Playing God

How scientists are reengineering the genetic code of life

Dear Rational Optimist,

James Lewis and James Springer, aka the “Jim Twins,” were separated at four weeks old and not reunited until age 37 when they were tracked down and studied as part of the Minnesota Study of Twins Reared Apart (MISTRA).

When comparing the lives of the Jim Twins, the MISTRA researchers were stunned—and not just because they were both six feet tall and weighed exactly 180 pounds. That could be explained by sharing identical genes.

What was not so easy to explain was that:

• Both had married women named Linda, divorced them, and then married women named Betty.

• One Jim named his son James Alan, while the other named his James Allan.

• They both drove Chevrolets, chain-smoked the same brand of cigarettes, and spent their vacations on the same tiny stretch of Florida beach.

• They both enjoyed carpentry as a hobby.

• Even their career paths ran parallel, with one working as a deputy sheriff and the other in private security.

And the Jim Twins were not unique: the MISTRA study uncovered a multitude of similar life experiences between twins separated shortly after birth.

Which opens the door to the intriguing possibility that, despite the common perception our lives and personalities are largely influenced by the environment we are raised in, much of our life path may be etched into our DNA.

In this Deep Dive we’ll look at the advancements scientists have made in understanding DNA, and how they are already using that knowledge to alter the very code of our lives.

While genetic engineering is already curing the previously incurable, after spending two months immersed in the topic, I believe it’s only a matter of time and logistics until it’s scaled up to solve the health problems of millions of people, including curing “final boss” diseases such as Alzheimer’s and coronary heart disease.

And that’s not the half of it.

Let’s get to it.

A Quick Historical Perspective

For thousands of years humans have been manipulating genes through selective breeding. While slow, the results of selective breeding have helped humanity flourish in too many ways to count.

A few examples.

Amazing Maize

About 10,000 years ago, corn as we know it today didn't exist. It was a wild grass called teosinte that had “ears” about an inch long with only 5 to 12 hard kernels.

Ancient farmers in Mexico selected the plants with the softest and largest kernels. In this way, over thousands of years, the weed was transformed into the soft corn, which is now a key plank in the foundation of global agriculture.

Wonder Wheat

In the late 1800s, shorter summers in the Canadian north made it too cold for traditional wheat. Autumn frost would often kill the crop before it could be harvested.

Starting in the 1890s, William Saunders, along with his sons Charles and Percy Saunders, began a decades-long search for “fast” wheat. By cross-breeding Hard Red Calcutta and Red Fife, they eventually developed Marquis wheat, commercialized in 1909.

While it doesn’t sound like much, the fact that Marquis wheat ripened 8 to 10 days earlier than any other variety allowed the Wheat Belt to move hundreds of miles north, transforming the Canadian Prairies into a veritable breadbasket. Descendants of Marquis wheat, in particular Red Hard Spring wheat, are now responsible for 45% of the wheat grown in North America.

While the Canadians had solved the problem of time, back in the day high-yield wheat grew so tall and thin the stalks would often buckle under the weight of the grain heads or be knocked down by a stiff wind.

Enter American biologist Norman Borlaug, who in 1944 moved to Mexico to begin what would be a 20-year quest to genetically alter wheat to be more robust.

Using the methods of the era, basically brushing pollen from one plant to another, Borlaug managed to combine a semi-dwarf Japanese variety with high-yield wheat to create dwarf wheat.

This shorter, sturdier plant put its energy into growing grain rather than height. For his work in curbing global famines, Borlaug became known as “the man who saved a billion lives” and won the Nobel Peace Prize in 1970.

The Modern Broiler Chicken

As recently as the 1950s, a chicken took about 70 days to reach a market weight of roughly 3 pounds.

Today, thanks to decades of selecting the fastest-growing birds, a chicken reaches 6 pounds in just 47 days.

If a human baby grew at the same rate, it would weigh upwards of 600 pounds by their second birthday.

No actual gene editing involved, just attentive farmers doing what they do best.

I could go on, as I am sometimes prone to do, but you get the idea.

And that idea is that genetic engineering, even in its most rudimentary form, can offer world-changing benefits.

Which brings us to a key point when talking about modern gene editing: what took farmers and researchers decades or even hundreds of years of manual labor would today require a single afternoon.

That’s because today’s scientists can simply open the “instruction manual” of any number of organisms and program them for the traits they are after.

Speeding Up Evolution

Humanity’s first attempt to speed up evolution kicked off in the 1920s and 30s when scientists realized that bombarding seeds with X-rays or dousing them in harsh chemicals could create potentially useful mutations.

Of course, as they had no control over what mutations might occur, it was just a game of chance.

Even so, by applying this brute-force approach to millions of different seeds, useful variations were created, including Red Ruby grapefruit and even the wheat most used in making Scotch whisky.

In fact, according to the FAO/IAEA Mutant Variety Database, mutation breeding has resulted in more than 3,400 varieties of genetically altered plants now being grown around the world.

The Era of Bacterial Factories

Seeking more control over genetic changes, in the 1970s scientists moved on to bacterial transformation, the earliest form of “cutting and pasting” genes.

The process involved snipping a specific gene from one organism and pasting it into a small loop of bacterial DNA called a plasmid.

To get the code to work, they “shock” bacteria (using heat or chemicals) into swallowing the modified plasmid. Once inside, the bacteria began to read and incorporate the instructions provided by the new genetic material.

Because bacteria reproduce so rapidly, a single modified cell can quickly become a colony of billions, all acting as tiny biological factories churning out the specific protein dictated by the new gene.

The breakthrough moment came in 1978 when Genentech, then a small startup, successfully inserted the human insulin gene into E. coli bacteria.

Previously, insulin had to be harvested from the pancreases of pigs and cows. This animal-derived insulin was not only expensive to refine but often caused allergic reactions in humans because it wasn't a perfect match for our own biology.

By programming bacteria to produce identical human insulin, Genentech launched the modern biotech industry. It proved that rather than waiting around for a useful mutation, we could create the mutations ourselves.

It was a massive leap, but at the time, it only worked for simple organisms. Complex human cells were a much tougher nut to crack. For starters, the entire genome of a bacterium like E. coli is about 4 million letters long, while the human genome is about 3 billion.

Moreover, while the genome of a bacterium operates in a straightforward way, interactions in the human genome create complicated proteins that fold in the very specific ways that make us humans such a complex species. More on that momentarily.

