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.

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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.

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.

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.

Rebalancing proteins in the blood is the single most promising strategy for age reversal in the present environment. There are two competing schools for how to approach this. I’m calling on both to put their heads together and develop a strategy that combines their insights.

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<rant>
Please forgive me while I rant for a paragraph before beginning this column in earnest. Len Hayflick demonstrated that senescence in many animal species, probably including humans, is promoted by lack of a simple, cheap enzyme (telomerase) that every cell knows how to produce. To anyone who hasn’t been indoctrinated into the selfish gene dogma, this would be a sure indication that the body is trying to kill itself. But fifty years on, Len is still saying that aging = entropy catching up to a body’s chemistry. An equally powerful discovery came from Irina and Mike Conboy, who have been at the forefront of experiments demonstrating that aging is centrally coordinated through signal molecules in the blood. In every context but this one, the Conboys will acknowledge that these molecules are subject to directional selection and are tightly regulated in the metabolism. But when the blood plasma fills up with pro-inflammatory cytokines during aging, the Conboys insist that this is an accident. The body made a mistake. They call it “deregulation”. And in case anyone misses the point, they add in parentheses, “(noise)”. These are exactly analogous to the directed changes that cause growth, puberty, cessation of growth, onset of menopause, etc. In those other context, the change in balance of plasma proteins are signals, but in the context of aging, they must be “noise”. 

And even more incomprehensibly, the “noise” to which they refer always goes in one direction, and that is producing too much of some signal molecules, and the “noise” always manages to emphasize exactly those signals that bring the body down in a hailstorm of inflammation. 

Evolution is a many-splendored thing, and natural selection is perfectly capable of producing well-regulated, interdependent communities. This has meant selection for Goldilocks rates of reproduction balanced artfully against death rates that are also well regulated under evolutionary control. 

And YES, it does matter whether you think of aging as signal or noise. (I apologize again as my rant spills into its fourth paragraph.) It matters because if aging comes from a set of signals, we know well how to block those signals, e.g., with drugs that jam their receptors. But if it’s noise, the task is so much more difficult because it unfolds differently in every individual. 

If you want to hear more of this kind of thing, please read my book, or just refer to the dusty archives of my blog.
</rant>

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It’s no secret to readers of this column that I think altering the balance of signal molecules in blood plasma is the most promising road to anti-aging in humans. There are now two competing approaches to this project. The Katcher school says that there are youthful factors missing in the blood of old animals, while the Conboy school says that there is an excess of pro-aging factors. Both are quick to say that yes, it is a balance of pro-aging and anti-aging factors in the blood that ultimately determines the animal’s fate. But Katcher says that if you deliver the right combination of youthful factors, they will reprogram the epigenetics so that the pro-aging factors retreat as a side-effect; while the Conboys claim that if you dilute the blood, removing equal proportions of pro-aging and anti-aging factors, that dilution is sufficient to reset the aging clock, and stimulate new production of the youthful factors. 

Problems with the Katcher protocol

Until last week, Katcher had the more compelling data (IMHO), because he demonstrated dramatic epigenetic age reversal in rats. But last spring, the disappointing results in a small lifespan trial (8 rats) makes us wonder if his protocol needs a lot of fine tuning before it’s ready for prime time. And another weakness in his protocol is that he doesn’t know what is in the blood-derived E5 elixir that does its magic. He tells me there are efforts underway to identify the active components of E5. I think this determination is a high priority with global implications for health, so, by my lights, the analytic work on E5 should be a top priority. But there is a financial incentive not to know what are the active components of E5. This is because Katcher’s Yuvan Research has a patent on the process of extraction, but the components themselves are natural proteins, and thus they cannot be patented. So as soon as the information about the active components of E5 become public, his process patent risks becoming worthless. Other, larger laboratories than Yuvan will be able to synthesize the chemicals and sell them. I fear that research is being held back, and for what? I don’t even believe that the strategy of secrecy can secure the patent rights for Yuvan, because the knowledge will inevitably leak out, and Yuvan doesn’t have the resources to pursue multi-million dollar court battles over patent rights.

Human trials of plasma dilution

Now there is a new article from the Conboys analyzing results of plasma dilution in three human subjects. They show improvements suggestive of rejuvenation in several biomarkers. They do not report methylation age. They do begin the analysis process, and offer suggestions about what may be the most important pro-aging components of blood plasma that must be removed or inactivated.

Why don’t they measure methylation age using any of the available clock algorithms? There is a short statement why they don’t believe in methylation clocks, and they express the opinion that another biomarker of aging, one not based on “machine learning or large data sets” is urgently needed by the community. I believe that methylation clocks are the best means we have at present to evaluate the effects of anti-aging interventions, and in this one respect I find myself (for a change) aligned with the majority view in the field. The Conboys owe us a better explanation why they have gone to such great lengths to report other biomarkers of aging, but they don’t offer us the simple one that most researchers rely on.

