It’s December 23rd and you want to send some homemade Christmas cookies to your aunt in New York some 3,000 miles away (you live in Oregon). FedEx overnight shipping to the rescue!  If we tracked our package we would find that it requires some special handling on its journey.  By the time it reaches your aunt it has undergone many hand offs, each one bringing it closer and closer to its final destination.   FedEx is the brain-child of Fred Smith, the founder and CEO of FedEx, who for almost 50 years now has been fine-tuning this shipping company into the marvel of precision it is today.  On a typical day the combined mail delivered by FedEx, UPS and USPS totals 436 million deliveries (1) (2) (3). The daily delivery problem we’re faced with in staying alive makes that number pale in comparison. We need a delivery system capable of delivering 35 quadrillion times that many packages, and at all times of the day!  What are the packages? They are the oxygen molecules we breath in on a daily basis. Our goal in this article is to track the delivery and hand off of these 1.58 x 10 ^ 25 oxygen molecules to our 40 trillion body cells.

             Take a deep breath.  Now imagine we’ve shrunk down so we can actually journey with the air you just breathed in as it makes its way down your trachea and through the smaller and smaller bronchioles until it reaches a tiny sac (alveolus),  like hikers finally reaching the end of a cave. In our case the “cave” is smaller than a grain of salt. Don’t blink because in the next 1/2 second we’re about to witness the first hand off that takes place in oxygen’s journey to your cells.

By the way, its a wonder we made it past all the defense traps the respiratory system is equipped with to stop dirt, dust, bacteria, and viral particles from entering the lungs. Did you notice the tiny hairs in your nose, the sticky mucus layer both in the nose and in the throat, and the moving carpet called cilia in the bronchi which can trap and then transport particles back up to the mouth where they can be swallowed? There’s one more guardian we have to watch out for - the alveolar macrophages, which are able through a deadly assortment of weapons to take out dangerous intruders who make it to the alveoli.

“Hey, it’s dark down here; someone turn on the lights!”  Ah, that’s better.  Wow! Before us in our tiny cave are trillions and trillions of gas molecules flying around and bumping into each other. Nitrogen is by far the most numerous, followed by the slightly larger oxygen molecules.   It’s not all chaos, however. The oxygen molecules seem to be moving with coordinated precision through the crowded airspace towards the lining of the alveolus. But, where are they going? “Hey, wait for us!”  

Oxygen molecules don’t come with addresses, and even if they did no one is around to read and sort them.  Instead, they must rely on either their concentration gradient or a chemical attraction with another molecule to be delivered.   The concentration gradient for oxygen describes the movement of oxygen molecules from areas where they are tightly packed (high concentration of oxygen) to areas of lower concentration.  That is called “moving down the concentration gradient”.  For example, let’s say there are 100 oxygen molecules inside an alveolus, and only 10 oxygen molecules on the other side.  What will happen?  Oxygen molecules will move down their concentration gradient – they will migrate towards the lower concentration until the two sides have equal concentrations.  Gas molecule concentrations are measured in partial pressures which is another way to measure the concentration of oxygen molecules in an area. (see appendix A) ALERT: MATH AHEAD

At sea level air pushes on surfaces with a combined force of 760 mmHg, meaning this pressure can support a column of liquid mercury that is 760 mm high. Though nitrogen in the air does the most work, oxygen also contributes 159.1 mm Hg of force (see table below). How does this help our cells receive their delivery of oxygen? Like a bloodhound on the trail of a rabbit oxygen molecules we breathe in can “sniff out” the partial pressures of oxygen around them and always move towards areas of lower concentrations. The PO2 (partial pressure of oxygen) inside our alveolus is around 100 mmHg, while the PO2 within the capillary on the other side of the alveolus is only around 40 mmHg. Now we understand why the oxygen molecules are moving through the alveolus.  They are being drawn there by the lower concentrations (partial pressures) of oxygen!

And, what is on the other side waiting to pick them up and deliver them? The oxygen molecules find something similar to Splash Mountain, the log ride at Disneyland which picks up and carries riders through a water-filled channel, only what we’re experiencing is on a miniature scale. The fluid we see is your blood plasma, filled with moving little “cars” which are your red blood cells. We are now face to face with the world’s most amazing transportation system!

