Why is competence useful for a starving cell?

Why is competence useful for a starving cell?

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I know that some bacteria become competent when there is not much food available in their environment.

I don't really understand why this is useful for the cell. I've seen some other organisms form a biofilm or get together to become a slime when starved and I understand the utility of this mechanisms (reducing energy consumption and being able to move around easily to look for nutrients).

The only plausible explanation that I see is that being competent might be useful to take advantage of the DNA of dead cells. Am I right?

Labtutorials in Biology

Transformation is the process of introducing foreign DNA (e.g plasmids, BAC) into a bacterium. Bacterial cells into which foreign DNA can be transformed are called competent. Some bacteria are naturally competent (e.g B. subtilis), whereas others such as E. coli are not naturally competent. Non-competent cells can be made competent and then transformed via one of two main approaches chemical transformation and electroporation. It is important to note we have tested transformations of the distribution kit with this protocol. We have found that it is the best protocol. This protocol may be particularly useful if you are finding that your transformations are not working or yiedling few colonies.

In nature what happens is shown on the following two videos:

Escherichia coli competence gene homologs are essential for competitive fitness and the use of DNA as a nutrient

Natural genetic competence is the ability of cells to take up extracellular DNA and is an important mechanism for horizontal gene transfer. Another potential benefit of natural competence is that exogenous DNA can serve as a nutrient source for starving bacteria because the ability to "eat" DNA is necessary for competitive survival in environments containing limited nutrients. We show here that eight Escherichia coli genes, identified as homologs of com genes in Haemophilus influenzae and Neisseria gonorrhoeae, are necessary for the use of extracellular DNA as the sole source of carbon and energy. These genes also confer a competitive advantage to E. coli during long-term stationary-phase incubation. We also show that homologs of these genes are found throughout the proteobacteria, suggesting that the use of DNA as a nutrient may be a widespread phenomenon.


Long-term survival and competition patterns…

Long-term survival and competition patterns of com gene mutants. (A) Superimposition of nine…

Relative fitness of com mutants.…

Relative fitness of com mutants. (A) Schematic representation of the construct used for…

Average growth yields of wild-type…

Average growth yields of wild-type (WT) or com mutant cells in minimal medium…

Catabolism of nucleobases, nucleosides, and…

Catabolism of nucleobases, nucleosides, and dNMPs by wild-type (□) and com mutant (○)…

Model of DNA uptake and catabolism in E. coli . The outer membrane,…

Escherichia coli competence gene homologs are essential for competitive fitness and the use of DNA as a nutrient

Natural genetic competence is the ability of cells to take up extracellular DNA and is an important mechanism for horizontal gene transfer. Another potential benefit of natural competence is that exogenous DNA can serve as a nutrient source for starving bacteria because the ability to "eat" DNA is necessary for competitive survival in environments containing limited nutrients. We show here that eight Escherichia coli genes, identified as homologs of com genes in Haemophilus influenzae and Neisseria gonorrhoeae, are necessary for the use of extracellular DNA as the sole source of carbon and energy. These genes also confer a competitive advantage to E. coli during long-term stationary-phase incubation. We also show that homologs of these genes are found throughout the proteobacteria, suggesting that the use of DNA as a nutrient may be a widespread phenomenon.


Long-term survival and competition patterns…

Long-term survival and competition patterns of com gene mutants. (A) Superimposition of nine…

Relative fitness of com mutants.…

Relative fitness of com mutants. (A) Schematic representation of the construct used for…

Average growth yields of wild-type…

Average growth yields of wild-type (WT) or com mutant cells in minimal medium…

Catabolism of nucleobases, nucleosides, and…

Catabolism of nucleobases, nucleosides, and dNMPs by wild-type (□) and com mutant (○)…

Model of DNA uptake and catabolism in E. coli . The outer membrane,…

Why Cells Starved Of Iron Burn More Glucose

Duke University Medical Center scientists have found a mechanism that allows cells starved of iron to shut down energy-making processes that depend on iron and use a less efficient pathway involving glucose. This metabolic reshuffling mechanism, found in yeast cells, helps explain how humans respond to iron deficiency, and may help with diabetes research as well.

"If we can understand what metabolic changes happen along a gradient of iron deficiency, then we might be able to identify signatures of a modest iron deficiency in humans," said lead researcher Dennis J. Thiele, Ph.D., who is the George Barth Geller Professor of the Duke Department of Pharmacology and Cancer Biology, "We could head it off at the pass."

