Thanks to high-profile longevity influencers and biohackers, gene therapies have moved from the fringes into pop culture.
Actually, some extreme biohackers have performed DIY gene editing using special “CRISPR/cas9” kits for over a decade.
As with most technological innovations, the price has come down dramatically. What used to require an entire lab and hundreds of thousands of dollars can now ship to your doorstep for under $2,000.
But just because you can now edit your genome, should you?
In this short article, I’ll break down why biohacking gene therapies fail the simple bioharmony safety test for healthy folks and the reasons I recommend avoiding them.
Once expensive & limited to labs, biohackers now experiment with CRISPR gene therapy at home for under $2,000 while newer plasmid therapy costs ~$25,000
However, it’s still extremely risky with gene editing causing “chromosomal mayhem” [R]
Only 12% of already-limited research on gene therapy trials used the newer plasmid technology and it still has myriad issues [R]
Scientists were totally wrong about the Human Genome Project, and until several years ago, 98-99% of the genome was considered “junk DNA”
Despite not fully understanding the human genome or the consequences of making tweaks, some folks are going forward with gene therapy
The only ideal applications currently are to address rare disease, genetic disorders, and some cancer therapies
What is Gene Therapy?
Gene therapy is a biohacking technique that alters your genes to ostensibly treat disease or enhance health.
Gene therapy was originally introduced to fix genetic disorders, certain cancers, and chronic diseases that currently “lack effective treatments”.
There are three main gene therapy strategies:
- Gene augmentation: A healthy gene is inserted into cells to replace or supplement a faulty gene
- Gene correction: CRISPR and other technologies “precisely” edit the DNA sequence to correct a mutation
- Gene inhibition: Problematic genes are turned off (silenced) using RNA interference or antisense oligonucleotides
Delivery technologies
| Delivery Method 🧬 | How It Works 📝 | Advantages 📈 | Challenges 📉 |
|---|---|---|---|
| Viral Vectors | Uses modified viruses to deliver genetic therapeutic genes into your cells | High efficiency & can treat many different types of cells | Can cause immune reactions |
| Lipid Nanoparticles | Wraps genes in tiny bubbles of fat that cells can easily absorb | Can deliver large genes & safer than some methods | Doesn’t always work well inside the body |
| Electroporation | Uses electric pulses to create tiny holes in cells, allowing genes to enter | Good for treating tumors directly, improves cell survival and gene delivery | Requires careful setup as it can damage cells |
| Direct Injection | Injects genes directly into the body (e.g., muscles, brain) | Results in a much higher level of gene expression | Doesn’t always get genes into cells effectively |
Gene therapy must deliver the payload into cells via one of two mechanisms.
Scientists generally classify the way gene therapies deliver genetic material into two categories, each with distinct pros and cons:
- Viral vectors: Modified viruses, like adenoviruses or lentiviruses, deliver the therapeutic gene into cells. This method is more studied, targeted, and long-lasting but far more dangerous and expensive
- Non-viral methods: These include lipid nanoparticles, electroporation, or direct DNA/RNA injections. This method is theoretically safer, more accessible, but lacks research, doesn’t last as long, and may still cause toxicity
Both have major drawbacks and extremely limited safety data or research.
Why I’m Not Getting Follistatin or Klotho Gene Therapy
At its inception, scientists viewed the Human Genome Project as among the most important projects of all time.
Decode the genome, and we have a way to solve all disease.
Or so they thought.
Turns out that humans do not have 100,000 genes as predicted. Rather, a measly ~24,000. Similar to that of mice, roundworms, water fleas, and even rice Share on XWell, non-coding DNA makes up 98-99% of the human genome. It always has.
Scientists generally considered it “junk DNA” up until some time between 2012 and 2020 when they discovered other roles such as:
- MicroRNAs (miRNAs): Regulate gene expression (epigenetics)
- Long noncoding RNAs (lncRNAs): Play roles in transcriptional regulation, chromatin remodeling, and even disease mechanisms
- Small interfering RNAs (siRNAs): Involved in gene silencing and defense against viruses
Suffice to say, we still don’t fully understand the human genome.
How can you effectively artificially manipulate something you don’t fully understand?
