CRISPR and the Human Genome

Introduction to CRISPR

Recent advances in genome sequencing and gene editing will soon enable amazing feats like curing genetic diseases, eradicating disease-carrying mosquitoes, and allow us to genetically modify food to feed the world.  Five years ago these ideas fell into the realm of science fiction, but due to these advances they will soon be a technological reality.  Humans will soon have the ability to direct their own evolution through the germ line editing of human embryos.

CRISPR/Cas9 is the tool that will enable this.  The CRISPR/Cas9 system was discovered in 2006 as bacterial defense mechanism that can detect and remove DNA from viral invaders.  When the CRISPR/Cas9 enzyme is combined with a programmable RNA guide strand, it has the ability to cut DNA with high fidelity.  This enables researchers to add, remove, or edit a gene at any location in the genome.

The public is largely unaware of the implications of CRISPR/Cas9 and how fast the research is advancing.  It has been described as the most important technology since PCR, and in just several years from its discovery, it has revolutionized the fields of biology, biochemistry, and molecular biology.  The beauty of CRISPR/Cas9 is how simple of a technology it is and how easy it is to use. It is already being used today by thousands of scientists in hundreds of research labs around the world.  You can even order your own customized CRISPR enzyme on a plasmid for the low price of $65 from Addgene.

Jennifer Doudna is a professor of Biochemistry at UC Berkeley, and is one of the co-discoverers of the CRISPR technology. In August of 2012, her group published the first paper that directly showed the mechanism of CRISPR/Cas9 in removing virus DNA from bacteria cells, and a follow up paper only five months later showing it can be used to edit human cells as well.  These landmark papers were the starting point of a whirlwind of new CRISPR gene editing advances.

By mid-2015 a Chinese research group had already used it to edit the genome in non-viable human embryonic cells.  British scientists recently received approval to edit human embryos to study what causes the high rate of miscarriage associated with in vitro fertilization (IVF).  DuPont predicts that it will have CRISPR/Cas9 modified foods on dinner plates by 2018. Bayer and CRISPR Therapeutics announced a $335 million joint gene editing venture.  Last August the Broad Institute raised $120 million from Bill Gates and other investors to develop gene therapies in adults.  Harvard Biologist George church recently held a closed door meeting with 150 top researchers and lawyers to discuss building a synthetic human embryo.

The CRISPR world is coming and it is coming faster than most people realize.

Realizing this, the world's leading CRISPR researchers held an international summit in Washington DC at the end of 2015 to discuss the scientific, ethical, and governance issues associated with human gene-editing research.

Stop and think about that for a moment.  The global gene editing research leaders, realizing that this technology is improving faster than anyone could have possibly imagined, and just held an impromptu meeting to discuss ethical issues like human germ line editing (aka designer babies).  What was science fiction just five years ago is now pushing our ethical boundaries of today.

I wrote this article to continue that conversation and to explore the latest developments of gene editing technology, to explore the ethical implications, and to share my own views.

Genes and Physical Traits

The effect of genetics on human traits is a highly politicized issue.  In the United States, there are people on the political right who flat out deny evolution, and there are members of the political left that seem to think evolution is for animals, but not for humans, especially when it comes to psychological traits.  Both of these views are in conflict with the evidence.  A 2015 Nature Genetics meta-analysis looked at the results from over 50 years of twin studies and found that for any given trait, physical or mental, was influenced roughly 50/50 by their genetics and their environment.

Recent studies have identified the genes responsible for the variation in physical traits such as height, skin pigment, and eye color between individuals.  A 2014 study published in Nature Genetics used a data set of 253,288 individual genomes to discover that at least 697 genes play a role in determining a person's height, and account for approximately 60-80% of the variance in height among people. It is also known that two mutations to the FGFR3 cause more than 99% cases of achondroplasia, a common type of dwarfism.  Another study published in Nature showed that a mutation in the MC1R gene is causes red hair and fair skin.  Additionally, a 2011 Nature Review showed it is possible to predict an individual's eye color with 90% confidence based on mutations in only six genes.  Another recent 2016 study published in Nature shows evidence that facial features such as nose shape and chin size are controlled by just five genes. 

