Series: Sickle Cell Disease (Part 3)

                As a final wrap up to this Sickle Cell Series, I will explore what kind of problems people with Sickle Cell Disease face.  In my first post, I described how genes are passed from parent to child to demonstrate the probability of a child inheriting a good hemoglobin gene or a bad hemoglobin gene.  In the second post, I clearly defined the difference between a good hemoglobin gene (which leads to a healthy hemoglobin protein and healthy red blood cells) and a bad hemoglobin gene that yields improperly behaving hemoglobin protein that distorts the red blood cells to a long, sickled shape.

                This leaves us asking the question: What do sickled red blood cells do to the body?

                If you remember from the Sickle Cell Introduction post, I said each person has one of three combinations of hemoglobin genes: two bad genes, two healthy genes, or one of each.  We know how patients with two healthy genes are – happy and healthy!  What about the other two?

Two unhealthy hemoglobin genes, the patient has Sickle Cell Disease: 

              

Hemoglobin’s role is to carry oxygen from the lungs to the far reaches of the body.  Cells require oxygen for their health and function (see Carbon Monoxide post).  Hemoglobin is carried in cells called red blood cells.  Healthy red blood cells are circular and flexible.  Blood (of which red blood cells are a key component) travels through veins and arteries (also known as blood vessels) in the body.  In some places, these vessels become very narrow.  Healthy red blood cells can squeeze through and continue moving along with relative ease.  Unfortunately, sickled red blood cells are sticky and have lost their flexibility.  These cells get stuck in narrow areas.  This difference is nicely illustrated in Figure 53.1, which comes from the National Heart Lung and Blood Institute webpage covering Sickle Cell Disease.

What kind of problems does this lead to?

Pain.  Red blood cells are piling up and trying to pass through areas of narrow vessels, which include the chest, abdomen and joints.  Doctors refer to these times as crises.  The pain can last a few hours or a few weeks.  These crises can happen as often as a dozen times a year and may require hospitalization.  Small blood vessels are also present in the eye so when sickled cells block them, patients may develop vision problems due to retina damage.

Anemia. The sickled red blood cells are weak.  Healthy red blood cells live for about 120 days, but the sickled ones only last 10 – 20 days.    The body is constantly short of red blood cells, which means it's short on hemoglobin and cells are short on oxygen.  This is why Sickle Cells Disease is sometimes referred to as Sickle Cell Anemia.

Spleen damage. The spleen is important for healthy red blood cell function and the body’s ability to deal with infection (quite frankly, just looking up what the spleen does makes me want to write a post on it.  I had no idea!).  Sickled red blood cells can damage the spleen which results in a patient having frequent infections.

Other problems. Delayed growth, swollen hands and feet.  Children with sickle cell disease typically start to show symptoms around 4 months of age.

In my research for this post, I found a blog written by a girl suffering from sickle cell disease.  Beginning in 2007, the blogger used this platform to discuss her trials.  As she states in her first post “My illness does not define me ---I define my illness.  This is my story.”  Reading unfiltered first-hand accounts, which is one of the most useful and unique things about blogs, from someone suffering with this disease is both poignant and fascinating.  In 2010, she moved on to writing on the Sickle Cell Warriors website.  Check them out!

On healthy and one unhealthy hemoglobin gene, patient has Sickle Cell Trait

                Since sickled cells are less common in these patients, their symptoms are usually mild and sometimes unnoticeable.  Rare complications do exist so don’t think that they don’t have any adverse effects, but in general it is seen as a mild problem.  It should also be noted that at low oxygen pressures, cells tend to sickle, especially when coupled with extreme exercise.  This is why Ryan Clark was dissuaded from playing football in Denver; the mile high city has lower air pressure and therefore lower oxygen pressures.

                What is most interesting about sickle cell trait is its resistance to malaria infection.  Without getting into the specifics of malaria infection (because it’s a bit complicated), just know that malaria is caused by a parasite that infects the red blood cells.  Scientists found that red blood cells from sickle cell trait patients sickled in response to parasite infection.  As described above, sickled red blood cells live a much shorter time than healthy red blood cells.  This means that infected, sickled cells will be destroyed quickly by the body.  Less red blood cells with the parasite means less infection and it is more likely that the patient will survive malaria.

                Fascinating!  This is why in incidence of malaria and sickle cell disease tend to be found in the same regions.  Such a detrimental defect in hemoglobin should have been weeded out by natural selection a long time ago (in that those with two unhealthy hemoglobin genes would die before they ever had children either due to Sickle Cells Disease or malaria infection and the gene would not have been passed on), however it persisted.  Those with just one unhealthy hemoglobin gene were more like to survive malaria so the gene hung around in these populations.

