Why is a lack of oxygen fatal to cells?

Why is a lack of oxygen fatal to cells?

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In animals temporary anaerobic respiration leads to the breakdown of the pyruvate formed by glycolysis into lactate. The buildup of lactate in the bloodstream is accompanied by a large number of protons causing lactic acidosis, which is detrimental to the health of the organism. This is one of the main suggestions I have come across for why a lack of oxygen is fatal to cells, however the LD50 for lactic acid as referenced by the COSHH MSDS seem awfully high (even if the route is by ingestion rather than directly into the bloodstream) for this to be a cause of cell death:

Toxicological Data on Ingredients: ORAL (LD50): Acute:

3543 mg/kg [Rat (Lactic Acid (CAS no. 50-21-5))].

4875 mg/kg [Mouse (Lactic Acid (CAS no. 50-21-5))].

I also wonder if this is a larger problem for an organism as a whole rather than on a cellular level.

The alternative, I suppose, is that glycolysis alone does not provide sufficient ATP for vital cellular processes to occur. If this is the case, which ATP requiring processes are most vital for the short term survival for a cell?

Here's an illustrated example in neurons:

ATP, of course, is generated by aerobic respiration. The critical biochemical reaction in the brain that is halted due to lack of ATP (and therefore O2) is the glutmaine synthetase reaction, which is very important for the metabolism and excretion of nitrogenous wastes:

The body uses this reaction to dump excess ammonia (which is a metabolic waste product) on glutamate to make glutamine. The glutamine is then transported via the circulatory system to the kidney, where the terminal amino group is hydrolyzed by glutaminase, and the free ammonium ion is excreted in the urine.

Therefore, as you'd expect, under hypoxic conditions in the brain, excess ammonia builds up which is very toxic to the cells. Neurons are also highly metabolically active, which means they generate more waste products. A buildup of nitrogenous waste products in the cell (and bloodstream) can be potentially fatal due to it's effects on pH (screws up enzymes and a whole slew of biochemical reactions).

In addition, the buildup of ammonia will cause glutamate dehydrogenase to convert ammonia + aKG to glutamate, which depletes the brain of alpha-ketoglutarate (key intermediate in TCA cycle). This basically creates a logjam in the central metabolic cycle which further depletes the cell of energy.

This is just one example of many. Of course, there are many, many other critical metabolic processes that require ATP (i.e. the Na+/K+ ATPase pump that regulates neuronal firing and osmotic pressure), but nitrogen metabolism was the first that came to mind :)

Energy production starts with glycolysis, which generates NADH and pyruvate. Pyruvate goes to the mitochondria to make more NADH (or FADH2, which is similar to NADH) in the Krebs Cycle. NADH is used to power the electron transport chain, which gives most of the energy the cell uses. The last step of the electron transport chain consumes oxygen (Complex IV reduces oxygen to water).

If you do not have oxygen, the electron transport chain will not work. If that doesn't work, the Krebs Cycle slows. If that's not consuming pyruvate, glycolysis slows. The cell dies from lack of energy. It has less to do with the acid buildup as a consequence of lactate as it does with buildup of NADH and the consequent slowing of the central metabolism.

The issue is most pronounced in multicellular organisms because it's much more difficult to get oxygen to all your tissues, so "think" tissues have cells that are already close to hypoxia already.

Multiple Causes of Low Oxygen (Hypoxia)

Recognition of inadequate oxygen delivery to the cells can be difficult in the early stages because the clinical features are often non-specific. Progressive metabolic acidosis, hyperlactataemia, and falling mixed venous oxygen saturation (SvO2), as well as organ specific features[1] are not noticed usually until its too late and serious disease sets in.

Speaking from the perspective of intensive care, Drs. R M Leach, D F Treacher say, &ldquoPrevention, early identification, and correction of tissue hypoxia are therefore necessary skills in managing the critically ill patient and this requires an understanding of oxygen transport, delivery, and consumption.&rdquo[2] This holds true for many acute and chronic medical conditions.

Without oxygen, our brain, liver, and other organs can be damaged just minutes after symptoms start. Hypoxemia (low oxygen in your blood) can cause hypoxia (low oxygen in your tissues) when your blood doesn’t carry enough oxygen to your tissues to meet their needs. The word hypoxia is sometimes used to describe both problems.

Researchers found that an increase of 1.2 metabolic units (oxygen consumption) was related to a decreased risk of cancer death, especially in lung and gastrointestinal cancers so it really behooves us to study hypoxia. There are many reasons, common to large segments of populations, that pull oxygen levels down in cells, with one or two or even more of these reasons present in many if not all who are chronically ill.

Mineral deficiencies help create hypoxic conditions, especially when they are needed to neutralized chemical and heavy metal toxins. Also, certain minerals are needed by the red blood cells to do their jobs efficiently. Magnesium deficient diet leads to significant decreases in the concentration of red blood cells (RBC), hemoglobin and eventually a decrease in whole blood Fe.[3]

In fact, we find many ways in which magnesium deficiency leads to problems with oxygen transport and utilization (see below.) Iron of course is at the heart of hemoglobin so any deficiencies there are telling. And because many pharmaceutical drugs drive down magnesium levels they must be considered as major causes of lowered oxygen delivery to the cells. Said in a slightly different way, pharmaceutical drugs are a major cause of disease and death.

