Digging into how Single Molecule, Real Time (SMRT) technology.
1/ The SMRT technology takes advantage of DNA synthesis. To understand it, we must do a brief review of DNA synthesis. When DNA gets copied, a single strand of DNA gets copied by the DNA polymerase enzyme.
2/ The nucleotides are picked up by the DNA polymerase and incorporated into the new strand of DNA that is being built that is an exact opposite copy of the template strand.
3/ The $PACB Sequencer uses nucleotides that are each marked with a different dye color on their phosphate group. Each different base of A, G, T and C are marked with a different color dye.
4/ As the tagged nucleotide is incorporated into the new stand of DNA, that dye is cleaved off of the phosphate group. The Sequencer uses light wave lengths to read those lights emitted from when the dye is released from the phosphate.
5/ This allows for the real time sequencing of a single piece of DNA. Using this process, they can sequence up to 15,000 bases of DNA with over 99.9% accuracy. This system can read DNA, RNA and even epigenetic patterns of the DNA.
6/ This is what is classified as long read sequencing as the older short reads could only sequence up to 1,000 bases. The Sequel II can run 8 million DNA samples simultaneously at a time.
7/ There are a lot of consumables that go into this process which makes the consumable about half of the sales for $PACB. They generate sales of the machines, but they also generate reoccurring revenues from the consumables.
8/ This process differs from that used by Oxford Nanopore. They use a signal frequency that changes as each base of the DNA passes through the nanopore. The signal will have a different frequency change based on which nucleotide passes though the nanopore.
9/ There are advantages and disadvantages of each technology. $PACB tends to be more expensive and does shorter reads then Oxford Nanopore. The time and accuracy tends to be better for $PACB.
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This company is all about what we do with that genetic data after we got it.
1/ The sequencing companies make the machines to actually sequence the DNA or RNA. $NVTA is about taking that genetic data and translating it into something that can be used my medical professionals to treat patients.
2/ This is about using automation, software and a database to use the genetic data acquired by the sequencing. I call this the Genomics Application company.
They are building the best long and short read company in sequencing.
1/ They already have the long read sequencing with the SMRT technology. They have an install base of 326 instillations as of Q3. That has a lot of potential to grow. Half their revenues comes from the selling of the consumables that goes into running those devices.
2/ As the Base grows, this becomes like the Apple model with and ecosystem. They buy the device and then you earn revenue off the use of that device.
Taking a look at the use of CRISPR CAS9 use in ex-vivo cell therapies.
1/ $CRSP is using the same CRISPR/CAS9 system as $NTLA. This is made up of the CAS9 enzyme which has 2 nuclease domains that do the cutting of the DNA into a Double Stranded Break. It also includes a guide RNA for searching the DNA for the correct site.
2/ The biggest danger of the CAS9 enzyme is that cuts both strands of the DNA at the same location. Without the use of a template strand, this will trigger Non Homologous End Joining which is a very inaccurate process.
Taking a look the science behind CRISPR CAS9 and in-vivo liver editing.
1/ $NTLA is using the CRISPR/CAS9 system. This is made up of the CAS9 enzyme which has 2 nuclease domains that do the cutting of the DNA into a Double Stranded Break. It also includes a guide RNA for searching the DNA for the correct site.
2/ The biggest danger of the CAS9 enzyme is that cuts both strands of the DNA at the same location. Without the use of a template strand, this will trigger Non Homologous End Joining which is a very inaccurate process.
Taking a look at the preclinical data for their programs so far.
1/ They have two main programs around correcting Sickle Cell disease. Their first program BEAM-101 is doing a simple gene knockout on the gene that suppresses Fetal Hemoglobin expression causing the reactivation of the Fetal Hb gene.
2/ Their second program uses base editing to change the defective base in the Sickling Hemoglobin to a Makassar that works normally.
This will be a look at the underlying technology of base editing. I plan another guide for the science and maybe another for the corporate.
1/ They are using base editing technology. This takes the CRISPR CAS9 enzyme along with the guide RNA attached to a deaminase enzyme to make a modification to a single base of the DNA.
2/ The guide RNA looks for a photospacer sequence in the DNA. That is just a matching sequence of DNA that matches the guide RNA. Next to the photospacer sequence will the the Photospacer adjacent motif (PAM).