Thus, even though scientists now knew how to “cut and paste” genes with simple organisms in a lab dish, they were still flying blind when it came to the human genome.

Cometh the Human Genome Project

Launched in 1990, the Human Genome Project (HGP) was a massive international effort to sequence all 3 billion letters of the human genome, the basic instruction book for the human species.

Critics at the time argued it was too expensive and perhaps even technically impossible. The skepticism had some merit; in the early days, decoding the genome involved PhD students spending long days reading tiny stretches of code by hand with the help of radioactive dyes and blurry films.

Defying the long odds, the Human Genome Project succeeded, marking the moment scientists stopped guessing about our genomes and moved forward with a clear understanding of how the human instruction manual works.

For example, before the HGP, the prevailing wisdom was that every human trait was controlled by a single, isolated gene. A gene for intelligence, a gene for aggression, or a gene for athletic ability, that sort of thing.

The HGP shattered that myth, revealing that our traits result from a complex interaction between roughly 20,000 genes and the regulatory switches that control them.

Importantly, the project gave us the equivalent of GPS for human biology, including the exact coordinates for where diseases live. And it revealed that many of the most devastating conditions are caused by nothing more than a single-letter “typo” in our 3-billion-letter library.

In addition to showing scientists where to make the desired edit, it also gave them the tools needed to run computer simulations to ensure that attempts to fix a “broken” gene wouldn’t accidentally damage a healthy one nearby.

Interestingly, the HGP also proved that the DNA of any two humans on Earth, regardless of where they are from or their physical appearance, are 99.9% identical. That fact allows researchers to work towards a single solution to a genetic problem that can then be applied to all humanity.

Of course, useful technology invariably follows an exponential improvement curve. What took the HGP 13 years and billions of dollars in the 90s can be done today in less than 24 hours for about $300, allowing pretty much anyone to have their personal genome mapped.

From Scissors to Erasers

In 2012, the world was introduced to CRISPR-Cas9. Think of it as a biological search-and-replace tool borrowed from the immune systems of bacteria. CRISPR allows us to find a specific address and cut the DNA at the molecular level.

But cutting can be messy. When you break both strands of DNA, the cell rushes to repair it, but it doesn't always do a perfect job. If the repair is sloppy, the cell can die or become cancerous.

Today, the frontier has moved to base editing and prime editing.

• Base Editing is the equivalent of a chemical eraser. It can find a single wrong letter and convert it into the right one without breaking the DNA strand. This is the technology currently being used in trials to cure rare diseases caused by one-letter genetic abnormalities.

• Prime Editing is the latest and greatest. It doesn't just swap a letter; it searches for a damaged sequence, deletes it, and writes in a new sentence of healthy code. It only nicks one side of the DNA, making it far safer and more precise than anything that came before.

I realize that those descriptions are basic. However, in the interest of time and trying to avoid writing something you might read as a sleep aid, I’m mostly staying out of the technical weeds. For those of you who enjoy getting into the small print, you’ll find a more detailed explanation of how modern gene editing works in the Addendum.

AlphaFold and the Origami of Life

As with so many scientific breakthroughs in the modern era, artificial intelligence plays an outsized role in gene editing.

While the human genome is 3 billion letters long, letters are only half the story. To function, the proteins those letters build must fold into complex 3D shapes. If a protein folds incorrectly, you have a problem.

For 50 years, predicting how a protein would fold was one of the grand challenges of science. That’s because while the human genome contains about 20,000 protein-coding genes, those genes can produce millions of different protein variations.

And determining the 3D shape of just one protein used to require years of expensive lab work, which made mapping them all seem an impossible task.

Enter AlphaFold

Developed by Google DeepMind, AlphaFold is an AI system able to predict the 3D structures of nearly every one of the 200 million or so proteins known to science. This breakthrough has been crucial because when scientists edit a gene, it’s essential they know what the resulting protein will look like.

Thanks to AlphaFold, scientists can now predict exactly how a gene therapy will reshape a protein.

Practical implications of this breakthrough?

A Cure for Alzheimer’s?

For decades, Alzheimer’s research was stuck in a loop. Scientists knew amyloid plaques and tau tangles were bad actors but didn’t have a way to see how specific genetic typos changed the physical shape of these damaging proteins.

Thanks to AlphaFold, scientists can now predict how a protein will reshape itself, allowing them to identify drugs that fit the proverbial genetic lock, accomplishing the desired medical outcome.

As you read this, companies such as Lexeo are advancing gene therapies which, with a single treatment, promise to provide protection against further mental degradation in Alzheimer’s patients.

The Phase 1/2 human trials are essentially complete, with pivotal Phase 3 studies expected to begin this year.

While the treatment won’t reverse Alzheimer’s damage, if it works, it will slow down or stop further damage, giving hope to the hundreds of thousands of people diagnosed with this dread disease every year.

If successful in clearing FDA hurdles, the Lexeo treatment is expected to become available as early as late 2028.

(In the Addendum, I include more on the Lexeo Phase 3 trial and how you or someone you know with the condition might join the study.)

And Now, AlphaGenome

During the research for this Deep Dive, the next big leap forward in the science of genetic manipulation—AlphaGenome—was released.

While AlphaFold predicts how proteins fold, AlphaGenome is a “predictive simulator” for the entire genome. Using a 1-million-letter context window, it simulates how an edit in one area ripples through the body’s complex “web.”

This improves on previous techniques by moving beyond simple search and replace (which was often blind to side effects) to a “flight simulator” model. Scientists can now quickly predict the biological consequences of an edit before ever touching a living cell, significantly lowering the risk of “off-target” effects.

The Story so Far

Summing up to this point, scientists now know:

• How to precisely target genes that need to be repaired or altered to produce the desired result.

• They can cut or edit genes safely.

• How the gene will act after it is altered, including the proteins that will be affected by the gene modification.

• And critically, thanks to AI, they can now research and implement genetic modifications in a fraction of the time it used to take.

Simply put, scientists have the knowledge and tools to cut, paste, type over, or otherwise alter the genomes of any organism on Earth, including humans.

Which means that, going forward, where genetic manipulation solves a problem or improves an outcome, expect it to be attempted.

Here are just a few examples of the previously implacable diseases now being tackled.