Radiation exposure leads to hypoxic conditions because so much oxidative stress is created. Local recurrence and distant metastasis frequently occur after radiation therapy for cancer and can be fatal. Evidence obtained from radiochemical and radiobiological studies has revealed these problems to be caused, at least in part, by a tumor-specific microenvironment hypoxia.[4]

Any element that threatens the oxygen carrying capacity
of the human body will promote cancer growth.

Dealing with issues such as chronic stuffy nasal congestion can lead to poor quality sleep, insomnia, or, in the worst-case scenario, sleep apnea, a chronic disease in which oxygen levels decrease during sleep to the point where your heart and your brain don’t get enough air to function properly.

Professor Lum, in his review "The syndrome of habitual chronic hyperventilation" (published in: Modern trends in psychosomatic medicine"), wrote, "Most authors, with the exception of Rice (1950), have described the clinical presentation of hyperventilation as a manifestation of, and secondary to, an underlying anxiety state" (p.197, Lum 1976).

It has been hypothesized that immobilization stress induces the formation of reactive oxygen species, which weakens the brain antioxidant defenses and induces oxidative damage. High levels of stress can be induced by various disturbances such as pain, cold, sexual violence, death of loved ones, accidents and a host of other things like divorce.

Stress potentially upsets many physiological processes including respiration. We breathe faster when stressed out and that forcibly drives down oxygen delivery to the cells. Low oxygen is caused by a sympathetic or fight or flight system that is in overdrive because this causes shallower breathing.

In all serious disease states we find a concomitant low oxygen state.
Low oxygen in the body tissues is a sure indicator for disease.
Hypoxia, or lack of oxygen in the tissues, is the
fundamental cause for all degenerative disease.
Dr. Stephen Levine – Molecular Biologist

Faster, deeper breathing exhales more carbon dioxide. When we breathe more than the norm (and this is a case for over 90% of people today) cell oxygen level is reduced, and we suffer from cell hypoxia. Dozens of studies have shown that modern "normal subjects" breathe about 12 L/min at rest, while the medical norm is only 6 L/min. As a result, blood CO2 levels are less than normal. Arterial hypocapnia (CO2 deficiency) causes tissue hypoxia that trigger numerous pathological effects. Hypocapnia creates tissue hypoxia (low body-oxygen content), and this suppresses the immune system, deprives the cells of the ATP they need, and eventually leads to cancer.

Another reason cells lose oxygen is high sugar intake. Otto Warburg said that glucose brings down a cell&rsquos ability to use oxygen. One of the principle ways sugar does this is by creating inflammation in the capillaries and other tissues, thus cutting down on oxygen delivery to the cells.

Inappropriate polyunsaturated fatty acids (PUFAs) into the phospholipids of cell and mitochondrial membranes. Such incorporation causes changes in membrane properties that impair oxygen transmission into the cell. Trans fats, partially oxidized PUFA entities, and inappropriate omega-6: mega-3 ratios are potential sources of unsaturated fatty acids that can disrupt the normal membrane structure.

We find sepsis often leads to death because the defining characteristic of sepsis is progressive blood flow dysfunction in the microvasculature of organs remote to the original site of injury. Previous work has established that microvascular oxygen transport is compromised in sepsis due to a loss of perfused capillaries.[5]

Hypoxia is characteristic for sites of inflammation and lesion, and since most people suffer from some sort of inflammation in one part of the body or other, we need to declare inflammation as a main cause of low oxygen levels.

Beware the Dangers of Oxygen

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There’s a caustic substance common to our environment whose very presence turns iron into brittle rust, dramatically increases the risk of fire and explosion, and sometimes destroys the cells of the very organisms that depend on it for survival. This substance that makes up 21% of our atmosphere is Diatomic oxygen (O2), more widely know as just oxygen.

Of course, oxygen has its good points. Besides being necessary for respiration and the reliable combustion engine, it can be liquefied and used as rocket fuel. Oxygen is also widely used in the world of medicine as a means to imbue the body with a greater amount of the needed gas. But recent studies indicate that administering oxygen might be doing less good than hoped⁠&mdashand in fact be causing harm. No one is immune to the dangers of oxygen, but the people who might most suffer the ill effects are infants newly introduced to breathing, and those who are clinically dead.

There are a variety of injuries and ailments for which modern medicine dictates oxygen therapy. The common wisdom is that by filling the lungs with pure O2, one is pushing more of the vital gas into the blood, and thus to organs that are weakened and in need of support. It has also long been known that even at partial pressures, pure oxygen can be toxic⁠&mdasha fact with which scuba divers and astronauts are intimately familiar. Recent studies have indicated that the human body responds to pure oxygen, even at normal pressures, in a negative way.

When pure O2 is introduced to the lungs, autonomic reflex increases respiration. The increased rate of breathing means that a much larger load of carbon dioxide is released from the body, which causes the blood vessels to constrict. Despite the increased amount of available oxygen in the lungs, the circulatory system is hampered, and cannot deliver precious O2 as well as it could when breathing normal atmosphere.

