This is the first post in what I hope will be a series of posts arguing that genetically engineering humans may provide a huge benefit to individuals and society as a whole. In the interest of creating something readable, this post will largely ignore the controversies and unintended consequences of such a project, but I plan to address those in later posts. It will also ignore perhaps the most impactful genetic change of all: increased intelligence. Such a change deserves a post of its own.

I'm also going to be avoiding the 800 pound elephant in the room: the long history of eugenics and the terrible ideologies that embraced it. Ensuring that whatever programs are implemented do not promote some terrible genocidal agenda and do not create some permanent two-tiered society is obviously at the top of the priority list for anyone looking to do real genetic engineering. But like with genetic engineering for intelligence, there is too much to address in one post so I will be saving that for a later one.

A quick disclaimer before I begin: when I first sat down to write a post about genetic engineering, I planned to thoroughly research everything I wrote about and give links to most of the claims I made. While I will do so for what I judge to be the less commonly understood facts presented in this piece, this will not be as thoroughly researched and comprehensive as I originally planned.

As a result, many of the conclusions I draw in this piece will be based on my own incomplete knowledge and are therefore liable to be wrong. If you spot any particularly glaring errors, or if the pacing is off, or if you get too bored and don't finish reading please let me know in the comments. That being said I think I have read enough about this topic to have something worth reading.

Part 1: A Changing World

Human history is a story of accelerating change. The rapid growth in brain size and general intelligence that took place between 3 million and 50,000 years ago enabled the explosion of human populations and power that culminated in our modern globe-spanning civilization. There is still some debate in the field of anthropology about WHY exactly evolution favored larger brain sizes and increased intelligence so consistently for so long. Whatever the reasons were, they must have been very compelling. Relative to resting metabolic rate -- the total amount of calories an animal burns each day just to keep breathing, digesting and staying warm -- the human brain demands more than twice as many calories as the chimpanzee brain, and at least three to five times more calories than the brains of squirrels, mice and rabbits.

This massively increased brainpower had one particularly notable effect: humans became able to communicate via language, a far more flexible and sophisticated form of communication than that used by any other species. This unique ability probably played a fundamental role in the development of agricultural societies, which was the first step in the march towards modern civilization.

The agricultural revolution led to an explosion in the size of the human population, and the industrial and green revolutions lead to a rate of population growth unprecedented in human history. This massive population growth and increased technological sophistication has dramatically altered human lifestyles. For most of human history, individuals lived in groups of at most a few hundred and subsisted off of a combination of hunting, gathering, fishing, and scavenging. This lifestyle gave us many of our current traits including our upright posture, our teeth (which are optimized for eating a combination of meat and plants), our large brain sizes, our penchant for gossip, and many other human characteristics.

When agriculture spread throughout the world beginning around 12,000 years ago at the end of the last ice age, it dramatically altered human lifestyles and diets. Humans began to live shorter less healthy lives, back neck and tooth problems became much more prevalent and diseases began to spread in the dense sedentary societies that sprung up around the world (particularly in Asia and Europe).

In a very real sense, the agricultural revolution made life worse for the average human. But because life was not so bad that sedentary individuals were less likely to pass on their genes, and because agriculture could support far more humans with the same land area, there was no path back. Humans across the planet turned to agriculture not because it provided for a better, happier life, but because they were stuck in a Malthusian trap.

A Genetic Mismatch

The decline in lifespan, decrease in height, increased incidence of bone and joint issues, the rise of cavities, and the spread of infectious diseases that accompanied the agricultural revolution are attributable to a mismatch between human genes and human lifestyles. It is my contention that despite significant improvements in lifespan, sanitation, and food supply, the rapid progress of modern technology is creating a wider and wider gulf between the environment humans evolved to live in and the one in which we find ourselves today.

Humans are quite adaptable, so we have created ways to bridge the gap between these biological needs and the shape of modern living. Gyms and exercise equipment, for example, give people a way to maintain their physical and mental health in the absence of lifestyles that necessitate exercise as a required part of staying alive. But these solutions are extremely sub-optimal: humans now have to spend several hours per week running, swimming, biking and lifting weights for no particular reason other than to maintain health. And while many people might argue that “exercising makes me feel better and look better and live longer” (all true by the way), it is still the case that our ancestors got the same benefits in the process of doing something they had to do anyways (hunting and gathering).