Genes and Mental Traits

It is undeniable that genes influence physical traits in humans, but what about mental traits?

Evolutionary psychology is the principle that evolution influences not only our physical traits, but our mental traits as well.  There are those that subscribe to the theory of mind that the brain of a child is a blank slate and it is only through the environment that anything can be written onto it.  This view is almost certainly false, because a blank slate has no mechanism in which it can learn.  A human brain needs to have innate learning mechanisms already in place, and for a biological brain these have to be heritable.  Steven Pinker thoroughly debunks the notion of the blank slate in this book “The Blank Slate, the Modern Denial of Human Nature”.

With that said, evolutionary psychology is a difficult field to study because of the challenge associated with forming testable hypotheses that explain evolutionary events that happened millions of years ago.  One must proceed with caution because it is easy to rationalize your way into holding a potentially discriminatory position through lazy or incomplete thinking.  However, as scientists we should never be afraid to ask questions and gather evidence, no matter how the results may contrast with popular beliefs at the time.   

Many critics of evolutionary psychology fear that it may lay the groundwork to justify social inequality or discrimination against individuals or groups of humans.  Their general argument goes as follows:  If the ancestors of one group of humans experienced different natural selection pressures than the ancestors of another group of humans, then the average properties for any given trait may be different between the two groups.  If this trait is valued by society, there exists a biological justification for discrimination between groups.

I reject this line of thinking.  If the fear is that the wealthy simply have better genes than poor people, and by scientifically confirming it will somehow justify inequality, it won't matter because it will be true anyways.  In this hypothetical scenario, rich people will go through their lives ignorant of their innate genetic advantages, while the poor are continually disadvantaged through genetic bad luck.  To intentionally move forward in ignorance for fear of what may be true is not useful if one cares about maximizing equality in society.

Recent studies have looked at the effects of genes on individuals and populations on mental traits ranging from depression, a nation's happiness, psychopathy, intelligence quotient (IQ), general cognitive ability, and even their preference for cilantro. 

This NY Times article reports that researchers discovered that 20% of Americans have a mutation to FAAH, a gene that regulated production of anandamide , a molecule that interacts with cannabinoid receptors, and generates a feeling of bliss.  Out of 2,100 volunteers they found that people who had two copies of the mutant FAAH gene had roughly half the rate (11%) of cannabis dependence than those one or no mutant gene (26%).  A population study found that a mutation in the FAAH gene is consistently and highly correlated with levels of happiness between different nations.

A study of 28,000 European adults that compared the amount of Neanderthal DNA that they had to behaviors found that a significant fraction of the variation in risk for depression and even tobacco use.  A 2015 Nature Translation Psychiatry study found that genetic variation of the SKA2 gene is a predictor of suicidal behavior and post traumatic stress disorder.  A survey of nearly 30,000 people uncovered a single gene mutation that was found to be the cause of an individual's preference for cilantro.  Those who did not have the mutation reported a distaste for cilantro and that it tasted like soap.

These examples confirm that genes undeniably influence human mental traits, but its critical to remember that the environment matters as well.  Genes may boundaries on human physical and mental abilities abilities, but they do not represent destiny.  A psychology professor who studies psychopaths discovered that he had many of the gene variants that corresponding to psychopathic behavior, including a variant of the MAO-O gene.  Brains scans confirmed that he literally had the brain of a psychopath.  Considering that he was married, had kids, and never committed murder, he concluded that he was a “pro-social psychopath,” or someone who has difficulty feeling true empathy for others but still keeps his behavior roughly within socially-acceptable bounds.  He attributes his behavior to his warm and loving childhood during the developmental stages of his life when the empathy parts of his brain were being wired.

IQ is not a perfect or complete measure of intelligence.  However, what it does do very well is measure the psychological traits that are valued by western society.  Unsurprising, a 2013 study of 6,870 individuals found that IQ and happiness are strongly correlated.

It is foolish to suggest that IQ is governed only by genes, as it has been clearly demonstrated that environmental factors play a significant role.  A relaxed, well-rested, well-fed person who values and has access to education is probably going to score higher on an IQ test than a genetically identical person who is stressed, tired, chronically malnourished, who does not value, and has poor access to education.  An ideal environment can allow an individual to meet their genetic potential.