"This basic science discovery in yeast sheds important new light on how humans may respond to iron deficiency, which is the most common nutritional disorder," said Duke School of Medicine Dean Nancy C. Andrews, an expert in human diseases of iron metabolism.

The findings, published in the June issue of Cell Metabolism, are also potentially important for those studying diabetes. "Evidence is growing that if there is an iron imbalance in the beta cells of the pancreas, these cells won't produce insulin properly," Thiele said. "Now we know what happens in yeast in terms of glucose (sugar) utilization. We need to learn whether the same cause and effect holds true in mammals."

Iron deficiency anemia affects nearly 2 billion people worldwide, most often pregnant women, premature babies, and young children, Thiele said. Anemia profoundly affects cognitive development, and motor and neuronal development, he said.

The scientists wanted to know how organisms establish a balance of iron in their cells. "We now know when yeast cells encounter iron deficiency, they reorganize their metabolism by degrading specific messenger RNAs (mRNAs) and leaving other messenger RNAs alone, which begins a sequence of events," said Thiele. Messenger RNAs are molecules that carry coding information from the DNA to the structures that make proteins, which in turn regulate the body's structures and functions.

The first response to iron deficiency is to shut down the energy hub of the cell, the mitochondria, which takes glucose and turns it efficiently into cell energy fuel, or ATP. The mitochondria depend greatly on iron. As a cell becomes more starved for iron, it "dials down" the mitochondrial processes by degrading the mRNAs encoding the proteins involved in such processes, and thus, some iron is freed up, Thiele said.

The second response is to shut down iron storage pathways and other, more dispensable biochemical reactions that depend on iron. "When you are low on iron, you don't want to save it and take it out of use," Thiele explained.

The third response is to increase glucose utilization pathways outside of the mitochondria, which is a much less efficient way to produce energy. Glucose molecules processed for energy outside of the mitochondria create about 18 times less energy, said co-author Sandra Vergara, a doctoral student in Thiele's lab.

"Cellular iron balance follows the rules of economics," Vergara said. "During scarcity, the cell prioritizes the utilization of iron, saving it for more essential processes. This prioritization comes at a cellular cost, which is reflected in the higher demand for glucose, so the cell can keep the correct amount of energy flowing."

If we run low on ATP, we become tired and lethargic, which are symptoms of iron deficiency, Thiele said. "Iron is hard for humans to get from plant sources, which form the basis for most of the world's diet." Iron is very abundant in nature, but cells have a hard time taking it up, because it can change its form inside the body.

Thiele stressed that the findings show what happens during iron deficiency in baker's yeast cells, but probably in some way do extend to people. "Nearly 35 percent of all known human disease genes have a counterpart in the yeast genome. A scientist is always conservative about extrapolating. I think we can make predictions that the metabolic reshuffling that we observe in yeast, the same types of key proteins and enzymes that are involved during iron deficiency, are likely to follow similar patterns in human cells."

Most of the primary metabolism pathways are conserved at the molecular level from yeast to humans, Vergara said.

The third co-author on this work was Sergi Puig, who was a postdoctoral fellow in the Thiele lab and now is an assistant professor at the University of Valencia in Spain. This research was funded by a grant from the Spanish Ministerio de Educacion y Ciencia and FEDER funds from the European Community, an NIH grant from the National Institute of General Medical Sciences and an NIH predoctoral fellowship.


The following are some of the symptoms of starvation:

Changes in behavior or mental status Edit

The beginning stages of starvation impact mental status and behaviors. These symptoms show up as irritable mood, fatigue, trouble concentrating, and preoccupation with food thoughts. People with those symptoms tend to be easily distracted and have no energy.

Physical signs Edit

As starvation progresses, the physical symptoms set in. The timing of these symptoms depends on age, size, and overall health. It usually takes days to weeks, and includes weakness, fast heart rate, shallow breaths that are slowed, thirst, and constipation. There may also be diarrhea in some cases. The eyes begin to sink in and glass over. The muscles begin to become smaller and muscle wasting sets in. One prominent sign in children is a swollen belly. Skin loosens and turns pale in color, and there may be swelling of the feet and ankles.

Weakened immune system Edit

Symptoms of starvation may also appear as a weakened immune system, slow wound healing, and poor response to infection. Rashes may develop on the skin. The body directs any nutrients available to keeping organs functioning.