                Much more exists on the malaria/sickle cell trait topic as well as everything else discussed in this series.  I tried to give you as many resources as possible at the end of my posts.  Don’t take my word for it or as the last word on these subjects – there is so much more to learn!

REFERENCES

Symptoms of sickle cell disease: http://www.nhlbi.nih.gov/health/health-topics/topics/sca/

 

Symptoms of sickle cells disease: http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324/DSECTION=symptoms

Sickle Cell Blog: http://sicklecellblog.blogspot.com/2010_05_01_archive.html

Sickle Cell Warriors: http://sicklecellwarriors.com/

 

Malaria and Sickle Cell Trait: http://sickle.bwh.harvard.edu/malaria_sickle.html

 

Series: Sickle Cell Cells (Part 2)

NOTE: At the end of my introductory post on this topic, I said that I’d next cover patient symptoms (similar to what I did for the Henrietta Lacks/HPV series).  However, after further thought, I’ve decided that for this disease it makes the most sense to go from DNA problems, to protein problems, to cell problems, and finally patient symptoms.  

Also, it might be useful to re-familiarize yourself with the Central Dogma post and the Carbon Monoxide  post before reading this one.

My first post on this topic covered inherited disease.  I discussed how mutant genes are passed from parent to child.  Remember, a gene is a series of DNA bases that encode a particular protein (Central Dogma Post).  DNA is copied into RNA, which then goes to the ribosome where the RNA is translated.  Consecutive sets of three RNA bases encode for one amino acid.  The ribosome reads the sets of RNA bases, recruits the correct amino acid, and creates a protein chain. 

A mutant gene has a mistake in the DNA.  The mistake is simply an incorrect A, G, C or T.  Somewhere along the way, one base was switched for another.  When the RNA is copied from the DNA, the mutation is copied and the ribosome will translate exactly what the RNA says.  I will explain the implications of this very clearly in Figure 52.1.

 In the case of Sickle Cell Disease, one gene is mutated: the hemoglobin gene.  In my Carbon Monoxide post, I discussed a bit about this protein.  In summary, hemoglobin is a protein found in red blood cells and is responsible for carrying oxygen to all parts of our bodies.  It’s a special protein in that four individual molecules of hemoglobin come together in red blood cells to make oxygen delivery more efficient.

A normal, happy hemoglobin gene has the sequence shown on the top of Figure 52.1.  Underneath, I’ve shown how the ribosome reads the sets of three RNA bases and what amino acid each triplet encodes.  

On the bottom of Figure 52.1, I show you the hemoglobin gene found in Sickle Cell patients.  Look at it really carefully.  The difference is so small: A to T.

Unfortunately, the set of three RNA bases changes from GAG to GTG.  The ribosome reads GAG as one amino acid, but GTG is different amino acid.  Underneath the RNA sequence, I’ve shown what amino acids are encoded by this mutated gene.

This means that these hemoglobin molecules have an incorrect amino acid in them.  Sometimes this isn’t a big deal for proteins (good idea for a future post, I think), but in this case, it is a disaster.  

This one little amino acid change precludes the hemoglobin molecules from forming nice, discrete sets of four proteins in red blood cells.  Instead, many hemoglobin molecules come together at once and form long strands of protein.  Figure 52.2 shows you how this distorts a healthy red blood cell’s shape to form a more sickled (curved and pointy) shape both in cartoon format and by showing you actual red blood cells from a microscope image.

Remember from my first post, I told you that humans have two copies of each gene.  If you have two healthy copies of the hemoglobin gene, then all your hemoglobins are happy and your red blood cells look like the top of Figure 52.2.  If you have two bad copies of the hemoglobin gene, then the vast majority if your cells look like the bottom of Figure 52.2 and you have Sickle Cell Disease (also called Sickle Cell Anemia, which I’ll discuss in greater detail in my next post).  

One last option exists where you have one good hemoglobin gene and one mutated one.  Some of your cells will sickle, while some of your cells will not.  You are said to have Sickle Cell Trait in this circumstance since you show some sickled red blood cells, but not to the same extent as those with Sickle Cell Disease.  Interestingly, there a evolutionary advantage to having Sickle Cell Trait.

Sickled red blood cells can cause a variety of problems.  What those problems are and how it affects the health of the patient will be covered in the next post!

Note: The hemoglobin protein is much longer than the six amino acids I show you in Figure 52.1.  I just highlighted the area where the mutation lies for clarity.