Sickle Cell Disease

In 2019 Victoria Gray, who had lived in excruciating pain since she was a baby, became the first person to undergo gene therapy for her condition. She was 32 years old at the time she agreed to join an early clinical trial for CRISPR. Scientists used CRISPR to essentially trick her body into starting the production of fetal hemoglobin, effectively overriding the defective gene causing her so much pain.

Remarkably, the treatment was essentially “one-and-done” and, six years later, Victoria is still pain-free, with zero reported side effects.

The treatment involved editing her stem cells in petri dishes before introducing them into her biome, a complex and expensive process. But it provided proof positive that the process works. With repetition and refinement, complexity and costs will come down.

During 2026 the treatment is expected to be approved for children as young as five, offering a functional cure for this painful condition going forward.

Tay-Sachs

Historically prevalent in the Ashkenazi Jewish community due to centuries of relative isolation, Tay-Sachs leads to a total collapse of the nervous system and death before age five. Because Tay-Sachs is usually caused by a single-letter typo, it’s the perfect target for Base Editing.

When Siena Margani was diagnosed shortly after her first birthday in 2017, her parents were told to simply take her home and prepare for the inevitable. However, thanks to a breakthrough dual-vector gene therapy which successfully induced Siena’s body to produce the missing HexA enzyme.

While not a total cure, it marks a turning point for the disease, with rapid progress now being made toward “typing over” the mutation in carriers. In the not-too-distant future, we should reach the point where no child will ever be born with this once-incurable condition again.

Those are just a couple of examples of how gene therapies are already changing lives for the better. Going forward, expect a steady stream of good news.

For example, scientists are also making steady progress on a one-and-done genetic fix for high cholesterol and type 1 diabetes.

Make no mistake, this show is only just hitting the road. The genetic solutions are there; it’s just a matter of time before they are perfected and made more widely available.

Companies Building the Future

When researching this topic, one of the things that stood out to me was how quickly CRISPR went from academic paper to being used in a medical intervention.

Specifically, it went from a paper published by Jennifer Doudna and Emmanuelle Charpentier in an academic journal in 2012 (for which they won the Nobel Prize in Chemistry) to the first cure being approved and applied just 11 years later, in 2023.

Considering we’re talking about a procedure to literally reprogram human DNA, that’s impressive.

Today, with a number of gene therapies proven to be effective and viable, scientists and researchers are accelerating their efforts to cure the incurable and otherwise engineer organisms in ways that will be beneficial to humanity.  

Following are just a few of the companies and laboratories working on genetic engineering. The list is just a sample of some of the leaders. Note that a number of the early pioneers, such as Genentech, have been bought out by the pharmaceutical giants who are hard at work at developing their own gene therapies.

Intellia Therapeutics (NTLA)

Founded in 2014 by Nessan Bermingham of Atlas Venture and later joined by CRISPR pioneer Jennifer Doudna, Intellia is focused on in vivo (inside the body) editing. While others are editing cells in a lab dish before putting them back into the biome, Intellia pioneered the use of “lipid nanoparticles,” microscopic fat bubbles able to deliver CRISPR directly into a living patient’s liver via a simple IV drip.

• Primary Focus: Intellia’s lead program treats ATTR Amyloidosis, a condition where the liver produces “trash” proteins that clog the heart. Using a single infusion, it aims to turn off the faulty gene, offering a permanent cure. It’s now expanding toward common metabolic diseases like high cholesterol, aiming to replace a lifetime of daily pills with one permanent edit.

  
  

Beam Therapeutics (BEAM)

Founded in 2017 by the team of David Liu, Feng Zhang and J. Keith Joung, Beam specializes in Base Editing, chemically changing one letter typos into another without breaking the strand.

• Primary Focus: Beam is working on curing diseases like sickle cell or Alpha-1 Antitrypsin Deficiency. One practical application involves the BRCA1 mutation, which can give a woman up to an 80% lifetime risk of breast cancer. The actress Angelina Jolie carries this mutation, which is why she underwent a preventative double mastectomy at the height of her career. Now imagine being able to have that single “letter” corrected through base editing—effectively rewriting the high-risk code back to a healthy sequence and reducing the risk of breast cancer to that of the general population.

As an aside: while the science is nearing maturity, the regulatory hurdles for preventative edits (e.g., editing a healthy individual to preclude a future cancer) are significantly higher than for curative edits. Consequently, most current BRCA1 research remains in the ‘pre-clinical’ phase. Scientists are focused on proving they can provide a permanent solution in lab-grown tissues before applying to the FDA for permission to move into human trials.

Prime Medicine (PRME)

Another David Liu startup, Prime Medicine is researching the many potential uses of Prime Editing, which earlier I termed “search and replace” for the genome. This is currently the most versatile tool in the gene-editing toolkit because it can handle complex deletions or long-string swaps that simpler tools cannot.

• Primary Focus: Prime targets errors like those found in Tay-Sachs, where it can “search” for a 4-letter mistake and “replace” it with healthy code. Its goal is to build a “universal editor” that can be reprogrammed in a matter of weeks to address virtually any genetic disease.

Lexeo Therapeutics (LXEO)

Founded in 2020 by Dr. Ronald Crystal (a pioneer of gene therapy at Weill Cornell), Lexeo focuses on the “final frontier” of genetics: the human brain and heart. Unlike the editing companies above, Lexeo is focused on delivering a protective version of a gene to override a harmful one.

• Primary Focus: Lexeo’s flagship program, LX1001, targets the APOE4 gene—the strongest genetic risk factor for Alzheimer’s. By flooding the brain with a protective “APOE2” protein, it aims to stabilize the brain's environment and stop the progression of dementia in its tracks.

CRISPR Therapeutics (CRSP)

Co-founded by the co-creator of CRISPR, Emmanuelle Charpentier, CRSP was the first company in history to win FDA approval for a CRISPR-based medicine (Casgevy for sickle cell). Since then, the company has leveraged its breakthrough clinical success to move beyond rare blood disorders.

• Primary Focus: CRSP’s current mission is to bring gene editing to the masses by targeting cardiovascular and autoimmune diseases. It has expanded into pediatric medicine and is advancing “in vivo” programs that aim to treat heart disease and type 1 diabetes with the same precision that is curing sickle cell.

Verve Therapeutics (Subsidiary of Eli Lilly—LLY)

Verve is a leader in the attempt to make humanity “heart-attack proof.” Verve uses base editing to permanently lower bad cholesterol by turning off the PCSK9 gene in the liver, effectively replacing a lifetime of daily statins with a single treatment. Its work was sufficiently promising that the company was acquired by Eli Lilly for over $1 billion in 2025.

