One of the largest animals known, the giant squid is also one of the most elusive, appearing to us mainly as body parts sporting telltale suckers that have washed ashore. A full grown giant squid can’t be comfortably stuffed into an aquarium tank. So most of us know about it from fiction.

Giant Squid in Culture

The giant sea monster of Scandinavian folklore, the Kraken, terrified sailors in vessels along the coastal waters of Norway and Greenland. It was likely a giant squid, as was Homer’s tentacled Scylla in The Odyssey. Jules Verne’s 20,000 Leagues Under the Sea, written in 1869, famously featured the animal.

More recently, the 2005 film The Squid and the Whale evokes the image of a giant squid battling a sperm whale depicted in a mesmerizing diorama at the American Museum of Natural History. Director Noah Baumbach borrowed the image as a metaphor for the battling parents of his young protagonists.

True squid stories are intriguing too.

The first description came from Captain Peter M’Quhae of the HMS Daedalus. On an August afternoon in 1848, the ship was sailing between the Cape of Good Hope and the island of St. Helena off the coast of Africa, when a huge sea serpent arose from the depths. Many men witnessed the event, and their tales made their way into the newspapers.

The beast, according to captain and crew, was 60 feet long and had gotten quite close to the ship. The captain sketched it, and newspaper readers offered a variety of explanations. Had the sailors seen a dinosaur, an uncommonly long eel, a giant seal, or a gargantuan snake that had lost its way?

In 1857, Japetus Steenstrup, a zoologist at the University of Copenhagen, assembled eclectic clues to the giant’s identity: the smaller squid relatives that people ate, tentacled slimy things washing ashore, a marooned mysterious giant beak, and sailors’ supposedly tall tales.

A Little Help from Cephalopod Relatives

Getting enough remains of fresh giant squids to probe their DNA is tough, but researchers have determined from analyzing mitochondrial DNA that giant squid are all the same species. But that’s just a handful of genes. Many copies of a full genome are needed to overlap them sufficiently to derive a complete genome. Otherwise, gaps remain.

Museum samples generally don’t work – between decay and preservatives, the DNA is hard to extract and keep intact. Fortunately, fishermen aboard a ship near New Zealand were able to send a freshly frozen tissue sample from a giant squid to the multinational research team, who went to work on the genome. “These new results may unlock several pending evolutionary questions regarding this mantled species,” said lead investigator Rute da Fonseca from the Center for Macroecology, Evolution and Climate at the Globe Institute of the University of Copenhagen. The report appears in GigaScience.

Alas, many of the squid genes were shattered. So the researchers turned to analyzing messenger RNAs (mRNAs) and proteins from easier-to-handle relatives. A genome is like a hard copy, an instruction manual present in every cell. In contrast, collections of RNAs and proteins differ in different cell types, painting portraits of a living organism’s functions.

But RNA is more delicate than DNA and wouldn’t persist in a lump of rotting squid flesh. So the researchers collected mRNAs from relatives: the common clubhook squid, the Humboldt squid, and the purpleback flying squid, sampling from brains, livers, and sexual organs. They also collected proteins from the muscular mantles of museum specimens of the California two-spot octopus, the Pacific oyster, and the giant owl limpet.

Matching the RNAs and inferring DNA sequences from the proteins’ amino acid sequences, the researchers were able to flesh out the genome of the giant squid.

Protein Families

The giant squid’s genome includes 33,406 protein-encoding genes splayed across 2.7 billion DNA bases, compared to our 20,000 or so genes in a 3.2 billion base genome. About half of its genome is repeated sequences, most of which can jump around, but that’s not surprising. The genomes of corn, insects, and humans are also half or more repeats, with jumping genes too. These sequences, perhaps raw material for evolution, account for much of the variation in genome size among species. Size doesn’t really matter.

The genome of the giant squid also resembles those of other animals in that it includes gene families, groups of genes with related functions. It harbors the dozen WNT genes found in all mollusks. This gene family encodes secreted glycoprotein growth factors that take part in the cell-cell signaling that controls cell proliferation in early development and later in maintaining tissues. Humans have 19 WNT  genes.

