Don’t mess with the Genetic Code

The work of George Church combines a broad knowledge of science with an ambitious imagination. Our world needs visionaries, and Church is one of a kind. His Harvard laboratory is at the cutting edge of several key areas of biochemistry. Please construe the following criticism narrowly. There’s just one of his ideas that I think is dangerous enough that I am moved to speak out against it. Changing the genetic code is a really, really bad idea.

I’ve heard Dr Church speak three times in the last month, and each time he has mentioned a technology to make humans resistant to all viruses. He has already done a proof-of-concept experiment, creating a strain of E coli that uses a different genetic code from all other life on earth (including, of course, all viruses). Since viruses use the host cell’s machinery for translating their own genome, the virus won’t be able to replicate in a host with a modified genetic code.

Changing the genetic code is not the same as “gene editing” or “gene therapy”. Gene therapy involves changing one gene (perhaps throughout the cells or a particular organ, perhaps in every cell in the body). Changing the genetic code is a global search-and-replace in the entire 3 billion base pairs of the human genome. It’s a hundred million changes, all of which have to go just right, together with a change of instructions about how to interpret the new code.

What is the Genetic Code?

Roughly speaking, DNA is an information molecule and proteins are service molecules. Most of the functions of a cell are performed by proteins, including signaling, energy transduction, locomotion, filtering, promoting beneficial chemical reactions and inhibiting others — essentially all the functions of metabolism are accomplished by proteins.

A protein molecule is a chain of (usually) thousands of amino acid units strung together in a particular order. There are 20 amino acids to choose from, and they have differently shaped fields of electric charge around them that make them attract or repel other amino acids. So a string of amino acids that is a protein wants to fold into a unique, characteristic shape, and the shape determines its function in the metabolism.

Example: This is what the insulin protein looks like after it is folded up.

DNA lives in the cell nucleus and is copied and passed from mother to daughter when a cell divides in order to clone itself. One of the functions of DNA is to carry information about how to build proteins. (In fact, this was the first and primary function of DNA that was discovered in the 1950s.) DNA is constructed of millions of four nucleic acid subunits strung together in a particular order. (Note that a nucleic acid is not an amino acid.) DNA is built from only 4 nucleic acid subunits (usually abbreviated A, C, T, and G) compared to 20 amino acids subunits used to construct proteins.

The “genetic code” is a mapping between DNA and proteins. Each sets of 3 nucleic acids specifies a particular amino acid. A “gene” is a stretch of DNA that contains instructions for making a particular protein. So, for example, a stretch of DNA that is 30,000 base pairs long may contain instructions for creating a protein of length 10,000 amino acids. Only about 3% of our DNA consists of genes. To “read” these instructions is the function of a ribosome. Ribosomes are organelles, little chemical factories, millions in every cell, where proteins are made.

The genetic code constitutes a language through which DNA (mediated by messenger RNA) tells the ribosome what amino acids to string together in what order. The messenger RNA copies a gene and then leaves the nucleus to look for a ribosome. The ribosome reads the message. Every time it sees the 3 nucleic acids GCT, it adds an amino acid called Alanine. If it sees GGA, it adds a Glycine, and so on. A combination of 3 DNA units specifies each protein unit, with some redundancy. Redundancy means, for example, that TCT, TCC, TCA, and TCG all correspond to the single amino acid called Serine.

(U is another way of saying T in this language. DNA uses T, while RNA uses U for the same meaning.)

The association of a particular triple with a particular amino acid is thought to be mostly arbitrary. It’s just a language that DNA uses to talk to the protein factory.

One of the deepest truths about biology is that this arbitrary language, this same language, is shared by all living things. All living things, from the toadstool to the bowhead whale, use the same language to communicate between the DNA and the ribosome.

This means that all life can exchange DNA with all other life. From bacteria to baboons, we all speak the same language

This is also powerful evidence that all life is related. Life arose once, and differentiated on a vast tree over the course of 4 billion years. You and I and the toadstool and the bowhead whale are all cousins.

This is a doodle from Darwin’s notebook in which he first conceived the Tree of Life.

