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Precision Gene Editing
mpthompson writes "NewScientist.com is reporting that scientists at Sangamo Biosciences have developed a method of editing DNA mutations with unprecedented precision without weaving in potentially harmful foreign genetic material. Different combinations of amino acids are designed to latch on and cut the DNA at exactly the place where the mutated gene lies. This triggers the body's natural repair process which corrects the gene where the DNA was cut. The technique will be used to target diseases caused by single-gene mutations such as combined immune deficiency (X-SCID) - or bubble boy disease - and sickle cell anaemia."
The article only mentions cutting the DNA and then "allowing the body's natural repair processes" to do the rest - it seems that this technique could also be useful in inserting genes at precise locations in DNA instead of letting viruses and bacteria insert genetic material wherever they please? I am no genetic engineer, can anyone comment?
So this treatment actually alters the genetic code of a human? So any genetic disease would not get passed down to future generations? How is something like this administered? Our DNA is found in every cell of our body.
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Fairfax Underground: Fairfax County message board and public records
If sick people can get cured by something like this, we can't afford not to exploit it.
Let's just not forget that there is not such thing as evil knowledge. The way we use it makes good or evil.
Errr...only if you affect the germ cells (sperm&eggs). Otherwise no altered trait can be passed along.
they say diarrhea is hereditary, it runs in the jeans...
A feeling of having made the same mistake before: Deja Foobar
While I see where you are coming from, this process is no different than surgery on a fundamental level. Similar to removing a tumour or cist, it is a proceedure that if done properly can vastly improve the quality of life for the patient. According to the article after the 'cut' is made the body repairs the strand itself, so no insertion of new genes are required.
"and it is among the benefits of science that it equips the future for its duties."
-- Alfred North Whitehead, 1927
I know people who are geneticists, and who work in a lab where they are able to essentially make a mouse to order. You want one that grooms obsessively, here you go! Want one that glows in the dark? You got it. Just because they do it through genetic manipulation rather than breeding doesn't make it any more evil than other means.
What it does do is accelerate our ability to learn about life. Should we take things in measured steps? Absolutely! We should also have been more careful about asbestos, lead based paint, DDT, agent orange and more. But should we ignore these amazing advances? Absolutely not!
The CB App. What's your 20?
Before the first atom bomb was detonated, there were some scientists that thought that the nuclear reaction would spread and ignite the entire atmosphere. Despite their reservations, the tests were done anyway. Screwing up has never been a risk people considered worthy enough to stop a scientific experiment.
Rhymes that keep their secrets will unfold behind the clouds.There upon the rainbow is the answer to a neverending story
>
> Just wondering.
Funny you should ask. I just got this video from Paul Simon.
It's a turn-around jump shot
It's everybody jump start
It's every moderator throws a hero up the crackpipe
Singin' filk is magical and magical is pain, think of the boy in the plastic bubble
I'm a Slashbot with a baboon brain
(And I believe)
These are the days of lasers on a shark's head,
Lasers on a shark's head somewhere,
Staccato signals of constant information,
A loose affilliation of megabytes
And gigabytes and baby...
These are the days of miracle and wonder,
This is a long-distance boast,
The way the duplicate posts appear in slo-mo,
The way we go for first post.
The way we look to a Netcraft BSD troll,
That's dying like a server at NewSci,
These are the days of miracle and wonder
And don't cry baby, don't cry...
I have a feeling that this has to do with homologous recombination, where damage to a certain gene causes the chromosomes to auto-repair themselves by copying the target gene from the "good" chromosome. At least that's my take on why they would mention damaging the DNA to repair it.
I am defenseless. Use your button. Mod me down with all of your hatred.
Great, now the gene splicers have the equivalent of a hex editor, but still have no clue what they are editing. It's like hacking binary code out of one program and inserting into another program and somehow getting it to work.
Until we have a better handle on Gene Expression and how to actually interpret the genetic code we should proceed cautiously.
To quote Dr. J. Craig Venter, Time's Scientist of the year (2000).
"We know far less than one per cent of what will be known about biology, human physiology, and medicine.
My view of biology is 'We dont know shit.' "
If any am being overcautious or am ill-informed please feel free to correct me. I try to live by the motto, "Just because we can do something, doesn't mean we should." This applies to System Administration as much as it does to gene-hacking.
"short term good"? This has the potential to eradicate several crippling diseases and increase the quality of life of an innumerable number of people. You're going to have to give a better reason against gene therapy than "you're acting as god." You're personal religious opinions are not welcome in a diverse global arena, which is (or ought to be) tailored toward the pursuit of the greater good. You only serve to alienate those of us who may not subscribe to the notion that scientific progress runs counter to moral norms (a concept whose ontological coherence is debatable).