• Primary Focus: Verve’s lead program, VERVE-102, is designed to provide lifelong protection against coronary artery disease. By focusing on the world's leading cause of death—heart disease—it’s shifting the medical paradigm from chronic management to a permanent, one-and-done preventative shield.

Why would a company such as Lilly, whose core business is selling recurring treatments (daily pills), be researching one-and-done gene therapies? Answer in the Q&A in the Addendum.

Editas Medicine (EDIT)

Editas is often called the “CRISPR 2.0” company because it utilizes a unique enzyme (Cas12a) that is arguably sharper and more precise than the original version of CRISPR. This allows Editas to make complex edits in dense areas of the genome other tools might struggle to navigate.

• Primary Focus: Its lead candidate, EDIT-401, targets extreme high cholesterol (hyperlipidemia). Editas is advancing toward its first human proof-of-concept studies later this year, aiming to prove that its next-gen scissors can outperform traditional cholesterol treatments such as statins by a wide margin. In one study, a single dose achieved a 90% reduction in LDL cholesterol within just 48 hours.

Mammoth Biosciences (Private)

Co-founded by Jennifer Doudna, Mammoth is focused on shrinking the standard CRISPR tools, which are often too bulky to fit into the delivery vehicles needed to reach certain parts of the body. Mammoth’s ultracompact systems are designed to be small enough to travel where others can’t.

• Primary Focus: Mammoth is building a pipeline to treat difficult-to-reach tissues like the lungs and skeletal muscle. Its goal is to bring curative edits to patients with cystic fibrosis and muscular dystrophy by solving the delivery problem that has long limited the field.

Metagenomi (MGX)

One of the more interesting companies working in genetics, Metagenomi uses AI to scan the natural world—from soil and water to extreme deep-sea environments—for natural gene-editing tools that evolved in bacteria over millions of years.

• Primary Focus: Metagenomi’s lead program, MGX-001, is a potential one-time cure for Hemophilia A. The system utilizes a novel nuclease, MG29-1, discovered in the extreme conditions of a deep-sea hydrothermal vent.

  
  

  By late 2026, the company expects to file its final paperwork with the FDA to begin human trials, with the goal of providing hemophiliacs with stable, lifelong protection from bleeding events.

It’s also worth mentioning companies like eGenesis and Revivicor that are editing pig genomes to create “humanized” organs. In 2024, the first living human received a gene-edited pig kidney. While the patient died two months later, the cause of death was a pre-existing heart condition, not organ rejection.

Within a decade, it’s anticipated we’ll be able to manufacture organs as needed, ending a shortage that kills 17 people every day in the US alone.

Finally, per our recent Deep Dive on research into longevity, labs like Altos Labs (backed by Jeff Bezos) are researching “Epigenetic Reprogramming,” hoping to reset the repair genes that turn off as we age.

The Final Mile: Overcoming the Delivery Challenge

While the ability to edit the human genome has been proven, the “final mile” of genetic medicine—delivering those edits safely and precisely to the correct cells—remains the industry’s greatest hurdle.

One cautionary tale comes in the form of 18-year-old Jesse Gelsinger, who in 1999 joined a gene therapy clinical trial at the University of Pennsylvania. Jesse suffered from a rare liver disease, but it was manageable with diet and meds. He volunteered for the trial to help find a cure for babies with a more fatal version of the disease.

The scientists used a weakened cold virus modified to carry healthy genes into his liver. Tragically, Jesse’s immune system saw the virus and went into a massive, uncontrolled inflammatory response. His organs failed, and he died four days later.

Jesse’s death, which halted gene therapy research for nearly a decade, underscored the fact that the delivery of the gene editor is often more dangerous than the editor itself.

Today, researchers focus on three primary danger zones:

1. Off-Target Effects: This is when the “GPS” gets the address wrong. Instead of cutting a disease gene, it accidentally cuts a healthy gene. It’s like a surgeon trying to remove a tumor but accidentally nicking a major artery.

2. Mosaicism: This happens when the repair only works in some of the cells but not all. This leaves the patient with a patchwork of edited and unedited DNA, which can cause unpredictable health issues.

3. Immune Overreaction: Our bodies are designed to attack foreign invaders. If the immune system “sees” the CRISPR proteins or the delivery vehicle, it can attack the very cells scientists were trying to save.

How Scientists Are Making It Safer

• Lipid Nanoparticles (LNPs): Instead of using viruses (which may trigger immune responses), companies like Intellia use tiny fat bubbles. Our bodies are made of fat, so the immune system usually ignores them, allowing the treatment to be delivered safely.

• High-Fidelity AI: As discussed, AlphaFold and other AI tools allow scientists to pre-scan the genome. They check millions of possible “off-target” sites before the patient is ever treated, ensuring the location for the edit is unique and safe.

• Kill Switches: Scientists are developing “Anti-CRISPR” proteins. If a doctor notices an adverse reaction in a patient, they can administer a reversal agent that shuts down the gene-editing machinery instantly, stopping it from making any more cuts.

Alternative Delivery Mechanisms

In addition to researching safety guardrails, scientists are exploring a number of new delivery mechanisms.

Engineered Virus-Like Particles (eVLPs): These look like viruses to gain cell entry but contain no viral DNA to trigger an immune alarm. They are flexible and allow scientists to target the heart or brain specifically.

• Human Testing: Several companies (such as Profluent and Beam) are moving toward human trials by late 2026 or 2027.

Exosomes: These are natural bubbles cells use to communicate with each other. Because they are native to the human body, they are nearly invisible to the immune system and can cross the all-important and very challenging blood-brain barrier.

• Human Testing: Active in 2026. Companies like Capricor and Evox already have programs in Phase 1/2 trials for muscular dystrophy and rare metabolic disorders.

Synthetic “GPS” Polymers: Unlike standard fat bubbles, these are plastic-like chains that can be programmed to ignore the liver and only release their cargo when they hit the specific pH or enzyme signature of the lungs or kidneys.

• Human Testing: Following successful large-animal trials completed in 2025, pilot human studies for polymer-delivered RNA are slated to begin in early 2027.

AAV-Alternative Capsids: Scientists are using AI to design entirely “new-to-nature” viral shells (capsids) that do not match any virus the human immune system has ever seen, preventing the pre-existing immunity response that disqualifies many patients today.

