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  • This episode of Real Engineering is brought to you by Skillshare, home to over 25,000

  • classes that could teach you a new life skill.

  • 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 deemednormal

  • 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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