About a year ago, I participated in a clinical study at Cornell. There are tons of studies we always get emails about through the hospital/university broadcast system: a lot of them offer some monetary compensation to volunteers and some are just interesting or involve cool tests that otherwise would be very expensive or not even available. This particular study was about strokes connected with blood clots formed in the venous system and traveling through the heart into the brain. It involved a lot of blood tests and a heart ultrasound, which was really cool. I got to watch my heart on the monitor while they were looking for possible small holes between the different chambers of my heart. The good news is that my heart does not have any holes it shouldn't. The bad news is - well, worse, not necessarily bad - is that I have some genetic risk factors associated with blood clot formation.
Part of the study involved genetic testing for known mutations in genes participating in the blood clotting process and it turned out that I had 2 mutations associated with a high risk of venous blood clot formation. Actually, I would rather call these single nucleotide polymorphism or SNP as we call them in the lab. They are variations in the genetic code which affect a single base - the basic unit of the genetic code, denoted with the letter G, C, A or T - which can lead to changes in the amino acid sequence of the protein the gene codes for, in some cases can be more severe or even silent. Often, SNP's are associated with particular diseases. It's not always known why or how these things work. In my case, I have 2 heterozygous SNPs - meaning that I have a good and a bad copy at that particular position in the gene - in 2 different genes, both of which increase the risk of blood clot formation. Each are relatively common in the population, but having both is not as common and is associated with further increased risk.
When I first found out about this, being a scientist and a one particularly interested in medicine and the clinical applications of basic science, I started reading articles and looking into what this means. In the case of these SNPs, it's actually well understood what happens with the proteins. One of them is called Factor V Leiden, in which the base substitution changes the amino acid in the protein, which is the site of cleavage by another protein, called Protein C. So what this means is that my Factor V protein cannot be cleaved very well by Protein C and thus, is more stable, and since it's involved in forming blood clots, well there you go, more Factor V means more blood clots. The other mutation is in the prothrombin gene, at a position which is important for breaking down the RNA that is made from the DNA that encodes for this gene. RNA is normally a short-lived molecule, it's a transition state between DNA (which is what all genes are made of) and protein (which is the actual functional unit that does the work in the body). In my case, prothrombin RNA is more stable than it should be and so more protein is made from it, which leads to increased levels in the blood, again leading to increased blood clotting.
Like with everything in our bodies, there is a delicate balance between between factors that help form blood clots - therefore, preventing us to bleed out when we have a wound - and those that prevent formation of blood clots when we don't need them: i.e. when we are not as risk of bleeding out. If the balance is broken in either direction, we can get sick. Now, there are mutations, which actually cause a certain disease. For example, sickle cell anemia is caused by a single base substitution in the Hemoglobin beta gene, which changes only one amino acid in the protein sequence, but it causes hemoglobin molecules to stick to each other, causing rigid and misshaped red blood cells and inefficient transport of oxygen. Most of the time, however, a single base mutation doesn't directly cause any disease, it just increases the chance of certain diseases. In the case of blood clotting factors, it's difficult to know exactly what it means when a person has increased levels of some blood clotting factors in the blood. It will affect different people differently, depending on many other things. There could be other, unknown variations in the person's genetics or environment that might have a bigger impact. Numbers - risk factors - are based on the limited amount of studies which have been conducted. It's almost impossible to know what the net outcome in a particular person will be.
After doing some research on my mutations, I found out that one of the specialists - Hematologist - in the field is at Cornell. I made an appointment with her and went prepared with all this knowledge. I am not writing this to complain about this doctor; I am a lot more interested in how the basic science and genetics are connected with clinical decisions. But I have to mention that I had a very bad experience with this doctor. I had to wait forever and when she finally made it in to see me, she only had a few minutes, in which she proceeded to scribble down some numbers and warn me not to take any long flights. I told her that was going to be difficult as my family lived in Europe. To that, she gave me a "well, if you want to risk your life, go ahead" look. The numbers she scribbled down said 1 in 10,000 - the risk of deep vein thrombosis in the general population - and 35 in 10,000 - my risk. She also listed about 15 more things that have an impact on blood clotting, including but not limited to cholesterol, blood type, blood pressure and hormonal therapies or pregnancy in women.
So what's the significance of 35 versus 1? 35 in 10,000 is still very rare. Would it be better not to even know about these things? I think that now that we have the entire sequence of the human genome available, we think we know a lot, which is true in a sense. However, there is even more we don't know. We don't really know how to connect the dots yet. There is just too much information out there, too many genes involved in one process, too many factors to know what the significance of each is. I think that as we learn more about these disease associations and the computing power increases, information like this will one day possibly be very useful in designing individualized therapies and in predicting disease outcomes. But right now, we simply have too much scattered information and not enough knowledge or technical availability to put all of that together.
With that being said, I definitely think that it's good to know about these things. Well, maybe if it was a mutation that would definitely cause me to develop some deadly incurable disease in 10 years, I would not want to know. Or would I? Some might. I prefer the future staying a mystery. However, there are choices we can make based on even this limited amount of knowledge. In my case, I should never smoke - no that I should otherwise - should not take hormonal birth control - which I know stopped - should walk around more on long flights - get so uncomfortable sitting for long anyway and I am always jittery, constantly shifting positions - and if/when I get pregnant, I should take blood thinners. These are all easy things to do, they don't even require any life style changes.
I have to admit that I didn't take this very seriously at all at first. Psshh, what is 35 in 10,000? Why should I inconvenience myself? Then, this week, I heard that one of the young rising star Sloan Kettering Chemistry professors suddenly died. He woke up during the night, had trouble breathing, went to the hospital where he died a few hours later. 44 years old. Healthy. They think he had a pulmonary embolism caused by a recent surgery, possibly. Maybe he had some mutations similar to mine. Maybe he didn't. I guess it doesn't matter anymore. But could it have made a difference to have known, if that was the case? Absolutely. Surgery is a risk factor for developing blood clots. So he might have been put on blood thinners after the surgery and told to look out for pain in his legs (where deep vein thrombosis mainly occurs and from where blood clots often break off and travel to the lungs) and even when he had trouble breathing, he might have realized what was happening if he had all the information available. But right now, unless you are involved in a clinical research study quite randomly, or have a family history of blood clots, you might find the needed information. It's too expensive to do these genetic tests on every single person.
Maybe one day our knowledge in Biology, Biotechnology and computer science will reach a point at which it is no longer a challenge to run genetic screens testing for maybe all the known SNPs on every person when they are born, and armed with the information, more intelligent and informed life choices can be made. I hope that day is not far away and that all the hard work people are doing in the lab will one day be translated into every-day clinical use. But even then, we should still live every day to the fullest, because the knowledge we will gain will not change the fact that we can never know the future and can never know which might be our last day on this Earth.
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