    In order to service 40 trillion customers (our cells) with deliveries of oxygen and food, and to pick up waste materials, each of us comes equipped with over 60,000 – 100,000 miles of blood vessels when put end to end. (4) That is enough to wrap around the entire world 2-4 times!  The tiniest blood vessels are the capillaries, which are so small that red blood cells must wind slowly through them in single file order. They are 1/10 the size of human hair (5) and one cell thick, making it easy for oxygen gas molecules to diffuse through them.   

Guess where lots of these tiny capillaries can be found?  That’s right, coating each of our ½ billion alveoli in our lungs.  Scientists estimate that 70% of the surface of our alveoli are coated by these capillaries. (6)   What are they doing there?  Waiting to pick up passengers! 

The “cars” of this transportation system are the red blood cells (RBC).  Did you know there are more red blood cells in our body than all the rest of our cells combined? They make up around 70% of our 40 trillion cells (around 28 trillion).   And they are so cool looking! They look like designer tubes floating down rivers, and that’s what they do during the 3-4 months they “live”.  Their winding path takes them to the lungs around 675 times each day to pick up the waiting oxygen molecules and hand them off to the body’s cells.  Deep in our bone marrow are red blood cell manufacturing plants which pump out an average of 2.5 million new red blood cells every second of the day. (did he just say “every second”?)

Hiding inside the red blood cells, though, are the actual “seats” that carry oxygen. These are protein molecules called hemoglobin (hemo refers to blood).  Red blood cells are one of the few cells in the body which don’t have a nucleus, and for a good purpose – they need every bit of room to house the 250 million hemoglobin proteins each one is equipped with! Hemoglobin proteins are, in my consideration, the real star in the “Delivery Problem” as it is within these molecules that oxygen is transported.

  Let’s find out some of the incredible design features within the hemoglobin protein. Within their intricate structure are 4 heme groups which each house 1 iron atom (Fe). These iron atoms are the reason that blood is red.  When oxygen combines with iron it forms a red compound called iron oxide. When this coats metal such as on this hammer we call it rust (Fe2O3).   When our oxygen molecules “climb on board” a red blood cell they combine with iron in the hemoglobin, giving blood its bright red color.  Blood which has already unloaded its oxygen passengers becomes a darker red color.  (Activity 2 explores the interaction between oxygen and iron)

How many oxygen molecules does each red blood cell carry? Each of the 4 iron atoms in hemoglobin is able to attract and bind 1 oxygen molecule to it, so each hemoglobin can carry 4 oxygen molecules.   Multiply that by 250 million hemoglobin “seats” in one red blood cell and you see that one red blood cell can load around 1,000,000,000 (1 billion) oxygen passengers!   Wow, talk about packing a lot in a small space!

 As we pass out of the alveolus ourselves we notice that trillions of oxygen molecules are now flooding into the surrounding capillary and are being pulled towards the nearest red blood cell. These deoxygenated red blood cells seem to be a darker red color because their “seats” (hemoglobin) are empty, having already delivered their last set of passengers.  

             Let’s focus on just four of the trillions of oxygen molecules we’re surrounded by, and hope that makes our job of tracking their delivery to the cells that much easier (we’ll even give them names - Oxy and Moxy, Doxy and Poxy). As we struggle to keep our eyes on them we look just in time to see Oxy, followed by the other three, being pulled towards and enter the nearest red blood cell. Quicker than the blink of an eye we too enter the RBC, only to be surrounded by millions of hemoglobin proteins. Hey, where is Oxy heading now? Even before we have time to put our question into words we see him heading straight towards and bonding with one of the four iron atoms in the nearest hemoglobin protein, reminding us of an amusement park rider being strapped in to his favorite ride.  Every time an oxygen molecule binds to a hemoglobin, the PO2 (partial pressure) of the blood increases, which decreases the concentration gradient, making it more difficult for other oxygen molecules to board.  Once the PO2 increases to a level equal to the PO2 in the alveoli no more oxygens will board the hemoglobin. 

“Whoa, what just happened?”  Right when that first oxygen molecule was fastened to it the hemoglobin molecule changed its entire shape.  This changed shape is what is responsible for the change in color, as now light reflects off it in a slightly different manner. More importantly, though, it somehow increases its power to pull more oxygen molecules towards it. We call this having a “stronger affinity for oxygen”. There go the second and third oxygen molecules (Moxy and Doxy), also binding to 2 other iron atoms with an even stronger attraction.  Here comes the 4th oxygen molecule binding to the last iron atom in the hemoglobin.  This shape-changing ability of hemoglobin is an example of positive cooperativity.  By one estimate the attraction between oxygen and a hemoglobin carrying 3 oxygen molecules is 300 times greater than the attraction between oxygen and deoxy-hemoglobin (hemoglobin not carrying any oxygen). (9)  It seems obvious that this system which transports oxygen has been precisely designed down to the last detail! 