Accumulated DNA damage triggers genetic aberrations, senescence [26], and loss of cell function and leads to age-related diseases [24].

It’s a popular theory aging that DNA damage is an important driver of aging , but I don’t believe it.

Interestingly, the procedure of small animal plasma exchange to dilute the circulating factors in plasma effectively reset the age-elevated systemic proteome and restored youthful healthy maintenance and repair of muscle, liver, and brain, without any added young blood, young plasma, or young factors [15–17].

This is a crucial point. How strong is the evidence? The three references are all previous publications from the Conboy lab. Ref 15 describes results of delivering young blood into old mice, an experiment which cannot tell us whether dilution alone rejuvenates gene expression. Ref 16 is about plasma dilution in mice and humans. This study establishes that something in old blood inhibits satellite (stem cell) growth, necessary for healing and repair, and that dilution is sufficient to restore youthful activity of these cells. Some evidence is noted of changes in the global proteome toward a more youthful state. Ref 17 establishes that plasma dilution is sufficient to enhance cognitive performance and reduce inflammation in old mice.

There is a section of the paper documenting “proteome noise”, which the Conboys propose as an important biomarker of aging. I disagree, of course. I see the directed changes in gene expression as the important drivers of aging, and the random changes are secondary. Much of the Conboys’ paper is devoted to analyzing noise in the proteome of subjects, and interpreting this as an aging biomarker which moves in the direction of youthfulness after plasma dilution. I admit much of the biochemistry is above my pay grade. I can’t comment on the merits of their proposed components of a new proteomic clock. But from the vantage of scientific methodology, developing appropriate biomarkers of aging should be a separate endeavor, done in advance. Criteria for successful rejuvenation should be established ahead of time, and not developed on the fly with results of the experiment already in hand.

I would have liked to see methylation age before and after treatment. I understand that the Conboys have reasons for not giving credence to the methylation algorithms. But how about A1C or CRP? These are measures of insulin resistance and inflammation, respectively, that are standard blood tests, but are not mentioned in the Conboy paper. How about any measures of cognitive or physical performance? There are no phenotypic aging markers in the Conboy paper.

Breaking new ground

The Conboys identify two proteins, TDP43 and TLR4, that were previously unfamiliar to me, but are markers of an aging proteome. The former is associated with cancer, the latter with dementia, and both increase with age. Both are attenuated with the Conboys’ plasma dilution protocol. I recognize that it is labor-intensive work to identify specific protein targets and test them individually, but this is the kind of work I think is most valuable going forward.  

How I think about aging

My (tentative) model:   “Old” and “young” are always in the body’s repertoire of behaviors, and the body will choose according to the signals it receives. The age state of the body is stored in the epigenetic state of cells, and communicated through hormones and other signal molecules in the blood. Some of these molecules also act as transcription factors, and they can feed back to affect the epigenetic state of dispersed cells. This is the reason for hope that a younger environment in the blood can effect long-lasting rejuvenation.

The great task before the Conboys and Katcher and other researchers in plasma rejuvenation is to identify which of the hundreds of proteins that change with age are the few transcription factors that are capable of reprogramming expression of the rest. 

Risks: 

• There is no guarantee that a small subset of proteins exists that can do the job, but we won’t know until we look. 
• And there remains the possibility that a central clock in the hypothalamus is able to override records of biological age in the epigenetics of dispersed cells. If this turns out to be the case, then we have to find ways to breach the blood-brain barrier and reprogram the hypothalamus.

A modest proposal

Harold Katcher, Mike and Irina Conboy are at the forefront of anti-aging technologies today. Both labs are very close to having an effective treatment for humans, close in the sense that there remain no conceptual hurdles, but only the predictable quotidien work of expert lab biochemists. In other words, a lot of work remains to be done, but the map is drawn.

Aging is not a cell-autonomous function, but happens under system-level control, with information about the body’s age communicated by signal molecules in the blood. This is the key insight on which Katcher and the Conboys agree.

To those of us watching from the outside, it is clear that a rebalancing of young and old plasma components will have a dramatic effect on health and lifespan. The remaining task is to identify a minimal set of those factors that must be removed (or neutralized) and those that must be added to the blood of an old person in order to trigger a global resetting of the epigenome toward full youthful gene expression.

We, the consuming public, would benefit greatly if the Conboys would hire Katcher to come work in their lab. Their two conceptions need not be antithetical. Let’s call on them to work together to identify that minimal set of blood factors, resetting of which can accomplish robust rejuvenation.

The importance to humanity of this research agenda must override the personality differences, the philosophical differences, the legal and IP problems that must be overcome to make this collaboration possible.