Mirror-image life (also called mirror life) is a hypothetical form of life using mirror-reflected molecular building blocks. This alternative life form has never been discovered in nature,
although certain mirror-image components of molecular machinery have
been synthesized in the laboratory and efforts to chemically synthesize a
mirror-image ribosome have been ongoing since 2016. In principle, entire mirror organisms could be created, although "the creation of a mirror-image organism lies well beyond the reach of present-day science".
Concept
Homochirality
Many
of the essential molecules for life on Earth can exist in two
mirror-image forms, often called "left-handed" and "right-handed", where
handedness refers to the direction in which polarized light skews when
beamed through a pure solution of the molecule, but living organisms do
not use both. RNA and DNA contain only right-handed sugars; proteins made by the ribosome are exclusively composed of left-handed amino acids. This phenomenon is known as homochirality. It is not known whether homochirality emerged before or after life,
whether the building blocks of life must have this particular chirality,
or indeed whether life needs to be homochiral. Protein chains built from amino acids of mixed chirality tend not to
fold or function well, but mirror-image proteins have been constructed
that have identical function but on substrates of opposite handedness.
Possibility of mirror-image life
The possibility of mirror-image life has been discussed since Louis Pasteur's 1860 work on molecular asymmetry.
Advances in organic chemistry and synthetic biology may, in the
distant future, lead to the possibility of fully synthesizing a living
cell from small molecules, which could enable synthesizing mirror-image
cells from mirrored versions (enantiomers)
of life's building-block molecules. Some important proteins in the
central dogma of molecular biology have been synthesized in mirror-image
versions, including polymerase in 2016.
Reconstructing regular lifeforms in mirror-image form, using the
mirror-image (chiral) reflection of their cellular components, could be
achieved by substituting left-handed amino acids with right-handed ones,
in order to create mirror reflections of proteins, and likewise
substituting right-handed with left-handed nucleic acids. Because the phospholipids of cell membranes are also chiral, American geneticist George Church proposed using an achiral fatty acid instead of mirror-image phospholipids for the membrane.
Electromagnetic force (chemistry) is unchanged under such molecular reflection transformation (P-symmetry).
There is a small alteration of weak interactions under reflection,
which can produce very small corrections that theoretically favor the
natural enantiomers of amino acids and sugars, but it is unknown if this effect is large enough to affect the
functionality of mirror-image biomolecules or explain homochirality in
nature.
Potential risks and debates
In
December 2024, 38 scientists, including several synthetic biology
researchers and two Nobel laureates, warned that the creation of
mirror-image life could cause "unprecedented and irreversible harm" to
human health and ecosystems worldwide. The potential for mirror-image bacteria to escape immune defenses and
invade natural ecosystems might lead to "pervasive lethal infections in a
substantial fraction of plant and animal species, including humans."
Given these risks, the scientists concluded that mirror-image organisms
should not be created without compelling evidence of safety.
In a Science News story, Andrew Ellington
of the University of Texas at Austin criticizes the above article: "I
think it's irresponsible for [the authors] to make this policy call.
It's like banning the transistor because you're worried about cybercrime
30 years later." He also argues that it remains uncertain whether
mirror-image organisms would ever pose a significant threat. Biosecurity
expert Gigi Gronvall of Johns Hopkins University describes the concerns
raised in the paper as "very theoretical". While supportive of open
discussions about potential risks, she contends that research and
funding bans are premature: "That really puts the cart before the
horse."
In a Nature News story, Sven Klussmann of Aptarion Biotech, a company that develops
mirror-image nucleic acid drugs, says: "we should not panic yet, and we
should not restrict research too early." David Van Valen of the
California Institute of Technology and founder of Aizen Therapeutics, a
company that develops mirror-image peptide therapies, says: "I think
most of the concerns that people are raising are overblown."
