“Upgrading Humans” – Human Genome Editing with CRISPR

You might have played one of those games, where you can customize your character’s appearance and upgrade certain abilities.

What if it’s true that it might be possible to do so in real life with actual humans?

It’s possible to play with the genetic code to do wonderful things and also the “crazy scientist” stuff with (you guessed it) CRISPR.

The power to alter human genes has long been a recurring theme in science fiction.

Still, this once-fantastic vision is now quickly becoming a reality thanks to the development of CRISPR-Cas9 genome editing technology.

However, with great power comes great responsibility, and the ethical implications of gene modification in humans are far-reaching and complex.

Gene Modification in Humans

Gene modification or genome modification or genetic therapy is a process used to modify a cell or an organism genetically. In humans, gene modification can be done in somatic cells and germline cells.

Modification of somatic cells (all the cells of the body except reproductive cells, i.e., egg or sperm) is already taking place including in-vivo editing to tackle diseases like sickle cell anemia and HIV, and gene editing in somatic cells is legal in many countries and acceptable for treatment.

Heritable genome editing, on the other hand, refers to changing the DNA in a way that the changes are passed down to future generations.

The moral and ethical considerations raised by gene alteration of germline cells make it a contentious issue.

Gene Editing/Therapy in Somatic Cell 

Gene editing in somatic cells involves manipulating the DNA in non-reproductive cells of a human.

This targeted gene editing would only cure a disease or disorder in the person on whom the therapy is being performed, not their descendants.

Gene therapy of somatic cells in humans has progressed relatively faster than heritable gene editing for obvious ethical reasons.

Somatic gene therapy is mainly carried out by two methods:

• In-vivo 
• Ex-vivo

In-vivo includes the insertion of functioning genes directly through the bloodstream of the patient, the sickle cell anemia therapy was done in-vivo in the patient.

Ex-vivo gene transfer is used to treat genetic problems by replacing malfunctioning cells inside of the patient with new, altered cells that have the desired functions.

Heritable Germline Editing in Humans

A person can use germline editing in two manners, first and also ethical one from the current viewpoint is, knocking out the problematic gene from the DNA causing a certain genetic disorder.

Germline modifications are done inside the egg cell, sperm, or an early-developing embryo to copy the change into all the cells. So, germline editing affects both the person whose DNA is being edited and also his/her descendants.

Another one is human germline editing which is not so ethical from a bio-ethical point of view, it can be used to permanently modify the lineage of a person as changes done are permanent.

Scientists express their concerns about Designer Babies, such as producing extraordinary babies to add superhuman traits to children and whether it will create discrimination among people.

Designer Babies

“Designer baby” is a term assigned to a baby whose genome is altered or selected, mainly not to include a particular gene related to a disease or a genetic disorder.

The process of making designer babies usually includes analyzing different human embryos to identify particular genes related to specific diseases and selecting embryos with the desired genetic makeup.

All of this is done through a process of PGD or Pre-implantation Genetic Diagnosis, or another process that is a bit problematic, consisting of directly editing the embryo’s genome before birth, this method is not usually performed.

The problematic issue with CRISPR is that one could “manufacture” genetically enhanced babies with desired traits instead of using the novel method for therapy and medicinal uses.

However, discoveries about the DNA repair system ease the skepticism, you can’t add what is not already there in the DNA.

DNA Repair System

DNA holds all the information we need to function and if its functional and essential parts suffer damage, cells can’t function at all.

Whenever DNA suffers damage, from double-stranded breaks, like done in CRISPR, the cell tries to fixate damage in mainly two ways, depending upon the type of damage.

Either the cell jams up the loose DNA ends together to quickly compensate for the damage done even if it poses a danger to the stability of the genetic code or the cell will fix the damage by copying a DNA template instead.

When a cell is preparing to divide it creates a few copies of the DNA, so the cell will use a copy of the DNA to fix errors.

In that way, researchers can introduce a template DNA strand in the cell while injecting CRISPR, to make the desired changes to the DNA.

