And with our current understanding of human physiology and genetics, that is definitely not the case.

Human beings have always yearned to better themselves – to rise beyond nature’s lottery. We are so immersed in our modern enhancements that we are often oblivious to them. LASIK surgeries (or glasses, for that matter!), cochlear implants, plastic surgeries, and birth-control pills are all examples of things we do to overcome what we perceive as our natural limitations. But what gets people really wound up is the idea of genetic enhancement – improving traits by changing the genes inside of us.

We can define genetic enhancement as the manipulation of one’s genome to modify a non-pathological feature. So if I take a gene or a set of genes known to make Usain Bolt the fastest man alive and add them to myself, I am genetically enhancing myself. However, in reality, enhancements are much more complicated than just replacing a few genes.

Gene therapy for genetic disorders – at least, those that result from a single genetic mutation – has come a long way in the past three decades. In 2017, we witnessed several milestones, including the treatment of hemophilia and of Spinal Muscular Atrophy. But gene therapy is still complicated, with severe side effects and unforeseen consequences. For example, in early 2000s, successful gene therapy for Severe Combined Immunodeficiency was overshadowed by the development of cancer in two patients. I'd argue that for deleterious mutations, the risks are justified by the promise of treating a disease. But for enhancements, we are nowhere close to a clear justification. We know of many genetic changes that in theory should create "superhuman" traits in people, but they come with debilitating consequences.

Imagine changing a single gene so that you no longer feel pain. There are people with mutations that result in not feeling pain, a condition known as congenital analgesia. Not only is this not a superpower, but people with congenital analgesia cannot live normal lives. They burn their hands on stoves without realizing, or have severe organ malfunction without feeling any pain.

Or imagine having bones that are several times denser than the average human’s, bones so dense you could get hit by a car and walk away unscathed. In reality, people with mutations that result in unbreakable bones suffer from a condition known as Sclerosteosis. Their bones can be so dense that their brains crush under the force of their own skull. One cannot help but wonder about other genetic changes that may appear to add to our human powers, but are just terrible diseases in reality. The bottom line is that we do not know all the outcomes of creating a single mutation in an individual, and chances are we will not know enough anytime soon.

Even if a mutation appears to have beneficial effects on the individual, we do not know all the potential side effects in the near and far future. Every now and then, based on our studies on model organisms, we come across single genes with dramatic effects on a single trait. In 1999, researchers expressed a protein that binds hippocampal receptors in the brains of mice in an attempt to improve their cognitive ability. The mice showed remarkable memory and cognitive performance, which led to the researchers naming the mice Doogie, after the genius television character Doogie Howser.

Almost 20 years later, we now know about 35 mutations in mice that improve learning and memory. We still do not know a lot about the downside to these mice, but several strains raise alarming concerns: many of the mutations that increase cognitive ability may have detrimental effects. The Doogie mice described above may be intelligent, but they have an increased sensitivity to pain. As another example, the Hras strain of mice, may excel at solving puzzles, but they have a heightened fear response. Other strains with phenomenal intelligence at complicated tasks like solving puzzles fail at simple ones like remembering where they hid their food.

The challenges are amplified when we consider that most traits are the results of tens, hundreds, or even thousands of genes, interacting in different organs. You may want to get taller, but there are about 200 genes that play a role in determining your height in your early development. Another problem is that we only move in one direction in time: we get old. Even if you could go in all your cells and change every single one of those height-altering genes for the tallest versions possible, your body is no longer in the developmental stage for those changes to manifest themselves. You can't become super tall or super fast if you already developed with your own average genes interacting in your body.

This takes us to a whole new level of augmentation: embryo editing. Gene editing on a single-cell embryo means that the change will be passed on to the next generation(s). However, embryo editing is still in its infancy. Even the most outstanding breakthrough in embryo editing, published last year, was met with outrage and disbelief by the scientific community; a group of prominent scientists challenged the basic tenets of the paper, arguing that editing in embryos was not achieved as seamlessly as the authors had suggested.

Overall, we are nowhere close to being able to safely edit the genomes of embryos or adults. So before we start trying to turn ourselves into Usain Bolt, let's learn more about how our genes make us who we are.

