Artificial Chromosomes: Care for a Pair?
⌘ How about a new pair of chromosomes to add to the 23 pairs you already own? They make a great vehicle to insert new genes to reprogram cells, to replace defective or damaged genes. Current forms of gene therapy use modified viruses to deliver a stripped down version of a gene into cells. But these minigenes are hard to control. They may insert randomly into the chromosome and disrupt some essential function (“insertional mutagenesis”), trigger undesired immune response to the viral carrier, or rarely, activate a cancer-causing gene. Artificial chromosomes offer an alternative system of gene delivery.
⌘ Of YACs, BACs and Life HACs: Yeast artificial chromosomes (YACs) were first introduced 30 years ago, followed by bacterial versions (BACs) which are used in research as a convenient way to clone and sequence DNA from other genomes. More recently, human artificial chromosomes (HACs) have been successfully introduced into mice to cure Duchenne muscular dystrophy (http://goo.gl/xuvSS).
⌘ How to Build a HAC: You probably know that DNA combines with proteins (called histones), like pearls on a string, which are then packaged and condensed into a chromosome. Chromosomes have short repeating fragments of DNA sequence, known as alpha satellites that can stretch for millions of base pairs, to form a centromere (the central knot of the X-shaped chromosome in the image below). The tips of the chromosome are capped with other protective repeating units called telomeres. Then there are the origins of replication, which are designated start sites for copying. An artificial chromosome has all these features too. It can be made by a top down approach: small fragments of telomere sequence (TTAGGG)n are introduced into a cell where they insert into chromosomes, triggering the loss of all sequences distal to the point of insertion. This eventually whittles down a chromosome until only a functional stump, about a tenth the size of a normal chromosome, remains. Alternatively, they can be assembled by a bottom up approach starting with de novo assembly of blocks of alpha satellite DNA. Entire genes, such as the large dystrophin gene defective in muscular dystrophy, can now be inserted, using special targeting sites (loxP).
⌘ Why are they better? Because the artificial chromosome has a centromere tethering it to the mitotic spindle during cell division, it can be partitioned into newly divided cells to survive stably in the long term. Second, there is no upper size limit to DNA cloned in a HAC: a gene with all its neighboring regulatory elements can be used so as to faithfully mimic the natural pattern of gene expression. In fact, groups of genes encoding complex pathways can be carried on a single HAC. Third, because of the lack of viral sequences, HAC vectors minimize harmful immune responses in the host and the risk of triggering cancers.
⌘ Scientist Gregory Stock thinks it may be another 20 years before we see artificial chromosomes put to use in humans. For now, artificial chromosomes are still difficult to introduce into cells, with efficiencies as low as 1 in 10,000. “Bioengineers tend to underestimate the complexity of human biology,” he says. “These developments often come at a slower pace than we imagine. But they’re inexorable.”
▶ Image and Pop Sci story on the future of HACs: http://goo.gl/FfE5c
▶ Reference Paper on HAC (open access and easy to read introduction): http://goo.gl/cmkla
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madame scientist's not-so-mad musings 
Just got more interesting. Thanks Rajini Rao
nice
I had no idea what HACs were, even though I know of YACs and BACs hehe. Great post!
How does the cell decide which gene gets expressed – the natural or the artificial
Good question, Samir Patil . The cell may express both: the defective (natural) gene that causes a genetic defect in the host, and the artificial one that corrects for it. It depends on the promoter or “on-switch” that is used to control the gene placed in the artificial chromosome. The goal would be to mimic artificial chromosome gene expression as closely to normal by restricting it to only those cells that would normally express it.
Buddhini Samarasinghe , I saw an article about it on G+ but the comments were all of the Jurassic Park “what could go wrong” scenario, so I did some digging of my own 😉
Enoch Jenkins , me too! Here’s to the hope that we may one day be able to correct inherited gene disorders.
Brandt Hambrick – Or some other catastrophe. I love technology, but this and “medical” nanobots scare the heck out of me.