Ronald Harper, a neurobiology professor at UCLA, conducted observations on a group of healthy teenagers breathing various gas mixes using functional magnetic resonance imaging (fMRI). His findings showed that in some subjects the pure O2 caused the brain to go clinically bonkers. Brain structures such as the hippocampus, the insula, and the cingulate cortex all displayed an adverse reaction they in turn spurred the hypothalamus, the body’s main regulatory gland, into a fervor. The hypothalamus regulates a myriad of things, including heart rate, body temperature, and is the master of a variety of other glands. The introduction of pure oxygen prompts the hypothalamus to flood the body with a cocktail of hormones and neurotransmitters which serve to hamper heart rate, and further reduce the circulatory system’s effectiveness. But Harper also found that by adding a mere 5% CO2, all the detrimental effects found in pure oxygen are negated.

There are circumstances, however, where even the proper mix of gases would prove inadequate. Modern medicine has long taught that after respiration stops, the brain can only survive for six minutes without oxygen before its cells begin to die in droves. In order to combat this, standard procedure has been to aggressively attempt to restore breathing and heartbeat immediately upon cessation. The base premise on which this protocol is designed may be in error.

Upon examining heart cells and neurons deprived of oxygen under a microscope, Dr Lance Becker of the University of Pennsylvania found there was no indication that the cells were dying after five or six minutes. In fact, they seemed to endure the state for up to an hour without adverse affect. Given this unexpected observation, the researchers were forced to investigate why human resuscitation becomes impossible after only a few minutes of clinical death. The answer they uncovered was that the body’s cells were not dying of oxygen starvation they were expiring due to reperfusion⁠&mdashthe sudden reintroduction of oxygen to a dormant cell.

Inside the cells, the culprit seems to be in the mitochondria, which is the cell’s power plant where sugar and oxygen are converted to usable energy. Mitochondria are also responsible for apoptosis⁠&mdashthe organized, controlled self-destruction of a cell. Normally apoptosis occurs in situations such as the cell being damaged beyond repair, infected by a virus, an attempt to prevent cancer, or aiding in initial tissue development. The process effectively kills and dismantles the cell allowing the body’s usual waste management functions to carry the cell’s remains away. For reasons not entirely clear, reperfusion triggers apoptosis⁠&mdashthe oxygen intended to save the cell actually causes cellular suicide.

Armed with this new information about how cells react to oxygen, it is clear that current emergency care is not altogether ideal, and new protocols are under investigation. Dr Becker proposes that induced hypothermia may slow cell degradation, and if a means can be found to safely reintroduce oxygen to tissues, a clinically dead person⁠&mdashwho still has trillions of living cells⁠&mdashcould be resuscitated after being an hour dead.

This glorious future is still on the horizon, but to imagine the practical application leads one to ponder the multitude of accidents and injuries that are currently fatal, but will one day be treatable. Emergency Medical Personnel could arrive on the scene, and inject the patient with a slurry of ice and salt that lowers the body temperature to about 92° F. In a hypothermic state, the patient is hauled to the hospital, where instead of frantically trying to restart the heart, doctors patch up the problem, prevent apoptosis , and then restart the heart. Though it won’t save everyone, these findings may lead to a future where a person made up of perfectly good human cells is not written off as dead merely because their heart has stopped beating. The miracle of modern medicine, it seems, is on the cusp of determining the true distinction between dead and mostly dead.

Part 2: Chicago Cyanide Murders&mdashA Case Study in Cellular Respiration

Background In September of 1982, Mary Kellerman gave her 12-year-old daughter a painkiller when she awoke during the night complaining of a sore throat. At 7 am. the next morning, her daughter was found collapsed on the bathroom floor, and later pronounced dead.

Adam Janus, a postal worker in another Chicago suburb also died unexpectedly, though originally it was thought he had suffered from a heart attack. While his family gathered to mourn their loss, his brother and sister became ill and later died.

In the days that followed, three more unexplained deaths occurred in nearby Chicago suburbs. Investigators found that all of the victims had taken an extra strength Tylenol hours before their death. They suspected that someone had tampered with the medication.

Symptoms exhibited by each of the victims included:

  • weakness, dizziness, sleepiness
  • flushed, bright red, skin tone
  • headache
  • shortness of breath and rapid breathing
  • vomiting
  • confusion and disorientation

1. In your opinion, are the seven deaths connected? What additional information would you need to determine if they are connected?

2. If poison is suspected in the deaths, how would you proceed with the investigation?

Autopsy Report:

The medical examiner concluded that each of the victims had died of hypoxia. Hypoxia means that the person suffered from a lack of oxygen, or they were suffocated. The reason for the hypoxia is not always clear at the first examination.

The medical examiner also showed the tissue samples from the heart, lungs, and liver showed massive cell death. On further investigation, it was shown that the tissues had major mitochondrial damage. Even though the victims died of hypoxia, their level of oxygen in their blood was approximately 110 mm Hg. The normal range is 75-100 mm Hg.

