I’ve said before that I don’t feel like I can reasonably invest in any biotech company since they all feel like a gamble, but for the gamblers out there I took a look at the science behind Vertex Pharmaceuticals (VRTX).

Vertex has a drug called CTX001 which has been in the news as it seeks FDA approval to treat sickle cell anemia and beta thalassemia.  Sickle cell anemia happens when the hemoglobin in your blood has a mutation that makes it fold into the wrong shape, this makes red blood cells become sickle shaped instead of their usual donut shape, and these sickle-shaped red blood cells get caught in the tiny capillaries of your body.  This causes damage and a lack of energy as blood isn’t able to efficiently transfer nutrients and waste into and out of your cells.  Sickle cell anemia reduces one’s life expectancy to around 40-60 years.  Beta thalassemia is another hemoglobin disease this time caused by reduced production of hemoglobin itself.  Less hemoglobin means less nutrients and waste can be transferred by the blood, meaning the body can’t work as efficiently.  Beta thalassemia in its major form has a life expectancy of around 20-30 years.  

Despite the fact that both diseases are caused by mutations in hemoglobin, the mutations are very different from each other and so it surprised me that both were being treated by a single CRISPR drug.  How CRISPR works is that a protein uses a piece of DNA to very specifically target itself towards an area on a gene of interest.  The protein can then cut into that gene of interest and if another piece of DNA is on the protein, then that other piece of DNA can be incorporated into the gene by the cell’s DNA repair machinery.  This process is somewhat random in nature, it’s hard to ensure that your other piece of DNA gets incorporated and even harder to ensure that it is incorporated in just the right orientation, just the right position, and just the right way so as not to cause problems down the line.  Since sickle cell and beta thalassemia are caused by mutations in very different places within the hemoglobin gene, a CRISPR drug that is targeted towards the sickle cell mutation site should not be able to also hit the beta thalassemia mutation site.

But the trick is that CTX001 isn’t targeting hemoglobin, it’s targeting fetal hemoglobin.  When a baby is in the womb, it needs to take oxygen from its mother’s blood stream to survive.  If a baby’s hemoglobin were the same as its mother’s, this process would be inefficient because both the baby’s and mother’s hemoglobin would bind to the oxygen equally well and there would not be enough oxygen flowing from the mother’s blood into the baby’s.  It would be like a tug of war where both sides are of equal strength.  However, fetal hemoglobin binds to oxygen more strongly than adult hemoglobin, and this ensures that a baby can take the oxygen it needs from its mother’s blood stream.  Fetal hemoglobin usually stops being produced around the time the baby is born, and after the body switches over to purely adult hemoglobin by around 6-months after birth.  What CTX001 does is it tries to switch on the production of fetal hemoglobin in people suffering from sickle cell anemia and beta thalassemia.  If they can produce fetal hemoglobin instead then it can compensate for the fact that their normal hemoglobin isn’t working properly, and should reduce their symptoms and prolong their lives.

How CTX001 does this is by altering the promotion of the fetal hemoglobin gene.  The promoter regions of genes are the segments of a gene that help the gene get transcribed into new mRNA.  That mRNA will then get translated into a new protein.  The promoter of fetal hemoglobin does not usually allow the gene to get transcribed into adulthood, so no fetal hemoglobin gets made.  But altering the promotion of the gene would allow it to be transcribed, and thus translated, and so fetal hemoglobin would be produced in the body.  Now here’s where it gets a bit tricky: they aren’t actually altering the promoter region of fetal hemoglobin, but rather the promoter region of another gene called BCL11A.  I wanted to explain how promoters work, but there’s more to explain now because biology is complicated so bear with me:

The reason the promoter region of fetal hemoglobin doesn’t normally allow transcription (and thus production of the gene) is because of a repressor called BCL11A.  BCL11A is a protein that sits on the promoter of fetal hemoglobin and refuses to budge, this prevents any other protein from accessing the fetal hemoglobin gene and thus prevents fetal hemoglobin from being transcribed.  Now BCL11A is produced by its own gene, and CTX001 alters the promoter region of BCL11A in such a way that no BCL11A can be produced.  Without BCL11A, there is nothing to repress the promotion of fetal hemoglobin.  Without the repression of fetal hemoglobin, its promoter region is accessible and it can be transcribed.  With the transcription of fetal hemoglobin, the fetal hemoglobin protein will be produced in the body.  And with the production of fetal hemoglobin, the diseases caused by malformed adult hemoglobin (sickle cell anemia and beta thalassemia) should be reduced.

But it’s still not over!  How the hell would CTX001 find every red blood cell in the body and do its thing?  It doesn’t have to!  Hematopoietic stem cells are the stem cells which produce red blood cells (and it’s red blood cells which will carry the hemoglobin or fetal hemoglobin in the blood).  Hematopoietic stem cells can be extracted from the patient’s blood and then altered with CTX001 so that they will produce fetal hemoglobin.  The cells which are successfully altered can then be transferred back into the patient.  Before the altered cells are given back to the patient, the patient is given busulfan to kill off stem cells.  This is necessary to kill off some of the stem cells which are producing the malformed hemoglobin so that the new stem cells producing fetal hemoglobin can reproduce and become the majority.  The patient is then monitored for improvements in their sickle cell anemia or beta thalassemia condition.

So this process is long, involved and complicated.  Just to list all the things that could go wrong: when altering the promoter the DNA could accidentally be mutated towards being cancerous, killing of so many stem cells using busulfan could have harsh side effects, the infused hematopoietic stem cells might not reproduce and become the majority, and even then the DNA of the promoter might not be altered enough so that fetal hemoglobin becomes the majority of the hemoglobin in the body.  But I’m sure every step is heavily monitored by Vertex during the treatment process.  So is Vertex Pharmaceuticals a buy?  I have no idea, if you believe the Efficient Market Hypothesis then all their upside is already priced in, but they’re in phase 3 of clinical trials and if you’re a gambling man I see nothing wrong with their scientific thesis.  So idk, go ahead?