But CRISPR's therapeutic promise was brought into question in January, when we witnessed earth-shattering news headlines such as “CRISPR’s Future Threatened by Human Immunity to Cas9” and “CRISPR Hits a Snag.” This was in response to a preprint (not peer-reviewed) article from the Porteus Group at Stanford, who reported that some people may have pre-existing immunity to certain types of CRISPR-Cas9 genome editing. Although the lack of peer-review means that these findings have not been thoroughly scrutinized, coming from a prestigious lab, they are most likely true and deserve our attention. However, even assuming that all these findings are factual, they do not present massive hurdles to the clinical use of CRISPR.

CRISPR is a bacterial immune system, which stands for “clustered regularly interspaced short palindromic repeats” that together with CRISPR-associated (Cas) proteins, protect the bacterium against attacks by bacteria-killing viruses. There are thousands of different CRISPR systems in bacteria all around the world. Some of these CRISPR systems use a Cas protein called Cas9, a protein that can be guided to target the DNA of a virus and cut them to terminate the attack. That’s what makes Cas9 useful: it is programmable – you can guide it to a region of DNA that you want to cut. In theory, this means we can use Cas9 to treat genetic diseases by cutting the disease-causing gene and replacing it with the correct DNA sequence; this is what makes CRISPR a breakthrough.

When the first Cas9s were being developed as genome editing scissors, they were taken from common human bacteria. For example, the Cas9s from Streptococcus pyogenes (the bacterium that gives you strep throat) and Staphylococcus aureus (mostly harmless) were among the first used editing genomes of human cells. This is where CRISPR-Cas9 meets human immunity.

Cas9 and immunity

Our immunity works in part by developing antibodies against things that look foreign. Therefore, if the immune system has encountered a bacterial protein before, there is a good chance that we have antibodies against those proteins. The preprint asked whether people may have antibodies against those two commonly used Cas9 proteins, especially since our bodies have most likely encountered these proteins before.

They tested blood serum from 12 healthy donors for their ability to recognize Cas9 and showed that most people have antibodies against those two Cas9 proteins.These results suggest that our bodies may not only inactivate Cas9 using antibodies, but we could even have a systemic reaction to Cas9 therapy.

However, if we consider the following factors, the discovery of a pre-existing immunity in some people may not really be a snag, just another thing to consider when seeking to develop CRISPR for therapeutic applications.

This is because, like any other study, this one comes with many limitations and caveats. The first thing to consider is that this immunity that researchers may have found may not be universal. We do not know the demographics of the subjects of this study, but it is almost certainly not representative of even the people of California, let alone the rest of the US or the world.

Another fact to keep in mind is that even though these are common bacteria, they are not found in everyone. In addition, not every strain of Streptococcus pyogenes or Staphylococcus aureus has CRISPR-Cas9.

Taken together, the fact that some people do possess pre-existing immunity to these Cas9 is, without a doubt, a significant finding, but how broadly it affects the global human population has not been addressed.

Another important consideration is that we are not limited to those two Cas9s addressed in this study. Just like fish in the sea, there are thousands of bacteria that have CRISPR-Cas9. An easy bypass would be to select Cas9 proteins from bacteria that are not found inside or even close to humans. For example, a recent study shows that Cas9 from a thermophilic bacterium (grows at high temperatures) can be used for editing in human cells. Even for those Cas9 proteins from humans, we can probably find ways to decrease their chance that they are recognized by the immune system, even though this is yet to be done.

To take things further, not all CRISPR systems found in bacteria use Cas9 to target DNA. A more recent discovery uses another protein called Cpf1 (or Cas12a) that can also be used in humans. Whether humans have pre-existing immunity against different Cpf1 proteins has not been studied. In reality, our knowledge of the human immune response to these foreign proteins is very limited, and more tests are needed (and probably on the way).

Ex vivo therapy

Even assuming we all have immunity against all Cas9s out there, an easy bypass would be using Cas9 outside the body. Ex vivo therapy refers to taking cells from a patient, Using Cas9 to treat the genetic disorders in cells in a dish, and returning them to the body.