In a Nature Comment piece titled "Mirror of the unknown", Ting Zhu of Westlake University, one of the leading scientists in
mirror-image molecular biology, notes that "all biological structures,
functions and even organisms could be recreated in their mirror image,
the possibilities — good and bad — in a looking-glass world are
endless". He seeks to bridge divergent views amid growing debates: "In
the face of vast unknowns, the noble path of pre-emptively protecting
humanity from potential risks in the distant future can be slippery. And
we should tread cautiously." Zhu emphasises: "It is crucial to
distinguish mirror-image molecular biology from the creation of
mirror-image organisms", and proposes: "Holistic guidelines could be
developed for research on synthetic or semi-synthetic molecules,
biological entities and modified organisms — irrespective of their
chirality." He adds: "Scientific exploration is not a glorious march
towards increasingly precise understandings of a universal truth. It has
a long and difficult history of trials and errors, uncertainties and
risks, controversies and doubts. Yet through rational dialogue and
objective analysis, a responsible, open and rich human adventure can be
charted, for the world of the unknown is infinite."
Direct applications
Direct application of mirror-image organisms could be mass production of enantiomers (mirror-images) of molecules produced by normal life.
Enantiopure drugs: Some pharmaceuticals have shown different activity depending on enantiomeric form.
Aptamers (L-ribonucleic acid aptamers): "That makes mirror-image biochemistry a potentially lucrative business. One company that hopes so is Noxxon Pharma
in Berlin. It uses laborious chemical synthesis to make mirror-image
forms of short strands of DNA or RNA called aptamers, which bind to
therapeutic targets such as proteins in the body to block their
activity. The firm has several mirror-aptamer candidates in human trials
for diseases including cancer; the idea is that their efficacy might be
improved because they aren't degraded by the body's enzymes. A process
to replicate mirror-image DNA could offer a much easier route to making
the aptamers, says Sven Klussmann, Noxxon Pharma's chief scientific
officer."
L-glucose, enantiomer of standard glucose:
Tests showed that it tastes likes standard sugar, but is not
metabolized the same way. However, it was never marketed due to
excessive manufacturing costs. More recent research allows cheap production with high yields; however
the authors state that it is not usable as a sweetener due to laxative
effects.
In fiction
The creation of a mirror-image human is the basis of the 1950 short story "Technical Error" by Arthur C. Clarke. In this story, a physical accident transforms a person into his mirror
image, speculatively explained by travel through a fourth physical
dimension. H. G. Wells' The Plattner Story (1896) is based on a similar idea.
In the 1970 Star Trek novel Spock Must Die! by James Blish, the science officer of the USS Enterprise
is replicated in mirror-image form by a transporter mishap. He locks
himself in the sick bay where he is able to synthesize mirror-image
forms of basic nutrients needed for his survival.
An alien machine that reverses chirality, and a blood-symbiont
that functions properly only when in one chirality, were central to Roger Zelazny's 1976 novel Doorways in the Sand.
On the titular planet of Sheri S. Tepper's 1989 novel Grass, some lifeforms have evolved to use the right-handed isomer of alanine.
In the Mass Effect series, chirality of amino acids in foodstuffs is discussed often in both dialogue and encyclopedia files.
In the 2014 science fiction novel Cibola Burn by James S. A. Corey,
the planet Ilus has indigenous life with partially-mirrored chirality.
This renders human colonists unable to digest native flora and fauna,
and greatly complicates conventional farming. Consequently, the
colonists have to rely upon hydroponic farming and food importation.
In the 2017 Daniel Suarez novel Change Agent,
an antagonist, Otto, nicknamed the "Mirror Man", is revealed to be a
genetically engineered mirror-image human. Serving as an assassin due to
his complete immunity to neurotoxins, which he coats himself with in
the form of a cologne-like aerosol, he views other humans with disdain
and causes them to feel an inexplicable repulsion by his very presence.
The concept is used during Ryan North's 2023 run on Fantastic Four as an existential threat towards the human population.
Functionalities can be added to nanomaterials by interfacing them
with biological molecules or structures. The size of nanomaterials is
similar to that of most biological molecules and structures; therefore,
nanomaterials can be useful for both in vivo and in vitro biomedical
research and applications. Thus far, the integration of nanomaterials
with biology has led to the development of diagnostic devices, contrast
agents, analytical tools, physical therapy applications, and drug
delivery vehicles.