• Human Testing: Active in 2026. Next-gen capsids from companies like 4D Molecular Therapeutics are currently being tested in patients with cystic fibrosis and heart disease.

  
  

Who Will Solve Gene Therapy Delivery?

Below is a brief look at five companies working on the delivery challenges.

Generation Bio (GBIO)

GBIO is focusing on creating “redosable” genetic medicines that function like a durable, extra-chromosomal piece of DNA within the cell. Because its delivery system does not use a virus, the approach may allow patients to receive multiple doses over their lifetime to maintain therapeutic levels.

ReCode Therapeutics (Private)

ReCode’s process allows it to add a specific functional lipid to standard nanoparticles, essentially giving the medicine a GPS coordinate. This technology has successfully directed genetic cargo to organs beyond the liver, specifically the lungs and spleen.

At this writing, it’s in Phase 2 clinical trials for inhaled mRNA therapies targeting cystic fibrosis and Primary Ciliary Dyskinesia (a rare genetic disorder where the tiny, hair-like structures lining your airways and other organs do not move correctly).

Entos Pharmaceuticals (Private)

Its focus is on engineering “hybrid” proteins—Fusogenix Proteo-Lipid Vehicles (PLV)—that combine two different proteins into one which can (a) deliver the gene therapy to the right location, and (b) fuse with the targeted cells so that the therapy is incorporated into the cells.

This approach is designed to be less toxic than traditional methods and is being researched for a wide range of applications, including oncology and neurology, through high-profile collaborations with companies like Eli Lilly.

Arcturus Therapeutics (ARCT)

Its focus is on making genetic medicines more efficient, using mRNA that, once inside the cell, can “copy itself,” achieving the desired therapeutic results with much lower doses.

At this writing they are making significant strides in clinical trials for rare respiratory and liver diseases, including a major 12-week study for cystic fibrosis.

Intellia Therapeutics (NTLA)

Mentioned earlier, Intellia is a leader in in vivo CRISPR delivery. The company’s research focuses on using lipid nanoparticles to deliver CRISPR machinery directly into a patient’s bloodstream via a simple infusion.

Intellia was the first to prove that this method could successfully knock out disease-causing genes in the liver, and as of 2026, it’s pushing these systemic delivery methods into Phase 3 trials for rare protein-folding disorders.

As part of my research for this Deep Dive, I listened to a number of lengthy interviews, including with CRISPR pioneer Jennifer Doudna, and it’s clear that while there is much to be optimistic about when it comes to the rapid advancements in gene therapies for humans, top researchers working in the field believe the delivery problem is far from being solved and may prevent wider adoption of gene therapies for another decade.

Definitely something to keep an eye on.

Risks and Controversies

Of course, anytime scientists tinker with DNA, the stakes are binary: a miracle cure or a catastrophic error. In addition, there are ethical concerns I’ll touch on shortly.

Misuse

In the same interview with Jennifer Doudna just mentioned, she discusses some of the recent work at a research institute she is affiliated with at UC Berkeley. Specifically, reprogramming the biome of the microbes in the stomachs of cows to reduce their methane emissions.

I won’t take a stance here on the whole “cow farts killing the planet” thing, but arming humans with the ability to genetically change the natural order of things based on an issue du jour is worrying.

What, for example, might have been the result if genomic editing had been around during the peak of Paul Ehrlich’s mental breakdown over the imaginary global population crisis back in 1968—a worry that, at the time, led to the forced sterilization of millions of individuals in India?

Or when China decided to use draconian measures to force a one-child policy on its citizens?

Could a genetic “solution” have been developed to limit fertility? Perhaps.

I know that’s an extreme example, but does it fall within the realm of reality given the mass madness we humans periodically succumb to?

When you think about the coercive mandates around the mRNA COVID vaccines, mandates that spread like bureaucratic wildfire around the world, it doesn’t seem so far-fetched.

Speaking of genetically engineered sterility, there is a real-world case: malaria-carrying mosquitoes.

Malaria: The Biological Reset

According to the WHO, over 200 million people, mostly in Africa, catch malaria each year, with over 600,000 fatalities.

Instead of just trying to find better drugs—which the parasite eventually learns to evade—scientists are now using CRISPR to edit the sex-determining genes of the Anopheles mosquito in order to force the trait of female sterility to spread through the entire population.

In the old days, it would take centuries for a trait like that to take hold. Today scientists can collapse a local mosquito population in just seven to eleven generations—mosquito generations, that is, which works out to only about four to six months.

While one might take pause at the idea of eliminating a species of insect, when you consider the damage done by malaria over the centuries and the persistent nature of the Anopheles mosquito, which grows from an egg in a puddle of water into a mature mating mosquito in only two weeks, defeating malaria through genetic editing seems the wise choice.

That said, scientists, perhaps concerned about both the optics and potential risks of deleting a species from the world—for example, negatively impacting other species that rely upon mosquitos as a food source—are also working on genetically programming malarial immunity in the offending mosquitos so they can no longer carry the disease to humans.

I include that example to show the versatility and potential of gene editing, as well as highlight the sort of God-like decisions humanity will soon be asked to make.

Germline Editing

Up to this point we have been discussing genetic manipulations that target non-reproductive cells in order to treat individual patients.

In contrast, germline editing involves tampering with the cells in sperm, eggs, or even early-stage embryos.

With germline editing, any edits made become a permanent part of that person's DNA and will be inherited by their descendants.

In the case of a genetic condition such as Tay-Sachs, germline editing would seem desirable, but there are legitimate concerns germline editing could trigger unforeseeable abnormalities, which might not appear for several generations.

Due to those and other concerns, any form of germline editing outside of the lab is currently illegal in most countries.

As an aside, a Chinese scientist named He Jiankui let his curiosity get the best of him and, in two separate procedures, performed a germline edit on three embryos to give them immunity to HIV. The three babies were then carried to full term and delivered. He was sentenced to three years in jail for his experiments but is now free and remains in contact with the families involved and reports the children are all healthy and normal.

I won’t go deeper into germline editing because it will remain locked in the regulatory safe for the foreseeable future, but I wanted to mention it here in an attempt of providing a reasonably complete picture of the topic.

Which Brings Us to Designer Babies

One of the concerns related to gene editing has to do with “designer babies.” You know, where affluent parents could pay a commercial lab to edit an embryo so that it was born with specific traits like eye or hair color, intelligence, height, etc.