There are many, many other such examples. Tooth issues such as wisdom teeth crowding out other teeth in our jaw, the frequency of cavities and tooth decay are also an example of a problem introduced by a change in our diet that accompanied the agricultural revolution. Frequent back and neck issues are also a result of a mismatch between our ancestral environment and our modern working conditions. Our tendency to focus on gossip about the lives of celebrities whose lives will never impact us is a relic of an ancestral environment in which the only people whose gossip we heard were those in our tribe (about whom it was useful to know gossip). Our preference for sugary foods devoid of essential nutrients are a relic of an era in which such foods were hard to come by and the risk of starvation was a much greater risk to reproductive success than the risk of obesity. And the disproportionate attention we pay to extremely low probability risks like terrorism and violent crime are a relic of an era in which human to human violence was much more common than it is today.

The incredibly high frequency of death from old age represents perhaps the greatest disconnect between the environment our genes were optimized for and the one in which we now live. As explained in this excellent quora post by Dr. Suzanne Sadedin, the average age at which an individual organism from a given species will die is determined by the rate of all-cause mortality in its natural environment. This evolutionary theory of aging, known as the Antagonistic Pleiotropy Hypothesis, is well supported by theoretical models, animal experiments and human correlational studies. The mechanism of action here is a set of genes with a specific characteristic: they increase reproductive fitness at a young age but decrease the window of reproductive opportunity (often by causing health problems at an older age). When all-cause mortality is high, such genes are beneficial as the organism carrying them is likely to have died by the time the downsides become relevant.

So if the antagonistic pleiotropy hypothesis is to be believed, how long would we expect humans to live for if they were genetically optimized for their current environment? Unfortunately, I wasn’t able to find any models predicting lifespan given all-cause mortality rates of a particular species. However, let us compare the mortality rates of hunter-gatherer societies with those of humans living in the developed world to give us a sense of how massive the difference is. Here’s a graph showing mortality rates in various Hiwi hunter-gatherer groups.

Here's another graph showing mortality rates in Canada.

It isn’t even close. The chance of death between the ages of 1 and 5 are somewhere between ten to thirty times lower in modern societies than in hunter-gatherer societies, and even at age 70 mortality rates are still at about a third of the levels they are in hunter-gatherer societies.

It therefore stands to reason that we could substantially increase the human lifespan by opting for genetic variants that give slightly lower reproductive fitness at a young age in exchange for longer life. It also stands to reason that given the low rate of all-cause mortality in modern society, this trade-off would INCREASE reproductive fitness.

There are many more things that were clearly important considerations in the past that are not as important today. For example, the cost of gaining access to more calories is not as high today as it was in the past. Are there genes that increase health or intelligence at the cost of increasing one’s basal metabolic rate? If so, such genes might have been selected against in the past. But with much easier access to calories today, such genes might provide a net benefit. Are there genes that increase intelligence at the cost of a larger fetal skull size? Babies with such genes might not have fit through the birth canal in the past, but we now perform c-sections on a regular basis. The possibilities here seem absolutely enormous and we already have specific examples of genes with trade-offs that don’t make sense anymore. Are there genes that increase the frequency and severity of the stress response, making us better at fighting off predators and other humans at the cost of longevity? If so, perhaps we decrease the expression of such genes to increase lifespan at the cost of not being able to win bar fights or do amazingly well at contact sports. You get the idea.

Part 2: Surpassing Evolution

Evolution works wonders over long timescales, but it is not efficient or even good at maximizing reproductive fitness. As Eliezer Yudkowsky once wrote, “the wonder of evolution is not how well it works, but that it works at all.” Such a process leaves much to be desired. In this section, I will be describing how genetic engineering will allow us to surpass the fitness maximizing constraints imposed by evolution, and by doing so improve the lives of humans and the rest of this planet’s species.

The first limitation I will be discussing is that of the local fitness maxima. One of the most frustrating things about evolution is that it can only make progress one mutation at a time. If gene B only provides a benefit when gene A is already present, gene A must spread through a breeding population before gene B. And if gene A does not by itself provide a reproductive fitness advantage, it becomes nearly impossible for gene B to ever spread. There are some exceptions to this (see Scott Alexander's excellent post on how weak competition can actually lead to increased fitness), but in general, this is the rule.