            In a marvel of precision and speed we notice that the red blood cell in front of us is almost completely saturated with oxygen, meaning almost 1 billion oxygen molecules have been securely fastened to the iron atoms in the hemoglobin. It is now bright red. Let’s jump on board ourselves to continue our tracking adventure through this liquid transport system. From the increasing noise level we seem headed back towards the heart.  We better tighten our seat belts! We’re in for the ride of our lives! Dropping through a one-way valve we find ourselves in the thick-walled muscular left ventricle, which with a mighty squeeze violently propels us up through the large aorta.  (Splash Mountain, stand down!) 

The turbulence behind we find ourselves being pumped through a network of smaller and smaller arteries until we reach a capillary lined with body cells on either side. Speeds are much slower here where the final delivery will take place, reminding us of how a delivery truck wanting to bring a package to your house must first exit the fast-paced freeway and make its way through commercial districts until it finally turns down your small residential road lined with homes.

            We’re almost ready to witness the final hand off of your oxygen molecules to your waiting cells.  But, wait. Remember how strongly your hemoglobin attracted and bound the oxygen to it due to its shape-changing ability? What if the hemoglobin molecules won’t let go of their precious cargo of oxygen?   That would be disastrous for you! Your cells must have a constant supply of oxygen in order to stay alive. Good news! The oxygen concentration gradient again comes to the rescue. With all the trillions upon trillions of oxygen molecules in our oxygenated blood the PO2 in the capillary we’re in increased from 40 mm Hg to around 95 mm Hg.  As you can see in the chart below the PO2 in tissue (our cells) at rest is around 40 mm, though in exercising tissue the PO2 can lower to 20 mm Hg.

 Let’s see what is happening with our 4 oxygen passengers. The last one to load is now being released and is heading towards the closest cell. Hey, there goes that hemoglobin little dance thing that changes the shape back to what it was before the oxygen was bound to it, We happily witness a second oxygen passenger, along with millions of others, obeying this concentration gradient and unloading.    The color of the blood becomes a darker red as more oxygen exits the “cars”.  However, this is causing the PO2 of oxygen in the tissue (cells) to rise and that in the red blood cells to decrease, making it increasingly difficult to unload the remaining oxygen passengers.    Here comes the 2nd oxygen unloading, followed by another shape-change which is making it easier to unload the 3rd and 4th oxygen molecules.

            Despite all the unloading help provided by the shape-changing positive cooperativity of hemoglobin, the amount of oxygen unloaded by your hemoglobin still falls short of your oxygen needs. There just happens (thank You, God) to be another chemical called  2,3 BPG for short (or 2,3 DPG) which, fortunately for you, is found in high concentrations in your red blood cells. When the 2,3 BPG molecule binds to hemoglobin it lower hemoglobin’s attraction to oxygen further, making it much easier to unload oxygen.  In fact, when scientists removed hemoglobin from the presence of 2,3 BPG they found it released only 8% of its oxygen passengers to exercising cells (20 mm Hg) compared to a release of 66% when 2,3 DPG was a factor (10).

While we’ve been traveling through your circulatory system you’ve been playing soccer! Your muscle cells must be starved for oxygen, as they’re working extra hard right now. As we peer into the cell we see the oxygen molecules being quickly transported to the mitochondria where they are needed to make ATP molecules, the molecule cells use for their own energy needs.  The final delivery has taken place, the last hand off.  What a delivery route it has been! 

We have a delivery system which makes FedEx pale in comparison, in numbers, in scale, in design, and in efficiency.  And to think that what we just witnessed takes place on a continuous basis, every second of our lives!

Take a deep breath and thank God for the amazing transportation system which is right now delivering the oxygen you just breathed in to each of your cells (particularly your brain which consumes around 20% of the oxygen you breathe in).  Thank God for the perfect design of hemoglobin, and how it is able to securely transport oxygen and then at the right time release it where it is needed.  Pray for those with the genetic disease of sickle cell anemia where one wrong piece of information twists the shape of hemoglobin causing it to be dysfunctional as an oxygen transport.  To learn more about how this disease affects people, and a new therapy involving CRISPR, which hopefully can replace defective genes with those for fetal hemoglobin see https://www.npr.org/sections/health-shots/2019/12/25/784395525/a-young-mississippi-womans-journey-through-a-pioneering-gene-editing-experiment.

