Biochem

From Kleptopedia

Medical biotechnology allows scientists to make changes to the genomes of living things. Genome editing, also called gene editing, is the modification of genes. It is a field of genetics that’s growing quickly. Genome editing could make these things possible… if people want them to be.

See this timeline for up to date developments in CRISPR/Cas9 genetic engineering.

CRISPR/Cas9

CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, is an innovative technology that allows geneticists to alter the genome by adding, deleting, or changing portions of the DNA sequence. CRISPR has entirely changed the genome engineering sector by providing a cheap and efficient way to alter DNA. The technology’s many potential applications include correcting genetic mutations, treating existing diseases in animals and humans, and enhancing varieties of crops. Its use in humans also poses a number of ethical dilemmas.

Check out this NYU CRISPR/Cas9 Report for detailed rundown of processes, possibilities and gene editing pros and cons.

HOW DOES CRISPR WORK?

The basic CRISPR-Cas9 system consists of two molecules that introduce one or more modifications into DNA. The first, Cas9, is an enzyme that acts as a pair of ‘molecular scissors’ that can cut both strands of DNA at a specific location so that pieces of new DNA can then be added, or existing DNA can be removed. A modified version of Cas9 has been developed to only cut one strand of DNA, while another has been developed to bind to DNA without any cut at all. The second molecule, a piece of RNA called guide RNA (gRNA), consists of a small piece of pre-designed RNA sequence (about 20 bases long) located within a longer RNA scaffold. The scaffold binds to DNA and the pre-designed sequence guides Cas9 to the correct location. The guide RNA has RNA bases that are complementary to those of the target DNA sequence. This should mean that the guide RNA will only bind to and deliver Cas9 to the target sequence. When Cas9 cuts the DNA, the cell recognizes that the DNA is damaged and tries to repair it. Scientists thus use the cell’s own DNA repair machinery to introduce changes to one or more genes in the genome.

CONSIDERATIONS

What are the pros and cons of having access to techniques like these? Scientists have the ability to change certain traits in an unborn child? CRISPR-Cas9 could potentially change the colour of that child’s eyes? Or eliminate the chances of them developing a genetic disease before they are born?

Scientists already edit plant genes to make plants more nutritious for the humans that eat them. Scientists also use CRISPR to edit animal genes so that the animals are better able to resist diseases. And the techniques that work on animals can also be used on humans. They can be used to help with many health problems, most obviously diseases that are caused by genetic problems.

A technique called germline editing is more controversial. Germline editing is the editing of reproductive cells. In humans, these are sperm and eggs. With this type of editing, scientists could make changes to humans that would be passed on to their children. This would mean that certain genetic diseases could eventually be wiped out altogether. But gene editing remains an extremely controversial topic. That’s because it raises some ethical concerns.

Gene editing could get rid of diseases that run in the family. But they could also change other features like hair colour, eye colour, or height. They could create a child based on the wishes of the parents-to-be. And this is a major concern for many people involved in the field.

CONCERNS

There is a high chance of errors occurring during the gene editing process. Errors can have devastating consequences. For example, a researcher can accidentally delete a gene. This can lead to developmental defects in the fetus. Any errors in germline editing could be passed on from generation to generation.

Once people have access to the technology, it might be hard to control what it’s used for. This could create a slippery slope. Parents-to-be might use the technology in ways that are considered sexist or racist. For example, if parents can choose their baby’s sex, is this a way of allowing sexism? If parents can choose physical traits that are more common in races they find more attractive, is this a form of racism? This technology could be extremely costly. This means that only some people will be able to afford it. However, there are arguments on the other side of these concerns, too.

How do scientists address the issues of safety and chances of error? Scientists state that nothing in the world of experimental science is 100% safe. The question is not “Is it safe?” Instead, it’s “Is it safe enough to be worth pursuing?” In other words, do the benefits outweigh the risks? Remember, gene editing could help scientists diagnose and eliminate diseases. Scientists and the body of government funding the research must agree on their answer to this question.

However, addressing the slippery slope issue seems to be more challenging. What qualifies as a correction of a deficiency? What qualifies as an unnecessary change? There is no clear-cut definition of either of these. So I encourage you, as future scientists, to think about the ethical boundaries and potential consequences of genome editing. Do you think the benefits outweigh the costs?

GENETIC ENGINEERING

Why should we care about genetic engineering? It could help eliminate hundreds of diseases. It could eliminate many forms of pain and anxiety. It could increase intelligence and longevity. It could change the scale of human happiness and productivity by many orders of magnitude. There are only a handful of areas of research in the world with this much potential.

