Biohacking, Stress and Gene Expression
Cells are organized organisms. They have a cookbook (aka DNA), every chapter of which is called a gene and contains the instructions to make the necessary tools. The tools are proteins able to perform biochemical reactions (enzymes). Some of these tools are made no matter what, and their genes are called constitutive, other tools are made only when needed, and their genes are called inducible. There are many mechanisms to open the cookbook at the right chapter, activate the inducible gene and manufacture the corresponding tool.
For instance, some bacteria produce DNA repair tools only after the DNA has been damaged. Some bacteria produce the enzyme to get energy from a particular sugar only when that sugar is nearby. Human cells produce Heat Shock Proteins only after having been under stress (UV, heavy metals, high temperature etc.). Conversely, there are mechanisms to modulate and hinder or slow down the production of tools when their genes are overexpressed.
Epigenetics and Biohacking
The art of controlling gene expression is called epigenetics. Some scientists think that it is possible to intervene by biohacking, that is, by playing with epigenetics and produce those tools necessary to maintain the skin in good shape and to maintain the homeostasis of young skin even in old age.
One can dream for instance, to enhance the capabilities of repair by inducing stress genes, to eliminate skin discolorations by inhibiting the transcription of the genes related to melanin production, or to enhance skin moisturization (and decrease itch) by activating the filaggrin gene whose expression is decreased by 70% in old age.
Molecular Biology in a Nutshell
DNA makes RNA makes Proteins is the so-called dogma of Molecular Biology. In the past, the question was “what part of DNA makes what RNA and how”. DNA and RNA are polymers made by four building blocks called A, C, G and T (U instead of T in RNA). The fundamental law that dictates the physical-chemical behavior of DNA and RNA (formerly called the Chargaff rule) is that when two DNA or RNA polymers anneal, G binds with C, and A binds with T (or U in RNA).
Complementary Sequences
Two sequences such as
A C A T C C G T T C A
U G U A G G C A A G U
Are said to be complementary. The essence of gene expression is exactly here. Enzymes called DNA-dependent RNA polymerases bind to well defined sites on DNA called promoters, copy the DNA sequence downstream by synthesizing an RNA molecule called messenger RNA (mRNA).
From mRNA to Proteins
The messenger brings the message to the ribosomes, large organelles in the cytoplasm, that translate the sequence of the message into the sequence of the protein it codes for, according to the genetic code, with one amino acid being sequentially incorporated in the nascent protein per every triplet of nucleotides in the mRNA.
Points of Intervention
To intervene in the pathway leading from the binding of the DNA-dependent RNA-polymerases to DNA to the release of the final protein, one could:
- Look for molecules able to hinder or facilitate polymerase binding
- Modify transcription rate of the messenger RNA
- Affect ribosome binding to mRNA
- Influence protein elongation rate
- Control turnover of messenger RNA
Classic molecular biology provides examples on how to intervene on gene expression. Viruses modify the binding to DNA of cellular DNA-dependent RNA-polymerases and make them transcribe viral instead of cellular DNA. The structural modification of a transcription factor following thermal stress makes it instrumental in inducing the expression of the heat shock genes and therefore the repair or removal of damaged proteins. Melatonin acts as a strong inhibitor of transcription of 5-lipoxygenase and is therefore a powerful anti-inflammatory agent.
A New Role for RNA
The observations reported in the seventies and eighties that RNA complementary to a messenger could shut down protein synthesis were initially seen as intellectual curiosities. This “complementary RNA” was called antisense RNA, and it was understood that by binding to the complementary messenger it created steric hindrance, preventing ribosomes from translating the mRNA into protein.
Forty years later, the 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation. Scientists have since uncovered more than one thousand genes for different microRNAs in human cells, showing that regulation of gene expression by microRNAs is widespread in higher organisms.
siRNA and miRNA
Small interfering RNA (siRNA) and microRNA (miRNA) bind to mRNA and:
- Trigger degradation of the messenger RNA
- Inhibit or slow translation into proteins
These mechanisms represent a powerful layer of gene regulation beyond classical transcription.
What About Skin Care?
siRNA and miRNA can hinder gene expression either by provoking degradation of mRNA or by inhibiting translation. In the treatment of diseases, they have a major advantage over pharmacological xenobiotics and monoclonal antibodies because they rely on base pairing with mRNA rather than recognizing protein structure.
This means that diseases not treatable by traditional drugs could theoretically be targeted through RNA interference, since any gene of interest can be addressed using siRNA or miRNA. Several studies indicate possible applications of these molecules in cosmetic science.
Challenges in Application
The main difficulty with topical use of RNA-based treatments lies in their instability:
- RNAs can be degraded by RNase enzymes
- Skin microbiome can contribute to degradation
- Delivery through the stratum corneum is complex
To overcome this, researchers suggest encapsulating interfering RNAs in liposomes, while ensuring that partial sequence mismatches do not create safety issues.
Frequently Asked Questions
What is gene expression in simple terms?
Gene expression is the process by which information stored in DNA is used to create proteins that perform essential functions in the cell. It follows the pathway DNA → RNA → Protein.
What is epigenetics?
Epigenetics refers to the control of gene activity without changing the DNA sequence itself. It determines which genes are turned on or off under different conditions.
How does stress affect cells?
Stress factors like UV radiation, heat, or toxins can activate specific genes, such as those producing Heat Shock Proteins, which help repair or remove damaged cellular components.
What is the role of RNA in gene regulation?
RNA molecules like siRNA and miRNA regulate gene expression by binding to messenger RNA, either degrading it or preventing it from being translated into proteins.
Can RNA be used in skincare?
Research suggests that RNA-based approaches could potentially target genes involved in skin aging or disorders, but challenges like stability and delivery need to be addressed.
References
[1] Pestka S, Daugherty BL, Jung V, Hotta K, Pestka RK. Anti-mRNA: specific inhibition of translation of single mRNA molecules. Proc Natl Acad Sci U S A. 1984.
[2] Paterson BM, Roberts BE, Kuff EL. Structural gene identification and mapping. Proc Natl Acad Sci U S A. 1977.
[3] Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs. Cell. 1993.
[4] Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of lin-14. Cell. 1993.
[5] Pingjing Zhang et al. Use of small RNA as antiaging cosmeceuticals. J Cosmet Sci. 2013.
[6] Chang YT et al. Small interfering RNA-based nanotherapeutics. Expert Opin Drug Deliv. 2023.