Also, make sure you check out # 7: “Solving the Transformation Problem” to learn about the special hemoglobin which babies in the womb have which has an even stronger attraction to oxygen molecules.

Questions:  What did evolving animals use to transport oxygen before hemoglobin?  Where did the DNA information to make hemoglobin proteins come from? 

How does our body know (if it evolves by blind chance):

To pump deoxygenated blood to the lungs and oxygenated blood out to the body?

To coat the alveoli’s surface with capillaries? 

To design a surfactant able to keep alveoli inflated? 

To design the 2,3 BPG molecule which assists hemoglobin in unloading oxygen?

Appendix A

When talking about air molecule concentrations we don’t count molecules, we use partial pressures.  Normal air pressure is measured in mm Hg  (mercury) because Evangelista Torricelli found that air pressure at sea level pushes down on the surface of mercury in a bowl with enough force to support a column of mercury in a tube around 30 inches high (760 mm).  Each different gas in the air (mainly nitrogen and oxygen) contributes their own partial pressure towards the total air pressure. (See table below) Partial pressures are similar to 3-4 people lifting a heavy beam; each one contributes their part of the entire weight. Your oxygen delivery system would fail miserably without the movement of molecules caused by concentration gradients.

Endnotes

1.  https://about.van.fedex.com/our-story/company-structure/corporate-fact-sheet/

2. https://pressroom.ups.com/assets/pdf/pressroom/fact%20sheet/UPS_Fact_Sheet.pdf

3.  https://facts.usps.com/size-and-scope/

4. https://www.fi.edu/heart/blood-vessels

5. https://www.livescience.com/39925-circulatory-system-facts-surprising.html

6. https://en.wikipedia.org/wiki/Pulmonary_alveolus

7. For those who like numbers, a microliter of blood (1 millionth of a liter which is 1/50 of 1 drop of water) contains around 5 million red blood cells.   In this miniscule drop of liquid are 1,250,000,000,000,000 hemoglobin proteins that can load up 5,000,000,000,000,000 oxygen molecules (5 quadrillion). https://www.medicalnewstoday.com/articles/319457.php#understanding-blood-count

8.  https://opentextbc.ca/biology/chapter/20-4-transport-of-gases-in-human-bodily-fluids/

1.5% dissolves in blood – 98.5% catches a ride on hemoglobin

9. https://en.wikipedia.org/wiki/Cooperativity

10. https://en.wikibooks.org/wiki/Structural_Biochemistry/Enzyme_Catalytic_Mechanism/Regulation/Regulation_by_2,3-bisphosphoglycerate

Activity 1: Surface Tension of Water

Materials: wax paper; eye dropper; liquid soap; water; paperclip; cup; rubbing alcohol

1. Place 2 drops of water on top of each other on the wax paper.  Observe the shape of the drop.  Pick up the wax paper and see if you can role the drop around the wax paper.  Are the water molecules more strongly attracted to each other or to the wax paper?  How can you tell?

2.  Add several drops of liquid soap to some water in a cup.  Place several drops of this water/soap liquid on the wax paper next to the pure water drop.  Contrast their shapes.  Try to roll the water/soap drop.

3. in a clean cup gently lower a paperclip onto the surface of water in the cup.  (bend another paperclip to make a cradle to lower it).  What is keeping the paperclip afloat even though it is more dense than water? 

4.  Carefully place one drop of soap in the cup while the paper clip is floating.  What happens and why?

5. Compare the size of a drop of water with a drop of rubbing alcohol on wax paper.  Why are they different?  Which molecules have a stronger attraction to each other? 

Activity 2: Iron and Oxygen

Materials: steel wool (fine); vinegar; jar; Optional: scale measuring .01 g; matches or 9-volt battery; steel pan; thermometer

1. Soak the steel wool in vinegar for 5 minutes

2. Remove and wring out and place in jar for 30 – 60 min. (if you have a thermometer insert into steel wool and find temperature every 5 minutes)

3. Remove and examine the steel wool for signs of rust. (compare it to another piece of steel wool)

What did the vinegar do to help this process?  What

Optional:

1. Place the steel wool on a metal pie plate (aluminum is fine) on top of scale so you can read the mass.

2. Record beginning mass of steel wool and plate.  Use a 9 volt battery or match to light the steel wool.

3. Record the final mass.  Did it go up or down?  Why?