The purpose of this post was precisely to combat uninformed, zombie apocalypse scenarios 😉 What exactly do you think will happen? If gene therapy were available right now, I’m guessing you would all sign up for it in a heartbeat. Or would you rather succumb to cancer, diabetes and all sorts of other genetic disorders?
Rajini Rao – If it gets into the wrong hands, it would wreak havoc; especially the “medical” nanobot technology. There’s a potential they could be airborne.
Thanks Rajini Rao I didn’t know about HACs. There’s a lot of promising gene therapy that worked in animals but not in the clinic. I wonder how much HACs would help and if some of the failed clinical trials would consider using HACs. Great post.
Nello Jennings here Rajini Rao explains all about the artificial chromosomes discussed in the article you shared the other day. I thought you would find this interesting.
Great post! In a more personal long note, gene therapy is no biggy. Nanobots are not real and are hundreds of years away (believe me I am trying to speed things up). The only thing that scares the hell out of me is uncivilized asocial and apathic behavior leading to the misuse or underuse of any technology – Monsanto style. But now I think I get it Brandt Hambrick : One misuse of gene therapy and telomer technology is trying to achieve “immortality” while being in a very uncivilized phase of our young history. In this context, a Zombie can be quite “real”: It would consist of an near-immortal apathic egomaniac (e.g. mixture of Jobs, Gates and Bush) which would hinder any real progress for the rest of humanity. I think it is time that natural philosophers start taking this threat very seriously. Should we call them Ultraconservative de facto Zombies? UFZs?
#ScienceSunday
David Lazarus , viruses can get airborne, as can certain small cells and microbes. Artificial chromosomes are very large, delicate pieces of DNA. They break and shear easily and once they do, they are exposed to degradation just as any random fragment released from billions of cells and microbes all around us. In fact, the challenge for this technology is to get them into cells. There is no plausible scenario on how they can become rogue and run away as nanobots.
The premise of “wrong hands” and evil scientists or governments belongs firmly in the realm of Hollywood movies 🙂 The protocols and paperwork to do any sort of animal/human research are quite daunting, as any life scientist knows, with a gauntlet of ethics certification and justification before proceeding with research.
THAT PICTURE IS SO AWESOME!!!!!! Rajini Rao
I love the picture too, Sally Larue . It inspired me to write up the post 🙂
Cool
Rajini Rao we had a group of high school students visit the facility on Friday. Someone happened to be imaging some mice at the time so I had to change my usual spiel to tell the students that there are an enormous amount of rules and regulations for animal research and that the mice are often treated better than most pets. I explained that the mice were being anesthetized just like people in the hospital.
A lot people are not aware of the regulations and paperwork that you and I have to deal with.
Why thank you. I have pictures of my own when u look for em ❤ But I love ur picture a lot. Rajini Rao
Chad Haney , I will confess that I’ve yet to take the human subjects protocol training online because it was soooo long and daunting. I simply needed to use some discarded patient tissue (with no identification). Need to add one more thing to my to do list 😛
I’m not doing human related work now so I won’t have to deal with HIPPA and IRB for a while.
Thank you Pam Adger I do.
nice
Perhaps with the help of a few round tables Gregory stock could be given a green light to start ape testing and in as few as 7-10 yrs given the okay for human trials.
Enoch Jenkins we do not yet understand the genetic basis of beauty or intelligence. We know that skin color is caused by multiple genes and the only research being done on it is on skin pigmentation disorders. Obviously, the purpose of this technology is primarily for medical therapeutics. Leave the wild speculation on eugenics for the Sci Fi community, it has no place here.
tecniq phreak Why don’t we start with human testing and in as few as 7-10 years get the okay for ape trials.