However, a 2014 study seems to indicate that genetics on average have more of an influence than the environment on IQ.  They show that between 40-80% of the variance in IQ is due to genetics, not environmental factors.  One twin study that compared IQ between sets of twins found that the IQ of identical twins were more similar (r = 0.86) than fraternal twins (r = 0.60), and both were more similar than adopted children compared to their parents (r = 0.19).  A 2001 Nature Neuroscience study used MRI to compare brain activity between identical twins and fraternal twins, and found a strong correlation between brain activity in gray matter and genetic similarity.

Scientists are now beginning to understand the how genes influence the neural networks that govern human cognitive abilities.  A 2016 study published in Nature Neuroscience  identified a network of over 150 genes that are expressed in the brain that reliably predict human cognitive abilities and memory.  A 2016 JAMA Psychiatry study looked at a population of 1,002 individuals and showed that a duplication of the 16p11.2 loci was associated with autism, schizophrenia, and a drop in 25 IQ points.  A 2016 study published in Nature discovered a positive link between cognitive function and physical health using a large dataset of 112,151 individual genomes.

As we move towards an increasingly technological and information based economy, with increasing amounts of automation for routine tasks, high paying and prestigious jobs are increasingly going to require creative and intelligent skill sets.  Groups and individuals who do not posses these traits are likely going to suffer socially and economically.  As we consider the effects of poverty and the effect that automation may have on the unemployment rate, it is worth considering that nobody alive today got to pick their genes.  Every single person alive today is an accident of biology, and their genes, for better or for worse, were selected by arbitrary and blind natural selection forces over many generations.  Due to the rapid and ever changing society that we live in, in many ways humans are survival machines genetically adapted to a world that no longer exists.  Much of human suffering can be attributed to this mal-adaption.

If a safe way exists to change our genes, than what are we waiting for?

The Dangers of Human Genetic Modification

There is a considerable difference between using CRISPR to modify disease causing genes in adults, and using CRISPR to enhance the traits of humans.  In both cases, the first step is to sequence the genome of an embryo, and the second step is to follow up by editing or removing the intended genes.  If this technology existed today, how many prospective parents do you think would elect to use it on their future children?

In a way, British parents have already answered the first part of the question.  British parents have access to a genetic screening test for unborn fetuses to test for an extra chromosome 21, the genetic condition that causes Down Syndrome.  Since the test has been implemented, 92% of expecting mothers decided to terminate their pregnancy when their unborn fetus tested positive.  It is clear that when given access to this kind of information without an available treatment also available, the overwhelming number of British parents decided to terminate their pregnancy.

What if genome sequencing improves to the point where it becomes trivially easy to sequence the full genome of every single unborn fetus?  Would British parents decide to terminate their pregnancy at the same rates for other genetic diseases?  This could lead to a nightmare scenario of "trial-and-error pregnancies" where parents are willing to repeatedly terminate their pregnancy, until they get the most genetically fit child possible.  It is not difficult to imagine that this could potentially discourage doctors from sharing genetic sequencing results with their patients.

Now imagine that if in addition to genetic sequencing, it was trivially easy to repair the disease causing genes as well. If given the option would a parent choose to cure their unborn child of one of the hundreds of known genetic disorders if it was safe to do so?  I think the answer would be overwhelming yes, but where do we draw the line on the use of this technology?  Choosing genes from either either embryo selection oand/or direct gene editing seems obvious to me, but what about other heritable traits?

This 2015 article in the Atlantic highlights numerous studies that show that people who are taller, more attractive, and smarter on average earn more money and live fuller, happier lives.  If a technology existed that would enable a parent to safely give birth to a child with these traits that they otherwise could not, is it moral to deny them access to this technology?  Does a parent have the right to edit the genes of their baby to give their future child the best chances to succeed in life?

Assuming the technology is safe and reliable, my answer to all of the above questions is yes.  We already select the genes of our children by choosing our sexual partners.  Except choose them based on features like how their smile makes us feel, the shape of their butt, and their personality traits which are already partly heritable, not on the content of their fully sequenced genome.  There is nothing sacred about our genes, they are the products of millions of years of arbitrary natural selection pressures.  Heritable personality traits that lead to successful evolutionary strategies eons ago may contribute towards human misery in modern society.  If we can safely change our traits to maximize our well being in the world that exists today, why shouldn’t we?