Nanomedicine seeks to deliver a valuable set of research tools and clinically useful devices in the near future. The National Nanotechnology Initiative expects new commercial applications in the pharmaceutical industry that may include advanced drug delivery systems, new therapies, and in vivo imaging. Nanomedicine research is receiving funding from the US National Institutes of Health Common Fund program, supporting four nanomedicine development centers. The goal of funding this newer form of science is to further develop
the biological, biochemical, and biophysical mechanisms of living
tissues. More medical and drug companies today are becoming involved in
nanomedical research and medications. These include Bristol-Myers
Squibb, which focuses on drug delivery systems for immunology and
fibrotic diseases; Moderna known for their COVID-19 vaccine and their
work on mRNA therapeutics; and Nanobiotix, a company that focuses on
cancer and currently has a drug in testing that increases the effect of
radiation on targeted cells. More companies include Generation Bio,
which specializes in genetic medicines and has developed the
cell-targeted lipid nanoparticle, and Jazz Pharmaceuticals, which
developed Vyxeos , a drug that treats acute myeloid leukemia, and
concentrates on cancer and neuroscience. Cytiva is a company that
specializes in producing delivery systems for genomic medicines that are
non-viral, including mRNA vaccines and other therapies utilizing
nucleic acid and Ratiopharm is known for manufacturing Pazenir, a drug
for various cancers. Finally, Pacira specializes in pain management and
is known for producing ZILRETTA for osteoarthritis knee pain, the first
treatment without opioids.
Nanomedicine sales reached $16 billion in 2015, with a minimum of
$3.8 billion in nanotechnology R&D being invested every year. Global funding for emerging nanotechnology increased by 45% per year in
recent years, with product sales exceeding $1 trillion in 2013. In 2023, the global market was valued at $189.55 billion and is predicted to exceed $500 billion in the next ten years. As the nanomedicine industry continues to grow, it is expected to have a significant impact on the economy.
Nanotechnology has provided the possibility of delivering drugs to specific cells using nanoparticles. This use of drug delivery systems was first proposed by Gregory
Gregoriadis in 1974, who outlined liposomes as a drug delivery system
for chemotherapy. The overall drug consumption and side-effects may be lowered significantly by depositing the active pharmaceutical agent
in the diseased region only and in no higher dose than needed. Targeted
drug delivery is intended to reduce the side effects of drugs in tandem
decreases in consumption and treatment expenses. Additionally, targeted
drug delivery reduces the side effects of crude or naturally occurring
drugs by minimizing undesired exposure to healthy cells. Drug delivery focuses on maximizing bioavailability
both at specific places in the body and over a period of time. This can
potentially be achieved by molecular targeting by nanoengineered
devices. A benefit of using nanoscale for medical technologies is that smaller
devices are less invasive and can possibly be implanted inside the body,
plus biochemical reaction times are much shorter. These devices are
faster and more sensitive than typical drug delivery. The efficacy of drug delivery through nanomedicine is largely based
upon: a) efficient encapsulation of the drugs, b) successful delivery of
drug to the targeted region of the body, and c) successful release of
the drug. Several nano-delivery drugs were on the market by 2019.
Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed to improve the pharmacokinetics and biodistribution of the drug. However, the pharmacokinetics and pharmacodynamics of nanomedicine is highly variable among different patients. When designed to avoid the body's defense mechanisms, nanoparticles have beneficial properties that can be used to improve
drug delivery. Complex drug delivery mechanisms are being developed,
including the ability to get drugs through cell membranes and into cell cytoplasm.
Triggered response is one way for drug molecules to be used more
efficiently. Drugs are placed in the body and only activate on
encountering a particular signal. For example, a drug with poor
solubility will be replaced by a drug delivery system where both
hydrophilic and hydrophobic environments exist, improving the
solubility. Drug delivery systems may also be able to prevent tissue damage through
regulated drug release; reduce drug clearance rates; or lower the
volume of distribution and reduce the effect on non-target tissue.
However, the biodistribution of these nanoparticles is still imperfect
due to the complex host's reactions to nano- and microsized materials and the difficulty in targeting specific organs in the body.
Nevertheless, a lot of work is still ongoing to optimize and better
understand the potential and limitations of nanoparticulate systems.
