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Wednesday, 6 February 2019

Otto Heinrich Warburg





Kenyataan Otto Heinrich Warburg




The Nobel Prize in Physiology or Medicine 1931
Otto Warburg
Born: 8 October 1883, Freiburg im Breisgau, Germany
Died: 1 August 1970, West Berlin, West Germany (now Germany)
Affiliation at the time of the award: Kaiser-Wilhelm-Institut (now Max-Planck-Institut) für Biologie, Berlin-Dahlem, Germany
Prize motivation: "for his discovery of the nature and mode of action of the respiratory enzyme"
Field: cell physiology, metabolism
Prize share: 1/1


Work
In our cells nutrients are broken down so that energy is released for the construction of cells. This respiration requires enzymes, substances that facilitate the process without being incorporated in the final products. Otto Warburg studied the respiration of sea urchins and other organisms at an early stage of development. By measuring oxygen consumption in living cells and studying which enzymes reacted, in 1928 he concluded that the respiration enzyme he was looking for was a red ferrous pigment related to the blood pigment, hemoglobin.




While working at the Marine Biological Station, Warburg performed research on oxygen consumption in sea urchin eggs after fertilization, and proved that upon fertilization, the rate of respiration increases by as much as sixfold. His experiments also proved iron is essential for the development of the larval stage.

In 1918, Warburg was appointed professor at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem (part of the Kaiser-Wilhelm-Gesellschaft). By 1931 he was named director of the Kaiser Wilhelm Institute for Cell Physiology, which was founded the previous year by a donation of the Rockefeller Foundation to the Kaiser Wilhelm Gesellschaft (since renamed the Max Planck Society).

Warburg investigated the metabolism of tumors and the respiration of cells, particularly cancer cells, and in 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme".[1] The award came after receiving 46 nominations over a period of nine years beginning in 1923, 13 of which were submitted in 1931, the year he won the prize.[3]

Nobel Laureate George Wald, having completed his Ph.D. in zoology at Columbia University, received an award from the US National Research Council to study with Warburg. During his time with Warburg, 1932-1933, Wald discovered vitamin A in the retina.



Cancer Hypotheses

Warburg hypothesized that cancer growth is caused by tumor cells generating energy (as e.g. adenosine triphosphate / ATP) mainly by anaerobic breakdown of glucose (known as fermentation, or anaerobic respiration). This is in contrast to healthy cells, which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end product of glycolysis, and is oxidized within the mitochondria. Hence, and according to Warburg, cancer should be interpreted as a mitochondrial dysfunction.
Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.
— Otto H. Warburg, [13]
Warburg continued to develop the hypothesis experimentally, and gave several prominent lectures outlining the theory and the data.[14]
Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the metabolic changes are considered to be a result of these mutations rather than a cause.[15]



The Warburg hypothesis (/ˈvɑːrbʊərɡ/), sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria.[1] The term Warburg effect describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen.[2]

Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924.[3] He hypothesized that cancer, malignant growth, and tumor growth are caused by the fact that tumor cells mainly generate energy (as e.g. adenosine triphosphate / ATP) by non-oxidative breakdown of glucose (a process called glycolysis). This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis, and is oxidized within the mitochondria. Hence, according to Warburg, the driver of cancer cells should be interpreted as stemming from a lowering of mitochondrial respiration. Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect.

Cancer is caused by mutations and altered gene expression, in a process called malignant transformation, resulting in an uncontrolled growth of cells.[4][5] The metabolic differences observed by Warburg adapts cancer cells to the hypoxic (oxygen-deficient) conditions inside solid tumors, and results largely from the same mutations in oncogenes and tumor suppressor genes that cause the other abnormal characteristics of cancer cells.[6] Therefore, the metabolic change observed by Warburg is not so much the cause of cancer, as he claimed, but rather, it is one of the characteristic effects of cancer-causing mutations.