How does Dr Church propose changing it?

This is the article in which Church proposes the project.

We might imagine that we have to reprogram millions of ribosomes in each of trillions of cells in the body to change the genetic code. That would be correct about reaching trillions of cells, but maybe incorrect about the ribosomes. As it turns out, all the ribosomes are reading from the same hymn sheet, and we can change the hymn sheet with standard genetic engineering.. The genetic code is itself encoded as proteins, and the proteins are made from a nuclear DNA template. So for example, there’s a particular protein that has a slot for the GCA combination and another slot that attracts Leucine. This one protein is responsible for one pairing in the genetic code. If this one protein is deleted from the genome, then no ribosome in that cell will be able to read GCA. The ribosome will choke when it gets to GCA and abandon work on the protein it started to make.

Part of what makes this feasible is that, besides GCA, there are other combinations that code for Alanine. So the plan might be to eliminate this one protein that translates GCT into Alanine, and then to go through the entire genome — billions of bases — and do a “global find and replace” operation. Every time there is a GCT, replace it with GCA, which also codes for Alanine. These two changes would put the cell aright again, so Alanine would appear in all the same proteins as before. But an invading virus wouldn’t know that the code had been changed. The virus might sometimes use GCT for Alanine, and it wouldn’t work. The ribosomes would be able to decode native DNA, but not the virus’s DNA.

Of course, while we’re genetic engineering, we could change that one protein in a way that makes CGA translate into Tyrosine instead. That change would be global. We would change the genetic code for all of the DNA in that cell that is engineered in this particular way.

The global find and replace function is called multiplex base editing, and it is already (the last decade) a developing lab technique. There are several ways to do it. For example,

A base editor is a fusion of catalytically inactive CRISPR–Cas9 domain (Cas9 variants) and cytosine or adenosine deaminase domain that introduces desired point mutations in the target region enabling precise editing of genomes. [ref]

In other words, CRISPR is used to locate particular sequences wherever they occur on the genome, and an enzyme called a deaminase is used to modify all of the copies of one particular nucleic acid base in that stretch of DNA. For example, deamination of T turns it into U, and the next step is to add a reagent that will change the U into something else, perhaps A in the example above.

Suppose humans were engineered with a different genetic code

We would still be able to eat food, because our bodies ignore the DNA in the food we eat. The DNA is de-activated but not digested. The proteins in the food we eat would be available just as before, because the body recognizes those proteins, irrespective of what genetic code was used to ake them.

However, the human body with changed genetic code could not be infected by viruses that use the old, standard genetic code. Viruses don’t have ribosomes of their own, but count on the host’s ribosomes to translate their genes into the proteins they need. Humans that were engineered to have a different genetic code would play a trick on the virus, translating its DNA (or RNA) into the wrong protein, or failing to translate it at all.

What could go wrong?

  • Our bodies contain hundreds of trillions of viruses. Western science has not begun to study these relationships, and we don’t know which are helpful, which are harmful, which are neutral. We cut off all symbiosis with viruses at our peril.
  • We do know that our gut microbiomes and skin microbiomes harbor thousands of species of bacteria, most of which are beneficial. Would they still be able to work with us if we used a different genetic code? (The known interactions all involve proteins, so that, presumably would be unaffected if the change in code went off without a hitch.)
  • A man and woman who have genomes that are coded differently could never have children together. Does Dr Church imagine switching over everyone’s genetic code in the same year so that such couples would never occur?
  • Horizontal Gene Transfer = exchange of genes between organisms that have no parent-child connection. We know little about it, except that HGT plays a major role in evolution, in the long run. Is HGT important in the space of a single lifetime? No study has asked that question.
  • We know that all of us are exhaling exosomes all the time, and that they send signals that are picked up by other humans and other animals and plants in the vicinity. Exosomes contain snippets of DNA. How would a person with a modified genetic code read these signals? How dependent are we on these signals? We don’t know.
  • DNA has other functions than coding for proteins. In fact, more than 97% our our DNA does not code for proteins. (This was once called junk DNA by people who theorized that it was just leftover debris from the past and silenced viral infections.) We have some ideas about what this DNA does for us. An obvious role is in epigenetics. It determines how DNA folds and unfolds, and so the 97% is important for gene expression. Would a change in the genetic code affect gene expression? We don’t know. What other roles are there for DNA? We don’t know. How would a global modification of DNA affect a living human? We don’t know.
  • There are therapies based on matching radio frequencies to a resonance of a chromosome. Don’t scoff— a brilliant Nobel laureate named Luc Montagnier spent much of his later life working on this stuff. Humanity would be foolish to bet the farm on his being all wrong.
  • The whole purpose of this exercise is to confer viral resistance. What if the viruses are on to us, and they evolve to adapt to our new genetic code? The rate of viral evolution ranges over 5 orders of magnitude and is a poorly understood. Viral adaptation to a new genetic code might never happen, or it might happen very quickly.
  • Changing the genetic code must be done in most cells of the body to stop a viral infection. Must the change reach every last cell? If the body becomes a chimera with the new genetic code in 90% of cells but 10% retaining the old code, will conflicts arise and the cells begin a civil war? In theory, mRNA does not pass between cells, so this should not be a problem, but we really don’t know.