Zooming out, genetic engineering could be viewed as a historical event on par with the cambrian explosion in how it changed the pace of evolution. When most people think of evolution they’re thinking about biological evolution through natural selection, but this is just one form. Over time, it will likely be superseded by other forms of evolution that act much more quickly. What are some of these? The candidates in my mind are (1) artificial intelligence, or synthetic life, breeding and mutating at a rapid rate (2) biological life, with genetic engineering being used to take a more directive approach, and (3) some merged hybrid of the two. Instead of waiting hundreds of thousands of years for beneficial mutations to show up (as with natural selection), we could start to see beneficial changes every year.

Consider where we are today:

  • Humans have been genetically engineering organisms for thousands of years using selective breeding (as opposed to natural selection).
  • Starting in the 1970’s, humans started modifying the DNA directly of plants and animals, creating GMO foods, etc.
  • Today, half a million babies are born each year using in vitro fertilization (IVF). Increasingly, this includes sequencing the embryos to screen them for diseases, and bringing the most viable embryo to term (a form of genetic engineering, without actually making edits).
  • In 2018, He Jiankui created the first genetically modified babies in China.
  • In 2019, a number of FDA approved clinical trials for gene therapies have begun.
  • So genetic engineering is already happening on humans today, and I don’t see any reason why it would stop.
  • With the creation of CRISPR and similar techniques, we’ve seen an explosion in research around making actual edits to DNA. I recommend reading Jennifer Doudna and Samuel Sternberg’s book, A Crack In Creation, for a great overview of this topic.
  • A lot of research is happening, but actually editing human DNA won’t be allowed. You don’t actually think people should be having designer babies do you?

Some will say that every child has the right to remain genetically unmodified, and others will say that every child has the right to be born free of preventable diseases. We make many decisions on behalf of children to try and help them have a better life, and I don’t see why this would be any exception.

Many new medical treatments have similar ethical issues as they are being developed. Typically, new drugs are tested on mice, then terminally ill patients, then slowly wider sets of people. They go through FDA trials for safety and efficacy. There is a well established path to test new therapies. Genetic engineering may have more potential (both for good and for harm) than most new medical treatments, but this doesn’t mean that a similar process can’t be followed.

The American National Academy of Sciences and National Academy of Medicine also gave qualified support to human genome editing in 2017 “once answers have been found to safety and efficiency problems…but only for serious conditions under stringent oversight.”

LUDDITE BULLSHIT

As for “designer babies”, people use this term to mean choosing traits like height or eye color that are not related to health. What's more, it won’t just be babies. Adults will be genetically modified at some point as well. For many it seems wrong to “play god” and move into this territory.

Think about surgery. Three hundred years ago, it must have seemed quite strange to “play god” and cut open a human body. Surgery was also an incredibly risky and crude process (someone’s arm or leg might be amputated on a battlefield in an attempt to save their life, for instance). Over time, surgery became much safer, and we started to use it in less life threatening situations. Today, people undergo purely elective or cosmetic surgery.

The same thing will likely be true with genetic engineering. It may start off being used only in dire situations where people have no other options, but eventually it could become safe enough where people genetically modify themselves for purely cosmetic reasons (for example, to change their hair color). In my view, there is nothing inherently wrong with people wanting to change, improve, or heal their own bodies, even if some uses are more urgent than others. And everyone should make this choice for themselves (I wouldn’t presume to make the choice for them). We won’t know the long term effects on people for many decades. I certainly wouldn’t want to be one of the first to get it done!

There is a misconception that the first edits made in humans will be totally unpredictable. There are some genes that one in ten people on earth have, that makes them healthier in some way. It will be safer than many people think to introduce this gene into someone who doesn’t have it, since it can be widely studied in the existing population. Most new drugs are introduced into the market with just hundreds or thousands of people who have taken it during trial periods, and this is a sufficient bar to demonstrate safety. So a gene that a billion people in the world already have could potentially be far safer than any new drug that has ever come to market.

In addition, new therapies are often tested on terminally ill people who have no other options, so healthy people likely wouldn’t be the initial market. This doesn’t mean that there can’t be other risks in the procedure, but the idea that an edit to a human genome would have entirely unpredictable results is false.

Many conditions are not controlled by one or two genes. So it won’t be as simple as you say to eradicate disease. This is true. Diseases exist on a spectrum from having a single gene culprit to having many thousands of risk variants which increase or decrease susceptibility to environmental factors. A growing body of research is advancing from uncovering these monogenic (single gene) causes of diseases to uncovering the causes of more complex (polygenic) diseases. Results are improving quickly as a consequence of larger datasets, cheaper sequencing, and use of machine learning. Even in a world where only simple gene edits were possible, a lot of human suffering could be eliminated. For instance, Verve is developing gene therapies to make heart disease, one of the leading causes of death in the world, less prevalent with relatively small edits. But other conditions, like depression or diabetes, don’t seem to be caused by a single gene, or even a handful of genes.