You can’t. Or at least, not safely and without significant risk.
With gene therapies, there’s virtually zero research. Worse, the limited research on the most popular forms show that it’s incredibly dangerous (more on that below).
CRISPR/Cas9 Gene Therapy
Biohackers were once seen as extremists because some infamous characters used experimental CRISPR technology on themselves to modify their genome.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a gene-editing technology derived from nature.
It’s actually a natural system found in bacteria and archaea that helps defend themselves against viruses and other foreign genetic elements by recognizing and cutting specific DNA sequences.
Biotechnology adapted a version of it called CRISPR-associated protein 9 (Cas9), a specialized enzyme that works like molecular scissors to cut DNA at specific locations.
Here’s how CRISPR-Cas9 works:
- Guide RNA (gRNA): A custom-designed RNA sequence guides the Cas9 protein to a specific DNA sequence in the genome
- Cas9 Enzyme: Once at the target site, Cas9 cuts the DNA at the specified location
- DNA Repair: The cell attempts to repair the cut, which can lead to:
- Gene Disruption: If repaired incorrectly, the gene might be disabled
- Gene Editing: Scientists can introduce desired DNA sequences during the repair process
What could go wrong?
As it turns out, a LOT.
This was literally the title of a 2020 study…
CRISPR gene editing in human embryos wreaks chromosomal mayhem
Chromosomal mayhem!
CRISPR shattered DNA and caused unforeseen deletions, insertions, and mutations.
Some of the other effects include:
- Large deletions, complex rearrangements, and mosaicism (where edited and unedited cells coexist) have been reported [R, R]
- Off-target mutations at genomic sites with sequences similar to the target DNA can lead to cell death or transformation into cancerous cells [R, R]
- Cancer development from editing errors involving oncogenes or tumor suppressor genes (like p53) [R]
- Immune complications from introducing foreign proteins like Cas9 [R]
- Minimal efficacy in some cases [R]
To top it off, as shown by the infamous case by Dr. He Jiankui, modifying your genes with CRISPR can have an irreversible impact on future generations [R].
While gene therapy makes sense in some cases discussed later, biohackers tinkering with gene editing is incredibly foolish and downright dangerous.
Plasmid Gene Therapy
Plasmid gene therapy, like Follistatin (FST) 344 gene therapy, works by delivering a circular DNA plasmid into cells to promote expression of the desired gene.
The two most anticipated gene targets are Klotho and Follistatin. Follistatin is a myostatin inhibitor known for promoting muscle growth and potential anti-aging effects.
The risks are largely unknown.
Why?
The technology has barely been studied or used.
One recent pre-print confirms that with the following,
“All FDA-approved gene therapies to date utilize viral vectors [24], and only 12% of gene therapy trials worldwide use plasmids”
So just 12% of the already very limited research on gene therapy used this newer plasmid technology [R].
While it appears to be far safer than CRISPR (which isn’t saying much), here are some of the known potential complications:
- Immune reaction since the body can recognize plasmid DNA as foreign and trigger inflammation
- Cell stress or death (apoptosis) if the payload causes excess expression of a particular gene like Follistatin
- Off-target gene expression, while more rare because plasmids generally target specific tissues, is still possible and can cause dysfunction
- Cytotoxicity when plasmids are delivered with high concentrations of polymers like PEI (potentially damaging tissues near the injection site)
- Biodistribution of plasmid DNA spread to non-target tissues where it isn’t normally active
- Persistence of plasmids, although marketed as a short-term (several year) therapy, some plasmids may persist as episomes
- Cancer risk increase, especially in tissues predisposed to growth dysregulation
Simply tweak this one gene, and one outcome changes. Nope, that’s now how it works.
For example, Follistatin not only blocks myostatin but also interacts with other TGF-β family proteins (like activins and bone morphogenetic proteins AKA BMPs).
In fact, the popular anti-aging GHK-Cu copper peptide works by increasing myostatin, the exact opposite of Follistatin.
Gene therapy design could use technology to target specific tissue types (i.e. skeletal muscle through a muscle-specific promoter), but they rarely do.
Minicircle’s plasmid Follistatin gene therapy study
It seems that all the biohackers and longevity influencers have been exploring gene therapy over the last few years.
