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On Nov 25th 2018 Dr. He Jiankui announced, via youtube, that he had decided to push humankind

across a controversial threshold.

This announcement was, of course, that his work had resulted in the birth of twins who

had both been subject to genetic engineering using CRISPR.

This was a threshold widely considered to be off limits.

In 2015 two of the foremost journals in research, Science [1] and Nature [2], both made similar

statements stating that modification of human germ cells, that is sperm and egg, should

be avoided.

The scientific community seemed to have come to an agreement not to experiment with this

technology until we could agree how and when to apply it to humans, but Dr. He Jiankui

has unceremoniously dragged us across this line in the sand, whether we like it or not.

Now, more than ever, there is an urgent need to stop and ask what the outcomes of this

work are for the individuals who have been subject to it and also how the rest of society

may be affected.

...

To understand all this we're going to need to understand how CRISPR technology works

and what the intrinsic shortcomings of this technology are.

DNA is made of nitrogen and carbon based rings which form 4 distinct chemical codes: Adenine

(A), Guanine (G), Cytosine (C) and Thymine (T).

These codes form an easily reproducible double stranded molecule which is read in group of

threes, called codons, which are contained within structures called genes.

These genes are simply the parts of the DNA that code for the more structurally complex

proteins, which in turn, form the biological machines and structures that are required

for all life on earth.

Due to DNA's ability to copy itself, until now the code in the DNA of all humans can

be traced faithfully to the first cells on earth.

Dr. He's work changed all of this by employing the use of the CRISPR-CAS9 technology to purposefully

change the DNA code in the two twins referred to as Lula and Nana.

As its name suggests, the CRISPR/CAS9 methodology is dependent on two key parts: CRISPR and

CAS9.

CRISPR is a kind of repeating DNA structure that was first discovered accidentally in

bacterial DNA by the Japanese scientist Yoshizumi Ishino in 1987 [3] . For 17 years following

this discovery, the exact function of these DNA repeats went undiscovered until it was

identified as the means by which bacteria identify and protect themselves against invading

viral DNA [4].

It turned out that these strange DNA repeats actually came from viruses.

Bacteria have the ability to cut up invading viral DNA, store it in their own DNA, and

then subsequently use it as a guide system for the enzymes CAS9, which destroys the viral

DNA sequence should it invade again in the future.

In order to do this, CAS9 uses the stored DNA to make something called a guide RNA.

This guide RNA is usually coded for by a CRISPR repeat, and guides CRISPR to DNA it should

cut.

There are two conditions for CRISPR's binding to its target.

First Cas9 must bind to the target sequence and a specific 3 code variation in DNA which

is called a PAM (protospacer adjacent motif).

Most PAMs can be recognized by Cas9 as they contain the code: *GG.

These recurring patterns are targeted by a bacteria's Cas9 system as they identify

the DNA of invading viruses.

This gives the bacteria an ability to target and destroy the viral DNA.

However, in the last 5 years, we have learned to leverage this ability to direct CAS9 with

guide RNA's of our own design to alter the genome of other organisms [5].

The guide RNA binds to a part of CAS9 called the alpha-helical lobe.

In turn, another domain of CAS9, the nuclease lobe, binds to any flanking part of the DNA

strands that matches with the guide RNA, causing the double helix structure of the DNA to unwind

[6].

This process is facilitated by the proximity between the DNA and the Cas9 complex and electrostatic

interactions that occur between the RNA and DNA.

At this point, 2 specific domains of the nuclease lobe cut the DNA.

Although we're not yet fully sure how this mechanism occurs, comparative studies suggest

that the most likely way is that the two seperate parts of Cas9 are able to rip protons from

water molecules, and in turns weaponize the deprotonated water molecule to break the DNA

apart [ref].

This is done at two sites in the DNA, one which cleaves the DNA at the target site (HNH)

and another which cleaves the DNA at a non-target site (RuvC).

At this point a number of things can happen depending on which approach is needed:

- Cas9 can be modified to include a deaminase enzyme which can target specific bases for

mutation, leading to brand new mutations.

- a process known as homology directed repair can be used to insert new DNA at the cutting

site.

-Or the targeted piece of DNA can be simply cut out and removed if it is deemed to be

undesirable.

Dr. He Jankui opted for the latter option and simply cut a section out of a gene called

CCR5.

The section that was cut corresponded to a mutation known as delta32, that confers it's

owners with protection to certain strands of HIV.