On a related note, this kind of attitude is precisely why scientific progress often stagnates. Irrational fear hinders societal good. Messing up a few times, as cold and calculating as this might sound, may be necessary in order to develop effective medicines and therapies and pinpoint options that do not work. The individuals who sign up for clinical trials are aware of the risks, and those who do should be applauded for their selfless contribution to the good of humanity.
Regardless of your personal beliefs, gene therapy is one of the most promising developments in medicine. It has the potential to revolutionize our perceptions of the human body.
Forgive me for not believing in your esoteric views of this "God" character nobody has any proof of, but I feel genetic manipulation is going to be one of the few things that allow us (the human race) to continue existing.
As time goes on, we defeat simple diseases such as the bubonic plague, then upgrade to tougher ones like smallpox. We're now at the point where the only communicable diseases that are seriously fatal are biologically engineered bacteria, and viruses. On top of that, we've still got Cancer to worry about, which is kicking our asses.
While it may be cheaper to produce drugs for everyone alive and distribute them to everyone, no company in their right minds would do this. But if we could figure out genetically how to teach our immune systems to deal with cancer, and certain foreign invaders, we could save millions simply by changing our children's genes.
I think the biggest paranoia attributed to genetic engineering is the fear of change; just because we know how something works now, and we assume that it'll continue working the same way into the future, we give up the notion that we can change things for the better or for the worse. Yes, we are foulable creatures, but at the same time, we now know how to clean up our mistakes. It's far past time we take our fates into our own hands. Why use medicines that can screw up other things in our bodies when we can simply prevent the problem from occuring naturally?
"Victory means exit strategy, and it's important for the President to explain to us what the exit strategy is." G.W.Bush
I think there is a natural equilibrium between nature and gene mutations. When the hand of man starts changing one side of the equation, can the consequences on the otherside be foreseen? For example, who is to say that some form of cancer today won't mutate to something 1,000 years from now that will save humanity from some enviormental change?
Rosco: "If brains were gunpowder, Enos couldn't blow his nose."
like the 'bubble boy' defect mentioned in the article, we often know the specific bit of code that causes the problem.
n odeficiency
"IL-7 signalling pathway
Most cases of SCID are derived from mutations in the c chain in the receptors for interleukins IL-2, IL-4, IL-7, IL-9 and IL-15. These interleukins and their receptors form part of the IL-7 signalling pathway.
The IL-2 receptor (IL-2R) gene is located on the X chromosome and mutation of this gene causes X-linked SCID.
Janus kinase-3 (JAK3) is an enzyme that mediates transduction of the c signal. Mutation of its gene also causes SCID."
http://en.wikipedia.org/wiki/Severe_combined_immu
TFA noted that the zinc fingers cue in on two sets of 6 base pairs to find the site that needs correction. Assuming randomness in the base-pair sequences, this 12 base-pair key will bind with approximately 1 out of every 16.8 million (actually 1 out of every 8.4 million due to complementarity of the base pairs). Given that the human genome has about 3.2 billion base pairs, this means that the modifier will match in 381 positions more or less.
Thus, this method will fix the error in one place and introduce an error in 380 other locations. The key needs more than 16 base pairs to be statistically assured of homing in on a unique mutation (depending on the statistics of DNA, it may need more or less).
Two wrongs don't make a right, but three lefts do.
I have not read the article, but repair processes can be "error prone". That is, the mechanisms cells use to repair DNA often involve high error rates.
/.ers may not appreciate is that typically, it is VERY, repeat VERY hard to get chemcial reaction specificity of anywhere close to 1e9 for reactions invovling DNA.
The human genome is 3e9 BP long (roughly..not counting indels, the unsequenced centromeres, etc etc)
So the chemical process of identifying the one single mutated basepair has to have a chemical specificity of >>1e9, because there are >>1e6 cells that are exsposed. That is, lets say you feed the reagent to a person. Millions of cells, each with 1e9 bp, are expsosed. Say the process has an error rate of 1e10 - many, many cells will have incorrect repairs done
This is just like error rates in, say, reading data from a harddrive: the larger the file, the lower the error rte has to be
What
I will rtfa,
Pharmacorp executive: "Let's see now, we can sell them a one-time treatment that cures them for the rest of their lives, OR we can charge them $1000/month for drugs to maintain their current status for the rest of their lives... well, obviously we'll choose the method that is best for the patient's well being, our profits be damned! I mean, it's not like we have a board of directors that will sack us if our revenues don't increase every quarter!"
I've abandoned my search for truth; now I'm just looking for some useful delusions.
Also, the large percentage of blood consisting of the red blood cells and platelets don't actually have any DNA in them to be mutated - these cells don't have nuclei.
Finally, in bone marrow transplants, one method of collecting the marrow cells to transplant is to hook the donor up to a machine through which their blood flows. In the machine, the stem cells (the cells that divide to produce all the elements of blood, including red blood cells and immune cells) are separated out, and these are the cells that are then transferred as the marrow transplant. You can find out more about this process here. The objective with this treatment is to cure the cancer - so if simply removing the cells from the body causes cancer, it would be a very counter-productive treatment.