Genes encoding proteins called protocadherins are “massively expanded” among the cephalopods. They oversee cell-cell adhesion, essential to the functioning of a nervous system. Like the WNT growth factors, the protocadherins are in vertebrate genomes too. They’re clustered, which suggests that they evolved from an ancient gene that repeatedly duplicated.

Other invertebrates and vertebrates have arrays of WNT and protocadherin genes. In contract, reflectins are specific to cephalopods, discovered in the Hawaiian bobtail squid. These proteins form flat structures that reflect ambient light, providing the trademark glow that a squid uses to blend in and communicate. In squids as well as octopuses, nine reflectin genes cluster on a chromosome.

RNA Editing and An Exploded Homeotic Gene Cluster

Two characteristics of the giant squid genome have broader implications.

The giant beast appears to be expert at editing its RNA. This skill enables the animals’ genomes to knit variations on proteins, particularly those involved in nervous system functioning.

At tens of thousands of places in the genome, the RNA-edited regions lie within “highly conserved” DNA sequences, which means that they’re identical, or nearly so, in many species. That is, natural selection has retained them over deep time because they do something essential to successful reproduction.

The other intriguing characteristic of the giant squid genome is the dispersion of its homeotic (Hox) genes. These genes control where body parts form in relation to each other, from flowers to flies to fungi to the more complex single-celled organisms.

A homeotic mutation mixes up body parts, and they’re behind some diseases of humans. I did my PhD work on the Antennapedia complex of homeotic genes in flies (see next week’s post), specifically mutations that put legs on their heads and antennae on their mouths. The homeobox – the 180-base-pair stretch within homeobox genes that controls the body “plan” – was discovered soon after I got my degree, in my lab (that of Thomas Kaufman at Indiana University). I’m a homeogirl.

The most amazing thing about the homeotic genes is that they are arrayed on a chromosome, in the genomes of all these diverse species, in the exact order in which they are deployed in development, like basketball players waiting on a bench at a game.

But that’s not the case in the giant squid genome. Instead, their homeotic genes are dispersed among chromosomes. Could this be why the body is so huge and blobby, seemingly lacking the nuances of a face, the intricacy of a flower, even the feathery filaments of a mushroom?

“Gain and loss of Hox genes has been attributed to fundamental changes in animal body plans,“ the researchers write. And loss of a major Hox gene in spider mites reduces the number of segments. So did some long-ago mutational event in the giant squid or an extinct ancestor explode the arrayed homeobox genes to new genomic addresses, while retaining enough function to form a body?

The Giant Squid’s Place in the World

It’s hard to tell whether a population that we can’t really observe is threatened, but the researchers point out that oceanic warming and acidification, pollution including mercury and flame retardants, depleted oxygen, and fishing are all threats to the giant squid, as they are to many other species.

“Consequently, there is an urgent need for greater biological understanding of these important, but rarely encountered animals, in order to aid conservation efforts and ensure their continued existence. With the release of this annotated giant squid genome, we set the stage for future research into the enigmas that enshroud this awe-inspiring creature, the species that has inspired generations to tell tales of the fabled Kraken,” the researchers conclude.

(Opening image of giant squid sucker rings credit: The Trustees of the Natural History Museum, London)

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Just when we thought octopuses couldn’t be any weirder, it turns out that they and their cephalopod brethren evolve differently from nearly every other organism on the planet.

In a surprising twist, in April last year (2017) scientists discovered that octopuses, along with some squid and cuttlefish species, routinely edit their RNA (ribonucleic acid) sequences to adapt to their environment.

This is weird because that’s really not how adaptations usually happen in multicellular animals. When an organism changes in some fundamental way, it typically starts with a genetic mutation – a change to the DNA.

Those genetic changes are then translated into action by DNA’s molecular sidekick, RNA. You can think of DNA instructions as a recipe, while RNA is the chefthat orchestrates the cooking in the kitchen of each cell, producing necessary proteins that keep the whole organism going.

But RNA doesn’t just blindly execute instructions– occasionally it improvises with some of the ingredients, changing which proteins are produced in the cell in a rare process called RNA editing.