1. Recall your knowledge of the function of organelles. What function of the cells was interrupted in these patients?

2. While poison is the main suspect in the case, what are other ways a person could die of hypoxia?

3. Analyze the oxygen levels of the victims. Were the levels higher or lower than normal? How can you reconcile this observation with the cause of death being hypoxia?

Toxicology reports show that the victims had been poisoned with cyanide. The poison was traced back to extra strength Tylenol where the murderer had opened the capsules and replaced acetaminophen (a pain killer) with cyanide. Cyanide acts very quickly, often killing within minutes of ingestion and authorities were slow to identify the cause of the deaths. Once the cause as identified, stores removed Tylenol and other drugs from shelves. While there were many suspects, no one was ever charged with the crime and it is still an ongoing investigation. Since the Chicago Tylenol murders, drug companies have drastically changed how medicines are packaged.

Why is cyanide such an effective poison? You might be surprised to learn that it directly interferes with cellular respiration that occurs in the mitochondria.

4. Recall that the mitochondrion is sometimes called the "powerhouse" of the cell. What does this mean? Why is the mitochondrion important?

Why Do We Need Oxygen?

It seems like a simple question, everyone knows you need to breathe to live. Have you ever thought about why oxygen is so important? The victims of the cyanide poisoning all had high levels of oxygen in their blood, but the poison was interfering with how the cells use that oxygen. To understand, we need to take a very close look at the structure of the mitochondrion.

Inside the mitochondrion, there are several layers of membranes. In fact, these membranes resemble the membrane that surrounds the cell. It has a bilayer of phospholipids and embedded proteins. On the diagram above, the proteins are labeled I, II, III, IV, and cytochrome C.

The proteins in the membrane pass electrons from one to the other this is known as the electron transport chain. The passing of these electrons allows ATP (adenosine triphosphate) to be generated. At the end of the electron transport chain, cytochrome C passes the electron to Complex IV and then to its final acceptor, oxygen. Oxygen then binds with proteins to create water. This process is continuous in cells, with ATP constantly being generated and oxygen being used as the final electron acceptor. Cyanide inhibits cytochrome C, preventing the last protein from doing its job. The electron stops at the end of the chain and cannot be passed to oxygen. The whole chain grinds to a halt and no ATP can be made.

1. On the model of the mitochondrion, highlight the area that is the ELECTRON TRANSPORT CHAIN. Place an X over the protein that is inhibited by cyanide. What is the relationship between the ETC and oxygen?

2. Cyanide is an extremely fast acting poison. In fact, it was developed as a suicide pill (called Lpill) during World War II so that British and American spies could avoid being captured alive. Given what you know about ATP and cellular respiration, explain why cyanide is so fast acting.

3. Given what you know about cyanide poisoning, do you think that giving a person oxygen would be an effective treatment? Why or why not?

In the death zone, your brain can start to swell, which can lead to nausea and a form of psychosis

Acclimatization to death-zone altitudes simply isn't possible, high-altitude expert and doctor Peter Hackett told PBS.

One of the biggest risk factors at 26,000 feet is hypoxia, a lack of adequate oxygen circulation to organs like your brain. If the brain doesn't get enough oxygen, it can start to swell, causing a condition called high altitude cerebral edema (HACE). Essentially, it's HAPE for the brain.

This swelling can trigger nausea, vomiting, and difficulty thinking and reasoning.

An oxygen-starved brain can cause climbers to forget where they are and enter a delirium that some experts consider a form of high-altitude psychosis. Hypoxic climbers' judgment becomes impaired, and they've been known to do strange things like start shedding their clothes or talking to imaginary friends.


Effectiveness of the Case Study

Our goal was to assess the effectiveness of using the case study to increase student comprehension and retention of cellular respiration concepts. We assessed student comprehension qualitatively by monitoring the discussions in the student groups and through the level and sophistication of questions the students asked during class. Semiquantitative assessments were made through a written exam and student satisfaction was assessed with a brief survey after the implementation of the case study.

Since the case was discussed during class in student groups, student-to-student teaching occurred as noted by the instructors. Usually, a student in the group would suggest an answer to his or her respective group and explain the reasoning and supporting evidence for the proposed answer. In response, some students proposed alternative answers to the case questions within the groups. Instructors monitored verbal responses within groups and mediated further discussion by asking questions to the groups that seemed to be off target. Although not all of the students were able to answer the case study questions initially, most students were able to provide correct answers after group discussions.

In one instructor's class, students performed better when taught using the case study relative to a previous semester in which cellular respiration was taught solely by the lecture method. The level and sophistication of the discussions and students' questions was much higher when the case study was used. In addition, when given very similar exam questions, 70% of the case study students answered correctly compared to only 50% of the students who were taught by lecture only.