While advancement of research proves that targeting and distribution can
be augmented by nanoparticles, the dangers of nanotoxicity become an
important next step in further understanding of their medical uses. The toxicity of nanoparticles varies, depending on size, shape, and
material. These factors also affect the build-up and organ damage that
may occur. Nanoparticles are made to be long-lasting, but this causes
them to be trapped within organs, specifically the liver and spleen, as
they cannot be broken down or excreted. This build-up of
non-biodegradable material has been observed to cause organ damage and
inflammation in mice. Delivering magnetic nanoparticles to a tumor using uneven stationary magnetic fields may lead to enhanced tumor growth. In order to avoid this, alternating electromagnetic fields should be used.
Nanoparticles are under research for their potential to decrease antibiotic resistance or for various antimicrobial uses. Nanoparticles might also be used to circumvent multidrug resistance (MDR) mechanisms.
Systems under research
Advances
in lipid nanotechnology were instrumental in engineering medical
nanodevices and novel drug delivery systems, as well as in developing
sensing applications. Another system for microRNA delivery under preliminary research is nanoparticles formed by the self-assembly of two different microRNAs to possibly shrink tumors. One potential application is based on small electromechanical systems, such as nanoelectromechanical systems
being investigated for the active release of drugs and sensors for
possible cancer treatment with iron nanoparticles or gold shells. Another system of drug delivery involving nanoparticles is the use of aquasomes, self-assembled nanoparticles with a nanocrystalline center, a coating made of a polyhydroxyl oligomer, covered in the desired drug, which protects it from dehydration and conformational change.
Manufacturing of Nanomedicines
The manufacturing of nanomedicines like lipid nanoparticles (LNPs), mRNA-loaded LNPs, liposomes and magnetic nanocarriers requires precise control of particle size,
surface properties and encapsulation efficiency for a safe in vivo use
and reproducable efficacy of the therapeutic. Traditionally, these
nanoformulations have been manufactured using batch processes, which can
have limitations such as variability in product quality and limited
scalability due to the limited mixing efficiency in batch processes. In
contrast, more modern approaches rely on continuous manufacturing techniques to enhance scalability and reproducability. Microfluidic methods and other rapid mixing methods
enable improved control over key process parameters during the
nanoparticle formation. These techniques allow the continuous production
of reproducable nanoparticles with narrow size distributions and highly
scalable throughput.
The large-scale production of mRNA-LNP Covid-19 vaccines (Comirnaty® and Spikevax®) relies on continuous processes like T-mixing (turbulent mixing). This method enables a efficient encapsulation of mRNA and a high
throughput which was critical for mass vaccine production during
Covid-19. However, scalability rely on parallelization of T-Mixers with multiple parallel operating pumps as the T-mixing is not scalable by increasing the inner dimensions of the T-Mixer. Characterization of Comirnaty® shows a broad particle size distribution (PDI ≥ 0,2), which is acceptable for vaccines but is suboptimal for small-molecule drugs due to higher regulatory requirements. To produce more refined LNPs with narrower size distributions, microfluidic mixers
are increasingly employed which can enable more uniform LNPs and a
higher scalability due to there inner microfluidic structure as
demonstrated in multiple recent studies.
Applications
Some nanotechnology-based drugs that are commercially available or in human clinical trials include:
Doxil was originally approved by the FDA for the use on HIV-related Kaposi's sarcoma. It is now being used to also treat ovarian cancer and multiple myeloma. The drug is encased in liposomes,
which helps to extend the life of the drug that is being distributed.
Liposomes are self-assembling, spherical, closed colloidal structures
that are composed of lipid bilayers that surround an aqueous space. The
liposomes also help to increase the functionality and it helps to
decrease the damage that the drug does to the heart muscles
specifically.
Onivyde, liposome encapsulated irinotecan to treat metastatic pancreatic cancer, was approved by FDA in October 2015.
Rapamune
is a nanocrystal-based drug that was approved by the FDA in 2000 to
prevent organ rejection after transplantation. The nanocrystal
components allow for increased drug solubility and dissolution rate,
leading to improved absorption and high bioavailability.