When such an edit happens, it can change how the proteins work, allowing the organism to fine-tune its genetic information without actually undergoing any genetic mutations. But most organisms don’t really bother with this method, as it’s messy and causes problems more often that solving them.

“The consensus among folks who study such things is Mother Nature gave RNA editing a try, found it wanting, and largely abandoned it,” Anna Vlasits reported for Wired.

But it looks like cephalopods didn’t get the memo.

In 2015, researchers discovered that the common squid has edited more than 60 percent of RNA in its nervous system. Those edits essentially changed its brain physiology, presumably to adapt to various temperature conditions in the ocean.

The team returned in 2017 with an even more startling finding – at least two species of octopus and one cuttlefish do the same thing on a regular basis. To draw evolutionary comparisons, they also looked at a nautilus and a gastropod slug, and found their RNA-editing prowess to be lacking.

“This shows that high levels of RNA editing is not generally a molluscan thing;it’s an invention of the coleoid cephalopods,” said co-lead researcher, Joshua Rosenthal of the US Marine Biological Laboratory.

The researchers analysed hundreds of thousands of RNA recording sites in these animals, who belong to the coleoid subclass of cephalopods. They found that clever RNA editing was especially common in the coleoid nervous system.

“I wonder if it has to do with their extremely developed brains,” geneticist Kazuko Nishikura from the US Wistar Institute, who wasn’t involved in the study, told Ed Yong at The Atlantic.

It’s true that coleoid cephalopods are exceptionally intelligent. There are countless riveting octopus escape artist stories out there, not to mention evidence of tool use, and that one eight-armed guy at a New Zealand aquarium who learned to photograph people. (Yes, really.)

So it’s certainly a compelling hypothesis that octopus smarts might come from their unconventionally high reliance on RNAedits to keep the brain going.

“There is something fundamentally different going on in these cephalopods,” said Rosenthal.

But it’s not just that these animals are adept at fixing up their RNA as needed – the team found that this ability came with a distinct evolutionary tradeoff, which sets them apart from the rest of the animal world.

In terms of run-of-the-mill genomic evolution (the one that uses genetic mutations, as mentioned above), coleoids have been evolving really, really slowly. The researchers claimed that this has been a necessary sacrifice – if you find a mechanism that helps you survive, just keep using it.

“The conclusion here is that in order to maintain this flexibility to edit RNA, the coleoids have had to give up the ability to evolve in the surrounding regions – a lot,” said Rosenthal.

As the next step, the team will be developing genetic models of cephalopods so they can trace how and when this RNA editing kicks in.

“It could be something as simple as temperature changes or as complicated as experience, a form of memory,” said Rosenthal.

The findings have been published in Cell.

A version of this story was originally published in 2017.

Did you catch all that?

In 1944, scientist Erwin Chargaff had read Oswald Avery’s scientific paper, which identified DNA as the substance responsible for heredity. Then scientists can remove, add, or replace the DNA where it was cut. The first genome editing technologies were developed in the late 1900s   Source

In 1953, Rich–working with famed chemist Linus Pauling at Caltech–was using X-ray crystallography to try to discover the structure of RNA, hoping to learn more about its role in life. One nagging question was whether RNA, like DNA, could exist in a double-stranded helical molecule.

The x-ray images weren’t helping much; they were fuzzy, inconclusive shadows of the gooey, glassy fibers that were pulled from a glob of RNA.

At Caltech, and later at the NIH, Rich and his colleagues “talked a lot about RNA,” he told a reporter from Chemical and Engineering News last month. “But nobody–including myself–suggested, ‘Why don’t you mix together PolyA and Poly U,’ the two differing stands of RNA. It wasn’t at all obvious that could work,” he said, in part because everyone felt an enzyme would be needed to stitch them together. “People had no idea that hybridization could occur by itself.”