There are several advantages to ex vivo therapy including: you’re not delivering anything foreign to the patient; it can be done in a more controlled and efficient fashion; in the case of editing genes, you can make sure that the cells you’re putting back in the patient have the corrected gene. For example, mutations in a gene called CYBB result in a debilitating immunodeficiency called chronic granulomatous disease (CGD). In a recent report, scientists used ex vivo CRISPR/Cas9 therapy to treat CGD in cells derived from patients. Ex vivo therapy cannot be used for all diseases, but it is still a way around the potential immune problem in many cases.

The last thing to consider is that scientists do not inject "naked" Cas9 directly into people's blood. Delivering Cas9 has been a challenge since the inception of CRISPR/Cas9 genome editing. For one, if the delivery agent itself is foreign, our immune systems will react immediately to neutralize it, making it obsolete at best and potentially dangerous if the reaction is severe. Whatever the mode of delivery, in most cases Cas9 is not being directly injected into the blood stream. Even though this does not eliminate a possible immune response, it suggests that the immune response to the delivery method may be more of a challenge than to the Cas9 itself.

More than triggering fears that CRISPR may not have the potential we first thought, this study should teach us several important facts about translating discoveries from the lab to the clinic. It tells us about yet another factor to consider before injecting Cas9 into people. This gets added to the countless other considerations when it comes to safety and efficacy of gene therapy using Cas9 or any other protein.

It also reveals the importance of developing parallel tools, even if at the time they seem redundant. It is imperative to develop new CRISPR systems as novel tools for gene therapy. And the most important lesson is that science is a complex enterprise, and nothing is ever straightforward. These apparent snags are exactly the kind of challenge that scientists need to evaluate their work and find new ways around possible challenges. And that is what make science fun.

Rosalind Franklin was born in the summer of 1920 in London into an affluent and educated family. From a young age, she showed exceptional talent and creativity that manifested in an early fascination with physics and chemistry. After college, she pursued a doctoral degree from Cambridge, and since this was during World War II, she worked on the porosity of coal for fuel purposes and other wartime devices. Her PhD thesis was titled, "The physical chemistry of solid organic colloids with special reference to coal."

After her PhD, she described herself while asking a friend about job openings as "a physical chemist who knows very little physical chemistry, but quite a lot about the holes in coal."

2. She captured photograph 51

You probably know that Watson and Crick published a paper in Nature in April 1953, proposing their model of DNA structure. You also know that they won the 1962 Nobel Prize for that paper. What you probably do not know is that in the same issue of Nature, there was a paper by Franklin and her doctoral trainee, Raymond Gosling. The paper was titled, "Molecular Configuration in Sodium Thymonucleate."

The paper provided experimental evidence that supported some of Watson and Crick’s purely hypothetical arguments. Specifically, the famous photograph 51 shows that DNA is in fact helical. In the conclusion of the paper she wrote, “Thus our general ideas are not inconsistent with the model proposed by Watson and Crick in the preceding communication.”

Prior to the publication of this paper, photograph 51 was shown to Crick without Franklin’s consent, which is still the topic of a debate over ethics and the Nobel Prize, which is more broadly controversial for rarely recognizing women. However, Franklin was given due credit in Photograph 51, a 2015 play about her life, which starred Nicole Kidman.

3. Franklin loved traveling and backpacking

Her love for science and discovery did not mean that she did not have hobbies. She traveled frequently to her favorite country, France, and backpacked through the French Alps. 

She wrote to her mother in 1946,“I am quite sure I could wander happily in France forever. I love the people, the country and the food.” She also traveled to the US for work, where she had made many friends throughout the years. 

4. After DNA, the discoveries continued with tobacco viruses

Franklin's colleagues at King's College were getting more and more hostile towards her, calling her "Rosy" and "Dark lady" behind her back. In 1953, One of Franklin's colleagues (and a Nobel laureate), Wilkins, wrote in a letter to Watson and Crick:

"I hope the smoke of witchcraft will soon be getting out of our eyes."

The growing sexism she faced drove Franklin out of King’s college, and she moved to Birkbeck College the same year. At Birkbeck, she distanced herself from DNA and started to work on another fascinating molecule, RNA, a molecule that carries genetic information and just like DNA, is vital to life. 