Genetic engineering opens up the possibility of escaping from the “local fitness maxima” created by this one-step-at-a-time limitation of evolution. I’m going to tell you the story of one of the most promising such interventions I know of: the project to move genes out of the mitochondria and into the nucleus of cells.

MitoSENS: Lending Evolution A Hand

MitoSENS is an ongoing project to address one of the fundamental causes of aging: damage to mitochondrial DNA caused by free radicals.

This story begins 1.45 billion years ago, when, during an unbelievably rare occurrence, a large cell swallowed a small one, the small one survived and multiplied inside the larger one and neither one died. This small cell was special: it was the ancestor of modern mitochondria, and it dramatically increased the amount of energy available to the large cell. This event was a seminal moment in evolutionary history, surpassed in significance perhaps only by the origin of life itself. As best we can tell, it only happened a single time in the 3.5 billion year history of life, and from that single ancestor all eukaryotic organisms (plants and animals) are descended.

For this reason, mitochondria (along with chloroplasts) are the only organelle in eukaryotic cells that can self-reproduce. A legacy of this independent origin story lives on within the membrane of every mitochondrion: 37 genes and 16,569 base pairs which form the last remaining vestiges of an organism that once lived independently in a much larger world.

You might suspect that 37 genes are not nearly enough for any organism to function, let alone reproduce. You would be correct. This was a bit of a mystery to me as well until I learned what evolution has been doing to mitochondrial DNA over the last billion years of evolution: it has been moving DNA out of the mitochondria and into the nucleus.

You see, mitochondria are one of the single biggest sources of free radicals in our bodies. In fact, the free radicals (AKA reactive oxygen species) that are produced by our mitochondria account for the vast majority of free radical damage in an average person’s body. The inside of a mitochondrion is one of the worst places to be if you are a molecule that values your current atomic arrangement. With no nuclear membrane to protect itself, mitochondrial DNA is exposed to the full fury of this onslaught of free radicals produced as a byproduct of ATP synthesis.

So the process of random mutation and natural selection has been hard at work moving genes out of the mitochondria and into the nucleus of the cell. I still haven't found a satisfying explanation of exactly HOW this transfer happens, but some process appears to have been hard at work over the last 1.5 billion years moving genes out of the mitochondria and into the nucleus of the cell. Proteins necessary for mitochondrial function and now produced outside the mitochondria and transported back inside via the TIM-TOM complex, a series of channels in the membranes of each mitochondrion that allow externally manufactured proteins to be moved inside the mitochondrion. This evolutionary process has moved almost all of the 3000 genes of the ancestor of mitochondria into the cell's nucleus. But evolution can only advance one step at a time, and there’s something special about those remaining 37 genes that makes them particularly resistant to evolution’s effort.

Two chief problems appear to be at the root of evolution’s inability to move those remaining genes out of the mitochondria: hydrophobicity and code disparity. Code disparity is a difference in the interpretations of codons in the nucleus and the mitochondria. A codon is a set of 3 base pairs that represent an amino acid or a regulatory signal such as "end of protein". At some point in evolutionary history, the interpretation of four of these codons was switched in the mitochondria. The first of the four that appears to have changed its interpretation is the codon formed by the base pairs UGA. UGA is used to encode a STOP signal (meaning the end of a protein sequence) in nuclear DNA. But some time around 1 billion years ago this codon’s interpretation was switched from being a STOP signal to encoding the amino acid tryptophan in the mitochondria. Once this happened, gene transfer from the mitochondria to the nucleus became significantly harder, because the proteins synthesized from such genes would be truncated at the location of every tryptophan in the structure.

The rest of the paper explaining why no more genes seem to have transferred is quite interesting and can be read here if you’re interested.

This is of importance because mitochondria free radical damage appears to play a critical role in aging via a process called the "Mitochondrial Free Radical Theory of Aging".

A full explanation of the theory is beyond the scope of this post (read chapter 5 page 68 of Aubrey de Grey's book Ending Aging if you want one.) But the shortest version ever is that a small proportion of mitochondria accumulate a specific set of mutations with age that turns the cell in which they reside into toxic waste production facilities. The ATP synthesis process that Mitochondria normally perform is shut down inside such cells, forcing them to turn to another energy production method whose byproduct is superoxide, a dangerous free radical. These free radicals end up colliding with low-density lipoprotein and creating oxidized cholesterol, one of the primary contributors to high blood pressure and heart disease.