Cabenuva is approved by FDA as cabotegravir extended-release injectable nano-suspension, plus rilpivirine
extended-release injectable nano-suspension. It is indicated as a
complete regimen for the treatment of HIV-1 infection in adults to
replace the current antiretroviral regimen in those who are
virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a
stable antiretroviral regimen with no history of treatment failure and
with no known or suspected resistance to either cabotegravir or rilpivirine. This is the first FDA-approved injectable, complete regimen for HIV-1 infected adults that is administered once a month.
Imaging
In vivo imaging is another area where tools and devices are being developed. Using nanoparticle contrast agents,
images such as ultrasound and MRI have a better distribution and
improved contrast. In cardiovascular imaging, nanoparticles have
potential to aid visualization of blood pooling, ischemia, angiogenesis, atherosclerosis, and focal areas where inflammation is present.
The small size of nanoparticles gives them with properties that can be very useful in oncology, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such
as size-tunable light emission), when used in conjunction with MRI
(magnetic resonance imaging), can produce exceptional images of tumor
sites. Nanoparticles of cadmium selenide (quantum dots) glow when exposed to ultraviolet light. When injected, they seep into cancer tumors.
The surgeon can see the glowing tumor, and use it as a guide for more
accurate tumor removal. These nanoparticles are much brighter than
organic dyes and only need one light source for activation. This means
that the use of fluorescent quantum dots could produce a higher contrast
image and at a lower cost than today's organic dyes used as contrast media.
The downside, however, is that quantum dots are usually made of quite
toxic elements, but this concern may be addressed by use of fluorescent
dopants, substances added to create fluorescence.
Tracking movement can help determine how well drugs are being
distributed or how substances are metabolized. It is difficult to track a
small group of cells throughout the body, so scientists used to dye the
cells. These dyes needed to be excited by light of a certain wavelength
in order for them to light up. While different color dyes absorb
different frequencies of light, there was a need for as many light
sources as cells. A way around this problem is with luminescent tags.
These tags are quantum dots attached to proteins that penetrate cell membranes. The dots can be random in size, can be made of bio-inert material, and
they demonstrate the nanoscale property that color is size-dependent. As
a result, sizes are selected so that the frequency of light used to
make a group of quantum dots fluoresce is an even multiple of the
frequency required to make another group incandesce. Then both groups
can be lit with a single light source. They have also found a way to
insert nanoparticles into the affected parts of the body so that those parts of the body
will glow showing the tumor growth or shrinkage or also organ trouble.
Nanotechnology-on-a-chip is one more dimension of lab-on-a-chip
technology. Magnetic nanoparticles, bound to a suitable antibody, are
used to label specific molecules, structures or microorganisms. Silica
nanoparticles, in particular, are inert from a photophysical perspective
and can accumulate a large number of dye(s) within their shells. Gold nanoparticles tagged with short DNA
segments can be used to detect genetic sequences in a sample.
Multicolor optical coding for biological assays has been achieved by
embedding different-sized quantum dots into polymeric microbeads. Nanopore technology for analysis of nucleic acids converts strings of nucleotides directly into electronic signatures.
Sensor test chips containing thousands of nanowires, able to
detect proteins and other biomarkers left behind by cancer cells, could
enable the detection and diagnosis of cancer in the early stages from a
few drops of a patient's blood. Nanotechnology is helping to advance the use of arthroscopes,
which are pencil-sized devices that are used in surgeries with lights
and cameras so surgeons can do the surgeries with smaller incisions. The
smaller the incisions the faster the healing time which is better for
the patients. It is also helping to find a way to make an arthroscope
smaller than a strand of hair.
Research on nanoelectronics-based cancer diagnostics could lead to tests that can be done in pharmacies.
The results promise to be highly accurate and the product promises to
be inexpensive. They could take a very small amount of blood and detect
cancer anywhere in the body in about five minutes, with a sensitivity
that is a thousand times better a conventional laboratory test. These
devices are built with nanowires to detect cancer proteins; each nanowire detector is primed to be sensitive to a different cancer marker. The biggest advantage of the nanowire detectors is that they could test
for anywhere from ten to one hundred similar medical conditions without
adding cost to the testing device. Nanotechnology has also helped to personalize oncology for the
detection, diagnosis, and treatment of cancer. It is now able to be
tailored to each individual's tumor for better performance. They have
found ways that they will be able to target a specific part of the body
that is being affected by cancer.