REFERENCES

More info on the hemoglobin mutation: http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml

Cell Images and more info from PubMed Health: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001554/

 

My Pyelonephritis

              It started Wednesday night with a painful bladder and frequent pee breaks.  I pretended that the racking chills and shaking I experienced on my way to work on Thursday was just stress.  Being cooped up in a train for forty five minutes with the above symptoms was enough to worry anyone.  I decided the mild pain and pressure in the middle of my back was due to leaning over my computer.  I happily assured myself that, after sitting at my desk for 1.5 hours without a bathroom break, there wasn’t anything seriously wrong.  Unfortunately, at 2am on Friday morning, the intense shivering gained a new symptom: vomiting.  Off the emergency room – I was not okay.

                This is why I love the city.  At any time of day, there is a place where everyone is awake and waiting to help you, get you some place or give you food.  Cabs were plentiful at 3am, cheery doctors and nurses were waiting for me, and some people-watching helped pass the time.  Please don’t think I was in a good mood (quite the opposite), but I appreciated the beacon of civilization in the middle of a miserable evening.  I didn’t feel so alone.

                A quick urine test sealed my fate – pyelonephritis, also known as a kidney infection.  Great.  May I have some antibiotics, please, sir?

How does this happen?  Urinary tract infections (UTIs) happen when bacteria get in the urethra/bladder.  They find it very cozy there and begin to multiply.  Early symptoms include bladder pain, frequent need to pee, and pain during urination.  If left untreated, the bacteria can spread up to your kidneys.  The symptoms then progress to back pain, fever, shaking chills and vomiting.  Women are more likely to get UTIs than men due to shorter urethras and proximity to a haven of E. coli.  

How does the test work? I had wanted a urine analysis on Thursday afternoon but was unable to get one (because of my own inability to procure a primary care doctor when switching insurance.  Seriously, this whole debacle was a series of failures on my part).  What would a urine analysis have shown?

                Human urine contains nitrate, shown in Figure 51.1.  Some bacteria are able to uptake nitrate and turn it into nitrite (Figure 51.1).  Presence of nitrite in your urine suggests bacteria are present!

               I got my urine analysis in the emergency room.  After telling my story to the doctor, she asked the nurse if my analysis showed blood because my symptoms were more in tune with kidney stones than an infection.  

               "No," he happily replied.  "No blood, but she had nitrites!"

How do the antibiotics work? In order to clear the infection, the bacteria must be killed so antibiotics are necessary.  The word antibiotic is quite simple: “anti” means against in Greek, while “bios” means “life.”  Many different kinds of antibiotics exist, but they all do the same general thing: disrupt bacterial cells without disrupting human cells.  How does one achieve this?

                In broad strokes, bacteria do the same functions as human cells: replicate their DNA, transcribe DNA into RNA, translate RNA into protein (Central Dogmapost), but the proteins they use to do it are a bit different than human proteins.  For example, a protein known as DNA Polymerase is responsible for replicating DNA in cells.  Human DNA polymerase looks very different than bacterial DNA polymerase.  If you can identify a drug that will – say – bind to bacterial DNA polymerase and make it unable to function, then the bacteria will die.  Since human DNA polymerase looks different, that same molecule can’t inactive human DNA polymerase.  Win.  You kill bacteria cells without killing human cells!

                Antibiotics target different things.  Some keep bacteria from making their cell walls, some inhibit different enzymes necessary for bacterial life.  My drug of choice is levofloxacin, which specifically blocks bacterial topoisomerase IV and DNA gyrase.  Both of these are involved in unwinding DNA for replication.  If the bacteria can’t unwind their DNA, they can’t replicate it or continue to grow.  

                After three doses of antibiotics, I feel almost human.  I have three more to go.  Bouncing back from this hasn’t been quite as fast as I’d hoped (today is the first day I can sit at my computer and focus on work), but the shivering chills have stopped and I’m slowly regaining my appetite.  I have weird cravings when I’m sick – tonight, all I want for dinner is fried chicken.

                Much more info is available on UTIs, kidney infections, and antibiotics.  Read more if you are interested!  Also, if you get any of those symptoms, go to a freaking doctor!  Don’t be stupid like me.

                My apologies for being a little MIA in the past week.  Obviously, this is why.  I’m working to update all my blogs now and catch up on work that I’ve missed over the past week.  I have all the Sickle Cell posts outlined so they should be up soon!