Other symptoms Edit

Other effects of starvation may include:

Stages of starvation Edit

The symptoms of starvation show up in three stages. Phase one and two can show up in anyone that skips meals, diets, and goes through fasting. Phase three is more severe, can be fatal, and results from long-term starvation.

Phase one: When meals are skipped, the body begins to maintain blood sugar levels by producing glycogen in the liver and breaking down stored fat and protein. The liver can provide glycogen for the first few hours. After that, the body begins to break down fat and protein. Fatty acids are used by the body as an energy source for muscles, but lower the amount of glucose that gets to the brain. Another chemical that comes from fatty acids is glycerol. It can be used like glucose for energy, but eventually runs out.

Phase two: Phase two can last for up to weeks at a time. In this phase, the body mainly uses stored fat for energy. The breakdown occurs in the liver and turns fat into ketones. After fasting has gone on for one week, the brain will use these ketones and any leftover glucose. Using ketones lowers the need for glucose, and the body slows the breakdown of proteins.

Phase three: By this point, the fat stores are gone and the body begins to turn to stored protein for energy. This means it needs to break down muscle tissues which are full of protein the muscles break down very quickly. Protein is essential for our cells to work properly, and when it runs out, the cells can no longer function.

The cause of death due to starvation is usually an infection, or the result of tissue breakdown. The body is unable to gain enough energy to fight off bacteria and viruses. The signs at the end stages include: hair color loss, skin flaking, swelling in the extremities, and a bloated belly. Even though they may feel hunger, people in the end-stage of starvation are usually unable to eat enough food.

Starvation is an imbalance between energy intake and energy expenditure. The body expends more energy than it takes in. This imbalance can arise from one or more medical conditions or circumstantial situations, which can include:

Circumstantial causes

  • Child, elder, or dependant abuse for any reason, such as political strife and war [7][8]
  • Excessive fasting

With a typical high-carbohydrate diet, the human body relies on free blood glucose as its primary energy source. Glucose can be obtained directly from dietary sugars and by the breakdown of other carbohydrates. In the absence of dietary sugars and carbohydrates, glucose is obtained from the breakdown of stored glycogen. Glycogen is a readily-accessible storage form of glucose, stored in notable quantities in the liver and skeletal muscle.

After the exhaustion of the glycogen reserve, and for the next 2–3 days, fatty acids become the principal metabolic fuel. At first, the brain continues to use glucose. If a non-brain tissue is using fatty acids as its metabolic fuel, the use of glucose in the same tissue is switched off. Thus, when fatty acids are being broken down for energy, all of the remaining glucose is made available for use by the brain. [ citation needed ]

After 2 or 3 days of fasting, the liver begins to synthesize ketone bodies from precursors obtained from fatty acid breakdown. The brain uses these ketone bodies as fuel, thus cutting its requirement for glucose. After fasting for 3 days, the brain gets 30% of its energy from ketone bodies. After 4 days, this may increase to 70% or more. [9] Thus, the production of ketone bodies cuts the brain's glucose requirement from 80 g per day to 30 g per day, about 35% of normal, with 65% derived from ketone bodies. But of the brain's remaining 30 g requirement, 20 g per day can be produced by the liver from glycerol (itself a product of fat breakdown). This still leaves a deficit of about 10 g of glucose per day that must be supplied from another source this other source will be the body's own proteins.

After exhaustion of fat stores, the cells in the body begin to break down protein. This releases alanine and lactate produced from pyruvate, which can be converted into glucose by the liver. Since much of human muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation. However, the body is able to choose which cells will break down protein and which will not. About 2–3 g of protein has to be broken down to synthesize 1 g of glucose about 20–30 g of protein is broken down each day to make 10 g of glucose to keep the brain alive. However, this number may decrease the longer the fasting period is continued, in order to conserve protein.

Starvation ensues when the fat reserves are completely exhausted and protein is the only fuel source available to the body. Thus, after periods of starvation, the loss of body protein affects the function of important organs, and death results, even if there are still fat reserves left. In a leaner person, the fat reserves are depleted faster, and the protein, sooner, therefore death occurs sooner. [ citation needed ] ) Ultimately, the cause of death is in general cardiac arrhythmia or cardiac arrest, brought on by tissue degradation and electrolyte imbalances. Things like metabolic acidosis may also kill starving people. [10]

Starvation can be caused by factors beyond the control of the individual. The Rome Declaration on World Food Security outlines several policies aimed at increasing food security [11] and, consequently, preventing starvation. These include:

Supporting farmers in areas of food insecurity through such measures as free or subsidized fertilizers and seeds increases food harvest and reduces food prices. [13]

Patients that suffer from starvation can be treated, but this must be done cautiously to avoid refeeding syndrome. [14] Rest and warmth must be provided and maintained. Small sips of water mixed with glucose should be given in regular intervals. Fruit juices can also be given. Later, food can be given gradually in small quantities. The quantity of food can be increased over time. Proteins may be administered intravenously to raise the level of serum proteins. [15] For worse situations, hospice care and opioid medications can be used.

