May 20, 2021

Episode 15 - The Ethics of gene editing, Broken Proverbs, Misheard Lyrics and the Rhythm of English


With CRISPR Cas9 gene editing a dystopian future could be just twenty years away. We look at the developments and consider the risks, benefits and ethics.
In a Podcasting first we now introduce a podcast with colour, literally with Pantone 448C.
Our songs under the Microscope continues its voyage into misheard lyrics.

We stress test some common proverbs and found them inaccurate at best and the purveyor of very poor counsel at worst.

Finally, we consider how language dictates the rhythm and pace of poetry and prose that can be written. Ian takes exception to the rule that you cannot write a Limerick in French; so he writes one.

Transcript

Episode 15

Hello, and welcome to Frenzied and Sustained.

In this week’s podcast for a post stupid society our Brainy Lecture considers the ethical considerations of gene editing and ponders a dystopian future that may be in only twenty years’ time. That is approximately the length of the opening sequence to The Irishman.

We undertook a scientific audit of common proverbs and found some horrendously broken.

Our Songs under the Microscope continues with its new top ten misheard lyrics.

In A Sauce A Sauce my Kingdom for a Sauce - we have a no-cooking required Tahinini and honey sauce. This is not an optional module.

We thought about what is missing from every other podcast and realised it was colour. So we are introducing a new section on colour and we are starting with the colour that launched a thousand lavatory brushes, Pantone 448C

In Literally the Last section we study the perculiar rhythms of English, we see how that has informed our dramatists and poets and we will find that these metres prevent the French from having their literature sound anything like Shakespeare.

You are listening to frenzied and sustained, now in colour,  and I  am Ian Spector and this is a 

Brainy lecture

As we discussed last week CRISPR Cas9 is a technology that allows scientists, including mad scientists, to locate a particular point on the subject’s DNA, make  cut at that point and then copy in new genes. This has been invented and it is only a matter of time before an evil genius discovers that you can buy a CRISPR RNA synthesis kit from BioVision on Amazon.com for $436.25 with free shipping.

The whole world essentially is able to edit the genome as it sees fit. Unlike earlier systems that required the creation of a new CAs9 for every gene that you wanted to edit, you can now just create your guide RNA or buy each one online at a price of $7 per base pair. So we have a cheap and easy way to edit the genome of cells of higher organisms virtually at will. What we can do with CRISPR Cas9 as an editable engineering solution is essentially limited by our own imagination. 

 Now, there are some hugely attractive aspects to CRSIPR Cas9 and as a species we absolutely want to harness these to treat disease. For example, it could be used to create new antibiotics. Now isn’t that just ironic.  because CRISPR systems actually evolved in bacteria… as a way to protect them. As we discussed last week the virus conducts its attack on the bacterium by injecting its DNA. The bacteria then inserts that DNA into its CRSPR sequence and puts it on a long strand of RNA with a Cas9 protein and sends it off into battle. When it comes across a matching piece of DNA (i.e. the marauding phage) the Cas9 cleaves it like in a slasher movie thus destroying it.

So the irony here is that they now programming the messenger RNA to look for the bacterium’s own DNA and cut it. Sounds a bit like cheating, but so cool. 

They form these messages  into circles of DNA called plasmids and then load these plasmids into  viruses that infect bacterial cells, (bacteriophages). 

When these engineered bacteriophages  infect the target bacteria, the cell thinks it’s under attack.  The enclosed DNA message is released,

and that triggers the bacteria’s own  Cas proteins to chop up its own genome thus killing the bacterium.

Obviously one of the first targets is the bacterium C. difficile, on account of it being, well, difficile a tuer. C Diff is diagnosed in around 500 000 cases in the US each year.

There is also active discussion about putting a gene drive CRSPR system into cedes aegypti mosquito to eradicate it from the face of the world. In return, and I am not making this up, there is talk of using this technology to resurrect a species that has long been extinct. George Church, a researcher at Harvard has proposed editing the genome of an Asian elephant to bring back the Woolly mammoth. Presumably he intends to include it in a new theme park.

The framework is just so flexible. It can be used to switch genes on or off that already exist in the genome, we can screen for the functions of specific genes on a genome wide basis, we can show when and how certain genes are being processed by a particular cell of a cell type, we can control a whole variety of cellular interactions in an almost infinite variety of conditions. The power of CRISPR Cas9 isn’t just that it edits, it is also that it can be used to create, to power, to report and to analyse the content of the genome.

Another area under furious development at the moment is rapid testing for diseases such as SARS Cov-2.