There is risk associated with both gene therapy action and in-action.  It is not inconceivable that one day CRISPR technology will be so reliable and our understanding of the human genotype-phenotype relationship so complete, that the risk of in-action will be greater than action.  It is at this point that we should fully embrace the gene editing technology.

How can we ensure that CRISPR is safe?

Despite our advances, no one can guarantee the safety of CRISPR gene editing in humans.  Ethically, I think we can only gain this knowledge through incremental research.  I envision CRISPR gene therapy research advancing in roughly the following way.

First, there will be further basic research in cell culture and improvements made to the CRISPR enzyme or the Cas9 RNA guide strand.  We are already making extremely rapid advances in this area.  For example, just within the last several of months there have been two reports of modified Cas9 RNA guide strands that significantly reduce or completely eliminate the number of detectable off-site CRISPR genomic cuts.  The British group has already received approval and funding to test CRISPR on human embryos to study infertility.

Second, CRISPR will be used to edit animals and foods.  Genetically modified mice will be used to create new models to study disease.  Chinese researchers have already genetically modified animals to make super strong beagles, autistic monkeys, and miniature pigs.  DuPont has announced their intentions to have CRISPR modified foods on dinner plates by 2017.  Again, it seems like we are well on our way in this second phase of research.

Once we are confident in the safety of CRISPR in animals and food, we will move onto gene therapies in adults.  In October, Elizabeth Parrish, a CEO of BioViva, a biotech startup company claims to have already undergone anti-aging gene editing therapy.  Another biotech company says it has plans to test CRISPR gene editing on people by 2017 to treat blindness.  

What lies beyond is the modification of embryos that are then brought to term.  This raises very serious moral concerns because embryonic modifications will affect not only the person, but their entire germ line as well.  Considering that an embryo cannot give consent for itself let alone every other human in its future germ line, this raises serious moral concerns.  We do not know what the unintended consequences of a large scale adoption of germ line editing could be.  What if problems don't arise until after several generations?  To completely understand this would require generational studies on CRISPR-modified individuals and populations.  If we decide to move forward with embryo gene therapies, it should only be in situations where the risk from the disease due to in-action is significantly greater than not performing CRISPR surgery.

Once we master curing genetic diseases, the next step is to modify our non-disease causing traits.  To feel comfortable about the safety of doing this (moral and philosophical concern aside), I would like to see at minimum, thousands of CRISPR-modified healthy babies, children, and young adults who have been cured of their genetic diseases, in addition to millions of healthy CRISPR-modified pigs, dogs, monkeys, and other animals.

Once we are absolutely confident that all the bugs are worked out, and we have a deep understanding of how genes work, combined with advances in IVF, epigenetics, and stem cells, should we move forward with multiplexing dozens, hundreds, or thousands of CRISPRs to modify as many embryonic genes as we see fit.  As we explore the solar system and the galaxy this may become a necessity.

Back to Reality

These are difficult moral questions that could be the basis of science fiction stories, but we need answers to these questions sooner than later.  Despite the fear of designer babies and increasing inequality, the technology to do all of these things is nearly upon us.  Do you have faith in the US congress to understand these nuanced issues and to properly legislate CRISPR germ line editing?  How many members of congress have the scientific credentials to understand what is at stake?

In my opinion, to ask if human genetic modification is ethical is the wrong question.  Competition in a global marketplace between countries with different value systems will make designer babies inevitable.  Imagine the benefits of a genetically modified society that no longer has the genes associated with cancer, heart disease, diabetes, obesity, depression and have the genetic predisposition for high IQ and creativity.  A society that fails to adopt these practices could be left behind both economically and culturally in the global arena.  In my opinion, this is not a question of if, it is a question of when and how.

Instead, we should be asking the following questions:  Who will develop this technology first?  How can we ensure that it will be safe?  How will we ensure equal access?  If only the biotech-minded billionaires have access to this technology today, in 30 years their children may become the genetic elites that rule over the rest of us.