Organizations Edit

Many organizations have been highly effective at reducing starvation in different regions. Aid agencies give direct assistance to individuals, while political organizations pressure political leaders to enact more macro-scale policies that will reduce famine and provide aid.

According to estimates by the Food and Agriculture Organization there were 925 million under- or malnourished people in the world in 2010. [16] This was a decrease from an estimate of roughly 1 billion malnourished people in 2009. [17] In 2007, 923 million people were reported as being undernourished, an increase of 80 million since 1990–92. [18] An estimated 820 million people did not have enough to eat in 2018, up from 811 million in the previous year, which is the third year of increase in a row. [19]

As the definitions of starving and malnourished people are different, the number of starving people is different from that of malnourished. Generally, far fewer people are starving, than are malnourished.

The proportion of malnourished and of starving people in the world has been more or less continually decreasing for at least several centuries. [20] This is due to an increasing supply of food and to overall gains in economic efficiency. In 40 years, the proportion of malnourished people in the developing world has been more than halved. The proportion of starving people has decreased even faster.

Year 1970 1980 1990 2004 2007 2009
Proportion of undernourished people in the less-developed world [17] [21] [22] 37 % 28 % 20 % 16 % 17 % 16 %

Historically, starvation has been used as a death sentence. From the beginning of civilization to the Middle Ages, people were immured, and died for want of food.

In ancient Greco-Roman societies, starvation was sometimes used to dispose of guilty upper-class citizens, especially erring female members of patrician families. In the year 31, Livilla, the niece and daughter-in-law of Tiberius, was discreetly starved to death by her mother for her adulterous relationship with Sejanus and for her complicity in the murder of her own husband: Drusus the Younger.

Another daughter-in-law of Tiberius, named Agrippina the Elder (a granddaughter of Augustus and the mother of Caligula), also died of starvation, in 33 AD, however, it is unclear if her starvation was self-inflicted.

A son and daughter of Agrippina were also executed by starvation for political reasons Drusus Caesar, her second son, was put in prison in 33 AD, and starved to death by orders of Tiberius (he managed to stay alive for nine days by chewing the stuffing of his bed) Agrippina's youngest daughter, Julia Livilla, was exiled on an island in 41 by her uncle, Emperor Claudius, and her death by starvation was arranged by the empress Messalina.

It is also possible that Vestal Virgins were starved when found guilty of breaking their vows of celibacy.

Ugolino della Gherardesca, his sons, and other members of his family were immured in the Muda, a tower of Pisa, and starved to death in the thirteenth century. Dante, his contemporary, wrote about Gherardesca in his masterpiece The Divine Comedy.

In Sweden in 1317, King Birger of Sweden imprisoned his two brothers for a coup they had staged several years earlier (Nyköping Banquet). According to legend they died of starvation a few weeks later, since their brother had thrown the prison key in the castle moat.

In Cornwall in the UK in 1671, John Trehenban from St Columb Major was condemned to be starved to death in a cage at Castle An Dinas for the murder of two girls.

The Makah, a Native American tribe inhabiting the Pacific Northwest near the modern border of Canada and the United States, practiced death by starvation as a punishment for slaves. [23]

Many of the prisoners died in the Nazi concentration camps through deliberate maltreatment, disease, starvation, and overwork, or were executed as unfit for labor. Many occupants of ghettos in eastern Europe also starved to death, most notoriously in the Warsaw Ghetto in German-occupied Poland. Prisoners were transported in inhumane conditions by rail freight cars, in which many died before reaching their destination. The prisoners were confined to the cattle cars for days or even weeks, with little or no food or water. Many died of dehydration in the intense heat of summer or froze to death in winter. Nazi concentration camps in Europe from 1933 to 1945 deliberately underfed prisoners, who were at the same time forced to perform heavy labour. Their diet was restricted to watery vegetable soup and a little bread, with little to no dietary fats, proteins or other essential nutrients. Such treatment led to loss of body tissues, and when prisoners became skeletal, the so-called Muselmann were murdered by gas or bullets when examined by camp doctors.

