Meta & Fysikken: Afsnit 86: CRISPR - DNA og gener
Vi dypper tæerne i et - for os - lidt fremmed emne: Vores gener og DNA strenge. Der sker ufattelig meget, og det sker ufattelig hurtigt i disse år.
Men med Karina’s vanlige søgen efter de to streger under facit, og Anders’ lavpraktiske forståelse for al viden, så får vi dannet os et lille overblik over hvad der foregår.
Her er Karina’s noter til dagens afsnit:
1: DNA: Basics -repetition
The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine, forming A-T and G-C base pairs.
Foldet ud er et menneskes DNA 2m
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2 :DNA and facial features
https://knowablemagazine.org/article/living-world/2023/genes-that-shape-facial-features
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3: Hvad var det lige CRISPR er?
https://videnskab.dk/krop-sundhed/10-aar-med-crispr-der-er-sket-en-kaempe-udvikling/
Clustered Regularly Interspaced Short Palindromic Repeats
CRISPR er en slags molekylær gensaks, der kan klippe i DNA hos både mennesker, dyr, planter, bakterier og virus.
Teknologien stammer faktisk fra bakteriers immunsystem. CRISPR er navnet på et område i bakteriers DNA, der består af korte, repeterende sekvenser. Mellem dem ligger et lille stykke DNA fra virus, der tidligere har angrebet bakterien eller dens forfædre.
Bakterien har altså lavet en to-do-liste over indtrængere. Når en virus går til angreb, kan bakterien lave en kopi fra sin huskeliste i form af et RNA-molekyle.
RNA’et slår sig sammen med et protein, der kan skære i genetisk materiale. Sammen leder de virussens genetiske materiale igennem for at finde noget, der matcher kopien. Når de finder det, skæres DNA’et i to.
Sådan kan virusser sættes ud af spil.
Princippet blev bevist i 2012, brugt for første gang i 2013 og de fik nobel prisen i 2020.
Når saksen skærer arvematerialet i to, forsøger cellen at reparere bruddet.
Når cellen reparerer klippet, kan det ske på to måder: Enten limer den enderne sammen. Så bliver det gen, der var der, normalt repareret, men der kan opstå fejl, der slår det ud.
Så introducerer reparationsmaskineriet af og til fejl i genet, så det ikke længere virker,« forklarer Eivind Valen, og fortsætter:
Eller cellen kan lave en mere avanceret reparationsproces, hvor forskerne snyder cellen til at bruge en skabelon, som de har tilføjet.
»Man laver en lang DNA-sekvens, som er identisk med det område, man har klippet i, men som indeholder visse ændringer, man gerne vil indføre,« siger Eivind Valen.
Cellen accepterer ofte denne sekvens og reparerer området baseret på den. Dermed er generne redigerede.
Et problem er, at det er den hurtige reparation, der sker oftest. Forskere har ikke desto mindre fundet metoder til at udløse den mere avancerede reparation oftere, så nye gener bliver sat ind.
CRISPR kan bruges til at redigere DNA fra dyr og planter. Men det er sværere at indsætte nye gener end at slå dem ud,
For eksempel kan de gøre jordbærplanter eller opdrættede laks mindre sårbare over for sygdomme.
CRISPR er blevet brugt til at forsøge at ændre risplanter til at producere større afgrødeudbytte, for at gøre appelsiner bedre beskyttet mod en sygdom og til at gøre hvede uden gluten.
Det originale CRISPR-værktøj hedder CRISPR/Cas9. Her er Cas9 det protein, der klipper. Det kommer fra en bestemt bakterie. I de senere år er der kommet flere versioner af saksen, som stammer fra andre bakterier.
Men Cas9 kan ikke helt klippe hvor som helst:
»Det kræver, at man har to G’er lige ved siden af det sted, du skal ramme. Det findes ikke altid i nærheden af det sted, man ønsker at ændre, og forskerne har derfor testet andre Cas’er, der har andre krav til DNA-baser
Kan andre ting end at klippe
Der er også lavet CRISPR-versioner, som ikke længere kan klippe.