During the class period following the case study, the students were given an oral and written quiz. The questions reviewed the steps of cellular respiration in detail. As a class exercise, the students were able to explain orally the steps of cellular respiration including the location of where each reaction occurs, the reactants and products, and the purpose of oxygen in this process. A similar case study question was presented to the students on a mid-term exam (Figure 1). This question asked about a different poison that blocked aerobic cellular respiration in the mitochondria. The students were asked to make a diagram of cellular respiration including the cellular location and number of ATP molecules produced during each step. The students were given data similar to the toxic flea dip case study from which they determined where the block in cellular respiration occurred. About 80% of the students responded with correct answers to this question. Another measure of assessment was a concept map as a final semester project. The class that did not use the case study was not given a concept map assignment. Of the students who used the case study, approximately 80% successfully integrated cellular respiration into their concept map, suggesting that they comprehended important concepts about cellular respiration.

Student Satisfaction

Using a feedback survey, we set out to probe student perceptions and to determine if the students felt that the case study increased their understanding of cellular respiration. In general, the students responded positively to the case study as a learning tool. After completing the case study, 75% of the students (21 of 28 students polled) felt that they understood the steps of cellular respiration and that the case study helped them learn concepts more effectively than a traditional lecture (Figure 2). When asked what the most useful part of the activity was for them, students most frequently responded with: the discussion, the questions, and the ability to use the information in a real-life situation (Figure 2).

Addressing Student Misconceptions

Previous studies have shown that misconceptions about cellular respiration can persist in the minds of students, even after they have been exposed to varied instructional methods (Haslam and Treagust, 1987 Songer and Mintzes, 1994). We observed that prior to instruction, the vast majority of students associated the word respiration solely with breathing. In addition, they were unable to accurately describe how animals utilize energy stored in food, or how oxygen is used in this process. After instruction using the case study, most students were able to accurately identify cellular respiration as the conversion of food energy into ATP. Furthermore, their responses on exam questions and in their concept maps suggested that they could explain why oxygen was required for the process.

What are the Symptoms of a Lack of Oxygen to the Brain

Known medically as cerebral hypoxia a lack of oxygen supply to the brain can jeopardize the health of this important organ, causing cell death and brain damage in the event that the brain is left for a long time without receiving enough oxygen. Detecting early symptoms is key so you can seek specialized medical care and guarantee the health of the organ, so at we explain what the symptoms of lack of oxygen to the brain.

The lack of oxygen to the brain may occur in various conditions, some are external and others are derivatives of certain health conditions. Among the external factors that can lead to cerebral hypoxia are:

  • Being at high altitude where oxygen is not enough.
  • Inhaling large amounts of smoke e.g. during a fire.
  • Carbon monoxide poisoning.
  • A drug overdose.
  • Problems encountered after general anaesthesia.

Various health conditions can also lead to our brain stopping receiving oxygen properly, among them are:

  • Suffering from cardiac arrest.
  • Choking or suffocating.
  • Having a stroke.
  • Any condition that creates pressure in the trachea.
  • Having low blood pressure.
  • Suffering from a disease that causes paralysis of the muscles that control breathing, such as ALS.

The symptoms of lack of oxygen to the brain are:

  • Feeling distracted or confused.
  • Altered movement or coordination.
  • Having difficulty making decisions or explaining.
  • In more severe states the lack of oxygen to the brain can lead to loss of consciousness and the difficulty or absence of breathing.

It is very important to understand that if you suspect that someone is suffering from the symptoms of lack of oxygen to the brain, you immediately contact emergency services. The faster the oxygen to the brain is restored, the less the damage caused by this serious condition will be. The consequences of cerebral hypoxia can be as severe as going into a coma, cognitive changes, impairment in motor reflexes, increase of heart rate and even brain death.

This is the reason why only urgent specialized medical care may improve the prognosis of this condition and reduce its negative effects on the brain.

This article is merely informative, oneHOWTO does not have the authority to prescribe any medical treatments or create a diagnosis. We invite you to visit your doctor if you have any type of condition or pain.

If you want to read similar articles to What are the Symptoms of a Lack of Oxygen to the Brain, we recommend you visit our Family health category.

A Frightening New Explanation for the Lack of Blood Oxygenation in Many COVID-19 Patients

One of the physiopathological characteristics of COVID-19 that has most baffled the scientific and medical community is what is known as “silent hypoxemia” or “happy hypoxia.” Patients suffering this phenomenon, the causes of which are still unknown, have severe pneumonia with markedly decreased arterial blood oxygen levels (known as hypoxemia). However, they do not report dyspnea (subjective feeling of shortness of breath) or increased breathing rates, which are usually characteristic symptoms of people with hypoxemia from pneumonia or any other cause.

Patients with “silent hypoxemia” often suffer a sudden imbalance, reaching a critical state that can be fatal. Normally, individuals (healthy or sick) with hypoxemia report a feeling of shortness of breath and a higher breathing rate, thus increasing the body’s uptake of oxygen. This reflex mechanism depends on the carotid bodies. These small organs, located on either side of the neck next to the carotid artery, detect the drop in blood oxygen and send signals to the brain to stimulate the respiratory center.

A group of researchers from the Seville Institute of Biomedicine – IBiS/University Hospitals Virgen del Rocío y Macarena/CSIC/University of Seville, led by Dr. Javier Villadiego, Dr. Juan José Toledo-Aral and Dr. José López-Barneo, specialists in the physiopathological study of the carotid body, have suggested in the journal Function, that “silent hypoxemia” in COVID-19 cases could be caused by this organ being infected by the coronavirus (SARS-CoV-2).