Starvation was also used as a punishment where victims were locked into a small cell until dead, a process which could take many days. Saint Maximilian Kolbe, a martyred Polish friar, underwent a sentence of starvation in Auschwitz concentration camp in 1941. Ten prisoners had been condemned to death by starvation in the wake of a successful escape from the camp. Kolbe volunteered to take the place of a man with a wife and children. After two weeks of starvation, Kolbe and three other inmates remained alive they were then executed with injections of phenol.

Starving Cancer by Cutting Off Its Favorite Foods, Glucose and Glutamine

Your body cells, particularly neurons, love the sugar glucose. This is the reason that your body closely regulates the level of glucose in your blood. Your brain would literally starve without it. If you do not consume enough carbohydrates in your diet, your body will synthesize the glucose you need.

Unfortunately, cancer also loves glucose. It loves it so much that cancer cells are willing to burn through glucose as quickly as possible, similar to the way muscle cells burn through glucose during rigorous exercise (a process known as glycolysis). Cancer cells also supplement their "diet" with glutamine, an amino acid found in proteins.

In order to implement this metabolic shift, cancer cells put more glucose transporters (which import glucose) into their membranes and rely on glutamine to satisfy other nutritional requirements. This has led to the hypothesis that blocking the import of glucose and the metabolism of glutamine could serve as powerful weapons against cancer. In other words, starving cancer cells of their favorite foods could inhibit tumor growth.

Starving Cancer Cells of Glucose and Glutamine

Reporting in the journal Cell Chemical Biology, a team of researchers led by Elena Reckzeh describe the discovery of a new, high-potency molecule (which they called Glutor) that blocked several varieties of the glucose transport protein. This is significant because previous inhibitors were low potency and/or only blocked one kind of glucose transport protein.

The first image depicts the molecular mechanism of their proposed chemotherapeutic strategy. The first part of the strategy involves treating cancer with Glutor, which will shut down glucose metabolism. Indeed, the authors showed that 44 different cancer cell lines were potently inhibited by Glutor in vitro. Non-cancerous cell lines were not inhibited.

The second leg of their strategy involves blocking an enzyme responsible for metabolizing glutamine. When the treatments are combined, they act together to suppress cancer cell growth. (See second image. The blue region depicts the synergy of the two drugs acting in concert.)

What the Discovery Means

While this discovery is certainly very exciting, many obstacles remain. For instance, chemotherapy always has side effects, usually due to the targeting of rapidly dividing cells. It's not only cancer cells that divide quickly so do immune cells, adult stem cells, and hair follicle cells, among many others. It is for these reasons that people on chemotherapy are usually immunodeficient and bald.

Additionally, an accompanying commentary by William Katt and colleagues indicated that there are no FDA-approved drugs that target glucose and glutamine metabolism. This is because previous drug candidates proved to be too toxic for use in humans.

So while the characteristics of Glutor are quite appealing from a pharmacologic standpoint, there is still much to prove before the drug could be available on the market.

Growth Phases

Bacteria grown in a closed environment -- otherwise known as a batch culture -- have been repeatedly shown to grow in certain patterns. The bacteria first adjust to the medium, or liquid food, in which they are grown, during what is called the lag phase. They then start dividing rapidly in what is called the log, or exponential, phase. As the population grows, food begins to run low. Growth slows down until it flattens out in what is called the stationary phase. As food continues to be depleted, cells begin to die and the population drops during what is called the death phase. Transformation of bacteria is most efficient during the log, or exponential growth, phase of the colony.

For Students & Teachers

For Teachers Only

The highly complex organization of living systems requires constant input of energy and the exchange of macromolecules.

Describe the processes that allow organisms to use energy stored in biological macromolecules.

Explain how cells obtain energy from biological macromolecules in order to power cellular functions.

Fermentation and cellular respiration use energy from biological macromolecules to produce ATP. Respiration and fermentation are characteristic of all forms of life.

Cellular respiration in eukaryotes involves a series of coordinated enzyme-catalyzed reactions that capture energy from biological macromolecules.