The big picture

I have advocated approaches to aging based on signaling. Aging is centrally orchestrated at the system level. We don’t have to reach into every last cell and fix the damage; we need only to restore the body to a young epigenetic state, and all the innate mechanisms of repair and renewal will be once again available.

Repair at the cellular level is more invasive. There is much opportunity for things to go wrong. I believe that this kind of approach is unnecessarily exacting and difficult.

Changing the genetic code is a cell-level therapy, which, in my calculus, is a strike against it. Furthermore, it goes beyond restoring the cells to a youthful state; it creates an artificial state with unknown consequences.

And why? People in the prime of life with young immune systems almost never die of viral infections. If we can achieve rejuvenation of the immune system via any of the means now on the drawing board, then changing the genetic code will be unnecessary.

George Church is a giant in the field of biochemistry. His visionary ideas and research projects are moving science and technology in many good directions. But he doesn’t think in terms of ecology. It’s true in general that biochemical science has advanced explosively in recent decades, leaving the study of ecology in the dust. Biochemistry has benefited from computer analysis. Ecology requires intensive field observations. But ecology is just as important to the understanding of life as biochemistry.

We can be confident that humans are intimately connected to the ecosystem that spawned us. There has been exactly one experiment in which a small group of humans tried to live in an artificial ecosystem for a year. It ended disastrously in just a few weeks. No one has begun to catalog the ways that we are dependent on the earth’s biosphere, or to ask how those connections would be changed if we used a different genetic code from every other plant, animal, fungus, microbe, and virus on the planet.

For the foreseeable future, changing the genetic code in the human body — even if it proves to be feasible — would be a reckless step into unknown territory for our species.

40 thoughts on “Don’t mess with the Genetic Code

  1. There are certainly some big unknowns with this type of editing, but none of the ones you listed feel like reasons to stop pursuing this line of research. Instead, we should try to answer the various questions and we can only really do that by experimenting. It is certainly possible that we’ll create a pig with these changes and find that it dies because it fails to interface with its surroundings, or it fails to breed with non-modified pigs. In that case, we’ll have more information and we can either try to address those problems or give up on the endeavor.

  2. Its an interesting idea. I did my medical science undergrad in biotechnology and don’t often get the time to keep up with the science as its been developing. You should post on some of the genetics breakthroughs even if its not your main area of interest.

  3. I don’t believe that the CRISPR tech is even close to precise enough to pull this off. Look at the number of off target modifications in the study by Chen et. al. as it stands that transfection method would make a real mess of a genome.

    But with that said, we should not write off new technologies because there are potential pitfalls. Such an interesting and groundbreaking (even if unlikely to work) possibility should be explored.

  4. Man does love to play God. What could possibly go wrong? Well, at the very least, given the propensity for viruses to mutate, they would evolve to translate the new genetc code to their advantage. Imagine the worst, most apalling nightmare sc-fi horror film and you will get the idea.