Ultimately Rich did try mixing the two strands, resulting in the discovery of double-stranded RNA, but to this day, he said, he can’t recall what prompted him to do so. “I’ve asked my colleagues and searched through my memory, and I don’t actually know.” But it did work, and that has made all the difference.  Source

In 1956Rich and Davies announced in the Journal of the American Chemical Society that single strands of RNA can “hybridize,” joining together to form a double-stranded molecule. As a result of the discovery and the work that followed, scientists now routinely identify, isolate, manipulate and replace the genes in living things. Such work led to the Human Genome Project and is pushing science toward a fundamental understanding of how life works.

The seminal discovery of double-stranded RNA by Rich and Davies came only three years after James Watson and Francis Crick stunned the scientific world by describing DNA’s structure as a double helix.

The announcement of the discovery of messenger RNA (mRNA) and the cracking of the genetic code took place within weeks of each other in a climax of scientific excitement during the summer of 1961. Although mRNA is of decisive importance to our understanding of gene function, no Nobel Prize was awarded for its discovery.  Source

The beginnings of an answer to this question were obtained in 1982, when it was discovered that RNA molecules themselves can act as catalysts. We have seen in this chapter, for example, that a moleculeof RNA is the catalystfor the peptidyl transferase reaction that takes place on the ribosome.   Source
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RNA Discovery

• Download PDF Copy

By Dr. Ananya Mandal, MDReviewed by April Cashin-Garbutt, MA (Editor)

The discovery of RNA began with the discovery of nucleic acids by Friedrich Miescher in 1868 who called the material ‘nuclein’ since it was found in the nucleus.

The discovery of RNA may be described chronologically as follows;

In 1944, scientist Erwin Chargaff had read Oswald Avery’s scientific paper, which identified DNA as the substance responsible for heredity. Then scientists can remove, add, or replace the DNA where it was cut. The first genome editing technologies were developed in the late 1900s   Source

Between 1890 and 1950

• RNA was found to be distinctly different from DNA. This was noted by its sensitivity towards alkaline caused by an additional OH-group on the ribose
• Nucleic acids were isolated from various organisms
• ATP and GTP were proposed to be the cell’s general energy source and building blocks for RNA
• Chemical analysis revealed that RNA shares three bases with DNA: adenine, cytosine and guanine. Uracil as a base unique to RNA was discovered in place of thymine in DNA.
• It was in 1939 that the role of RNA in protein synthesis was discovered.

Between 1951 and 1965

• During this time the RNA types that are useful in protein synthesis were identified. Messenger RNA (mRNA) as the carrier of genetic information, transfer RNA (tRNA) acting as the physical link between mRNA and protein, and ribosomal RNA (rRNA) present in ribosomes for protein synthesis were identified.
• RNA polymerase was identified and purified.
• Severo Ochoa won the 1959 Nobel Prize in Medicine after he discovered how RNA is synthesized.
• The sequence of the 77 nucleotides of yeast tRNA was found by Robert W. Holley in 1965. Holley won the 1968 Nobel Prize in Medicine for his research.
• This period also saw the discovery of the genetic code that three of the bases coded uniquely for an amino acid.
• RNA acting as genetic code in some viruses was identified.

Between 1966 and 1975

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• Transfer RNAs were sequenced and identified. The typical clover leaf shape of the tRNA was identified.
• X ray crystallography was used to know the shape of RNA
• In 1967 Carl Woese found the catalytic properties of RNA and speculated that the earliest forms of life relied on RNA both to carry genetic information and to catalyze biochemical reactions.
• This period saw the discovery of the Reverse transcriptase copying RNA into DNA. This was opposed to the central dogma that stated that RNA is made from DNA alone and not vice versa.

Between 1976 and 1985

• In 1976, Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2
• Splicing RNA was found. Introns were found to interrupt genes in their copying and the need to remove these by splicing was found.
• RNA as a biological catalyst was found. The RNase P was discovered. This led to the hypothesis of RNA as the genetic element of the “RNA world hypothesis”.
• Small RNA and protein complexes performing the splicing of the pre mRNA molecules were discovered.
• Spliceosomes as large RNA-protein complexes mediating nuclear pre-mRNA splicing were found

Between 1986 to 2000

• Editing and modifications of RNA in the cell was discovered.
• Maintenance of chromosomal ends using RNA templates in telomerases was discovered.
• Ribosomes were found to be the largest RNA enzyme

From 2000 to present

• Small RNA molecules that can regulate gene expression by post-transcriptional gene silencing were discovered
• Long non-coding RNA regulating gene expression was found. The first one was termed Xist. These were found to control epigenetic phenomena.
• Riboswitches were found that control gene expression
• Use of RNA intermediates by mobile DNA was found.