The electron transport chain transfers energy from electrons in a series of coupled reactions that establish an electrochemical gradient across membranes —

  1. Electron transport chain reactions occur in chloroplasts, mitochondria, and prokaryotic plasma membranes.
  2. In cellular respiration, electrons delivered by NADH and FADH2 are passed to a series of electron acceptors as they move toward the terminal electron acceptor, oxygen. In photosynthesis, the terminal electron acceptor is NADP + . Aerobic prokaryotes use oxygen as a terminal electron acceptor, while anaerobic prokaryotes use other molecules.
  3. The transfer of electrons is accompanied by the formation of a proton gradient across the inner mitochondrial membrane or the internal membrane of chloroplasts, with the membrane(s) separating a region of high proton concentration from a region of low proton concentration. In prokaryotes, the passage of electrons is accompanied by the movement of protons across the plasma membrane.
  4. The flow of protons back through membrane-bound ATP synthase by chemiosmosis drives the formation of ATP from ADP and inorganic phosphate. This is known as oxidative phosphorylation in cellular respiration and photophosphorylation in photosynthesis.
  5. In cellular respiration, decoupling oxidative phosphorylation from electron transport generates heat. This heat can be used by endothermic organisms to regulate body temperature.

Glycolysis is a biochemical pathway that releases energy in glucose to form ATP from ADP and inorganic phosphate, NADH from NAD + , and pyruvate.

Pyruvate is transported from the cytosol to the mitochondrion, where further oxidation occurs.

In the Krebs cycle, carbon dioxide is released from organic intermediates. ATP is synthesized from ADP and inorganic phosphate, and electrons are transferred to the coenzymes NADH and FADH2.

Electrons extracted in glycolysis and Krebs cycle reactions are transferred by NADH and FADH2 to the electron transport chain in the inner mitochondrial membrane.

When electrons are transferred between molecules in a sequence of reactions as they pass through the ETC, an electrochemical gradient of protons (hydrogen ions) across the inner mitochondrial membrane is established.

Fermentation allows glycolysis to proceed in the absence of oxygen and produces organic molecules, including alcohol and lactic acid, as waste products.

The conversion of ATP to ADP releases energy, which is used to power many metabolic processes.


The names of the specific electron carriers in the electron transport chain are beyond the scope of the course and the AP exam.

Specific steps, names of enzymes, and intermediates of the pathways for these processes are beyond the scope of the course and the AP exam.

Memorization of the steps in glycolysis and the Krebs cycle, and of the structures of the molecules and the names of the enzymes involved, are beyond the scope of the course and the AP Exam.

An Old Idea, Revived: Starve Cancer to Death

In the early 20th century, the German biochemist Otto Warburg believed that tumors could be treated by disrupting their source of energy. His idea was dismissed for decades — until now.

Credit. Photo illustration by Cristiana Couceiro. Source photograph from Getty Images and Wikimedia Commons.

T he story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes whatever caused cancer, he surmised, had something to do with chromosomes.

Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.

Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.

Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.

In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.

“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.

There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.

Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.

“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”

Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.

That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, speaks to the German obsession with cancer in the first half of the 20th century. At the time, cancer was more prevalent in Germany than in almost any other nation. According to the Stanford historian Robert Proctor, by the 1920s Germany’s escalating cancer rates had become a “major scandal.” A number of top Nazis, including Hitler, are believed to have harbored a particular dread of the disease Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. Whether Hitler was personally aware of Warburg’s research is unknown, but one of Warburg’s former colleagues wrote that several sources told him that “Hitler’s entourage” became convinced that “Warburg was the only scientist who offered a serious hope of producing a cure for cancer one day.”

Although many Jewish scientists fled Germany during the 1930s, Warburg chose to remain. According to his biographer, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab, “science was the dominant emotion” of Warburg’s adult life, “virtually subjugating all other emotions.” In Krebs’s telling, Warburg spent years building a small team of specially trained technicians who knew how to run his experiments, and he feared that his mission to defeat cancer would be set back significantly if he had to start over. But after the war, Warburg fired all the technicians, suspecting that they had reported his criticisms of the Third Reich to the Gestapo. Warburg’s reckless decision to stay in Nazi Germany most likely came down to his astonishing ego. (Upon learning he had won the Nobel Prize, Warburg’s response was, “It’s high time.”)