REFERENCES

UTI Info from the Mayo Clinic: http://www.mayoclinic.com/health/urinary-tract-infection/DS00286

Some medical info on urine cultures, common UTI bacteria: http://www.medindia.net/education/familymedicine/utinfection-urineculture.htm

Generalized antibiotic information: http://www.medicalnewstoday.com/articles/10278.php

Levofloxacin information: http://bacteria.emedtv.com/levofloxacin/levofloxacin.html

Series: Sickle Cell, Introduction

                 It’s just one nucleotide!  It’s just one little mistake in a hugely long DNA molecule that causes this disease.  That one little mistake causes soft, happy, healthy red blood cells to turn into arched, half-moon, sticky red blood cells that die quickly, but not before inflaming the patient’s blood vessels.  This leads to pain, anemia and death (with current advances, patients live into their 50s).    Such is the power of one little nucleotide.  Think about that.  

                If you have read my Henrietta Lacks & HPV series, you’ll note that my second post covered HPV-infected patient symptoms at a clinical level, my third post discussed cellular changes that could be seen on an infected cervix and my fourth post explained what was going on inside those infected cells.  We slowly worked our way down from patient level to cellular level to molecular level to explain HPV infection and how it leads to cancer.

                I came across a news article today discussing Ryan Clark and his sickle cell trait (see my Mini-Amedeo post called Sickle Cell Trait).  I was originally going to do a brief synopsis on the disease here and cross the subject over on to Dr. Amedeo with recent advances, but I have a new idea.  Instead, I’m going to work from patient symptoms, down to blood characteristics, and finally discuss what has gone wrong with the patient’s hemoglobin molecules to lead to such a disease.  

I’m a big fan of dissecting diseases in this fashion as a way of explaining them.

            In this, my introductory post, I want to simply establish the idea of inherited disease.

            Genes are strings of DNA bases that encode a protein sequence (see that pesky Central Dogma post).  Nearly every healthy human cell (notable exceptions: male sperm and female eggs) carries two copies of each gene and both are translated.  This kind of redundancy is useful.  What if one copy gets damaged?  One gene is churning out a dysfunctional protein but the other is putting out a perfectly normal version.  Granted, the healthy version will be in lower amounts, but it will still be there and sometimes that is good enough for keeping cells running appropriately.  

                What happens when both copies are damaged?  Well, your cells are now missing that protein.  Interestingly, proteins have redundancy in their functions (life has a lot of built in fail-safe mechanisms).  Sometimes if one protein is missing then another protein can step up and fulfill the function.  However, for some proteins, its loss of function leads to catastrophic results.  This is the case with sickle cell disease. 

                So what’s going on with male sperm and female eggs?

                These cells only have one copy of every gene.  When sperm meets egg, we have the meeting of each gene copy so the growing little baby will now have two copies of everything again.  This means that one gene copy comes from the mother and one comes from the father.  

                So… Mom has two copies of a gene.  One copy goes into one egg and one copy goes into another.  Dad has two copies of a gene.  One copy goes into one sperm and one copy goes into another.  Based on this knowledge, we can start to make some predictions about their children.

Case #1: Mom has two copies of the healthy gene.  Dad has two copies of the healthy gene.  This means that their child will get two healthy genes.

Case #2: Mom has two copies of the damaged gene.  Dad has two copies of the damaged gene.  This means that their child will also have two copies of the damaged gene.

                But, what if the case is more complicated?  What if each parent has a good gene and a bad gene?  What if only one does and the other has two bad genes?  What if the other has two good genes?  What do these situations mean for their child?

                Scientists use a little thing called a Punnett Square to figure it out.  As shown in Figure 50.1, the choices for one parent’s genes are written across the top and the choices for the other parent are written down the side.  Inside each box is written the choice from the top of its column or the end of its row.  The inside of the squares represent all the possibilities for the children.  

Figure 50.1 shows you an example for what happens when each parent has a good gene and a bad gene.  From the results, scientists can say “Your child will have a 25% chance (1 out of 4) of having two bad genes, a 50% chance of having one healthy and one bad (2 out of 4), or a 25% change of having two healthy genes.”  

 

Now, let’s go back to Sickle Cell Disease.  It is caused by two bad genes for the protein hemoglobin.  Just as explained above, people can exist with two healthy hemoglobin genes, two bad hemoglobin genes or one of each.  If you have two bad hemoglobin genes, you have Sickle Cell Disease.  If you have one healthy and one bad, you have Sickle Cell Trait.  If you have two healthy hemoglobin genes, you're normal!  Congrats.

Our next post will compare and contrast patient symptoms for those with Sickle Cell Disease and Sickle Cell Trait.  

Anemia: when the body does not have enough healthy red blood cells.

REFERENCES

Alberts et al. “Molecular Biology of the Cell, 4^th Edition.”  Garland Science, New York, New York. (2002).

Me, myself, and I