As we have seen the Cas9 protein is a highly focussed tool that will cut the target DNA at just the precise place. There are other Cas proteins that are much more indiscriminate.  Unlike  Cas9, which only destroy its target, these Cas proteins find their target they go on a cutting rampage and will cut anything nearby! This is called collateral cleavage. And collateral cleavage is what happened the time I shared a terminal shuttle at Dulles Airport with Dolly Parton.

The new system will take your sample, multiply the virus using a PCR process, then add some reporter RNA and the Cas proteins. If the virus is present then the Cas will set to work cleaving everything within reach, including the reporter RNA. When the reporter RNA is cut it fluoresces. 

We also saw last week how CRISPR Cas9 can be used to treat some monogenetic diseases, i.e. conditions caused by the fault in just one gene, such as muscular dystrophy, beta-thalassemia, cystic fibrosis, and Tay-Sachs disease. These diseases are rare but all together they represent thousands of cases a year.

On the other hand, most common diseases are influenced by many common genetic variants that each have a small effect on disease risk. In addition, the risk of developing such diseases is often influenced by environmental factors such as diet and lifestyle choices, and by circumstances that are difficult to predict. Editing a gene variant associated with such a polygenic disease will typically have little effect on risk of the disease. Preventing the disease might be expected to require dozens or more different edits, some of which could produce adverse effects because of other biological roles the gene may play and other genetic networks with which it interacts. 

Let’s consider some of the risks and ethical considerations.

Firstly apartheid. Within twenty years parents of jens will not want their children being held back at school by nats (sorry boomers, jens are the genetically enhanced humans and nats are the un-modified naturals). The parents, after spending $3million of giving their children the best genome that money can buy will not want to see it squandered by their children marrying a nat.

As the population of jens increases they will want to pay less health insurance than the nats as they are not going to be a burden on the health care system. This could leave more expensive and less extensive cover for nats.

What about when you are looking for an apartment and you see a sign saying ‘no nats’. Do the nats have to sit at the back of the bus (no they can sit where they like, jens don’t need to take public transport).

Will jens be allowed to compete in the olympic games. In fact, what is the point as some countries will produce a team of jens purely designed to compete in the olympics.

Will judges be more inclined to believe a jen or a nat if the invoice shows you ticked the enhanced honesty option.

As you walk into a bar you will be asked “are you jenic or not jenic”

Looking at Instagram, and looking at how children are conforming to fashion norms, what will that generation of influencers do when they have the full tasting menu of CRISPR Cas9 at their disposal.

Although gene therapy is often used to treat patients for their own benefit, the criminal justice system may require repeater or dangerous offenders to correct the genes associated with violence by genome editing technologies in the future. One of the biggest dilemmas here is to obtain informed consent for an underage person if the intervention is made during the development of the zygote. It is really difficult to get a zygote to sign a consent form.

When companies can earn billions with more exotic human upgrades, why would they bother diverting funds to research treating diseases that are not a feature of life for the fee paying jens.

Will the jens be programmed to forget all the bad human experience with eugenics in the past (ahh, this is different, this is eujenics not eugenics) See what I did, I spelled it with a j.

And finally, what about in a hundred years’ time when you can pick up a basic designer baby kit from Coles Supermarket in Sandy bay, Hobart, or in Walmart for 20 coin, and there is no genetic variation in the population and there is an outbreak of covid 2119 (probably some bloody nat having sex with a pangolin in a wet market again, those filthy bastards)  and all of humanity is wiped out. Well, all the jens, those bloody nats will still be around. Grrrr damn them and their genetic diversity.

These ethical issues need to be discussed now. CRISPR Cas9 is being used in thousands upon thousands of labs and mountain lairs round the world right now.

A very substantial portion of genome editing studies are supported by the defence ministries. These studies are commonly focused on increasing the tolerance of soldiers against biological or chemical warfare. CRISPR Cas9  technology has the potential to influence human performance optimisation. Studies are usually focussed on discovering different genes that can be harnessed from other species such as the ability to create a thermal image of the enemy using their eyes, in the way snakes do (Gracheva et al., 2010) and identifying new genes that can be associated with posttraumatic stress disorder, which is frequently experienced by soldiers (Cornelis et al., 2010). In a study by Zou et al. (2015), researchers developed dog embryos with higher muscle mass using CRISPR-Cas9. Another study showed that the the two anthrax toxin receptors tumour endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2)  could be silenced by tRNA interference (RNAi) technology.  Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, post-exposure therapy against anthrax.(Arévalo et al., 2014). 

