The Warburg Effect: Otto Warburg’s Cancer Metabolism Theory with Sam Apple

Sam Apple: Writer and Teacher

• Father is a writer, influenced Sam’s career choice
• Recognized writing as his strength in college
• Believes writing ability is innate, but can be improved with practice
• Teaches science writing and creative writing at Johns Hopkins

Identifying Good Writing

• Clarity, concise language, and logical flow are key
• Good writing depends on clear, concise thinking
• Good writers often revise their work multiple times
• Importance of feedback from others

Sam Apple’s Education

• MFA in Creative Nonfiction at Columbia University
• Focused on long-​​form nonfiction and storytelling
• Writing workshop format: students submit work and receive critiques from peers and professors
• Debate over the workshop approach: some argue it leads to formulaic stories, while others believe it’s essential for improvement
  Trial and Error in Writing
• Writing often involves trial and error, experimenting with different perspectives 
• Feedback from others is crucial for improvement
• Comparing oneself to exceptional writers can be discouraging, but it’s important to remember that good work can still be done without reaching their level

Otto Warburg’s Background

• Born in the late 19^th century to a prominent physicist father, Emile Warburg
• Grew up around famous scientists like Einstein, Max Planck, and Emil Fischer
• Decided to focus on biology and physiology, but always maintained an interest in energy and physics

World War I and German Scientists

• Many German scientists, including those of Jewish background, joined the war effort to prove their patriotism
• Warburg joined a cavalry regiment and fought on the battlefield
• Einstein urged Warburg to return home, potentially saving his life

Warburg’s Dedication to Science

• Described as having a “religious devotion” to science
• Believed that a scientist should be prepared to die for the truth
• Focused on science as a way to avoid looking inward and dealing with personal issues

Warburg’s Personal Life

• Struggled with being Jewish in Germany and being homosexual
• Lived with his male partner, Jacob Heiss, and was relatively open about their relationship for the time
• Never met Hitler directly, but there is indirect evidence that Hitler was involved in Warburg’s fate

Post-​​World War I and Warburg’s Work

• Returned to Berlin and was given a position at the prestigious Kaiser Wilhelm Institute for Biology
• Began his seminal work on cancer and energy metabolism
  Kaiser Wilhelm Society and Max Planck Society
• Kaiser Wilhelm Society: created to gather the best scientists and provide them with resources 
• Inspired by the Rockefeller model in the United States
• Otto Warburg returned to Germany before World War I to work in a lab
• Financial struggles due to wealthy funders going bankrupt

Otto Warburg’s Research Focus

• Initially focused on photosynthesis to potentially solve world hunger
• Shifted focus to cancer due to its increasing prevalence in Germany
• Aimed to make a world-​​changing discovery like his idols Robert Koch and Paul Ehrlich

Warburg’s Discovery: Cancer Cells and Fermentation

• Warburg discovered that most cancer cells ferment glucose instead of breaking it down with oxygen (oxidative phosphorylation)
• This shift to fermentation in cancer cells is now known as the Warburg effect
• Surprising because cells typically only ferment when oxygen is not available (anaerobic glycolysis)

Biochemical Pathways and Energy Production

• Fermentation of glucose yields significantly less ATP (energy) than oxidative phosphorylation
• Cells usually only resort to fermentation when oxygen is insufficient or when there is a high demand for ATP
• The Warburg effect is a paradox because cancer cells ferment glucose even when oxygen is available (aerobic glycolysis)

Warburg’s Hypothesis

• Warburg believed that there must be a defect in the mitochondria of cancer cells
• This hypothesis was influenced by Pasteur’s discovery that microbes could ferment without oxygen (the Pasteur effect)
• Warburg saw the relationship between respiration and fermentation as a seesaw: when one goes down, the other goes up
  Warburg’s Hypothesis and Cancer
• Warburg’s hypothesis: cancer cells undergo aerobic glycolysis to fermentation due to defective mitochondria 
  • However, he couldn’t prove this hypothesis
  • Early tests showed fermentation increasing while respiration continued
  • Later in his career, he insisted respiration was not continuing or had other explanations
• Warburg believed every disease has a primary and secondary cause 
  • Primary cause: most fundamental aspect (e.g., shift to fermentation in cancer)
  • Secondary cause: anything that causes the primary cause (e.g., chemicals, viruses)
• Warburg was concerned about environmental carcinogens 
  • Believed chemicals in food were poisoning cells and causing a shift to fermentation
  • Influenced American environmental policy through Rachel Carson’s Silent Spring