    Current estimates; we have 10 to the power of 31 viruses in the air around us. This is 10 million times more than all the stars in the known universe. And these are just the viruses in the air. To this, we need to add 10 to the power of 31 viruses in ocean water and 10 to the power of 30 viruses in the soil. The human body is home to 36 trillion viruses, including Corona, and 38 trillion bacteria. Viruses are so small that they float in the stratosphere, raining down on every inch of the earth’s surface every day. We are swimming in an ocean of genomic information. At least 50% of the human genes have come from unedited inserts from viruses. At least 10% of the human genome is inserted by retroviruses like HIV. We have vilified the very process that has built human life on the planet. If we continue to adopt a warfare attitude on the very thing that has built us, we will create our own demise. It is only in relationship with a complex biodiversity-ecosystem that we will reach our full biological potential, something we call health and wellness.
    Zach Bush MD, triple board-certified

  5. It is very typical of modern people to not have humility, and to think that “progress” must continue, however they define it. Mostly, they get blindsided because tech throughout the years has been too much to handle for humanity. This is actually quite obvious and why it is also present in archetypes and myths from our past for over 10,000 years.

    I am happy to see that Mr. Mitteldorf has a very keen awareness of the nuances and structure of nature, and can discern reality quite well. Most can’t, which is why a lot of people will die in the coming years due to many factors; the principal start of it was the experimental adenovirus and mRNA “therapies”.

  6. George Church believes that aging is genetic as well. I share Josh’s skepticism about the whole-sale genetic code changing to eliminate vulnerability to virii. Simple rejuvenation, which does not require whole-sale genetic reprogramming, is sufficient to make us resistant to infectious disease. I certainly would not want to be one of the test subjects in the experiment even though, unlike Fauci and Co, I consider George Church to be one of the “good” guys.

    Having said that, I think the research itself is valuable and should continue. We need to develop a comprehensive bio-engineering capability to allow for rebuilding of minds and bodies. For one thing, such a comprehensive bio-engineering will be necessary to reanimate people from cryonic suspension. And yes, anyone who thinks that they will not need cryonics as back up Plan B is a fool.

  7. DNA is a primitive, wasteful, error-prone way of programming our biology. Soon enough we will have quantum computers that do a better job. At that point we will be able to “inhabit” them and leave biology behind.

    • I hear you, but I don’t agree. There’s so much more of biology that we don’t understand than we do understand. We know that DNA has other functions than just coding for proteins. In fact, 97% of the human genome does not code for proteins. We have a lot to learn before we can modify our genomes significantly, let alone make changes to the very language our genomes are written in.

    • Why do people assume transferring consciousness to a computer constitutes some sort of continuation of life? Such a disruption strikes me as death. I don’t doubt that some futuristic computer with the proper data could convince my friends and family that it is indeed me; having my memories, acting like me. But would I (whatever that means) experience said convincing? I have a hard time wrapping my head around such questions. But surely there is at least room for doubt.

      • I think the common solution people have to the Ship of Theseus problem is one of continuity. You continue to be you as long as there is a continuous existence each step of the way (there is debate over whether sleep is discontinuous).

        If you hook yourself/brain up to some kind of BCI, and then over time use connected computing power more and more, eventually you’ll get to a point where the biological brain portion makes up an insignificant portion of what is “you”. At that point, one might consider just turning it off so you can “untether”, but throughout the whole process you would continually be *basically* the same you as the previous moment.

        This is, of course, purely theoretical, but it doesn’t require one of you committing suicide or anything. It just consists of at some point deciding that 0.001% of processing power that is still biological, and is already fully redundant with in-silico processes, can be disconnected, like disconnecting an old worn out hard drive.

      • “Why do people assume transferring consciousness to a computer constitutes some sort of continuation of life? ”

        You mean transferring state. If you can transfer consciousness, this would be the equivalent of transferring life.

      • Sometimes people who think they are intelligent, wise, smart of whatever adjective you think of are so hijacked by their own (foolish) ideology they fail to see how dumb their point of view or stance is. I’m flabbergasted about this question as well, as it is one of the most obviously ridiculous and stupid ideas I’ve ever heard come out of the mouth of “smart” people. But the age of spiritual decay and pride is so high, I’m quite sure I’ve recognized where it comes from. It’s quite sad actually.