-Søg og erstat
- Skifte et base par (bogstav)
-sætte sig og slukke elker tænde for et gen
-lime ekstra gener på
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4: GMO vs. CRISPR
https://videnskab.dk/kultur-samfund/professor-absurd-dom-saetter-crispr-i-baas-med-gmo/
EU lov: begge skal igennem dyre medicinske studier
Kun store selskaber har råd til det.
GMO- Genetisk Modificeret Organisme
Genetisk modificerede afgrøder er kulturplanter, der har fået indsat et eller flere gener i deres arvemateriale. De indsatte gener koder for et protein, der i sidste ende giver planten en egenskab eller fordel, for eksempel modstand mod en plantesygdom.
Gensplejsning tilfører egenskaber i planter – i modsætning til traditionelle forædlingsmetoder, hvor egenskaber typisk går tabt. Et eksempel på traditionelle forædlingsmetoder er krydsning af plantesorter, der bliver dyrket, og så bliver de mest egnede udvalgt og igen krydset.
Et andet eksempel er mutagenese, hvor planter bliver bestrålet eller udsat for muterende stoffer, og hvor målet er at mutere plantens arvemateriale for at få nye sorter.
I begge eksempler på traditionelle forædlingsmetoder mister planten typisk egenskaber, som vilde slægtninge har i naturen, men som afgrøden ikke har brug for på marken. Det er også grunden til, at vores afgrøder har meget lille genetisk variation. De er tabt undervejs i forædlingen.
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Også Nature Link:
https://www.nature.com/articles/d41586-023-03590-6
The first CRISPR medicine has been approved in the UK
The treatment, called Casgevy, edits the cells of people with sickle cell disease before infusing them back in.
Redigeret uden for kroppen
En grund til, at behandling for kræft og blodsygdomme testes først, er, at cellerne kan tages ud af kroppen, redigeres og derefter sættes ind igen.
For kræft bliver immunceller redigeret, så de kan blive bedre til at angribe kræftceller. Det er en meget spændende metode, som er blevet foretaget med varierende succes, fortællerEivind Valen.
CRISPR-behandling mod en genetisk blodsygdom kaldet seglcelleanæmi har været vellykket.
Her tages stamceller fra patienten og ændres, så de begynder at producere raske røde blodlegemer. Så sættes de ind igen. Resultaterne har været gode.
Når de redigeret celler sættes ind igen, så har man først sat kroppen igennem kemo for at slå de originelle celler ned. Dermed har de modificeret celler ikke konkurrence.
Når der klippes det forkerte sted
Det er mere sikkert at redigere cellerne uden for kroppen.
»Hvis noget går galt, kan man bare undlade at indsætte dem igen. Man kan tjekke, om cellerne er blevet redigeret forkert,« siger Eivind Valen.
Nogle gange klipper CRISPR det forkerte sted. Den klipper steder, der ligner det område, den skal klippe. Det kaldes ‘off-targets’.
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6: CRISPR curing HIV:
The news: Scientist are attempting a new trick: Using The gene-editing technology CRISPR to permanently cure people of HIV.
How they did it: A biotechnology company called Excision BioTherapeutics says it added the gene-editing tool to the bodies of three people living with HIV and commanded it to cut, and destroy, the virus wherever it is hiding.
What it means: The early-stage study is a probing step toward the company’s eventual goal of curing HIV infection with a single intravenous dose of a gene-editing drug. However, because the doctors withheld early data about the treatment’s effects, outside experts have been left guessing whether it worked.
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7: How gene editing could help curbhe spread of bird flu
The news: Gene editing could help prevent chickens from catching and spreading bird flu, new research suggests.