While eye and hair color involve relatively few genes and so could conceptually be influenced with genetic tweaks, these traits don’t have a single master switch. Rather, they are woven into a complex web of instructions where rewriting one line of code risks triggering unwanted consequences elsewhere in the biome.

When you move on to traits such as height, intelligence, personality and athletic ability you quickly run into the fact that these are governed by complex networks involving hundreds—or thousands—of genes, interacting with development and environment in ways we do not fully understand.

In other words, the popular trope of wealthy parents selecting traits from a catalogue reflects science fiction more than current—or even foreseeable—biology.

That said, there is a company named Nucleus that is taking a different and equally controversial approach to “designing” babies.

Namely, it uses the eggs and sperm provided by patients to produce a dozen or more embryos. It then does genetic scans on the embryos to determine the potential for possessing various attributes, including hair color, height, intelligence, even traits such as male-pattern baldness. It also screens the embryo for the potential to develop a gene-related disease. The pending parents then select “their best baby,” and the rest are destroyed.

I won’t go into the ethical and moral implications of this approach, but if you want to read more, here’s a link to a longer article on the topic from LewRockwell.com.

Cloning

Since cloning organisms first appeared on the scene in 1996 with the cloning of Dolly the Sheep, the cloning industry has matured into a multi-billion-dollar business.

While the primary use case for cloning has to do with cloning bacteria for things like insulin production, there are thriving businesses cloning what you might call “elite” animals. For example, a particularly productive breeding bull.

One of the more interesting use cases emanates from here in Argentina, where I am currently in residence. It revolves around Adolfito Cambiaso, considered the best polo player ever to have lived. Inspired by the cloning of Dolly, Cambiaso had the foresight to have the vet save genetic material from his favorite horse, which he subsequently cloned.  

In 2016, Cambiaso achieved a scientific milestone by playing an entire final match of the Argentine Open using six different clones of his prized horse.

Today Cambiaso operates a large operation selling the offspring from his cloned horses for up to $800,000 apiece.

In addition to commercial breeding operations, companies like ViaGen Pets and Sinogene offer pet cloning. While expensive ($35,000 to $50,000), the demand from high-net-worth individuals has turned this into a self-sustaining industry.

Speaking of cloning, which isn’t technically gene editing but rather copying and reproducing the entire genome of an organism, did you know the modern bananas you enjoy with your breakfast are clones?

Wild bananas are small, tough, and filled with large, hard seeds that can easily break a tooth. To transform them into useful food, scientists utilized a rare genetic fluke to create the Cavendish, the bright yellow banana found in every grocery store.

In nature, most organisms have two sets of chromosomes (one from each parent). Through specific crossbreeding, the Cavendish version now has three sets.

This extra set of instructions confuses the plant’s reproductive system, making it impossible for the plant to produce viable seeds. Those tiny, useless black dots in the center of your banana are the “ghosts” of seeds that never formed.

Which means that every banana you consume is a clone. To reproduce, banana farmers use cuttings from existing plants.

Concluding Thoughts

Baby KJ was born in late 2024 with a rare urea cycle disorder called CPS1 deficiency, which affects about one in 1.3 million newborns.

KJ’s body couldn't break down ammonia, which soon builds up to toxic levels and causes brain damage or death. For infants like KJ, the only treatment option was a risky liver transplant.

Within days of his birth at the Children's Hospital of Philadelphia (CHOP), doctors used rapid genomic sequencing to identify his specific mutation. Working closely with scientists at CHOP and Penn Medicine, the team spent just six months designing, manufacturing, and testing a bespoke base-editing therapy created just for KJ’s unique DNA sequence.

In February 2025, at about six months old, KJ became the world's first person to receive a personalized CRISPR gene-editing drug. Even though researchers were confident he only needed one infusion, they gave him three throughout the spring of 2025 just to be sure.

Today, his body is producing the missing enzyme. While he still follows a monitored diet, he can tolerate protein much better and needs far less supplemental medication, with the expectation he’ll live a long and normal life.

My purpose for wrapping up with the story of Baby KJ is because it demonstrates how far genetic engineering has come in recent years. From diagnosis to reprogramming a broken part of his genome took only about six months, time enough to save the baby’s life.

Scientists now have the know-how and tools to fix a very long list of health problems and to play God by speeding up evolution to create any number of beneficial mutations for the betterment of humanity.

While the safe delivery of genetic edits to more challenging parts of the human genome, outside of the liver, is still a way off, there’s no question those challenges will be overcome.

What does the future hold?

Will we see cures developed for pretty much every genetically caused disease? Almost certainly.

Will we see regulatory approvals for preventive cures? For inherited breast cancer, for example? Or, approval for germline editing to stomp out conditions such as Tay-Sachs once and forever? In due course, we will.

What about more complex genetic conditions like Down Syndrome? Because it is caused by an entire extra chromosome (Chromosome 21), it was long thought to be “un-editable.”

However, scientists have already begun experimenting with ways to silence that extra chromosome in a lab setting. While still in the early research stages, this chromosomal therapy hints at a future where we might mitigate the effects of the condition at the cellular level. Should this line of research pay out, it could open up a whole new chapter for medicine.

While modern genetic editing is still very expensive, mostly because it’s bespoke, the savings in ongoing medical costs can justify that expense. For example, it is estimated that the gene therapy for Hemophilia will cost about $3 million.

That’s a lot. But when you compare it to the $800,000 per year cost of the treatments now being used, not so much. For an insurance company on the hook for those annual costs, the one-and-done treatment feels like a bargain.

And, of course, as these technologies will only get more refined, costs will fall. That’s the way of the world.

While playing God gives rise to any number of ethical questions and concerns, after living and breathing this topic for over a month, I’m convinced genetic manipulation in its various forms, done responsibly, is essentially the speeding up of natural evolution, and that the benefits far outweigh the potential negatives.

In fact, as I wrap this Deep Dive, I have come around to believing that manipulating genes could be one of the single most important advancements in human history.

What do you think? What worries you about manipulating genes? Do you or someone you know have a condition where genetic editing might help?

Drop me a line at galland@rationaloptimistsociety.com. I read all my correspondence and usually respond.

In the Addendum just below, you’ll find lots of additional information on the topic.