In many respects we have been discussing the best case scenarios. What happens in the case of non-target effects of gene editing. Since gene drift will persist in a population, possible off-target mutations will continue in each generation. In addition, the number and effect of mutations may increase as generations progress. Another concern is the possibility that genes can be transferred to other species in the environment. Nature will always find a way (Jurassic Park et al 1993).

Frankly, I believe that the ability to fine tune our offspring is some considerable time off, the relationships between the many genes responsible for behaviours and appearance are not close to being fully understood, let alone knowing how to manipulate those genes.

Where I do have concerns, and immediate concerns, is the use of gene drives. Here we use CRISPR Cas9 to change a gene but also insert a copy of the CRISPR Cas9 into both chomosomes of every single individual. It instantly takes a heterozygous trait and makes it homozygous. This would have cause Gregor Mendel to lose his mind. You inherit one copy of a gene on one chromosome but it then copies itself onto the other chromosome.

So if, as they are doing this week in Florida, you introduce a mutated mosquito that can only have male offspring you will crush the populations in months. If you put an anti-malarial gene drive in just 1 percent of Anopheles mosquitoes, the species that transmits malaria, researchers estimate that it would spread to the entire population in a year. So in a year, you could virtually eliminate malaria.

Say you want to get rid of an invasive species, like get Asian carp out of the Great Lakes. All you have to do is release a gene drive that makes the fish produce only male offspring. In a few generations, there'll be no females left, no more carp. In theory, this means we could restore hundreds of native species

that have been pushed to the brink. 

The slight downside is an accidental release could cause a cataclysmic disaster on whole ecosystems. They could permanently change an entire species.

If some of our Asian carp with the all-male gene drive accidentally got carried from the Great Lakes back to Asia, they could potentially wipe out the native Asian carp population. And that's not so unlikely, given how connected our world is. This, of course, is why we have the  invasive species problem in the first place.

And that's fish.

How are we going to contain things that fly, like, you know, flies.

Next nightmare is the problem of gene flow, the gene drive may not stay confined within the target species as neighbouring species interbreed.

If that happens, it's possible a gene drive could cross over, so now our Asian Carp has infected all carp. That is a lot of male carp all fighting for the remote.

Here is a technology that any high school student can use with the risks of wiping whole species off the face of the earth. Until we find a way to reverse these gene drives can I ask you not to upset your teenage children by, for example, asking them to clear up their rooms.

Let’s cheer ourselves up with a CRISPR Cas9 gene top ten

Kicking us off at number 10 is Elton John with Goodbye Norma Jean

First time in the charts for David Bowie with the double hitter jean-genie

Kings of Leon reign over position 8 with Taper Jean Girl

Contentious entry at number 7 for Stevie Nicks with her Blue Denim she maintains are jeans

Stevie, try and be more like Hannah Montana at number 6 with Old Blue Jeans

New entry at number five for Michael Jackson and Billie Jean

Yes I know that `goodbye Norma Jean was the lyric and not the song title, Candle in the Wind 

Enjoying the Sunshine on Leith are the proclaimers, basking at number 4 with Oh Jean

Another first time visitor to the Frenzied and Sustained charts at number three for Meghan Trainor and her Genetics

Totally on message at number 2 for the Shook twins with Crisper

And at number 1 we have Little Mix and her 2012 hit DNA

When proverbs go wrong

I was doing an audit of proverbs to make sure that they are still fit for purpose. I found some worryingly broken examples.

I offered to buy a beggar a coffee and he asked for no sugar, clearly beggars can be choosers

I watched a kettle and it boiled

I went out for a walk and saw some ugly houses, ugly cars and ugly street urchins. Beauty was not in the eye of the beholder

I always put all my eggs in one basket then I put the heavy things such as tins in the others. This way I don’t break my eggs

Speaking as a veteran of my disastrous attempts at cutting my own hair, filling a cavity in my tooth, performing Lasiq surgery on both my eyes, and removing my own appendix, I am beginning to come to the conclusion that if you want something done right it is best to retain the services of an expert in the respective field.

I tried just laughing at my kidney stone but in the end IV Paracetomol was the best medicine

Anyone who says that no man is an island clearly has never seen pavarotti in the bath

I  always tried to leave them wanting more, until I was fired from my job in famine relief

Hang on who’s this….