However, the results from the 2017 study suggest otherwise.

Researchers were trying to fix the MYBPC3 gene causing a mutation for hypertrophic cardiomyopathy, in preimplantation embryos with CRISPR-Cas9.

MYBPC3 gene provides instructions for producing Cardiac Myosin Binding Protein C (MyBP-c) present in cardiac muscle cells, MyBP-c is related to the sarcomere.

The sarcomere is the fundamental unit of the contractile fiber composed of two types of filamentous proteins.

In their experiments, their team provided a strand of DNA to serve as a template to rewrite disease-causing mutation, but to their surprise embryos used the mother’s DNA as a guide to fix a disease-causing mutation in the MYBPC3 gene carried by the father’s sperm^[1].

The embryo not using the given template DNA sequence implies that the DNA in germline cells is possibly resistant to changes as it is the very fundamental cell that helps us reproduce so we need to keep it intact.

These embryos weren’t meant to be implanted in the uterus, genetically engineered embryos to grow in human beings are still a long way off, and this study was only legal in the US as it was privately funded.

CRISPR Babies – First Genetically Engineered Humans

A Chinese scientist He Jiankui used CRISPR to make 2 babies immune to HIV.

His action was widely condemned by the bioethical community and even the scientific community.

Twins, “Lulu & Nana” (real identity hidden), were born on 26 November 2018. These two babies are the first genetically engineered human beings in human history.

He altered the DNA of IVF babies to prevent them from getting HIV from their fathers. He aimed to modify a part in the sequence of the CCR5 gene to make babies immune to HIV.

The goal He was trying to achieve is beyond the CRISPR technology as of the current scenario.

Jiankui’s manuscript of his research paper even suggests that those edits were likely off-target, which means the genome of babies is mutated and there is a fair chance that babies might get a chronic health condition later in life.

Some scientists suggest that these children might have low life expectancy due to those off-target mutations.

Those babies are now toddlers, scientists suggest that those kids should be kept under high surveillance and routine checkups to identify any sort of health condition.

His study was later retracted from ‘Nature’, on 8 October 2019.

Due to this controversy, He Jiankui was imprisoned in 2019 and was released in 2022, He was also fined 3 million yuan.

His move was extremely bold and fearless despite the fact it was perilous. It cost him his career and worldwide criticism for this unethical deed.

What Humans Can Achieve With Genome Editing

CRISPR because sometimes you just need to edit your genes and move on.

Genome editing offers an enticing glance into the future where we could be able to alter our genetic code through gene editing opening up a world of intriguing possibilities for enhancing human health and wellness.

Humans can do bizarre things using CRISPR, as it can change anything that contains the “DNA” unit of life, and almost everything includes some form of DNA, whether it’s a bacteria, plant, or you. 

We might well be capable of eradicating crippling hereditary disorders through our capacity to modify our DNA.

Scientists have used CRISPR to treat diseases like sickle cell anemia in actual living patients and they are doing well so far.

Some studies on mice even evinced that CRISPR can be a potential cure for aging and life extension and CRISPR gene editing is also used to treat numerous genetic disorders and cancer.

CRISPR as a Cure for Human Aging

The most “promising” cause of aging is believed to be the dysregulation of genes, leading to a synchronized breakdown of all the systems that keep us alive.

We have identified numerous “vitality” genes, like Sirtuins that are related to longevity, and those genes can be used to treat aging and diseases related to it.

Gene therapy is an emerging solution to all medical situations that involve genes or anything related to genes.

With the advancement of technologies like CRISPR, we now have a decapitated hang on how the modified genes are expressed.

CRISPR gene editing was used on mice with a premature aging disorder (Hutchinson-Gilford progeria syndrome) and its results transcended expectations.

Progeria or HGPS is a genetic disorder that makes children age rapidly, the mutation occurs randomly and it’s not inherited.