Dr. He's data seems to suggest he may have artificially induced a mutation, similar to,

but not identical to the delta 32 mutation in these twins [7].

In order to do this, Dr. He had to first optimize the gene editing protocol in mice, monkey

and human cells.

The reason for this is to make sure the protocol has high specificity - simply put, that the

gene editing technique was editing the target DNA and not some other sequence.

This claim is of course key to the validity of the experiment.

Unedited embryos can be thrown away after all - but for obvious reasons, making unspecific

alterations to a human's genetic code would be a major red flag...and Dr. He's work

raises major red flags for this exact reason.

Their check for specificity of gene editing used parental genetics as a reference point,

an inadequate approach due to the fact that a parent's genetic material is subject to

a certain degree of randomization every time a sperm or egg is produced.

It's further complicated by the fact that no two sperm or eggs will be the same and

that their methodology did not account for the possibility that larger sections of the

genetic code could be deleted by their implementation of the Crispr/Cas9 system.

Further to this, from the data released so far we can tell that the mutation induced

in the twins does not exactly mirror the delta32 population that He is attempting to induce

in the twins [8].

Although the protein produced should in theory largely mirror the naturally occuring mutation,

we cannot tell that for sure because it has not been tested.

Standard practice at this point is to test these mutations in an animal model in order

to assess unexpected effects of the experiment.

This is perhaps the most troublesome part of this experiment.

Lulu and Nana are test subjects for a genetic mutation that we have not even taken the time

and care to test in animals.

Nonetheless, the mutation was induced in a total of 31 human embryos.

These embryos were grown for a period of 5-8 days and the 19 that were deemed “normal”

were taken forward.

Out of these 19 embryos 2 were implanted in the mother to give rise to the twins.

These concerns over Lulu's and Nana's well being are only one of a myriad of issues:

Perhaps most critically there was no medical need for this treatment in the first place.

It has been claimed that the biological father of the twins is HIV positive.

Given that the couple used IVF, and that there is no evidence that HIV would be passed on

from father to child using this method of conception.

The procedure was medically unnecessary.

Furthermore, He claims to have induced this mutation completely into at least one of the

twins.

To do this, He and his group would have had to check the DNA in every cell in the growing

blastocyst, a group of cells that exist from days 5-9 post fertilization that eventually

becomes the embryo.

Given that they would have to destroy the blastocyst to test all the cells, a clear

logistical problem exists in trying to qualify that the mutation exists in all the cells.

Accordingly, He and his group only checked a number of cells from the blastocyst.

This means both twins might have a condition called mosaicism, where the deletion only

occurs in a subset of their cells.

This means that different cells in their body, have different DNA.

In this context, the effects of this condition are completely unstudied.

Finally, the gene that He took aim at has also been reported to have a role in learning.

A link between the activity of the CCR5 gene product and the dampening down of the brain's

ability to form new neural connections has been previously described in mice models.

Theoretically, there is a possibility that the induced deletion could have a positive

effect on the twin's ability to learn.

Right now there are far too many unknowns to make an accurate prediction on what if

any effect this experiment will have on the two twins and there's an even bigger question

about what effect the announcement will have on the progress of the field.

Complicating this mess is the fact that this study did not go in front of an adequate ethics

approval board and default Chinese law prohibits any kind of follow up with the twins.

Because of this, we will likely never know what will become of Lulu and Nana.

Dr. He has stated that he plans to publish the work in a peer reviewed journal, but given

that he has gone M.I.A for almost 2 months now [9], the scientific community may never

have an opportunity to properly review and digest the impact of this work.

So where do we go from here?

There is no doubt that genetic engineering is a valuable tool that can potentially safely

increase human wellbeing and productivity.

It's not unlikely that plunging into these uncharted waters unaccounted and without approval

may have a chilling effect on the proper utilization and development of this technology though.

Perhaps, until a consensus on the way forward is established this is a good thing.

Thankfully, the World Health Organization has stepped up to take a moderating role in

the process and are establishing a working group to establish clear guidelines.

We need these guidelines because we've stepped into a new era of medicine.

One where the genetic modification of humans is not only a possibility but an increasingly

real option.

Humans have long sought to improve themselves through technology.

From the printing press to the internet, these inventions exist to expand our knowledge and

inform us.

Maybe one day we'll be able to alter our genes to make ourselves smarter, but in the

meantime we're already surrounded by tools for this, like watching educational videos

on YouTube, or watching in-depth tutorials and classes like the ones you'll find on

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