  8. Look, I hear you and agree with some of this. Let viruses and humans evolve as they will. Then again, gene-synthesis itself has many implications, whether a full re-write or not. And it doesn’t have to be an entire across-the-population endeavor, it couldn’t be anyway. It will be tightly controlled. We will learn from it and we will conceive of many applications related to this. I’m still for Church’s forward progress on this.

    • “It will be tightly controlled”. Fat chance. If there is money to be made, it will be survival of the fittest:). Think COVID and the human race massively adopting a dangerous, unproven mRNA vaccine technique that didn’t work and has left most of us with crossed fingers that we haven’t done irreversible damage to our genomes.

      • Like the covid-19 vaccines, the real issue is whether people are coerced into undergoing treatments based on this technology. As with any other medicine and bio-engineering, the foundational principle is informed consent and bodily autonomy.

        • “informed consent”. Not where I come from (Australia). Half the country mandated you got jabbed or lost your job. We truly live in a dog-eat-dog world.

          mRNA “vaccines” (including COVID) fiddle with the ACE2 receptor which is involved in so many bodily processes it doesn’t matter. Too late, we are finding lots of side effects involving ACE2.

          The process of developing COVID “vaccination” involves forcing our cells to manufacture COVID virus spike proteins via RNA transcription (hence mRNA). Do not believe Big Pharma when it says nothing can go wrong with this process. The whole business of mRNA cell manipulation is fraught with risk and the risk is high and the cost of something going wrong can easily be the extinction of the human race.

          The real pity with 96% of Australia getting jabbed is that 2/3 of people are naturally resistant to the disease (like me!). It is an illness of an unhealthy minority but the majority are paying the price. We have research in Australia on the go that can determine whether you have a natural resistance to COVID or not but I doubt if Big Pharma will let it go to completion.

          I have a simulation of a COVID virus on the Naked Scientists if you are interested.;topicseen#msg640534

  9. I love that Josh is willing to consider the possibility that certain frequencies may kill microbes and promote healing in various ways, without scoffing.

    It has been proven that when animals or humans hug, their heartbeats and breathing rates synchronize.

    Hugging is known to have positive and healing effects on humans and other animals.

    There are certain frequencies such as Alpha or Theta….when heard through music or binaural beats that are known to induce a healing meditative state. Delta induces sleep, also a healing activity.

    The Buddhists also use tones to heal or change their mood.

    I don’t advocate or not advocate the efficacy of a rife machine, and don’t know much about a rife machine.

    Still, it is interesting that at the “Rife” link it is mentioned that it is believed that mycoplasma or retroviruses are thought by some, to be the root cause of ALS.

    Various animals can transmit mycobacteria. Mycobacterium bovis is most commonly found in cattle and other animals such as bison, elk, and deer. The wild animals, may also transmit unknown viri.

    Handling the flesh, of those animals or touching their excretions or mucous secretions, can transmit mycobacteria to humans.

    The reason it is interesting is that two acquaintances over the years have developed ALS. One was a hunter who handled the animal’s raw flesh and ate it.

    The other was a taxidermist, who also handled dead wild animals.

    Just some food for thought.

    • The Rife “machine”.

      I did a “deep dive” on Royal Raymond Rife and the rife “machine” 4-5 years ago. Not as a believer, nor as a debunker. Purely looking at the evidence.

      The technique was (is?) in 3 different parts – 2 of which in modern times have been independently recreated by fully-credentialed scientists in accepted peer-reviewed journals, 1 of which has not. Here are the 3. This is a short precis, with most of the details left out.

      1. The Rife microscope – in the late 1920s ,Rife invented a microscope, that, while difficult to work with, allowed resolutions of electron microscope quality, on living cells. This was endlessly debunked as being impossible by the laws of physics. This was not true then, and not true now. In the mid 1990’s, a team created the fluorescent microscope, with equivalent resolutions, which was a variant of the Rife microscope. They got the 2018 Nobel Prize in Medicine for their work.