Warburg articulated his hypothesis in a paper entitled The Prime Cause and Prevention of Cancer which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau, Lake Constance, Germany. In this speech, Warburg presented additional evidence supporting his theory that the elevated anaerobiosis seen in cancer cells was a consequence of damaged or insufficient respiration. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar."[7]

Warburg's hypothesis has re-gained attention due to several discoveries linking impaired mitochondrial function as well as impaired respiration to the growth, division and expansion of tumor cells. In a study by Michael Ristow and co-workers, colon cancer lines were modified to overexpress frataxin. The results of their work suggest that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.[8]

Studies published since 2005 have shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHCA), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.[9][10][11][12] Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.[13] The chemical dichloroacetic acid (DCA), which promotes respiration and the activity of mitochondria, has also been shown to kill cancer cells in vitro and in some animal models.[14] The body often kills damaged cells by apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. The reactivation of mitochondria in cancer cells restarts their apoptosis program.[15] Besides promising human research at the Department of Medicine, University of Alberta led by Dr Evangelos Michelakis, other glycotic inhibitors besides DCA that hold promise include Bromopyruvic acid being researched at The University of Texas M. D. Anderson Cancer Center, 2-deoxyglucose (2-DG) at Emory University School of Medicine, and lactate dehydrogenase A [16] at Johns Hopkins University School of Medicine.




In plant physiology, the Warburg's effect is the decrease in the rate of photosynthesis by high oxygen concentrations.[1][2] Oxygen is a competitive inhibitor of the carbon dioxide fixation by RuBisCO which  initiates photosynthesis. Furthermore, oxygen stimulates photorespiration which reduces photosynthetic output. These two mechanisms working together are responsible for the Warburg effect.[3]

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol,[4][5] rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.[6][7][8] The latter process is aerobic (uses oxygen). Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,[9] a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.[10][11]

The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria because they are involved in the cell's apoptosis program which would otherwise kill cancerous cells. It may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate.[12] Evidence attributes some of the high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase[13] responsible for driving the high glycolytic activity. In kidney cancer, this effect could be due to the presence of mutations in the von Hippel–Lindau tumor suppressor gene upregulating glycolytic enzymes, including the M2 splice isoform of pyruvate kinase.[14]

In March 2008, Lewis C. Cantley and colleagues announced that the tumor M2-PK, a form of the pyruvate kinase enzyme, gives rise to the Warburg effect. Tumor M2-PK is produced in all rapidly dividing cells, and is responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of tumor M2-PK, their growth was curbed. The researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across different forms of cancer; but PKM2 was identified in all of the cancer cells they had tested. This enzyme form is not usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g. in healing wounds or hematopoiesis.[15][16]


Glycolytic inhibitors

Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of intense research as anticancer agents,[17] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid (DCA). Clinical trials are ongoing for 2-DG and DCA.[18]

Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.[19][20][21][22]Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.[23]

Dichloroacetic acid (DCA), a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, "downregulates" glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA might have therapeutic benefits against many types of cancers.[24][25]

High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to apoptosis. These findings have initiated further study of the effects of carbohydrate restriction on tumor growth. Clinical evidence shows that lower blood glucose levels in late-stage cancer patients have been correlated with better outcomes.[26]

A model called the reverse Warburg effect describes cells producing energy by glycolysis, but were not tumor cells, but stromal fibroblasts. Although the Warburg effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.[27][28]

Metabolic reprogramming is also observed in neurodegenerative diseases, Alzheimer's and Parkinson's. This metabolic alteration is described by the up-regulation of oxidative phosphorylation - called the inverse Warburg Effect.


Cancer Metabolism

Nutrient utilization is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in rate-limiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in cancer is largely due to oncogenic activation of signal transduction pathways and transcription factors.

Although less well understood, epigenetic mechanisms also contribute to the regulation of metabolic gene expression in cancer. Reciprocally, accumulating evidence suggest that metabolic alterations may affect the epigenome. Understanding the relation between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.[29]

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