Warburg’s Nobel Prize and World War II

• Warburg awarded the Nobel Prize in 1931 for his work on respiration 
  • Elucidated the process of electron transport chain and reaction with oxygen
• During World War II, Warburg stayed in Germany despite being Jewish and gay 
  • Rockefeller Foundation built a beautiful institute for him in 1931
  • Many of his colleagues fled, but Warburg remained in Germany
    Otto Warburg in Nazi Germany
• Otto Warburg, a Jewish scientist, refused to leave Nazi Germany 
  • Believed the Nazi phenomenon would be short-lived
  • Arrogant and narcissistic, couldn’t fathom being told what to do
  • Provoked Nazis, refused to do the Hitler salute or put up the Nazi flag
• Warburg’s survival during the war 
  • Initially served as propaganda value for the Nazis
  • In 1941, allowed to live on the condition he focused on cancer research
  • Hitler likely involved in the decision to let Warburg continue his work
• Hitler’s personal connection to cancer 
  • Lost his mother to breast cancer as a teenager
  • Mother’s death had a significant impact on him
    Hitler and Cancer Research
• Hitler’s mother underwent experimental cancer treatments, leaving her in pain 
• Hitler became obsessed with cancer and its elimination
• Nazis made some advances in cancer prevention, despite their monstrous actions
• German science was prominent before WWII, shifted to English post-WWII

Otto Warburg’s Contributions

• Deserved a Nobel Prize for his cancer work in the 1920s
• Made advances in understanding hydrogen transfers and coenzymes
• Discovered the role of nicotonic acid in NAD, leading to understanding of pellagra disease

Warburg’s Life Post-WWII

• Stayed in Germany after the war, but considered moving to America
• Returned to his institute in West Berlin, which was in the American sector
• Soviets tried to recruit him, but he ultimately stayed in the American side

Warburg’s Feud with Sidney Weinhouse

• Warburg had scientific feuds with other researchers, including Weinhouse
• Weinhouse was a mild-​​mannered scientist who disagreed with some of Warburg’s observations
• Warburg and Weinhouse had a public disagreement in the journal Science
  Cancer Theory Overthrown
• Winehouse challenged Warburg’s belief that cancer cells have defective mitochondria 
  • Found no difference in oxygen consumption between cells
  • No evidence of damaged mitochondria
• Warburg’s theory faded away as molecular biology and oncogenes gained prominence in the 1970s 
  • Warburg’s study of enzymes and cancer metabolism seen as old-​​world biochemistry
  • Focus shifted to DNA, signal transduction pathways, and molecular biology

Renaissance of Warburg’s Theory

• Late 1990s: revival of interest in cancer metabolism 
  • Key labs: Craig Thompson (now president/​​CEO of Memorial Sloan Kettering) and Chi Van Dang (formerly at Johns Hopkins)
  • Both labs traced signaling pathways back to metabolic enzymes
• 2009 Science paper by Matthew Vander Heiden, Luke Cantley, and Craig Thompson 
  • Acknowledged Warburg effect but offered a different explanation
  • Argued that cells might need to take up more glucose for bioenergetic reasons, not due to defective mitochondria
  • Cells need building blocks for growth, not just energy
  • This view is now more widely accepted, though some still support Warburg’s original theory

Debate Over Defective Mitochondria

• Some scientists, like Thomas Seyfried, believe Warburg was right about defective mitochondria
• Others, like Cantley, Thompson, Vander Heiden, and Nav Chandel, disagree
• Author leans towards the latter view, based on the majority opinion and the idea that proliferative metabolism is a fundamental program in cells 
  • Cells take up nutrients and grow when they have access to them, regardless of oxygen availability
    Cancer, Obesity, and Insulin
• Cancer is a problem of growth, driven by nutrients and hormones 
• Late 1990s: insulin hyperinsulinemia and obesity correlated with cancer
• Insulin could explain obesity, cancer, and why cancer was once rare
• Hyperinsulinemia may be a key factor in cancer prevention

Smoking and Cancer

• Smoking could be considered a prime cause of cancer
• Causes mutations in DNA that drive unregulated cell growth

Obesity and Cancer

• Strong correlation between obesity and cancer, but causation is less clear
• Obesity comes with many other factors (diet, sleep, exercise, etc.)
• Insulin may be the primary factor within the obesity paradigm driving cancer
• Hyperinsulinemia could be driving both obesity and cancer cell proliferation
  Metabolically Healthy Obese and Insulin Resistance
• Metabolically healthy obese individuals store more nutrients in subcutaneous fat, not visceral fat
• They do not have insulin resistance and are not more likely to get cancer
• Insulin resistance is seen in thinner individuals and correlates with cancer

Insulin and Cancer Correlation

• Unclear if insulin is the first step in the process or if a mutation occurs that allows cancer cells to take advantage of hyperinsulinemia
• Hyperinsulinemia may drive chromosomal insult through creation of reactive oxygen species in the mitochondria
• Nutrients play a role in epigenetics

Fructose and Cancer

• Recent research shows that fructose, independent of its effects on insulin, seems to drive certain cancers, particularly in the colon
• Fructose metabolism turns on the Warburg effect and allows ATP to go down and glucose to flow in
• This mechanism is not necessarily insulin-driven

Personal Insights from Writing the Book

• Humanizing Nazis and understanding their personal stories
• Learning about oneself as a writer and gaining confidence in taking on big projects
• Avoiding reviews of one’s work to maintain focus and confidence
  Sam Apple on Cancer Research and Feedback
• Sam Apple’s book: Ravenous Otto Warburg the Nazis and the Search for the Cancer Diet Connection
• Discusses the history of cancer research and the role of metabolism in cancer
• Highlights the importance of reducing hyperinsulinemia, improving metabolism, and reducing reactive oxygen species to improve odds against cancer