This disease is sporadic with around 400 cases worldwide, meaning the incidence of HGPS is approximately 1 in 8 million live births worldwide. ^[2]

Progeria is caused by a single-letter mutation in the LMNA gene that codes for Lamin A and Lamin C proteins, in this mutation cytosine is replaced by thymine, which affects the production of Lamin A protein, instead, it produces an abnormal progerin protein which makes cells age dramatically.

Instead of using the standard form of CRISPR, researchers used modified Cas-9 protein to edit the base pair to fix the problematic gene, this variation of CRISPR gene editing is called base editing.

Researchers used their ABE injections (Adenine Base Editors) in harvested fibroblasts from a progeria patient and transgenic mice with the human version of the Lamin A gene.^[3]

The base editor was injected into 2-weeks old mice, which is equivalent to a 5-year-old human child with progeria mutation, a single ABE injection boosted the average life span of mice to 215-510 days.^[4]

As the mice in trials had human genes the same approach could be used on humans to treat this genetic disorder.

This research, however, was about a premature aging disorder, aging is a complex process, and it includes several factors related to genes, environment, and lifestyle.

While some genes have been linked to aging, it’s unlikely that those genes alone could stop the aging process.

CRISPR can contribute to enhancing our knowledge of aging and its underlying processes but it can’t “treat” aging on its own.

We need further research to fully understand aging and its complex mechanism for developing effective interventions to slow down or even reverse the aging process.

Can Superheroes be a Reality with CRISPR?

CRISPR because with great power comes great responsibility. Who knows, maybe you’ll become the next X-gene mutant or a real-life Deadpool.

As you should know by now CRISPR can precisely modify an organism’s genome including humans, we should be able to do whatever we want if we exclude the retrospect of ethics from our viewpoints.

Manipulation of the human genome to give humans supernatural abilities is not a complex scenario to envision but it won’t be exactly like the stuff we visualize in superhero movies and TV shows.

Modern pop culture has fantasized about “DNA mutations” for giving a human superhuman abilities, but things always don’t go as planned, getting bitten by a radioactive spider might not give you Spiderman abilities but rather make you a blob of cancer.

Can You Become Flash? –  Increased Human Speed & Endurance 

I bet whenever you are late for lectures or school there’s that one moment where you wish you could sprint fast, like “Flash”, who possesses an unmatched speed of Mach 4.8.

As humans, we prefer to do things without putting in a lot of effort, so as a fellow human, I understand it sucks to train your muscles for running fast and increasing your endurance.

So the easy way would be genetically modifying your skeletal muscles to make them last longer and faster in a race or when you’re running late.

Skeletal muscles are composed of two types of muscle fibers; namely slow twitch (Type I) muscle and fast twitch (Type II) muscle. ACTN3 in type II fibers is responsible for generating powerful and explosive muscular contractions.

ACTN3 is a gene that codes for alpha-actinin-3 or the gene commonly referred to as the “speed gene”, and can pave the way for creating humans who can run longer distances without losing the speed but rather enhancing it.^[5]

A Group of Australian researchers modified the ACTN3 gene in mice using CRISPR, resulting in a 33% increase in mice’s endurance and they lasted longer than normal mice before exhausting themselves.

I reckon you won’t turn into Flash, but adding your speed and endurance won’t hurt as much.

Is Spidey Sense Possible? – Precognition

CRISPR is the closest thing to becoming a superhero without getting bitten by a radioactive spider.

Our all-time favorite superhero Spiderman possesses the ability to sense danger or as we like to call it “spidey sense”.

The idea of spidey sense comes from spiders and their ability to detect danger from far away, detection mainly happens from their eight eyes but they also spot predator danger from far away through little vibrations they get from their ultrasensitive hair.

However, it is not quite similar to Spiderman who seems to have an additional “sense” to tell if danger is nearby, if more research is conducted on how real spider sense works, it might be possible to improve the human sense of danger.

Manufacturing and spinning silk webs inside your body wouldn’t be a possibility unless you want to be a half-spider.

Is Superhuman Strength Possible? 