“Modesty was not a virtue of Otto Warburg,” says George Klein, a 90-year-old cancer researcher at the Karolinska Institute in Sweden. As a young man, Klein was asked to send cancer cells to Warburg’s lab. A number of years later, Klein’s boss approached Warburg for a recommendation on Klein’s behalf. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.” Klein also recalls the lecture Warburg gave in Stockholm in 1950 at the 50th anniversary of the Nobel Prize. Warburg drew four diagrams on a blackboard explaining the Warburg effect, and then told the members of the audience that they represented all that they needed to know about the biochemistry of cancer.

Warburg was so monumentally stubborn that he refused to use the word “mitochondria,” even after it had been widely accepted as the name for the tiny structures that power cells. Instead Warburg persisted in calling them “grana,” the term he came up with when he identified those structures as the site of cellular respiration. Few things would have been more upsetting to him than the thought of Nazi thugs chasing him out of the beautiful Berlin institute, modeled after a country manor and built specifically for him. After the war, the Russians approached Warburg and offered to erect a new institute in Moscow. Klein recalls that Warburg told them with great pride that both Hitler and Stalin had failed to move him. As Warburg explained to his sister: “Ich war vor Hitler da” — “I was here before Hitler.”

Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal,” Warburg wrote in 1956, responding to a criticism of his hypothesis that cancer is a problem of energy. “A man who knows nothing at all about engines, their structure and their purpose may discover the difference. He may, for example, smell it.”

The “complete combustion,” in Warburg’s analogy, is respiration. The “incomplete combustion,” turning nutrients into energy without oxygen, is known as fermentation. Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warburg thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.

If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.

Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism. In Thompson’s analogy, the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms. His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. But Thompson’s search for those mutations didn’t lead to an entirely new discovery. Instead, it led him to AKT, a gene already well known to molecular biologists for its role in promoting cell division. Thompson now believes AKT plays an even more fundamental role in metabolism.

The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat it instead stuffs itself with glucose. Thompson discovered he could induce the “full Warburg effect” simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible. When Thompson presents his research to high-school students, he shows them a slide of mold spreading across a piece of bread. The slide’s heading — “Everyone’s first cancer experiment” — recalls Warburg’s observation that cancer cells will carry out fermentation at almost the same rate of wildly growing yeasts.

Just as Thompson has redefined the role of AKT, Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.

Unlike healthy cells, growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn’t available. They’re “addicted to nutrients,” Dang says when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer: It’s not that other types of alterations can’t arise first, but rather that, when they do, the incipient tumors lack the access to the nutrients they need to grow. Dang uses the analogy of a work crew trying to put up a building. “If you don’t have enough cement, and you try to put a lot of bricks together, you’re going to collapse,” he says.

Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.

Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.


Warburg, too, appreciated that a tumor’s dependence upon a steady flow of nutrients might eventually prove to be its fatal weakness. Long after his initial discovery of the Warburg effect, he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warburg faced then is the same one that metabolism researchers face today: Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way. “You block glucose, they use glutamine,” Dang says, in reference to another primary fuel used by cancers. “You block glucose and glutamine, they might be able to use fatty acids. We don’t know yet.”

Given Warburg’s own story of historical neglect, it’s fitting that what may turn out to be one of the most promising cancer metabolism drugs has been sitting in plain sight for decades. That drug, metformin, is already widely prescribed to decrease the glucose in the blood of diabetics (76.9 million metformin prescriptions were filled in the United States in 2014). In the years ahead, it’s likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.

Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows, and used a centrifuge at his lab to make his cream and butter.

Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.

The insulin hypothesis can be traced to the research of Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell. Cantley now refers to insulin and a closely related hormone, IGF-1 (insulinlike growth factor 1), as “the champion” activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, “it really is insulin itself that’s getting the tumor started.” One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway “gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.” Cantley, who avoids eating sugar as much as he can, is currently studying the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers. He says that the effects of a sugary diet on colorectal, breast and other cancer models “looks very impressive” and “rather scary.”

Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die.

“I think there’s no doubt that insulin is pro-cancer,” Watson says, with respect to the link between obesity, diabetes and cancer. “It’s as good a hypothesis as we have now.” Watson takes metformin for cancer prevention among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. “It’s a hypothesis,” Weinberg says. “I don’t know if it’s right or wrong.”

During Warburg’s lifetime, insulin’s effects on metabolic pathways were even less well understood. But given his ego, it’s highly unlikely that he would have considered the possibility that anything other than damaged respiration could cause cancer. He died sure that he was right about the disease. Warburg framed a quote from Max Planck and hung it above his desk: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die.”

Watch the video: Κοινωνικές ικανότητες (June 2022).


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