      2. Filterable cancer transmission. Rife tried treating cancer with an early model of the rife “machine”, with consistent failure. The cancer kept coming back. That led him to the conclusion that cancer had to consist of at least 2 forms. So he did the following experiment. He inserted human breast cancer into a mouse model, let the tumor grow, then removed the tumor, macerated it, and then filtered the fluid through a 14 nm ceramic filter, and then injected the cell-free filtrate into another mouse. The mouse developed cancer. He serially did this for over 100 mice (fltrate-mouse, filtrate-mouse, from one to another). (This is easily reproducible, if one wants to.) 50 years later, this filterable transmission of cellular material was rediscovered, and called exosomes (most of which are larger (40-200 nm) but not all.) Rife found that to treat cancer with his “machine” he had to disrupt both the living cancer cells and the exosomes created by the cancer.

      Finally, we get to the rife “machine”. This has never been reproduced. As far as is known, there are no working (or non-working, but original and complete) machines to study. They used EMF (not audio) frequencies. I mention this, as no comment was ever made about the possibility of secondary harmonic frequencies that may have been made by the “machine”. Without this knowledge, one could never be sure that the reproduced ”machine” was doing exactly what the original did.

      The initial test of 13 terminal cancer patients gave a remission rate of 100% (1934). The effort to “shut down the process” is beyond the scope of this precis. Interested parties can research that themselves.

  10. Josh, there are two way at looking at magnification. One is the Abbe limit, that you described. By using reflection/refraction, one is limited to the wavelength of light.

    However, the Abbe limit does not hold for for generated light. That is the underlying concept behind the fluorescent microscope (and the Rife microscope, as well, but never understood or articulated at the time), is that emitted photons are not subject to the Abbe limit. A practical example are the very big telescopes. We have been able to resolve sunspots on Betelgeuse at 500 light years, because of directly emitted light, at magnifications far greater than those of a microscope.

    • It’s not clear to me why emitted photons should behave differently from reflected photons, but I’m going on my general knowledge of physics and haven’t looked into this subject as you have.

  11. “Roughly speaking, DNA is an information molecule and proteins are service molecules.”

    Or, in computer science, DNA is a Class and Proteins are objects (or instances of a Class).

    • Anthony – proteins are not a kind of DNA. Proteins have a whole different chemical structure. The fact that there is a language mapping DNA sequences onto protein sequences is the remarkable fact discovered by Crick in the 1950s.

      Protein molecules actually do things. DNA molecules simply store the information for how to make proteins.

      • “DNA molecules simply store the information for how to make proteins.”

        Classes do that for Objects in computer science. Plus a lot more. I think there is a whole lot of code in DNA, most of it in fact, whose purpose(s) we are unaware of. Could easily be the equivalent of functions etc. in computer Classes.

  12. The body has repair enzymes that can repair most errors. Cells can’t repair double-stranded DNA breaks, and I’m guessing the rejuvenation experts can’t either. When we look at the changes that occur as we age, it is clear that the body has less energy and the body adapts by turning off certain genes.

    But turning those genes back on won’t make you younger. That would kill you. But if you would supply the organism with new mitochondria, the switched off genes would spontaneously switch on. Mitochondria do not have developed repair enzymes as in nuclear DNA, they age much faster.

    If someone figures out how to supply cells with fresh mitochondria or how to ensure the multiplication of healthy mitochondria, then people will look significantly younger. And there will be no need to develop hypotheses about repairing the genetic code.

    • It’s true that we have less energy, fewer mitochondria, and less efficient mitochondria. But why is that? Mitochondria are ruled by the cell nucleus, and gene expression in the nucleus slows the mitochondria down, after decades of optimal performance.

  13. There are 3 problems that immediately come to mind with altering the genetic code in such a manner.

    1st. Some of the gene regulation appears to be done through the content of amount of certain nucleic acids in dna iirc.

    2nd. Altering the code in such away might affect the way rna enzymes interact with dna in unknown ways.

    3rd. Any hostile lab could easily release viruses adapted to the new code and we’d be back at square one.

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