This hypothesis, which has attracted the interest of the scientific community for its novelty and possible therapeutic significance, comes from experiments that have revealed a high presence of the enzyme ECA2, the protein the coronavirus uses to infect human cells, in the carotid body. In patients with COVID-19, the coronavirus circulates in the blood. Therefore, researchers suggest that infection of the human carotid body by SARS-CoV-2 in the early stages of the disease could alter its ability to detect blood oxygen levels, resulting in an inability to “notice” the drop in oxygen in the arteries.

If this hypothesis, which is currently being tested in new experimental models, is confirmed, this would justify the use of activators of the carotid body independent of the oxygen sensing mechanism as respiratory stimulants in patients with COVID-19.

Reference: “Is Carotid Body Infection Responsible for Silent Hypoxemia in COVID-19 Patients?” by Javier Villadiego, Reposo Ramírez-Lorca, Fernando Cala, José L Labandeira-García, Mariano Esteban, Juan J Toledo-Aral and José López-Barneo, 23 November 2020, Function.
DOI: 10.1093/function/zqaa032

Message from the Director, May 2021

Part of studying stem cells is the realization that the stem cell pattern of tissue formation, maintenance, repair, and role in diseases, has a long evolutionary history. Single cell organisms ((essentially stem cells)) eventually coalesced together with other cells to form organisms made up of many cells, and eventually many different types of cells. These multicellular (metazoan) species arose long before modern times.

Stem cells self-renew to make more stem cells, and also give rise to the functional cells in the tissue or organ in which they reside. Different stem cells make different tissues, and there is not interconversion between different kinds of stem cells that happen naturally. The general properties–but not the exact genes­–shared between different stem cells (say, between blood forming stem cells and skin forming stem cells) are the conserved suites of genes that must be turned on or off for each stem cell type. In general, stem cells self-renew to maintain the number needed for tissue or organ maintenance. Blood stem cells have the ability, at the single stem cell level, to self renew and differentiate. Through differentiation, they make all of the blood cell types for all blood functions, such as carrying oxygen, fighting dangerous microbial and parasitic invaders, clotting blood after an injury, hollowing out bone to make room for blood formation, etc. Skin stem cells express genes to allow their differentiation to all of the skin structures (whether hairy, hairless, pigmented, thick in palms and soles, or covered with fluids that keep skin functioning, and so on). These outcomes change through life, and these changes are also properties of skin stem cells.

This may seem simple, but we now know that the blood stem cells we have during development before birth differ from those that dominate in youth and through the reproductive period, which in turn differ from those that dominate as we age. The same could be said about how our skin stem cells differ over time (what happened to my hair? What causes wrinkles? Why do I have bags under my eyes?).

Since stem cells are likely born from pre-stem cells only during the embryo to fetal stage of development, the potential for the diversity of stem cells must be intrinsic in the numbers and types of stem cells first formed. For all systems, the changing diversity of stem cells may derive by precise instructions of how and when the stem cells of youth turn into the stem cells of aging…..and/or…..diverse stem cells are there from the beginning, but undergo competition and natural selection so that one type eventually wins over another. The changes from one type to the other, or the competition between the two types likely result from the accumulation of changes in the body with aging and exposure to damaging element—the changing soil in which the seeds—stem cells—find themselves.

Blood stem cells or skin stem cells didn’t start with humans. So over millions and millions of years, single cells gave rise to organizations of cells for each creature. As different species arose and won their own competitions and natural selection, they slowly traveled from their place of origin to nearby geographies, encountering the challenges from other species, including disease-causing microbes. All of these stem cell varieties arose and diversified in animals for hundreds of millions of years before humans, in just a few thousand years, changed everything in the world around them. Modern humans, nevertheless, still have stem cells much like ancient humans. The same could be said of all species.

As recently as 5-10,000 years ago, human lifespan extended not much longer than their reproductive lifespan. But with social organization and communication that could be remembered (oral histories) or written down(books), humans learned to develop safer environments, realized the value of sanitation, and developed a scientific approach to medicine, so that humans now live much longer than their reproductive lifespan. It is unclear if there has been positive natural selection to account for aging after reproduction cannot occur.

And even more problematic, humans invented transportation: boats, trains, planes and cars allowed geographically-limited species to travel. Environments formerly commonly used by large numbers of geographically stable populations became available to highly itinerant people. The disease-causing microbes limited to the geography of your ancestors were also limited to the geographies they inhabit, until mass transportation developed.

All vertebrates are protected by immediate activated innate immune cells such as macrophages and neutrophils that rapidly get rid of microbes by eating them and also adaptive immune system cells responsible for immunological memory—immune cells (memory lymphocytes) that live as long as we do, each precommitted to a single agent. The encounter with microbes or vaccines triggers the massive expansion of the lymphocytes responding to those microbes, creating a large pool of specific lymphocytes that can quickly act upon a second infection by the same microbe, thus giving rise to faster and more powerful immune responses. This is immunological memory. The innate cells don’t expand every time they re-encounter the same microbe, and they lack immune memory. But both come from blood-forming stem cells.