If you found this Deep Dive useful, please forward it to others and encourage them to join the Rational Optimist Society. It’s free, so there’s nothing to lose, only lots of upbeat news and valuable information to gain.

Until next time,

David Galland

For the Rational Optimist Society

Addendum

Genetic Glossary

• DNA: The “instruction manual” for your body. It is a long molecule shaped like a twisted ladder (the double helix) that carries all your genetic information.

• Gene: A specific “paragraph” or section of DNA that contains the instructions to make a single protein (like the ones that determine eye color or help blood clot).

• Genome: The complete set of all your DNA—essentially the entire library of instructions that makes you you.

• Chromosome: The physical “containers” for your DNA. Think of them as 46 individual books that make up your library. To fit all that information inside a tiny cell, your DNA is tightly coiled around proteins (like thread wrapped around a spool). Humans have 23 pairs (one from each parent), totaling 46.

• Base Pairs (A, T, C, G): The four chemical “letters” that make up the words of your DNA.

• Germline Editing: Editing DNA in embryos, eggs, or sperm. These changes are passed to future generations.

• Somatic Editing: Editing done to a living person's body cells (like blood). These changes fix the disease but cannot be passed to children.

• Lipid Nanoparticle (LNP): A microscopic bubble of fat used to carry gene-editing tools safely into the body.

• mRNA (Messenger RNA): The “photocopy” of your DNA instructions. Your cells don't read the original DNA directly; instead, they make a temporary mRNA copy that travels to the “protein factory” of the cell to tell it what to build.

• Mutation: A “typo” in the DNA code. Some typos are harmless, while others (like the one in Tay-Sachs) cause the body to make a broken protein or none at all.

• Gene Therapy: The process of adding a new, working copy of a gene into a person’s cells. It doesn't usually fix the “broken” gene; it just adds a healthy one to do the work instead.

• Gene Editing (e.g., CRISPR): A more advanced technique that actually “edits” the original DNA. It can cut out a “typo” and replace it with the correct sequence (like using a “search-and-replace” tool in a word processor).

• CRISPR-Cas9: The most famous gene-editing tool. It uses a “guide” to find a specific DNA sequence and a protein (Cas9) that acts like “molecular scissors” to cut the DNA at that exact spot.

• Base Editing: A high-precision version of CRISPR that can change a single “letter” of DNA (e.g., changing a C to a T) without cutting the entire DNA strand, making it even safer.

• Vector: The “delivery truck” used to carry genetic material into a cell.

• Viral Vector: A virus that has been “hollowed out” so its disease-causing parts are removed. Scientists use its natural ability to “infect” cells to sneak the healthy gene inside.

• Non-Viral Delivery: Using man-made materials instead of viruses to deliver genes. This is often safer and allows for repeat doses.

• LNP (Lipid Nanoparticle): A tiny bubble of fat (lipids) used as a non-viral delivery truck. It protects the fragile genetic medicine until it reaches the target cell.

• In Vivo: This means the treatment is injected directly into the patient's body (like an IV) to do its work.

• Ex Vivo: This means a patient’s cells (like blood cells) are removed, edited in a lab, and then dripped back into the patient (the method used for Victoria Gray).

• Specialized Fusion Proteins: Engineered “hybrid” proteins that combine multiple functions into one. In gene delivery, they act as both a GPS (to find the right cell) and a key (to help the medicine fuse with and enter the cell membrane).

Questions and Answers

Why Would a Company Such as Lilly Be Working on One-and-Done Cures? 

While many readers will assume that Big Pharma makes a lot of money from selling pills requiring daily consumption, they would be wrong. That’s because statin drugs have become generic, produced for pennies a pill and sold for perhaps $30 a month.

In fact, Lilly makes zero money from statins.

Therefore, by getting ahead of the herd in developing a one-and-done gene-editing procedure, they are undercutting the generic manufacturers and opening up a potentially impressive new revenue stream.

That’s because it is anticipated that one-time genetic treatments for conditions like HeFH where patients can’t control their bad cholesterol production with pills, or for people who have already had a heart attack and are statin intolerant, could run to $600,000.

However, a person with a serious cholesterol problem can end up costing insurance companies hundreds of thousands of dollars in treatments and hospitalizations due to heart attacks.

In that context, the high price of gene treatments begins to seem more rational. Especially in that the model Lilly (and others) are now working on would have the insurance companies pay for the treatments in installments, with specific hurdles tied to results.

For example, for a person with HeFH, the insurance company might agree to pay Lilly, say, $60,000 a year for 10 years. But those payments would immediately cease if the person’s cholesterol rose over a certain ceiling, or the person had a heart attack.

Of course, over time, these treatments will become more commonplace and therefore less expensive, but in the meantime Lilly et al will have a feasible business model which allows them to recoup the billions spent developing these therapies (which includes the cost of acquiring companies such as Verve) and to turn a profit by developing life-saving therapies.

Are the Crops Created Using CRISPR Considered Genetically Modified Organisms (GMOs)?

In a word, “yes.”

While some of you dear readers may shudder at the idea of foodstuffs emanating from GMO crops, that is a fear I don’t share. Mainly because we have gone from the world of my youth when millions regularly died of famine, to today, where they are all but non-existent. When they do occur it is not for a lack of food availability but deliberate political decisions, invariably made in conflict zones.

That said, I do sympathize with anti-GMO arguments related to companies patenting seed types, and then licensing them to farmers for only one growing season. To wit, farmers are no longer able to keep their own seed banks, which kind of puts the brakes on the sort of selective breeding that produced such abundance over the eons.

Another consequence is that over 60% of the seed industry is controlled by just three firms.

Again, I don’t need to go deeper into this sub-topic, but I will mention that the United States Department of Agriculture has provided regulatory relief for US companies working on genetically engineering crops. Basically, if the genetic editing being done could have been achieved through selective breeding over a couple of decades, then no regulatory approval is required.

The Europeans, as is their pro-regulatory nature, take a dim view of that approach and so levy all manner of bureaucratic burden on GMO products, no matter how they are created.

Are You or Someone You Know a Candidate for the Next Alzheimer’s Trial?

As we move from the era of “managing symptoms” to “engineering cures,” clinical trials are the primary bridge to the future. For those carrying the high-risk APOE4 gene, the transition from observer to participant is a personal decision that requires navigating specific medical and genetic criteria.