A Sauce A Sauce my Kingdom for a Sauce - Tahinini and honey sauce

I love this sauce. It is so wonderfully balanced. For reasons I simply don’t know I only ever seem to serve this over grilled aubergines, or something else you call them in the US, like bread fruit, any way aubergines I can’t think of the word. It will come to me.

Here are the ingredients.

1 tbsp tahini paste

2 tbsp natural yoghurt

1 tbsp lemon juice

1 tsp runny honey

1 garlic clove, peeled and crushed

1-2 tbsp hot water

You simply mix the ingredients together then add the hot water to give it the consistency of very thick cream.  Season with salt and pepper and really taste it well to get the balance between the salt, the sweet and the sour. Drizzle over a little good olive oil to serve 

Actually I have used this with griddled courgettes but I cannot think of the name in America for courgettes either so I was not going to mention it. Is it egg plant? Seriously, you need to adopt the metric system.

Right time to pay some bills.

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Songs Under the Microscope - Misheard lyrics edition

Following on from the resoundingly positive feedback from last week’s feature on misheard lyrics we are back with a new top ten.

In at number 10 Abba’s dancing Queen gets less abuse where it turns out that “See that girl, watch her scream, kicking the dancing queen” was written as  “See that girl, watch that scene, dig in the dancing queen”

Down to number 9 a previous number 1 for the Eurythmics and 'Sweet Dreams (Are Made of This)' they no longer “travel the world in generic jeans” but instead ”travel the world and the seven seas”

Jimi Hendrix is rushing back in the closet at number 8 in Purple Haze, he is now denying  “Excuse me while I kiss this guy” and claims quite implausibly to be singing “Excuse me while I kiss the sky”

A meat based new entry at number 7 with 'Two Tickets to Paradise' by Eddie Money. The world has been singing “I’ve got two chickens to paralyse” for way to long instead of the much more valuable  “I’ve got two tickets to paradise”

Medical emergency gets averted at number 6 with 'Lucy in the Sky With Diamonds' by The Beatles. Latest research seems to suggest that the line: “The girl with colitis goes by” might have been written as  “The girl with kaleidoscope eyes”

Dire Straights back in the chart at number 5 with their Atkins Diet update, they will no longer get  "Money for nothin' and your chips for free" but would prefer money for nothing and their chicks for free 

The food based themes continue with Paul Young at number 4  "Every time you go away, you take a piece of meat with you".  He now prefers the more canibalistic  "Every time you go away take a piece of me with you" 

Up four places to number 3. with Taylor Swift’s Blank Space: "All the lonely Starbucks lovers". She claims it is "Got a long list of ex-lovers"  she is definitely singing Starbucks, Taylor Swift’s mother said it was Starbucks and Starbucks themselves were sad about the correction. The only people who are not sad are all the Costa Coffee Lovers

At number 2 is Johnny Nash: "I can see clearly now Lorraine is gone". wishes in future to be sung "I can see clearly now, the rain is gone" 

At number 1 for the third week running is  Selena Gomez on Good For You with "I'm farting carrots". Since her treatment for lupus she is now singing "I'm 14 carat"

And now a new section specially made for Podcasts - Colour, or for our American friends with their pathological hatred of the letter U, Color.

This week  we are forcing our eyes to look at a colour (color) that was invented to be the ugliest colour in the world. So that you can play along at home I will include the pantone code for you so you just need to google Pantone 448c. I can only describe this colour as gastroenteritis, as the inside of Snape’s laundry basket, as motorway service station lavatories. Its inventors even called it blocked drain, well they didn’t but they might have. They called it Opaque couché and described it as a drab dark brown. It was selected to be the least attractive colour for Australian cigarette packaging, presumably to represent the colour inside smokers’ lungs, or inside their underpants when they discover the colour inside their lungs. So google Pantone 448c and leave me your thoughts on Frenzied and Sustained .com. By the way, as 97% listen on mobile devices I realise that it is not that convenient to type a message so you can leave me a voice message by clicking on the microphone symbol on the bottom right hand corner of the Frenzied and Sustained website.

Literally the last section

English possesses  natural rhythm, 

It’s based on the sound of the beating heart

Ten beats in each line considered in pairs

Stress then you miss as you limp down the line

From tales you tell as you walk down the lane

Its natural gait just ambles along

So easy to hear and pleasant to write

A friend riding with you into the night

That introduction was written in the classic Shakespearian form of the iambic pentameter. 

It is said that only in English could the greatest writer be a dramatist. And that is due to the iambic pentameters. Each line has ten syllables, each two joined together as iambs, with stresses alternating on and off like the beating of the heart. Whenever the action got intense or emotions rose high, Shakespeare would turn to iambic pentameter. It is considered so natural and so close to human speech his actors and players found it really easy to learn their lines.

