The mysteries of DNA

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.

Moving forward

Good news: first official draft of my thesis is done, printed and ready to be turned in. Only one printer in lab has run out of toner. In fact, I gave it to 2 out of the 5 people I need to give it to already today! 2 and a half weeks to defense date! But now, after a half a bottle of wine, I am not really bothered by that. Maybe tomorrow.

Half assed

Today was the annual NYC Half Marathon - one of many half marathons in the city, but the only one for which they close a significant portion of midtown and the West side and the only one that runs through the heart of the city: Central Park, Times Sq, and down to Battery Park all the way on the West Side Highway, passing Ground Zero among other things. The only way for us mortals - i.e. not professionals or people who qualify for races with having super fast half marathon or marathon times - to get into this race is through a lottery. All the races in the city are capped since the roads just can't take that many people. For the marathon, they start the race in 3 waves 30 minutes apart, and even so, the 45,000 or so runners blend into one never ending river running down the streets. In any case, a lot more people want to run these races than there is room for in the city. This is particularly a problem this year; running has become newly trendy.

I can definitely understand the phenomenon. It hasn't even been 5 years since I started running - it's going to be 5 years in June at the NYRR Mini Women's 10K, which was the first running race I ever participated in - so I am pretty sure I am still a beginner and I am one of the people who just newly discovered the wonders of running. However, for me it was love at first sight. Or first run, I guess. I ran that first race - bib number 6709, which I still have taped to my desk, as a reminder - without any expectations or plans. And then I just got hooked. Signed up for more races, started training more like a real runner, with some real goals, distance or time-wise. Soon, I was looking for a half marathon to sign up for - Brooklyn Half - and then the only logical next step was a marathon. After my first, I just got more hooked, I immediately wanted to prove that I could do it again and I could do it better and faster. I know that there are many others like me out there, hooked for life after their first race. In the past few years, these races have been getting a lot more attention around the city, particularly with the NYC Marathon being so popular. It seems that almost every other person I talk to these days says that it's one their goals in life to run a marathon. Which is great, don't get me wrong, it's really great, in fact, it's so wonderful that more and more people are discovering how great running is. But come on, there is no way that every other person is going to run a marathon one day.

So here is why I am upset: I know at least 2 people personally, who have made it into the NYC Half by playing the lottery, and then never bothered to train for the race, and then didn't even bother to run it! I am not even talking about the ridiculousness of the system, how people from out of town had something like 8-fold higher chance of being selected from the lottery, and people from outside the US were nearly guaranteed entry. That's not their fault, it's because NYC desperately wants tourists - like we don't have enough already - and NYRR desperately wants the higher entry fee from foreign entrants. It just baffles me how many people do things half-assed. It's not just about running races, in general, what's the point of giving just minimum effort when others would love to have the chance to try their hardest? I suppose life is just unfair like that. And in many other ways, but that's for another time.

Standing there in Central Park on Sunday morning in the freezing cold, cheering for some of my half-assed friends - who at least made a very good effort to run and finish the race - there was nothing I wanted more than to be in the crowd of runners. Oh well, not this time, but I'll be there in 2 weeks and even though we won't run through Times Sq and there will be no roads closed for that race, Central Park will be filled with thousands of women proud to be running and I'll be there among them!

Lessons to learn

... or not.

Just another Monday in lab:

At lunch-time, a bunch of us are in the break-room, it's George's birthday today. Janice asks him if he's doing anything special.
"First thing, I have to stop fighting with my wife." He says that for the past couple of days, they've both been talking to their 9 months old daughter, "Tell your Mom this and that..." "Tell him that I don't want to do this and that...", poor baby wondering what her parents are up to. I say half jokingly "George, don't teach your daughter things like that." He answers, also half jokingly: "Don't ever get married." I tell him I am not planning to.

5 minutes later, I am talking to Janice by her bench, asking if we have any plans for happy hour on Friday, it's our turn to host. She says, as if surprised by my inquiry "But it's only Monday!" To which, Aruni, who's 7 months pregnant interjects "It's never too early to think about happy hour. Ahh, last night I had a half a glass of really cheap wine, and it was soooo good!" I turn to Janice: "See, what they are trying to teach us, never get married, never get pregnant..." to which she jokes "We just play with other people's kids..." and I add "...and with other people's husbands?"

Time

Time is a funny thing. It seems to race relentlessly forward. We try so hard to stop it, expand it, knowing all too well how little we are given in the end. And yet, we can not help but almost ignore the present, the moment, which is nearly unidentifiable, unmeasurable. What's a moment? As soon as you start thinking about that question, it's already passed and belongs to the past. And then the future quickly becomes the present moment, and this just keeps repeating itself throughout our lives, while we so rarely manage to be part of our own present moment.

The last sentences of a book I read recently go like "Move forward, into the empty plane. Find the book you wrote, and read it until the end, but don't turn the last page yet, keep stalling, see how long you can keep expanding the infinitely expandable moment. Enjoy the elastic present, which can accommodate as little or as much as you want to put in there. Stretch it out, live inside of it." Should be my new philosophy to live by. It's hard though. Earlier in the book, the protagonist says "Life is, to some extent, an extended dialogue with your future self about how exactly you are going to let yourself down over the coming years." I read this line like 20 times before I started to get a feel for it. I just hope that my present self would not be disappointed by how my future self turns out one day. Isn't that all we can hope for anyway?

Why is it easier to live in the past, or the future, for that matter? Maybe it's safer: past has no mystery to it, it's all done and decided, carved into memory - even though our brains alter our memories, the ultimate outcome is usually known. Our neuronal circuits make it possible for us to go back in time and relive past moments: perhaps the biggest gift and curse of the human intellect. Living in the future is also safe: I have complete control over the outcome. Whatever my imagination comes up with, that is the way "future" is, as imagined in the present. How much of our time is wasted while we are looking back into the memories, longing for something, someone at some time in the past, which we wish we could really recreate. How much time is wasted while we are trying to imagine our future, when all we need to do is to live fully in the present, which will then lead us into our future, with all its mysteries and unexpected twists and turns.

. . .

Just a couple of days ago, I was traveling. I had breakfast in Budapest, lunch in Warsaw, dinner somewhere over the Atlantic, suspended in space and time, and then a midnight snack in New York. It still seems strange to me how easy it is to do this in our time, to jump around in space like this, almost defying the laws of nature. Traveling West, you can expand your day by a few hours, make it last a little longer, seemingly stretching out the present. And during those hours, life seems to be on hold. Of course, it's not really like that, but I always have the eery feeling of somehow being outside of time during those long hours, not really progressing through my life. Maybe we're meant to be in the natural flow of time, perhaps that is how our brains are wired. I am always relieved being back on land, back in the flow of life, in which I can go forward.

And forward I go now, starting at this very moment, which has already passed.