Sepsis treatment
In contrast to dialysis, which works on the principle of the size-related diffusion of solutes and ultrafiltration of fluid across a semi-permeable membrane, the purification using nanoparticles allows specific targeting of substances. Additionally, larger compounds which are commonly not dialyzable can be removed.
The purification process is based on functionalized iron oxide or carbon coated metal nanoparticles with ferromagnetic or superparamagnetic properties. Binding agents such as proteins, antibiotics, or synthetic ligands are covalently
linked to the particle surface. These binding agents are able to
interact with target species forming an agglomerate. Applying an
external magnetic field gradient exerts a force on the nanoparticles, allowing them to be separated from the bulk fluid, thus removing contaminants.This can neutralize the toxicity of sepsis, but runs the risk of nephrotoxicity and neurotoxicity.
The small size (< 100 nm) and large surface area of functionalized nanomagnets offer advantages properties compared to hemoperfusion, which is a clinically used technique for the purification of blood and is based on surface adsorption.
These advantages include high loading capacity, high selectivity
towards the target compound, fast diffusion, low hydrodynamic
resistance, and low dosage requirements.
Tissue engineering
Nanotechnology may be used as part of tissue engineering
to help reproduce, repair, or reshape damaged tissue using suitable
nanomaterial-based scaffolds and growth factors. If successful, tissue
engineering may replace conventional treatments like organ transplants
or artificial implants. Nanoparticles such as graphene, carbon
nanotubes, molybdenum disulfide and tungsten disulfide are being used as
reinforcing agents to fabricate mechanically strong biodegradable
polymeric nanocomposites for bone tissue engineering applications. The
addition of these nanoparticles to the polymer matrix at low
concentrations (~0.2 weight %) significantly improves in the compressive
and flexural mechanical properties of polymeric nanocomposites. These nanocomposites may potentially serve as novel, mechanically strong, lightweight bone implants.
For example, a flesh welder was demonstrated to fuse two pieces
of chicken meat into a single piece using a suspension of gold-coated nanoshells activated by an infrared laser. This could be used to weld arteries during surgery. Another example is nanonephrology, the use of nanomedicine on the kidney.
The full potential and implications of nanotechnology uses within
the tissue engineering are not yet fully understood, despite research
spanning the past two decades.
Vaccine development
Today, a significant proportion of vaccines against viral diseases are created using nanotechnology. Solid lipid nanoparticles represent a novel delivery system for some vaccines against SARS-CoV-2 (the virus that causes COVID-19). In recent decades, nanosized adjuvants have been widely used to enhance immune responses to targeted vaccine antigens. Inorganic nanoparticles of aluminum, silica and clay, as well as organic nanoparticles based on polymers and lipids, are commonly used adjuvants within modern vaccine formulations. Nanoparticles of natural polymers such as chitosan are commonly used adjuvants in modern vaccine formulations. Ceria
nanoparticles appear very promising for both enhancing vaccine
responses and mitigating inflammation, as their adjuvanticity can be
adjusted by modifying parameters such as size, crystallinity, surface
state, and stoichiometry.
In addition, virus-like nanoparticles are also being researched.
These structures allow vaccines to self-assemble without encapsulating
viral RNA, making them non-infectious and incapable of replication.
These virus-like nanoparticles are designed to elicit a strong immune
response by using a self-assembled layer of virus capsid proteins.
Regulation
As
the development of nanomedicine continues to develop as a potential
treatment for diseases, regulatory challenges have assessed reproducible
manufacturing processes, scalability, availability of appropriate
characterization methods, safety issues, and poor understanding of
disease heterogeneity and patient preselection strategies. Global interaction of the various stakeholders is leading to harmonized regulation.
Several therapeutic nanomedicine products have been approved by the FDA and European Medicines Agency. For market approval, these therapies are evaluated for biocompatibility, immunotoxicity, and a preclinical assessment.