Who Qualifies? Participation in trials like LX1001 is currently reserved for those at the highest genetic risk. Because this therapy is designed to mitigate the damage caused by the APOE4 variant, the primary requirements are:

• The “Double 4” Signature: You must be APOE4 Homozygous, i.e., you inherited the gene from both your mother and father.

• The Early Window: Trials typically focus on individuals aged 50 or older who are in the “Mild Cognitive Impairment” (MCI) stage—the period when subtle memory changes have begun, but independence is still largely intact.

• The Biomarker Check: Potential candidates must show physical evidence of the disease via a PET scan or spinal tap (amyloid plaques and tau tangles).

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The Reality of Participation:

1. Safety First: Phase 1 and 2 trials are primarily designed to prove the treatment is safe and that the "protective gene" is actually being expressed in the brain.

2. Not a “Reset”: Gene therapy cannot currently bring back dead brain cells. The goal is to stabilize the brain's environment to prevent further decline.

3. The Commitment: These studies involve long-term follow-up (often five years or more) to monitor the durability of the genetic edit.

How to Find a Center Most US-based trials are conducted at major academic medical centers (such as Weill Cornell in New York or UCLA in California). You can search for active locations by visiting ClinicalTrials.gov and searching for identifier NCT04226170.

Should You Have Your Genome Mapped?

Why would a normal, healthy individual want to have their genome sequenced?  

Here are the four primary reasons a healthy individual in 2026 would invest in a full sequence:

1. Pharmacogenomics: The “User Manual” for Meds

This is the most immediate, practical benefit. Your genes determine how your liver enzymes break down medication.

• The Problem: Roughly 50% of people have a genetic variant that makes common drugs (like blood thinners, antidepressants, or even ibuprofen) either toxic or completely ineffective. I know of someone who, due to his genetics, pretty much dropped dead after being prescribed Warfarin.

• The Solution: With your sequence on file, a doctor never has to “guess” a dosage again. They check your code and see, for example, that you are a “poor metabolizer” of a specific drug, saving you from a dangerous adverse reaction or months of wasted treatment.
  

2. Identifying “Silent” Risks (Polygenic Risk Scores)

Most of us aren't killed by a single “broken” gene like Tay-Sachs. We are affected by Polygenic traits—the combined influence of thousands of tiny genetic variations.

• The Insight: Sequencing can provide a “Risk Score” for common killers like type 2 diabetes, coronary artery disease, or breast cancer. Once you have the data, if your sequence shows you are in the 99th percentile for heart disease risk, you don't wait for a heart attack. You start advanced screening and lifestyle changes decades earlier than you might have otherwise.
  

3. Family Planning and Carrier Screening

Many healthy people carry “recessive” mutations. You can be a perfectly healthy carrier of cystic fibrosis or sickle cell and never know it—until you have a child with another carrier. If you were thinking of starting a family, having your genome sequenced could be helpful. For example, if both you and your partner are carriers for a condition, modern IVF techniques (or the gene-editing tools we’ve discussed) could help ensure your children are born healthy.

4. The “Future-Proof” Asset

As gene-editing technologies like those from Intellia or Beam move from rare diseases to "common" ones, your sequence becomes your ticket to treatment. Per above, we are approaching a time when we can “edit” a gene called PCSK9 to permanently lower cholesterol. A healthy person might get sequenced now to identify if they are a candidate for this “genetic vaccine” against heart disease.

Of course, because your DNA doesn't change, you only need to sequence it once. As science discovers new things over the next 40 years, you simply re-run your digital file against the new discoveries.

Companies offering sequencing include:

1. Nebula Genomics

Founded by George Church, a pioneer of the Human Genome Project, Nebula is currently the most popular choice for high-resolution Whole Genome Sequencing (WGS).

• The Offering: It offers “30x Whole Genome Sequencing,” meaning it reads every letter of your DNA 30 times to ensure there are no errors.

• The Price: Typically around $299 for a standard kit with a lifetime membership.

As an added feature for its clients, the company uses blockchain technology to store your data. This means you own the encryption key to your genome, preventing the company from selling your data to pharmaceutical firms without your permission.

2. Dante Labs

Based in Europe but serving the US, Dante Labs was one of the first companies to offer sequencing to the masses. It’s known for providing the “VCF file”—the raw, massive data file of your entire 3-billion-letter sequence—which you can take to any specialized geneticist in the world.

• The Offering: It provides extensive medical-grade reports that look specifically for rare diseases and “carrier” status.

• The Price: Often runs “flash sales” as low as $399, though its standard professional reports can go higher.

3. Sequencing.com

This company acts as a platform where you can both buy a sequencing kit and then “upload” your data to use various health apps.

• The Offering: Sequencing.com sells its own WGS kits and offers a subscription to an “app market” that constantly updates your reports as new scientific discoveries are made.

• The Price: Around $399 for the initial sequence.

• The Edge: It is the most user-friendly. If a new study comes out about a “caffeine gene” or a “heart disease variant,” you don't need a new test; you just buy a $10 app on the platform to re-analyze the data you already have.

4. Helix

Helix works more closely with health systems (like the Mayo Clinic) to integrate your DNA into your actual medical records. Because Helix is “clinical grade,” its reports are often more easily accepted by insurance companies and doctors for preventative screenings.

• The Offering: It focuses on “Exome+” sequencing, which reads the most important 2% of your DNA (the parts that make proteins) plus key markers in the rest.

SOURCES

Gene drives to induce female sterility or malaria immunity in mosquitoes.  https://singularityhub.com/2025/12/18/this-gene-drive-stops-the-spread-of-real-world-malaria-without-killing-any-mosquitoes/

Article on CRISPR application for curing a rare form of blindness. https://www.sciencedaily.com/releases/2024/05/240506131535.htm

Baby KJ.

https://www.insideprecisionmedicine.com/topics/precision-medicine/first-personalized-crispr-gene-editing-therapy-patient-baby-kj-discharged/

Interview with Jennifer Doudna.

https://www.corememory.com/p/the-present-and-future-of-gene-editing-jennifer-doudna-crispr

Article on “Pick Your Baby.”

https://www.lewrockwell.com/2026/01/no_author/brave-new-world-ivf-companys-eugenics-tool-lets-couples-pick-best-baby-discard-the-rest/

Article on precision delivery.  https://www.insideprecisionmedicine.com/topics/precision-medicine/precision-delivery-the-final-mile-to-clinical-genetic-medicine/