So, just like the beating heart with its der dum rhythm iambic pentameter stresses on the second beat of the iamb.

Here are some examples

If petrol is the fuel of cars drive on

Magpies stole my watch and pencil curse them

Indoor rejoice as iPhones are recharged

Consuming fish without my sauce is wrong

A sauce a sauce my kingdom for a sauce

This iambic pentameter and is what gives Shakespeare’s plays and poetry their distinctive rhythm.

A French-speaking poet could not have written something that sounds like Shakespeare because the language you speak affects the poetry and verse that it’s possible for you to write.

Let’s start with English. English has what’s called “lexical stress”. There’s a difference in how we say the noun “a CON-test” versus the verb, “to con-TEST”.

Stressed syllables are part of speech and poetic writing in English, and if you put the stress on the wrong syl-LAB-le, it sounds ridi-CU-lous.

 

Stresses are built into the words that we use. Stress isn’t normally something you have to consider too much while writing,

In French, by default, stress lands on the last syllable of an utterance. Thus, it is said that one cannot write a Limerick in French.

 Oh no?

Il y avait une jeune femme de Rome

Dont les seins sont sortis comme des ballons

Le majordome est passé

avec ses yeux bleus glacés

Et les a rendus avec des cuillères chaudes

There was a young woman from Rome

Whose boobies popped out like balloons

The butler came by

with his icy blue eyes

And returned them with some warm spoons

I also love the rhythm of the dactyl. It can give such pace to the lines. I think of it like a horse cantering. 

The dactyl meter consists of a first stressed syllable followed by two unstressed syllables (rather like the opposite of the anapaestic in the Limerick)

Higgledy piggledy,

Bacon, lord Chancellor.

Negligent, fell for the

 Paltrier vice.

Bribery toppled him,

Bronchopneumonia

Finished him, testing some

Poultry on ice.”

So you can see two dactyls in each line.

I am a big Robert Browning fan, especially being in England when April comes and May follows. Here we have The Lost Leader (yours for just 1 penny) with usually 4 dactyls per line, come on,

Just for a handful of silver he left us,

Just for a riband to stick in his coat

Found the one gift of which fortune bereft us,

Lost all the others she lets us devote;

They, with the gold to give, doled him out silver,

So much was theirs who so little allowed:

How all our copper had gone for his service!”

By the way, this poem was an insult from Browning to William Wordsworth for kowtowing to Queen Victoria and turning his back on liberal values. I have to say the quality of insults was significantly higher in the early 19th century.

You see these meters do not respect punctuation or normal word breaks, the rhythm is everything.

The music genre that has most enthusiastically adopted iambic pentameter is hip hop, probably for the same reasons that Shakespeare did, natural rhythm and easy to remember lines.

In fact, we cannot help ourselves and we apply it to foreign words that have no lexical stress at all. For example in Japanese there all words receive equal stresses, but when we say edamame we pronounce it as two trochees with stresses on the ed and the mam. A trochee is the opposite of an iamb so instead of the cardio di dum we now how the dramatic dum di. The American poet Longfellow wrote the entire epic poem the song of Hiawatha in trochee. In fact it is in trochaic tetrameter with 8 syllables per line giving four feet. I will give you a small example from the song of Hiawatha but notice how very different it is from our iambic pentameters.

By the shore of Gitche Gumee,

By the shining Big-Sea-Water,

At the doorway of his wigwam,

In the pleasant Summer morning,

Hiawatha stood and waited.

All the air was full of freshness,

All the earth was bright and joyous,

And before him, through the sunshine,

Westward toward the neighbouring forest

Passed in golden swarms the Ahmo,

Passed the bees, the honey-makers,

Burning, singing in the sunshine.

Of course other languages have their own rhyme schemes and meters. It really makes you respect the work of translators who need to consider how the original author intended the poem to sound as well as the meaning and the rhymes. Of course the one person who dislikes the English forms is La jeune femme de Rome as she blames it for her wardrobe malfunction.

And that is the end of Literally the Last Section. It is also the end of this week’s podcast. In next week’s Frenzied and Sustained our Brainy Lecture considers Entropy and presents the theory that life is a consequence of entropy. We lament that entropy isn’t what it used to be. We will have more misheard lyrics under our microscope and Literally the Last Section asks the question “Was Indiana Jones just the worst archaeologist ever”? (he was).