CRISPR, invented in 2009, has made it easier than ever to edit DNA. CRISPR is simpler, faster, cheaper, and more accurate than older genome editing methods.  CRISPR is a powerful tool for editing genomes, meaning it allows researchers to easily alter DNA sequences and modify gene function. CRISPR can turn genes on or off, or make them work in a different way,
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The incredible origin story of CRISPR

The development of the revolutionary gene-engineering tool CRISPR is a tale fit for the big screen.

Jonny Thomson

“Science is less about eureka moments and lone geniuses and more about standing on the shoulders of giants.”

The story starts in 1987 when a Japanese research team headed by Yoshizumi Ishino was researching the microbe E. coli. They wanted to explore a peculiar gene called iap. This mysterious gene was unique, consisting of blocks of five identical segments of DNA divided by unique “spacer” DNA. But because this was the 1980s and the technology wasn’t sophisticated yet, the Osaka team didn’t really know what to make of the observations, or what to do with them.

Fifteen years (2002) later in the Netherlands, a team headed by Francisco Mojica and Ruud Jansen of Utrecht University renamed these “sandwiches” of iap to “CRISPR,” which means “clustered regularly interspaced short palindromic repeats.” What Mojica, Jansen et al. discovered was remarkable: These genes encoded enzymes that could cut DNA. Still, no one knew why this happened, and the implications of this weren’t fully appreciated.

Three years later (2005), Eugene Koonin at the National Center for Biotechnology Information, noticed that these unique DNA bits in the “spacers” looked remarkably like viruses. And so, Koonin theorized that certain microbes were using CRISPR as a defense mechanism. It was a bacterial immune system. He suggested that bacteria used CRISPR (and their cas enzymes) to take fragments of invasive viruses and then paste them into their own cut DNA, where they acted as a kind of bacterial vaccination against future viruses, or like an immune-system memory.

It was left for microbiologist Rodolphe Barrangou to prove Koonin right. CRISPR really was cutting and pasting DNA.

The eureka moment

The implications of this were rather lost on both Barrangou and the microbiologist community. Barrangou himself used (and monetized) this technology to make virus-resistant bacteria for his yogurt-making employer Danisco. But on the other side of the country, at the University of Berkeley, these findings were being read by two people who would transform CRISPR technology: Jennifer Doudna and Emmanuelle Charpentier.

 Doudna and Charpentier were experts in the field of RNA — the blueprints created by DNA that act as the messenger required to encode all the proteins of life. What they discovered is that the CRISPR system could be reprogrammed to cut and paste not only virus DNA, but also whatever isolated DNA they wanted. They published their findings in a now-famous 2012 Science article.

But what does “reprogram” actually mean? First, we have to understand that CRISPR not only cuts and pastes virus DNA into its own DNA (as an immune-memory system or look-up table), but also uses this information to cut up future invader viruses, which prevents them from replicating. It does this by releasing RNA matching the virus’ DNA (which it has stored) along with its own cas enzyme. If these two find any invader virus DNA, they latch on, and the cas enzyme cuts it in two. It’s an incredibly clever process.

This finding produced the eureka moment: “Oh my gosh, this could be a tool!” Doudna recalled. To make that tool, they simply needed to attach this cas enzyme to an RNA of their own choosing, so that the enzyme would find and cut the matching DNA to that RNA. It’s sort of like a microbial “find and cut” function. What’s more, they could then induce a cell to stitch genes to fill the gap — a type of “find and replace” function.