She used X-ray crystallography (a method to look at the shape of very small things like viruses) to explore the structure of the Tobacco Mosaic virus (TMV), an RNA virus that infects tobacco plants. Just a few years into this new arena of research, her team put together a clear model of TMV. Their model suggested that TMV is a barrel-shaped virus made up of proteins, with RNA molecules wrapped in the donut hole like a coiled rope. This work has since been extended to several other viruses, and has been fundamental to our understanding of viruses and RNA.

5. She worked until the last breath

In 1956, Franklin was diagnosed with ovarian cancer and started chemotherapy. But nothing could stop DNA’s Dark Lady and her love for science. She published seven scientific papers in 1956, and went on to publish six more in 1957, all while she was undergoing chemotherapy. This is how the crystallography pioneer John D. Bernal described Franklin’s final months: "Her devotion to research showed itself at its finest in the last months of her life. Although stricken with an illness, which she knew would be fatal, she continued to work right up to the end.”

Franklin succumbed to cancer in April 1958, but her legacy continues to this day. Photograph 51 is in almost every biology textbook around the world. Perhaps she was not appreciated in her time, but the future won't forget her.

Bacteria, on their part, have evolved an adaptive immunity to attempt to combat phages: CRISPR. The term was in the news a lot recently when the world was obsessed with the GIF of an 1878 galloping horse stored in bacteria and again when presented with the possibility of 'designer babies.'

But our basic knowledge of how CRISPR actually works is still very limited, and the recent findings, ripe with premature projection, get far ahead of the fascinating, complicated process we are just beginning to understand. There are thousands of different CRISPR systems in nature, and we have only studied a handful of them, yet our limited discoveries have resulted in several breakthroughs.

Here is what we do know: CRISPR works by snipping off a piece of the virus and sticking it into a specific part of its own bacterial genome that then works as a mugshot, allowing the bacteria to recognize the virus if it tries to strike again.

For CRISPR to work properly, bacteria need a captor to capture a piece of the enemy, and an executioner to use the mug shots to target the virus thereafter. These jobs are done by proteins, which we call CRISPR Associated (Cas) proteins. You may have heard of Cas9, which is in fact an executioner. Bacteria did not evolve Cas9 so we could edit embryos; it evolved to fight phages. (As you can tell from the number, there are other executioners in the bacterial world, only one of which is Cas9). This is where the story of the horse GIF diverges: it does not use Cas9.

The process of grabbing a piece of virus to stick into the CRISPR mugshot collection is called adaptation. In all CRISPR systems studied to date, two Cas proteins, Cas1 and Cas2, form an alliance to capture a piece of DNA from the invader. Now imagine that instead of random phage pieces, you bombard the bacteria with 'mugshots' that can be decoded as a GIF of a horse. Cas1/Cas2 will stick that video into the CRISPR mugshot collection. That is exactly what Seth Shipman and colleagues at Harvard did in July, as a great example of how basic research on bacteria can turn into transformative technologies. But again, we are just starting to appreciate the complexity in play.

Here are some of the things we do know from a decade of research on CRISPR adaptation in E. coli: four Cas1s and two Cas2s come together in a six-piece complex, take a piece of the invader, and stick it into the CRISPR mugshot collection. We also know that a separate protein, called the integration host factor (IHF), acts like one of people holding orange batons at the airport, telling Cas1/Cas2 where to land. But we had never seen the entire complex in action, until a study, published in Science last month, took advantage of structural biology to capture the structure of the captors in action.

Addison Wright and his colleagues at UC Berkeley show in that research that adaptation is far more interesting than we understood. The captor complex acts like a ruler, holding on to a snippet of a certain size, ready to be added to the collection next to the other mugshots. This is where IHF comes in; it holds onto that region of the bacterial genome, and bends it, which is like a secret message for Cas1/Cas2 to land there. As Cas1/Cas2 approaches, IHF holds on to Cas1 to ensure perfect landing, so that Cas1 can now integrate the new snippet into the mugshot collection.

I’d argue that the reason this is important goes far beyond our ability to record movies into bacteria. I mentioned previously that there are different executioners besides Cas9 (like Cas13a, Cas12), but Cas1/Cas2 seem to be the universal capturer proteins. They are fundamental to CRISPR working the way it does, and understanding them will reveal aspects of the microbial world that we never knew existed.

There are thousands of different CRISPR systems, some in our very own bodies. We're just starting to understand the intricacy of the microbial life going us all around us, and inside of us.