A frail young man turns into a nearly perfect human being with immense strength, stamina, agility, and intelligence through an experimental super-soldier serum and vita-ray machine incubation.

One of my fantasies is to conduct that experiment on someone, I don’t want to be imprisoned though.

Humans are not usually associated with strength, ants are better than us in strength, and genetics play a crucial role in the ability to build muscle and determine your strength.

A 2016 study, found that mutation in ACVR2B (Activin receptor type- 2B) is remarkably associated with Lean Muscle Mass, and low lean mass is considered a major cause of disability and diminished quality of life.

ACVR2B, codes for a receptor that inhibits the regulator myostatin, a protein that occurs in skeletal muscles to reduce growth. Even bodybuilders take supplements to increase the expression of the ACVR2B gene to increase muscle gains^[6].

Before you get happy or anything, these edits or traits can’t be given to a fully-grown human being, only to a blastocyst (embryo containing 6-10 cells) or a blastomere at best.

You might not have any hope for your superhero fantasies but your future children might do if you illegally modify their DNA and you are ready for imprisonment.

Conclusion – Can We Really Upgrade Humans using Genome Editing?

Genome editing is a technique for genetically altering organisms or cells; it can be applied to both somatic and germline cells.

Genetic problems are currently being treated therapeutically via gene editing of somatic cells.

Given that it includes making modifications to the DNA that are passed down to subsequent generations, heritable human genome editing is a controversial subject.

A person’s lineage can be permanently changed by germline editing, which can also be used to remove harmful genes that cause genetic illnesses.

The ethical and moral challenges of genome editing are crucial since there are worries that the production of designer babies could result in prejudice.

CRISPR can be used to target and correct specific genes linked to diseases and may be able to prevent or treat genetic conditions like cystic fibrosis, sickle cell anemia, and Huntington’s disease by altering a patient’s genes.

Furthermore, this technology has the potential to improve human qualities like intelligence or physical prowess, albeit this is a more contentious field of study.

With additional research and development, CRISPR gene editing has a broad spectrum of potential uses that could aid millions of folks worldwide.

References

1. Hong Ma et al., ‘Correction of a pathogenic gene mutation in human embryos’, 2 August 2017, “We specifically targeted the heterozygous four-base-pair (bp) deletion in the MYBPC3 gene in human zygotes introduced by heterozygous, carrier sperm while oocytes obtained from healthy donors provided the wild-type allele. Moreover, DSBs in the mutant paternal MYBPC3 gene was preferentially repaired using the wild-type oocyte allele as a template, suggesting an alternative, germline-specific DNA repair response.”, https://www.nature.com/articles/nature23305[↩]
2. Y. Doubaj et al., ‘Three cases of Hutchinson-Gilford progeria syndrome’, Science Direct, 19 January 2011, “Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease, characterized by several clinical features that develop in childhood, in particular, an accelerated aging aspect. Its incidence is 1–4 per 8 million newborns.”, https://www.sciencedirect.com/science/article/abs/pii/S0929693X10005178?via%3Dihub[↩]
3. David R. Liu et al., ‘In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice’, Nature, 6 January 2021, “Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates.”, https://www.nature.com/articles/s41586-020-03086-7[↩]
4. David R. Liu et al., ‘In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice’, Nature, 6 January 2021, “A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days.”, https://www.nature.com/articles/s41586-020-03086-7[↩]
5. Daniel G. MacArthur and Kathryn N. North, ‘A gene for speed? The evolution and function of α-actinin-3’, n.d, p.[7], “We reasoned that if a-actinin-3 performed some crucial role in fast muscle fibers, it was likely that humans who expressed a-actinin-3 (those with RR or RX genotypes) would have an advantage over a-actinin-3-deficient (XX) humans in terms of sprint or power performance.”[↩]
6. Yann C Klimentidis et al., ‘Genetic Variant in ACVR2B Is Associated with Lean Mass’, PubMed, 1 July 2017, “ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass.”, https://pubmed.ncbi.nlm.nih.gov/26848890/[↩]