LL Pete , that’s a flippant remark straight from the gut. Offering your body to science, are you? 🙂
hi
Dan Addison
Joe Dunlavy , programming viruses is an alternative method to deliver genes to target cancer cells. The gene of interest is spliced into the viral genome, so that the modified virus can still bind and enter the host cell but can no longer cause disease. I had a post explaining the approach http://goo.gl/v4fwr . The viral genes can still trigger an immune response, and have a size limit to what they can carry. So artificial chromosomes offer a different approach to the same purpose.
What would be some good books (or textbooks) to study this subject? Im a mechanical engineer and im really interested in getting my Masters in neuro or bio engineering, this subject fascinates me to no end! Any suggestions?
Ryan Thackston , glad to hear of your interest! Actually, it’s difficult for me to recommend books written on biology for the non-scientist because…I don’t read them myself! (I read the primary literature in my area of research and get new information outside my immediate interest from going to seminars and conferences). Perhaps some of our readers will have some good suggestions – tagging Suhail Manzoor , Bill Collins . Or perhaps science educators like Shannan Muskopf and BiologyCorner have recommendations. I’m here if you have questions!
Well what are some good textbooks or even some of your favorite research papers (I can figure them out given some time) for scientists of biology? I really want to know all sides of the knowledge!!
Ryan Thackston , give Dennet’s Dawrin’s Dangerous idea a go. Though its fun to get one deeply immersed in the the nitty gritty of Biology, I love the 36 thousand view on the landscape, its positively insidious 🙂
I’m afraid I haven’t come across many books on genetic engineering that have been appropriate for non-scientists or high school biology students. This field is moving so fast, it’s hard for me to even keep up with all the new developments. I imagine it would be just as difficult for a writer to get a book published before the information had become obsolete or replaced with a better idea. I see this as a better idea than the virus-delivered genes for reasons Rajini Rao already said. This holds promise if we could figure out how to get the extra chromosomes into the target cells.
I do recommend for general biology books:
“The Immortal Life of Henrietta Lacks” by Rebecca Skloot and “Stiff” by Mary Roach
Here is a free review on human artificial chromosomes that I liked:
http://www.pnas.org/content/98/10/5374.full
Also check out the second reference in the post, which is more heavy reading but the introduction is clear.
The best resource is PubMed (http://www.ncbi.nlm.nih.gov/pubmed): type in your key words in the search box and look for free reads or reviews (set the article type in the left column).
Thanks for the reading suggestions, Suhail Manzoor and BiologyCorner 🙂
Thanks! Ill read some more on this
Mary Roach is an interesting author! Her “Unpacking for Mars” is really interesting too
Ryan, the is one book I would absolutely, unequivocally recommend : Song of the Dodo. Its the only biology book that managed to chock me up. The most beautiful of science literature you will ever find.
Suhail Manzoor thanks ill look into it!!
Thanks for posting this!!
I am totally flattered that I’m a reference source! So that said, there are some good suggestions here. I would heartily recommend Stephen Jay Gould, and for the culmination of his career there’s The Structure of Evolutionary Biology for a great grounding in all sorts of topics.
That’s a good one, why didn’t I think of Stephen Jay Gould. Thanks, Bill Collins !
Thanks Bill Collins!!! I got alot of reading to do lol
Hananya Naftali whats wrong with you? You have posted the extact same thing on every ‘whats hot’ post. And a bible thumper like you appreciating chromosomes and dna and evolution? Seriously, whats your game here? Clearly, you are a fake.
Google’s algorithms must have demoted me, Kiril Minanov 🙂 You can stop by any time.
I love the picture su very nice look
very nice pecture
Tegan Borg, glad you found this interesting! Let me know if you have questions.
I have just had time (as usual) to read through the post & links Rajini Rao and ordered G. Stocks book Redesigning Humans. I am wondering how he came to predict that “it may be another 20 years before we see artificial chromosomes put to use in humans”.
Oh, back of the line please for me 🙂 (unless of course I get sick)
Rajini Rao this picture I love it so I’m gonna put u as a mini star in my job hun. Would u love that?
Hi
Great post, please continue to post such informative info