But it does give us the ability to create the equivalent of patch files for bad/defective genes when a good/functional version of the gene is available.
There are many genetic diseases where the mistake in the DNA is well characterized, and it is very clear exactly what difference between the normal version of the gene and the defective version causes the disease, even if we don't have a full understanding of what the hell gene does; we just know to a high degree of certainty that a particular error causes a particular phenotype.
This new technology, if it lives up to the hype it's given here, could mean we can fix these kinds of diseases.
In fact that's exactly what the article says: "This triggers the body's natural repair process, called homologous recombination, which corrects the gene where the DNA was cut, The researchers provided the cells with a copy of the correct gene as a template."
If they were to concentrate this work on Myotonic Muscular Dystrophy, they could likely achieve a success very quickly. It is caused by an unstable CTG sequence of DNA that expands in length when replicated. The progression of the disease is characterized by the number of expansions. Since it is an unstable sequence and of little use, simply cutting it out of all DNA should "cure" the disease. I put the "cure" in quotes because reversing the damage is likely not possible, but it could at least eliminate it from future generations and stop the progression.
Highly efficient endogenous human gene correction using designed zinc-finger nucleases
FYODOR D. URNOV1, JEFFREY C. MILLER1, YA-LI LEE1, CHRISTIAN M. BEAUSEJOUR1, JEREMY M. ROCK1, SHELDON AUGUSTUS1, ANDREW C. JAMIESON1, MATTHEW H. PORTEUS2, PHILIP D. GREGORY1 & MICHAEL C. HOLMES1
1 Sangamo BioSciences, Inc. Pt. Richmond Tech Center 501, Canal Blvd, Suite A100 Richmond, California 94804, USA
2 Department of Pediatrics and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, USA
Correspondence should be addressed to M.C.H. (mholmes@sangamo.com) or M.H.P. (matthew.porteus@UTSouthwestern.edu); requests for materials should be addressed to M.C.H.
Permanent modification of the human genome in vivo is impractical owing to the low frequency of homologous recombination in human cells, a fact that hampers biomedical research and progress towards safe and effective gene therapy. Here we report a general solution using two fundamental biological processes: DNA recognition by C2H2 zinc-finger proteins and homology-directed repair of DNA double-strand breaks. Zinc-finger proteins engineered to recognize a unique chromosomal site can be fused to a nuclease domain, and a double-strand break induced by the resulting zinc-finger nuclease can create specific sequence alterations by stimulating homologous recombination between the chromosome and an extrachromosomal DNA donor. We show that zinc-finger nucleases designed against an X-linked severe combined immune deficiency (SCID) mutation in the IL2Rbold italic gamma gene yielded more than 18% gene-modified human cells without selection. Remarkably, about 7% of the cells acquired the desired genetic modification on both X chromosomes, with cell genotype accurately reflected at the messenger RNA and protein levels. We observe comparably high frequencies in human T cells, raising the possibility of strategies based on zinc-finger nucleases for the treatment of disease.
Most human monogenic disorders remain difficult to treat because therapeutic transgenes do not undergo homologous recombination (HR) into the mutated locus1, 2, and gene addition by virus-driven random integration remains a challenge owing to transgene silencing, improper activity or misintegration3, 4. Furthermore, targeted alteration of DNA sequence in vivo--in principle, a powerful basic research technique for studying genome function--in mammals requires sophisticated targeting vectors and drug-based selection1, 2, which limits the use of this approach5-7.
The C2H2 zinc-finger, originally discovered in Xenopus8, is the most common DNA binding motif in all metazoa9. Each finger recognizes 3-4 base pairs of DNA via a single alpha-helix10, 11, and several fingers can be linked in tandem to recognize a broad spectrum of DNA sequences with high specificity12-14. Engineered zinc-finger protein (ZFP)-based DNA binding domains with novel specificities have been extensively applied in vivo to target various effector domains12, 15. Work from the Chandrasegaran laboratory has shown that a ZFP can be coupled to the nonspecific DNA cleavage domain of the Type IIS restriction enzyme, FokI, to produce a zinc-finger nuclease (ZFN)16, which then cuts the DNA sequence determined by the ZFP16, 17. An important specificity mechanism derives from the requirement that two ZFNs bind the same locus, in a precise orientation and spacing relative to each other, to create a double-strand break (DSB; Fig. 1a)17. One mechanism by which eukaryotic cells heal DSBs is homology-directed repair (Fig. 1b)18-20, which transfers information missing at the break from a homologous DNA molecule (Fig. 1b). Work from the Jasin laboratory21, followed by that of others22, 23, demonstrated that the endonuclease I-SceI can potentiate HR into loci previously engineered to contain its own recognition site, and the Carroll24, 25 and Baltimore26 laboratories have shown that a ZFN-invoked DSB increases the rate of HR in model systems.
Figure