Sweeping advances in precision technologies.

21 February 2014

When we think of 3D printing, we usually think of stuff on the macroscale, like automobile engines or replacement parts of some kind. Unless it's in another context, however, we rarely stop to consider the applications of this technology on a finer scale. A couple of weeks back a research team at the Karlsruhe Institute of Technology in Germany announced a breakthrough: The Nanoscribe, a 3D printer which uses laser light to selectively harden liquid plastic in a successive deposition process. The Nanoscribe can fabricate objects the width of a human hair with amazing precision and a fair amount of detail. The Nanoscribe seems especially good at building structures which are built out of self-supporting meshworks, similar in structure to bone or wood. After fabrication the microscale structures are coated with aluminum oxide, which makes them lighter than water but also gives them a tensile strength rivaling some formulations of steel. I don't know what applications you're thinking of, but I'm wondering if perhaps the prosthetics used to treat otosclerosis could be fabricated this way. Or possibly dental prosthetics, which I don't know anything about...

At a conference a couple of weeks ago one of the speakers twigged me to a technique in genetic manipulation that I hadn't heard of previously called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). That afternoon I tasked some of my net.spiders with watching out for references to the technique and compiling links. What they eventuallly returned was fascinating: Existing techniques for genetic manipulation are tricky at best, fraught with peril and misfires. Only recently were CRISPRs, or short sequences of DNA that read the same backwards and forwards interspersed between genes found to be anything other than an unusual feature of the human genome. Rather than using completely custom proteins which are difficult to engineer at the best of times, or proteins which don't pass through cell membranes into the nucleus particularly well, the CRISPR technique (which is distinct from the genetic structure with the same name) utilizes a deoxyribonuclease (a protein which cuts DNA strands) called Cas9 with a bit of RNA attached to it. The idea is that the RNA acts as both a targeting and a grappling mechanism for the DNAse. By exploiting the RNA/DNA transcription relationship, the DNAse can be brought to bear in a much more precise manner. Additionally, RNA synthesis in the lab is well enough understood that it is considered a routine laboratory practice so targeting mechanisms are relatively easy to fabricate. Individual genes can snipped out of a strand of DNA in vivo. In fact, if necessary individual base pairs can be isolated using this technique. To give you an idea of how important this technique is, let's put it into perspective. To create a strain of lab mouse which has a single mutation in its genome, let's say diabetes, can take upwards of a year of work both trying to modify the genomes of mice with various techniques and breeding them over and over to make sure that the trait takes and expresses itself. To create a strain of lab mouse which has multiple mutations in its genome can take literally years of work because the alterations have to be made one at a time, validated, and care must be taken so that further genetic manipulation does not undo the previous edits. Feng Zhang, a researcher at MIT, was able to accomplish the latter using the CRISPR technique in about three weeks.

Think about that for a minute. A brand new subspecies of mouse inside of a month. A couple of weeks after that a cohort of macaques were engineered using the CRISPR technique to turn off the genes Ppar-γ and Rag1 simultaneously, which code for fatty acid storage and the activation of immunoglobulin V-D-J respectively. Sounds trivial, but two at once in a mammalian genome is a record. The team at MIT was able to compile a dictionary of CRISPR sequences (called knockouts) in the human genome, which account for nearly every gene we know about in a fairly short time and made the entire library available to others doing research in genetic manipulation. A cursory search located only one knockout library (and a pay-for-play one at that) but this seems like an interesting place to poke around. As for the obligatory human trials, so far the technique has been used in vitro to correct the mutations which cause cystic fibrosis and sickle cell anemia in cultured human cells as well as re-engineering them to be resistant to HIV infection. For an encore they used the same technique to destroy HIV already hidden within human cell cultures by corrupting the virus' DNA.

In other biotech news a new treatment for adult B acute Lymphoblastic leukemia has been published. It seems to be one of the more aggressive forms of adult leukemia and is rapidly lethal unless caught in the early stages. The technique is an immunotherapeutic one which involves genetically modifying the patients' own T-cells to recognize the protein CD19 (which only the rogue lymphoblasts express) as pathogenic and allowing them to attack. T-cells read and parse patterns of antigens on the surfaces of cells to determine if they pose a threat or not, so this represents a significant step forward because it's damned difficult to get an immune response against some part of the body unless you really, really don't want one... in clinical trials 14 of the 16 patients went into remission, the longest for two years. The procedure is still in development but the rate of remission is fairly consistent across every set of clinical trials, which means that it's a promising technique, potentially in conjunction with another method backing it up.