Dont 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.Theres 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.Ive heard Dr Church speak three times in the last month, and each time he has mentioned atechnology to make humans resistant to all viruses.

He has already done aproof-of-concept experiment, creating a strain ofE colithat uses a different genetic code from all other life on earth (including, of course, all viruses).Since viruses use the host cells machinery for translating their own genome, the virus wont 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.Its 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 nucleic 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.Its 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 languageThis 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 Darwins notebook in which he first conceived the Tree of Life.How does Dr Church propose changing it?This is the articlein 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, theres 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 wouldnt know that the code had been changed.The virus might sometimes use GCT for Alanine, and it wouldnt work.

The ribosomes would be able to decode native DNA, but not the viruss DNA.Of course, while were 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 calledmultiplex 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 CRISPRCas9 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 codeWe 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 dont have ribosomes of their own, but count on the hosts 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 containhundreds of trillions of viruses.Western science has not begun to study these relationships, and we dont 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 everyones 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 exhalingexosomesall 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 dont 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 calledjunk DNAby 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 dont know.

What other roles are there for DNA? We dont know.How would a global modification of DNA affect a living human? We dont know.There aretherapies based on matching radio frequenciesto a resonance of a chromosome.Dont scoff a brilliant Nobel laureate namedLuc Montagnierspent 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 over5 orders of magnitudeand 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 dont know.The big pictureI have advocated approaches to aging based on signaling.Aging is centrally orchestrated at the system level.We dont 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 doesnt think in terms of ecology.

Its 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 tolive 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 earths 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.