All of these innate and adaptive immune cells worked fine for the young, and for old folks who did not travel beyond a geography with a limited diversity of microbes. They could live on their immunological memory, just as other functions also shifted from activity to memory. But recently, stem cell scientists in the institute and their trainees around the world found that as all vertebrates age, blood stem cell competitions in post-reproductive, aging individuals result in a few innate immunity-biased blood stem cells becoming the dominant pool of blood stem cells that mainly make scavenger macrophages and bacteria-fighting), which are incapable of expanding and keeping immune memory cells. These blood stem cells make few new lymphocytes, because in the pre-modern era the long-lived memory lymphocytes protected individuals from the microbes they grew up with.

But now trains, planes and cars bring new microbes to which individuals cannot readily make new immune responses, because the old folks’ blood stem cells make precious few new lymphocytes to combat them, and immune memory can’t be developed. Infected individuals arriving via modern global transportation have brought disastrous pandemics, such as HIV-AIDS, Zika, Ebola, Bolivian Hemorrhagic Fever, and of course, SARS-2 covid-19. More of us old folks get dangerous infections, and our degree of illness and mortality is much greater, even under the best of care. We need much higer doses of vaccines to make sure the few new lymphocytes we do make have time to encounter the vaccine and make new memory cells against these pathogens.

This isn’t just a property of blood. It also works for brain stem cells, skin and hair stem cells, and even the wound repair fibroblasts, including those just under the skin.

Back in olden times four-legged vertebrates were preyed upon by larger vertebrates and birds that attacked from above, opening wounds mainly in the back skin. Escapees from these attacks had skin-healing stem cells and wound-healing fibroblast stem cells that rapidly made large, thick, and (to some nowadays) ugly scars. But cuts on the gums in the mouth healed without scars. It happens over and over again, and most of us don’t even think about it. But a young surgeon in training nearly 30 years ago started to operate on animal fetuses to prepare to try to save human fetuses with dangerous anomalies and malformations that could compromise birth itself, or could be fatal just after birth. That young surgeon was Mike Longaker, now a co-director of the Institute, who noticed that the animal fetuses that he operated on before birth didn’t have scars after they were born.

Nearly 10 years ago Mike and his trainees had the idea that there may be a diversity of fibroblasts, including some that had intrinsic gene-expression properties that made masses of collagen, and others that made not so much. He discovered that the fibroblasts on the back of mice that made big scars came from a genetic pathway called engrailed, and these dorsal-dermal fibroblasts made much more collagen per cell than those on the soft underside covering the belly. That discovery led him and colleague Geoff Gurtner to search for how engrailed gene function could give rise to these strong, but ugly scars—the extreme of which are keloid scars that are disfiguring and cannot be healed by cutting out the scar. You can read about this discovery in this issue.

Fibroblasts can cause a number of diseases and a number of non-healing scars. So discovering the mechanisms by which these dorsal-dermal, engrailed-derived fibroblasts and their stem cell precursors work and could be made to heal without scarring, could also be the basis for preventing scarring after surgery in the abdomen or pelvis or chest. These surgical adhesions that form in some people after surgery are more likely to cause disease than heal. This new understanding could also be the basis for ameliorating scarring with fibroblasts in scleroderma, lung fibrosis, and liver fibrosis—a field led by pathologist and stem cell faculty member Gerlinde Wernig.

This story of discovery and translating discovery is a theme in our institute. The fact that we are confronted by stem cell variations that came from olden times is just a new ‘wrinkle’.

How the Antarctic Icefish Lost Its Red Blood Cells But Survived Anyway

In 1928, a biologist named Ditlef Rustad caught an unusual fish off the coast of Bouvet Island in the Antarctic. The "white crocodile fish," as Rustad named it, had large eyes, a long toothed snout and diaphanous fins stretched across fans of slender quills. It was scaleless and eerily pale, as white as snow in some parts, nearly translucent in others. When Rustad cut the fish open, he discovered that its blood, too, was colorless—not a drop of red anywhere. The crocodile fish's gills looked odd as well: they were soft and white, like vanilla yogurt in contrast, a cod's gills are as dark as wine, soaked in oxygenated blood.

Later, Johan Ruud and other researchers confirmed that the Antarctic icefishes, as they are now known, are the only vertebrates that lack both red blood cells and hemoglobin—the iron-rich protein such cells use to bind and ferry oxygen through the circulatory system from heart to lungs to tissues and back again. At first blush, biologists regarded icefishes' pallor blood as a remarkable adaptation to the Antarctic's freezing, oxygen-rich waters. Perhaps icefishes absorbed so much dissolved oxygen from the ocean through their gills and ultra thin skin that they could abandon those big, spongy red blood cells. After all, the biologists reasoned, thinner blood requires less effort to circulate around the body and saving energy is always an advantage, especially when you are trying to survive in an extreme environment.