How they did it: Researchers used the gene-editing tool CRISPR to alter the DNA of 10 chickens to resist the bird flu virus and then exposed all of them to a low dose of it. Only one of the 10 chickens caught the virus, and that chicken did not pass it on to any others.
Why it matters: Bird flu has killed millions of both wild and farmed birds across the world in recent years. It’s increasingly affecting mammals as well, making the task of finding ways to curb it even more urgent.
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8: Forskning i mikro organismer (herunder bakterier)
https://en.wikipedia.org/wiki/Microorganism
har ledt til et forsøg hvor man har modificeret et bakterie til at bekæmpe kraft i mus:
https://www.technologyreview.com/2023/04/13/1071557/bacteria-engineered-fight-cancer
(man får kun en gratis artikel, derefter koster det. Derfor er det copy pastet her:)
Simply introducing a microbe to the skin of an animal can also trigger an immune response—albeit one that doesn’t cause all the usual signs of an infection, like pain, fever, or sickness. This is somewhat surprising, says Michael Fischbach at Stanford University, because these microbes don’t tend to be harmful: “They’re our friends.” Adding a microbe to the skin of a mouse, for example, can have an effect similar to giving the same mouse a vaccination, he says.
Modified microbes
Fischbach and his colleagues wondered if they might be able to hijack this effect to tweak the immune response.
The team started the investigation by choosing a microbe that is commonly found on human skin. S. epidermidis is thought to be a member of the human microbiome, and it doesn’t typically cause disease. The microbes the researchers used were originally collected from behind the ear of a human volunteer, says Fischbach.
The researchers modified these microbes by inserting a new gene into them. The gene codes for a protein that sits on the surface of some cancer cells. The idea is that if the immune system generates cells that recognize the microbe, these cells will also recognize tumors.
The team then applied these “designer bugs” to mice by wiping them over the heads of the animals with a cotton bud. Another group of mice had regular, unmodified samples of the bacteria smeared onto them. In both cases, the microbes quickly made a home for themselves on the mice’s skin, says Fischbach.
At the same time, the mice were injected with skin cancer cells. These cells were taken from other mice that had cancer, so they had the target protein on their surface.
Tumor target
Over the following days and weeks, these cancer cells grew into tumors in the mice that had been given the regular microbe. But the progression of the cancer was significantly slowed in mice that had been given the engineered microbe.
“You could see these huge tumors growing on the side of the mice that had been swabbed with normal S. epidermidis,” Fischbach recalls. But “you couldn’t see anything” in the mice that had been given modified microbes, he says. He points out that this particular type of cancer is notoriously aggressive and difficult to treat in mice.
“We were surprised by the magnitude of the response,” says Fischbach. “It’s surprisingly potent, given how mild a treatment it is.” The treatment also worked in mice that already had tumors. The tumors appeared to shrink in animals swabbed with the engineered microbes. The team’s findings were published in the journal Science.
Fischbach and his colleagues have a bit of work to do before they start trialing engineered microbes in people. First, they’ll need to find a good candidate microbe. They don’t yet know if S. epidermidis triggers the same immune response in people—it’s possible that another microbe might work better.
They’ll also have to choose a suitable cancer protein to target. This has proved a major challenge in the development of mRNA vaccines for cancer, which also rely on triggering an immune response to a cancer protein: there’s often no obvious candidate.
Once the researchers have worked out which microbe they’ll modify, and how, they’ll trial it in animals to check that it’s safe. Fischbach has plans to start trials of designer microbes in people with cancer within the next few years.
And while the team will focus on cancer, engineered bacteria could be used to treat other diseases, as well as allergies, Elaine Fuchs at the Rockefeller University in New York and her colleagues write in an accompanying commentary in Science. More research into the use of modified microbes “could pave a way to safer, more effective and widely applicable therapeutics,” the team writes.
“What’s exciting to us is the idea that you could just rub this behind somebody’s ear and walk away,” says Fischbach. “And then, 10 days later, you might see a potent immune response that, in principle, persists indefinitely."