I should point out here that the following explanation is not universally accepted. There is at least some criticism of the “Mitochondrial free radical theory of aging” proposed by de Grey, and the issue doesn’t seem quite settled one way or the other. However, given evolution’s long history of moving mitochondrial genes into the nucleus, it seems very likely that there is a fitness advantage to doing so even if a reduction in the rate of aging is not THE specific reason.

Since we know how to translate mitochondrial genes into nucleus-encoded genes by swapping the codons that cause the code disparity, we could engineer nuclear copies of all the genes. Even after the genes inside the mitochondria are damaged, imported proteins would allow the mitochondria to continue functioning, preventing not only a significant portion of aging damage but simultaneously providing a cure for several dozen mitochondrial genetic diseases such as Leber Hereditary Optic Neuropathy (LHON) and Kearns Sayre syndrome. In fact, clinical trials to express the protein that causes LHON in the nucleus are in clinical trials right now

In short, genetic engineering might allow us to permanently fix a significant source of aging damage and genetic disease with no significant downsides.

Promoting Heterozygous Advantage

Sickle cell anemia is an interesting genetic disease. It is caused by a mutation in the gene that codes for the protein hemoglobin, which is responsible for carrying oxygen in the blood. The disease is recessive, meaning only an individual with two copies of the recessive variant will experience disease symptoms. Those suffering from the condition are often wracked with pain, have restricted blood flow to vital organs, and have difficulty performing moderate exercise.

Carriers (people with one normal copy of the gene and one mutated copy) have an interesting advantage not enjoyed by the rest of us: they are notably more resistant to malaria. Other than this, they only seem to have symptoms under extreme dehydration or oxygen deprivation.

Carriers of the sickle cell disease, therefore, have a notable fitness advantage in environments in which a low percentage of the group of available partners are carriers and the risk of death or disability from malaria is high. This is why when we look at maps of the distribution of malaria and the distribution of people who have (or whose ancestors had) sickle cell, they overlap quite nicely.

Ancestral homeland of individuals with sickle cell anemia

Historical range of malaria

Genetic engineering offers us the opportunity to avoid the “overdominance” problem of genetic conditions like sickle cell: we can ensure that EVERYONE in areas where malaria is a major risk has exactly one copy of the sickle cell gene. In other words, we can reach population states that evolution simply cannot.

Avoiding Losses from Zero-Sum Games

I left this example for last because I do not yet have a specific example of this phenomenon in humans, though I suspect that some exist.

Walk into any forest of old trees and you will likely notice that the first hundred feet or so of the trunk are devoid of any branches. In the competition for access to sunlight, trees grow nearly as tall as physiologically possible in an effort to pass the shading branches of their neighbors. While this tendency is a huge boon for lumber companies that take advantage of the long straight trunks to create lumber products at low cost, the trees themselves do not on net benefit from the arrangement. Each tree must invest considerable energy in producing a hundred or more feet of wood whose sole purpose is to elevate its canopy above those of its neighbors.

The forest as a whole is less successful than if all trees were to grow tall enough to spread their canopies fully but no taller. But alas, the trees have no mechanism for punishing uppity young saplings that dare to grow taller than their older neighbors. So all trees are forced to grow tall and the reproductive fitness of the forest as a whole is reduced.

This is a fairly standard example of the prisoner’s dilemma, a phenomenon in which two self-interested entities compete in a game, and both end up losing due to the lack of ability to punish cheaters. If you are not already familiar with the concept I would highly recommend reading the link above as it does a much better job explaining the setup than my one-sentence summary.

Though I don't have any specific examples, there likely exist specific genetic variants that impose a cost and exist solely to allow humans to compete better in zero-sum games. If we are able to identify such variants, it's possible that we could ban humans from having such variants, thus saving everyone from the cost of carrying such traits. Obviously such a scheme would carry some risk and may be rejected by most people as giving the government too much power, but it is nonetheless a benefit that can only be realized through genetic engineering. For that reason, it

Future Posts

I hope to continue this series. I'd like to devote an entire post to the topic of genetically engineering higher intelligence since this would likely be one of the most important things that we would choose to change. I'd also like to discuss HOW this could actually be done via embryo selection, gene-editing tools like CRISPR, and iterated embryo selection.

Let me know what you thought of this post. My goal here is really to create something that's informative and readable. So if this post could use improvement in either of those areas please let me know.