Luckily, machine learning (and techniques like deep learning) are well suited to solving complex, multi-variate, problems like polygenic risk scoring, and machine learning is improving at an incredible rate right now. Companies like GenomicPrediction have started offering polygenic risk scores to expecting parents. In addition, the datasets of sequenced genomes keep getting larger (some have over a million sequenced genomes at this point) which will improve the accuracy of the machine learning models over time.

Many things aren’t controlled by genetics. You can’t make happy/healthy humans just with genetic engineering. There are many environmental and lifestyle factors to consider, in addition to genetics. The lifestyle/nurture components are hard challenges in their own right, but thankfully we have some amount of control over them. For instance, we can eat healthier food, go for walks, or exercise. But in contrast, we have very little control of our genetics today.

Most people take it as a given that they can never change their genes, which is actually quite sad if you think about it. It feels terrible to be stuck in any situation where you’re powerless to change it. Imagine the person who continually struggles with their weight, no matter how much they focus on exercise and diet, comparing themselves to people who seem to eat whatever they want without gaining a pound. Nature can be very cruel to us, and genes can create an uneven playing field in life. Genetic engineering may not be the whole solution, but it would certainly unlock a big piece of it.

It’s a slippery slope from disease prevention to enhancement, where do we draw the line? There isn’t a clear line, and humans won’t draw one. The overton window will continue to shift as people become more comfortable with genetic engineering.

Genetic engineering will start by being focused on disease prevention, because this is the most socially acceptable form of it at the moment. But, for instance, if you have a gene that creates low bone density (making you predisposed to osteoporosis), and you correct this with genetic engineering, are your stronger bones preventing disease or are they an enhancement (enabling you to play sports and lift heavy things)? The answer is both. There are many blurry lines like this. To me, the goal is just to improve the human condition, so the distinction between preventing bad outcomes and creating good outcomes is less relevant.

In addition, it is worth noting that we do things all the time today to “enhance” the human body (wearing running shoes, putting on sunblock, corrective lens, etc). And we even do things to enhance ourselves genetically today, like choosing who to have children with or couples who do IVF screening. Genetic enhancement may be scary to some people today, but I think this is mainly just because it is new. Over time, it could be considered as normal as getting LASIK surgery to fix your eyesight.

If everyone wants to have a certain trait, won’t this create less diversity in the world?

There are some genes, like those which increase your risk of heart disease, which most people will want to eliminate. So in that sense there might be less genetic diversity. But I don’t think this will be an overwhelming trend for two reasons. The first is that there is great variety in human preferences (in what is considered beautiful, for instance) and the second is that many people have a desire to stand out and be unique. If it becomes cheap and ubiquitous to become some definition of beautiful then it will no longer hold the same cache, and preferences will evolve, just like in fashion. When you can be whomever you want, I think we’ll actually see much greater diversity, not less.

You can see a glimpse of what this might look in video games today, where people can create their own avatar. When people can be whatever character they want, the range of expression is much greater than in real life. Genetic engineering could also help same-sex couples have genetically related children, which would be a new development. And it could even lead to children which are the product of more than two people. Imagine a child that is the product of ten, or even a hundred, people.

Finally, we may see people change themselves in ways that can’t occur naturally today (webbed fingers? scales? night vision like a cat?). If we are truly able to master genetic engineering over the coming century, there will be many beautiful new forms of individual expression that we can’t even imagine today. The very idea of what it means to be human will change.

Many great entrepreneurs and artists had ADHD, Autism, depression, schizophrenia and other conditions which people may want to eliminate with genetic engineering. In this world, wouldn’t these qualities be eliminated in the name of conformity and risk aversion? Parents aspire for their children to be all sorts of things in life: artists, scientists, politicians, generals, religious leaders, entrepreneurs, etc. These each might have some genetic traits in common, and others that are very different. If it turned out that the best chance of becoming a successful artist was to start with a certain set of genes that included ADHD, I suspect many parents would still opt for this.

We will probably find ourselves in a world with far more brilliant outliers, if parents can get a genetic head start on raising the next Picasso or Einstein. Other parents will opt for balance. There is no right or wrong answer, just preferences. Finally, just because we see examples like the above today, doesn’t mean this needs to be the case in the future. Brilliant people are often “spikey” (outliers in a few areas with severe deficiencies in others), but in a world where genetic engineering is mastered there may be people with all the upside (and more), with little or none of the down side, so there is no guarantee the two need to be linked.

MODERN DAY EUGENICS?