Research for research’s sake

The implications of what Doudna and Charpentier discovered have opened new and unprecedented opportunities. Since their original 2012 paper, an increasing number of companies and research operations have been conjuring up exciting ways to apply CRISPR technology. Not only does it have huge application in biomedical fields, such as targeting the protein dystrophin responsible for many types of muscular dystrophy, but it also could transform agriculture, energy, and even mammoth rewilding.

As with any new technology, there are dangers and ethical questions surrounding the use of CRISPR, especially concerning the prospect of creating “designer babies”. In 2018, the issue stepped out of the theoretical realm when the Chinese scientist He Jiankui edited human embryos for the first time in history, in an attempt to make the babies resistant to the HIV virus. (He was sentenced to three years in prison.) Arguably, these are normal calibration issues that society must deal with when faced with a revolutionary technology.

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Jonny Thomson teaches philosophy in Oxford. He runs a popular Instagram account called Mini Philosophy (@philosophyminis). His first book is Mini Philosophy: A Small Book of Big Ideas.

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Science is a lot more boring than it is commonly portrayed. Movies often show montages of bespectacled scientists scribbling notes (probably on a chalkboard) before they finally punch the air in delighted revelation. Or maybe they show a huge team of researchers spending years on some scientific problem, and then the protagonist turns a blueprint upside down and says, “but could this be it?” Everyone is amazed.

The reality of science is far more prosaic. It is years upon years of hard graft, dead ends, worrying about funding, conferences, more dead ends, more hard graft, and a whole lot of collaboration. Science is less about eureka moments and lone geniuses and more about standing on the shoulders of giants. But occasionally, a development bucks the trend, giving at least some validation to the Hollywood tropes.  Source

spacer   Scientists are resurrecting the Whooly Mammoth starting in Siberia.

Beyond difficulty, some critics of de-extinction efforts have argued that projects like Colossal are a waste of resources — a pointless vanity project for millionaires and quixotic scientists. 

Depressing as it might be, without the pursuit of profit, power, and, sure, the vanity of it all, science would find it much harder to get the funding it needs to move forward. This is not just about mammoths; this is about conservation, gene editing, re-wilding, and the power of science itself. So, keep an eye on Colossal, and on this exciting new project. And probably avoid skiing in Siberia in the near future.   Source

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List of giant squid specimens and sightings  – Wikipedia

Procurement, preservation, and display

Preserved giant squid specimens are much sought after for both study and display.^[64] In the mid-1960s, marine biologist and giant squid expert Frederick Aldrich of the Memorial University of Newfoundland organised a “squid squad” with the intent of securing specimens for study. In the 1980s, Aldrich resorted to distributing eye-catching “Wanted” posters offering rewards for “finding and holding” specimens stranded on the Newfoundland coast, “the value being dependent on their condition”.^[65] Aldrich (1991:459) wrote that “[s]uch efforts were not futile, for in the intervening years I have secured either the specimens or information on 15 animals“, though according to Hoff (2003:85) the rewards went unclaimed.

Guerra et al. (2011:1990) estimated that around 30 giant squid were exhibited at museums and aquaria worldwide, while Guerra & Segonzac (2014:118–119) provided an updated list of 35 (21 in national museums and 14 in private institutions; see table below). The purpose-built Museo del Calamar Gigante in Luarca, Spain, had by far the largest collection on public display (4 females and 1 male^[66]), but many of the museum’s 14 or so total specimens were destroyed during a storm on 2 February 2014.^[67] At least 13 specimens were exhibited in Japan as of February 2017, of which 10 had been acquired since 2013.^[68]

A number of fragmentary giant squid remains were displayed as part of “In Search of Giant Squid“, a Smithsonian travelling exhibition curated by Clyde Roper that visited a dozen US museums and other educational institutions between September 2004 and August 2009.^[69] The exhibition opened its national tour at Yale University‘s Peabody Museum of Natural History, which has maintained a strong association with the giant squid from the time of the Newfoundland strandings in the 1870s. Preparations for the Peabody exhibition, overseen by site curator Eric Lazo-Wasem, uncovered giant squid material in the museum’s collections that was not previously known to be extant, including original specimens from Addison Emery Verrill‘s time.^[70]