One company called Minicircle is pioneering this, and they recently published a pre-print study that includes their protocol.
When I looked at it, I simply don’t get the appeal.
Here’s what they administered [R],
We injected polyethyleneimine (PEI)-complexed plasmid delivering the Follistatin (FST) 344 gene to 443 adult human volunteers of both sexes, age 23-88, median age 46
So this is a non-viral plasmid delivery system.
What were the results three months later?
Serum Follistatin increased from 8.58 ng/ml to 24.03 ng/ml. Body composition improved significantly, as mean fat-free mass increased 1.96 lbs and mean bodyfat reduced -0.87 % (as measured by DEXA).
Yes, for a 200 lb man like myself, that would be an average of <2 lbs of lean muscle built and <1.75 lbs of bodyfat lost three months after the therapy.
One lucky subject gained 12.15 lbs of fat-free mass.
One other important thing to note is that they used a CMV promoter (cytomegalovirus promoter) which drives the Follistatin 344 gene in a systemic, non-specific manner.
This makes off-target effects to organs (hypertrophy) likely:
- Heart
- Liver
- Kidneys
Biomarkers like high-sensitivity C-reactive protein (HS-CRP) and homocysteine improved. While glucometabolic markers (fasting blood sugar, Hb-A1c, fasting insulin, leptin) all slightly worsened.
Participants clustered into two groups, one with slight improvements and the others experienced significant cholesterol increases (low density lipoprotein or ‘LDL’).
Some markers of biological age improved (especially in the elderly), while the DunedinPACE rate of aging (gold standard for epigenetic age tests) didn’t move.
So, to recap, after three months the participants in this $20,000+ trial with unknown long-term safety data on average:
- Gained 1.96 lbs of lean mass
- Lost 0.87% of their bodyweight (1-2 lbs)
- Improved some biomarkers
- Worsened others
- Improved some measures of biological age
- No impact on real-time rate of aging
Sure, the technology is still in its infancy, but how is Follistatin gene therapy worth the potential major safety issues? Perhaps the Klotho gene therapy will be more effective and targeted, but still.
Even though researchers breed myostatin knockout animals, assuming we fully understand the ramifications of this manipulation is scientific hubris.
Still, plasmid gene therapy appears a whole lot safer than the industry standard CRISPR/Cas9.
When Biohacking With Gene Therapy Makes Sense
Gene therapy quite literally can save lives.
Even if it has massive off-target effects and would reduce quality of life in healthy populations, certain circumstances may warrant its use. But hopefully, with safer technologies than CRISPR.
Right now, the only uses and subpopulations that may consider genetic therapy biohacks include:
- Genetic disorders for things like cystic fibrosis, sickle cell anemia, & muscular dystrophy
- Cancer therapies like CAR-T cell therapy for leukemia & lymphoma
- Neurodegenerative treatments for conditions like Parkinson’s or ALS
- Rare diseases such as spinal muscular atrophy or Leber congenital amaurosis (inherited blindness).
Biohacking Your Genes: Decode Your DNA Before Experimental Therapies
The concept of using gene therapies to overcome biological limits appeals to the most adventurous and forward-thinking biohackers.
If we think back to the failure of the Human Genome Project, just two decades ago we were totally wrong about genes Share on XAgain, less than a decade ago the scientific community wrongly thought that 98-99% of DNA was “junk”.
The blossoming field of epigenetics has confirmed that all this “junk DNA” serves a vital process.
We’re currently in the same stage with gene therapies.
How can we “improve” something that we still don’t fully understand?
As biotech entrepreneur and Yale lecturer Dr. Gregory Licholai put it,
“We think we are editing one letter of the book of life, but [in actuality] entire pages might be getting altered in unintended areas.”
Is CRISPR Worth The Risk?
Time will tell the safety and efficacy of gene therapies. CRISPR was an abysmal failure. Will the 2.0 technology using plasmids work better?
Right now, it’s totally unknown. Poorly researched. With minimal upside. And significant downside. Plus, it’s incredibly expensive.
What about you? Will you edit your genome with this new technology? Drop a comment below and let me know your thoughts!