More recently, however, some biologists have proposed that the loss of hemoglobin was not a beneficial adaptation, but rather a genetic accident with unfortunate consequences. Since icefish blood can only transport 10 percent as much oxygen as typical fish blood, icefishes were forced to dramatically alter their bodies in order to survive. In this scenario, despite an evolutionary blunder that would be lethal to most fish, the icefishes' grit—as well as a little ecological serendipity—rescued them from their own bad blood. Scientists continue to revise icefishes' evolutionary history as new evidence surfaces, but their story is surely one of the most unique and bizarre in the animal kingdom.

Icefishes live in the Southern Ocean, which encircles Antarctica. Rotating currents essentially isolate these waters from the world's warmer seas, keeping temperatures low: temperatures near the Antarctic Peninsula, the northernmost part of the mainland, range from about 1.5 degrees Celsius in the summer to –1.8 degrees Celsius in the winter. Many fish in the Southern Ocean, including icefishes, produce antifreeze proteins to prevent ice crystals from forming in their blood when ocean temperatures drop below the freezing point of fresh water. Sixteen species of Antarctic icefishes comprise the family Channichthyidae, which falls under the larger suborder Notothenioidei. Among the hundreds of red-blooded Notothenioid species, only the icefishes lack hemoglobin. Together, the Notothenioids and icefishes dominate the waters they call home, accounting for approximately 35 percent of fish species and 90 percent of fish biomass in the Southern Ocean.

By comparing icefish DNA to the DNA of red-blooded fish, William Detrich of Northeastern University and his colleagues identified the specific genetic mutations responsible for the loss of hemoglobin. Basically, one of the genes essential for the assembly of the hemoglobin protein is completely garbled in icefishes. Although no other vertebrate completely lacks red blood cells, biologists have observed a diminishing of red blood cells in response to a changing environment. When it gets cold, it's advantageous for fish to make their blood a little thinner and easier to circulate. Fish that live in cold waters usually have a smaller percentage of red blood cells in their blood than fish that live in warmer waters. And fish in temperate regions decrease the percentage of red blood cells in their blood each winter to save energy. Relying on these facts, some biologists assumed that Antarctic icefish evolved incredibly thin blood as an adaptation to the Southern Ocean.

Kristin O'Brien of the University of Alaska Fairbanks and her colleague Bruce Sidell (who is now sadly deceased) decided to test this assumption. In a paper titled "When bad things happen to good fish," O'Brien and Sidell first point out that, compared to their cousins the Notothenioids and other similarly sized fish, icefishes have larger hearts and blood vessels. Although icefishes pump unusually thin blood through their bodies, their circulatory systems handle huge volumes. O'Brien and Sidell calculated that icefishes expend approximately twice as much energy as red-blooded Notothenioids moving all that extra blood. Whereas fish in temperate zones devote no more than five percent of their resting metabolic rate to their hearts, icefishes invest a whopping 22 percent of their body's available energy in their giant tickers.* O'Brien and Sidell also show that icefish have more blood vessels nourishing certain organs than red-blooded fish. If you peel back the outer layers of a typical fish's eye and fill the blood vessels with yellow silicone rubber, you will see a web of neatly segregated vessels tracing the contour of the eye like the ribs of a pumpkin. Do the same to an icefish's eye and you will find a dense, tangled mess like a plate of spaghetti.

Like other biologists in recent years, O'Brien and Sidell view the icefishes' large hearts and capillaries, high blood volume and dense nets of blood vessels as compensations for the loss of hemoglobin. But these adaptations alone might not have been enough to save icefishes from extinction—they likely benefited from fortuitous circumstances as well. Around 25 million years ago, the Southern Ocean flowing around Antarctica—which had broken away from other continents—began to cool. Not only did the colder water offer more oxygen, it also killed many species that did not evolve antifreeze proteins or otherwise adapt to the cold, creating a frigid sanctuary that the icefishes and their relatives have dominated ever since.

Today, however, icefishes face a new threat: manmade climate change. The Southern Ocean is getting warmer and possibly more acidic and less nutritious. O'Brien says researchers have shown that adult icefishes are more sensitive to changes in temperature than red-blooded fish—they cannot stand the heat. If Ruud was right—that "only in the cold water of the polar regions could a fish survive that has lost its pigment"—then the ongoing changes to the Southern Ocean might be the icefishes' undoing. Consider this version of their story: icefishes evolved to survive sub-freezing temperatures in one of the most extreme environments on Earth, only to lose their red blood cells to a genetic accident despite the mishap, they kept swimming, expanding their hearts and growing more blood vessels to get enough oxygen around their bodies now, people are turning the Southern Ocean into a habitat for which icefishes are completely unsuited, forcing them to adapt once again or perish. Personally, I'm clinging to the hope that even if icefishes do not have any hemoglobin in their blood, they have plenty of resilience coursing through their veins.

*Source for cardiac energy investment: Hemmingsen, E. A. and Douglas, E. L. (1977). Respiratory and circulatory adaptations to the absence of hemoglobin in chaenichthyid fishes. In Adaptations within Antarctic Ecosystems (ed. G. A. Llano), pp. 479-487. Washington: Smithsonian Institution.


Ferris Jabr is a contributing writer for Scientific American. He has also written for the New York Times Magazine, the New Yorker and Outside.