Gene therapy for the win, CRISPr with RNA, and growing telomeres without gene hacking.

Jun 05, 2016

The past couple of weeks have brought with them some pretty interesting advances in the field of genetic engineering. So, let's get into it.

The first is, as far as anybody can tell, a working genetic therapy regimen for SCID, or severe combined immunodeficiency syndrome. SCID has long been colloquially referred to as "bubble boy syndrome" after David Vetter was born in 1971.ev with the condition and a movie was released about his life in 1976.ev, due to the fact that children born with the condition utterly lack a functional immune system; the slightest illness is likely to kill them in short order. Of the hundreds of immune disorders that humans can be born with, SCID is interesting in that there are no less than thirteen genetic mutations which can cause simultaneous B- and T-lymphocyte dysfunction. While there have been a number of treatments developed over the years which have met varying degrees of success none of them has been called anything like a cure, let alone a commercially viable one. Pharmaceutical megacorporation GalaxoSmithKline has unveiled Strimvelis, a practical implementation of a gene therapy technique developed at the San Raffaele Telethon Institute for Gene Therapy in Milan that, as far as anybody can tell completely cures SCID. It involves extracting bone marrow from the patient, separating the stem cells from the marrow, and applying a retrovirus that deletes the defective gene and replaces it with a corrected sequence of base pairs. The modified stem cells are then re-inserted into the patient where they pick up production of B- and T-lymphocytes that function normally. Eighteen children over the last fifteen years have undergone treatment with Strimvelis and every one of them no longer show signs of being afflicted with SCID, a helpful sign if I ever saw one but, as with many things, guardian optimism is the way to go. Advisors in the EU formally recommended that Strimvelis go on the market in April, and there are reportedly plans on the desktop for seeking US approval in 2017.ev. Suffice it to say that this is going to kick over a lot of anthills when it hits the market; for a very serious disease this completely breaks the "treat it continually" model of commercial medicine, especially for a rare disease which perhaps one hundred people are born with every year.

It remains anybody's guess how GSK is going to make their projected 14% return on investment on Strimvelis. I'm kind of afraid to see what the price tag is going to be.

I write from time to time about CRISPr, a surprisingly simple genetic engineering technology which makes use of readily recognizable patterns in DNA and an enzyme called the Cas9 nuclease (which you can buy for a surprisingly reasonable price!) to precisely edit DNA inside of living cells that are part of fairly complex lifeforms (no bacteria here, we're talking mammal-scale). Until very recently it was thought by the scientific community that CRISPr could only be used to modify DNA. Seeing as how I'm bringing it up in a post you've probably guessed that this may not be the case... A research team at the Max Planck Institute in Leipzig discovered that an associated protein called Cpf1 can also edit RNA. In CRISPr/Cas9 the nuclease figures out where in the DNA to make a cut based upon the pattern of an RNA molecule (crRNA (CRISPr RNA)) in conjunction with tracrRNA (trans-activating crRNA) for targeting. In the particular scenario just discovered the Cpf1 protein can process the precursor to crRNA and cleave DNA in the appropriate location on its own without needing tracrRNA to position it appropriately. This has a couple of advantages; first, systems that have relatively few "moving parts" tend to be more resilient to unexpected changes in their environments. To put it another way, there are fewer things that could go wrong, even if going wrong means "nothing happened, we wasted our time." Second, this might make it easier to edit multiple locations simultaneously due to a lesser probability of cross-reactions or timing problems. Third, this makes it easier to circumvent the natural anti-data corruption mechanisms of DNA that make it hard to make meaningful edits. It's possible that the CRISPr/Cpf1 technique might supplant the CRISPr/Cas9 technique, but so far it's too early to tell; hell, we're still figuring out what the /Cas9 method's good for...

Long of interest to the anti-senescence research community has been the role telomeres play in the aging process. I can't find any references in here for the other articles I've written (time to rewrite my search engine) so to be brief, telomeres are repeated DNA sequences that are on the ends of chromosomes that carry out a number of tasks that are related to preserving the integrity of DNA as a cell replicates. Each time a cell divides a few hundred base pairs get knocked off of the telomeres, and when there isn't any left the cell stops replicating and undergoes apoptosis. In living things there is an enzyme called telomerase which prevents telomeres from shortening too rapidly, effectively helping to stave off the medical condition we call the aging process. There have been a few genetic engineering research projects that sought to increase functional lifespan by altering DNA to code for longer telomeres or higher levels of cellular telomerase but a research team at CNIO (the Spanish National Cancer Research Institute) has figured out how to create mice with extremely long telomeres without having to hack their DNA. Rather than breaking out the retroviruses the CNIO team instead elected to leverage the phenomenon of epigenetics, or frobbing genes on and off by sending particular signals to cells at particular times or under particular circumstances. Basically they cranked up the gene that produces telomerase in their experimental mice a couple of notches, resulting in the mice having extremely long telomeres on their chromosomes. Net result: The mice lived significantly longer than they otherwise would have with less net genetic damage through their lives and aging much more slowly than normal though their telomeres shortened at a normal rate. Interestingly, the lab mice also showed less incidence of various forms of cancers. Their next research project: Engineering mice that have telomeres that are twice as long as normal mice to see what happens.