Eugenics was about various political or government groups trying to modify the gene pool through use of force. The ideal outcome here is freedom of choice for every individual. When people can choose how they want to modify and heal themselves (and their children) I think this will be very liberating. There are people in society who might try to abuse this technology (just like any technology), but as long as it is broadly available I think this mitigates a lot of the risk. It’s unlikely that one country or political group would have exclusive access to genetic engineering for long (it is widely researched globally, with a lot of information exchange between groups, both formally and informally).

Some day, genetic engineering may even make it possible to create people who are more tolerant and accepting of others around them. Tribalism is a part of our evolution, and it may have a genetic component. Even children exhibit this quality from a young age. How interesting would it be if people were able to change on this dimension genetically? We don’t know how to do this yet, but it could be possible in the future.

Won’t this create a world of haves and have nots? What if it is only available to rich people? What if it turns out like Gattaca?

Just like many technologies, genetic engineering will almost certainly be available in developed countries first, and it will be expensive. But this is not unique. Cell phones, airplanes, and even basic sanitation are all unevenly distributed around the world. The beauty of technology is that it tends to drive down costs down over time, so it eventually reaches a wider group of people. The cell phone was once a tool only for rich people on Wall St, and it is now available to even the poorest people in the world. There is an open question about whether genetic engineering will follow a cost curve that is more like technology (lower over time following Moore’s law) or like healthcare (rising over time following Eroom’s law), but this has more to do with policy decisions than the technology itself. The main point is that high initial costs are not a good reason to prevent innovation from happening. If we took this approach, we likely wouldn’t have any of the improvements we see in the world today.

It’s also true that genetic engineering will offer advantages to those who can access it. This could create a less even playing field in some ways, but in other ways, it could actually make it more fair. Today, some people win the genetic lottery at birth while others lose (for instance, being prone to depression, a learning disability, etc). If any child could start on a level playing field genetically, this feels like a more fair world. Finally, genetic modification can also take place in adult humans. So even if someone doesn’t have access to it at birth, they may still be able to benefit from genetic engineering later in life.

Gattaca misses this last point, implying that you will always be left behind if weren’t born into an elite group. Reality will probably afford more social mobility, with adults benefiting from new genetic engineering treatments as well. It is a very entertaining film none the less, and I suggest anyone who is interested in the subject watch it.

What if people try to enhance traits like intelligence? Many intelligent people exist in the world today, and, at least the ethical ones don’t seem to pose too much of a problem. So let’s say we doubled the number of smart people in the world (using IQ or whatever definition of smart you prefer) through genetic engineering while keeping the percentage of ethical ones the same or greater. Or similarly, we could double the smartness of the existing people. Would this be a problem? Certainly, some good things would happen. The pace of improvement in society would likely increase, for instance, with many more smart, capable, people solving the world’s challenges.

The biggest negative change might be that the rest of us feel a little left behind or bewildered by all the new progress and areas of research, if we didn’t similarly have our intelligence increased. This boils down to a question of whether you think we should value overall growth in society, or one’s relative place in it, more highly. Each person should answer this for themselves (I don’t think there is one right answer). So it could be a mixed outcome, or very good, depending on your perspective. (Side note: this is a great short story about what it might feel like as society begins to advance.)

PUBLIC REACTIONS

One final thought experiment: if people want to become smarter, do we have the right to stop them? If it is by getting an education, most people would say no. If it is through genetic engineering, how is this different? Should parents be able to choose the genes of their child?

Parents choose all sorts of things that have a major impact on their children (what they eat, how they are educated, whether they are born at all, etc) as their guardian. This is a well-established concept in the law today, with guardians making major decisions for a child until they turn 18 (or an equivalent age in each country). Once children come of age, they will likely take control of their genetic modification, just as they can make a decision to get a tattoo.

It would be a shame if the genes parents chose for their children were fixed indefinitely into the future. As I’ve discussed elsewhere, it’s likely in the future that genes can be modified in living people, not just embryos. So hopefully children aren’t stuck with their parent’s genetic preferences for life.

Imagine that you’re an expecting parent. How much would you pay to have the peace of mind that your child will arrive healthy? Imagine you were an adult with a life-threatening disease. How much would you pay to receive a cure that required a genetic edit? The answer to these questions says a lot about how genetic engineering is likely to be adopted in the future.

Today, it is widely considered to be unconscionable to genetically modify humans. But I believe that within twenty years, we will see this view change dramatically, to a point where it will be considered unconscionable not to genetically modify people in many cases.

Genetic engineering is one of the highest potential areas of research today. I believe we should continue to invest it, and entrepreneurs should work hard to bring new products to market in this space. Yes, it has risks, and we must proceed with caution. But many new technologies have risks — even life-threatening ones — and we eventually are able to use them to greatly benefit the world. We shouldn’t let fear hold back progress on promising new areas of research.