On the Flu

The flu, as most all of us know all too well at this time of year, is an acute viral infection of the respiratory tract. The story of the flu is, in many ways, the story of human civilization itself: a tale of migration, mutation, and the unrelenting tension between our social nature and our biological vulnerabilities. We now know that influenza viruses are masterpieces of evolutionary engineering, shape-shifting pathogens that have perfected the art of survival through constant reinvention. But long before we understood viruses, influenza shaped human history with ruthless efficiency.

A/ Some scientists hypothesize that humans first acquired influenza when they began domesticating animals like birds and pigs. The rise of agriculture and permanent settlements provided ideal conditions to trigger a flu epidemic. One of the earliest written references  to a highly contagious disease with flu-like symptoms is found in the sixth book of “Epidemics” by the Greek physician Hippocrates written in 412BC.

B/ The word itself reveals a bygone view of the cosmos: influenza di freddo (“cold influence”) was first used in Florence, Italy in 1357 coming from the Latin word influentia which means “to flow into" or “influence,” a reference to the belief that an intangible fluid given off by stars affected human health. And thus the word originally was used to describe any disease outbreak that was thought to be influenced by the stars.

C/ Epidemiologists generally agree that the 1580 influenza outbreak is the earliest recorded flu pandemic. It began in Asia during the summer before spreading to Africa, Europe, and eventually across the ocean to the Americas. While the total death toll is unknown, it killed 8,000 people in Rome alone.

D/ In medieval Europe, influenza outbreaks became so predictable that merchants would plan their trading schedules around them. The virus typically struck in two-year cycles, leading to an economic rhythm where major fairs and gatherings would alternate between “flu years” and “safe years.” This pattern held until the Industrial Revolution's transformation of human mobility patterns upended the viral calendar.

E/ In 1743, what Italians called an influenza di catarro (“epidemic of catarrh”) spread across Europe, and the disease came to be known in English as simply “influenza” or “flu.”

F/ Other pandemics of this era included:

• The 1781 pandemic that started in China and then spread to Russia before eventually reaching Europe and North America over the next year. At the height of this pandemic, 30,000 were infected every day in St. Petersburg.

• The 1830 pandemic spread by ships from China to the Philippines, India and Indonesia. After crossing Russia to Europe, it eventually reached North America. While the mortality rate was low, this pandemic impacted 20%–25% of the population.

• The 1889 pandemic, the so-called Russian Flu, proved to be one of the deadliest pandemics in history. It infected 40% of the world’s population and killed about one million people. While it was the last flu pandemic of the 19th century, it was the first to rapidly spread around the whole world due to the modern transport infrastructure of railroads and transatlantic sea travel.


G/ During the American Civil War (1861–1865), soldiers were three times more likely to die from influenza than from battlefield wounds. This grim statistic led to one of medicine's first recognitions that disease could be a more formidable enemy than any human adversary. Union doctors began what might be considered America's first systematic disease surveillance program, tracking influenza's movement through military camps with a precision that would impress modern epidemiologists.

H/ The Spanish Flu outbreak of 1918 was caused by a new strain of the influenza A virus that started in birds (H1N1). After initially being reported in Europe, Asia and the United States, it rapidly spread around the world. About one-third of the world’s population was infected and 20 million to 50 million people were killed. At the time, there were no vaccines or drugs to treat influenza, so the public used gauze masks to try to stop the spread of disease, but the 1918 pandemic was so severe that it temporarily changed human demographics in ways that would ripple through generations. The average life expectancy in the United States dropped by 12 years in a single year—the steepest decline in American history. Perhaps even more remarkably, children born to women who were pregnant during the pandemic showed lower educational attainment, income, and socioeconomic status throughout their lives, creating what epidemiologists now call the “pandemic birth effect.”

I/ Until the 1930s, many physicians prescribed whiskey as a standard treatment for influenza. The practice was so common that during the 1918 pandemic, the U.S. government exempted whiskey from wartime alcohol restrictions when prescribed for flu patients. While the science behind this treatment was questionable, it inadvertently saved lives by keeping patients hydrated—though perhaps more cheerfully than necessary.

J/ In 1933, scientists at the National Institute for Medical Research in London isolated the influenza A virus from nasal secretions of infected human patients. This discovery would lead to the invention of inactivated vaccines in the late 1930s and 1940s with the first influenza vaccine approved in the United States for military use in 1945 and civilian use in 1946.

K/ During the seasonal flu epidemic of 1947, small changes in the composition of influenza viruses made existing vaccines ineffective. The World Health Organization (WHO) Influenza Centre was established in 1948 to identify new influenza viruses and control the spread of disease. In 1952, the WHO launched the first system to surveil circulating influenza virus strains and help researchers to determine the composition of seasonal influenza vaccines. This new system was put to the test in 1957 when a new influenza A virus struck East Asia. First reported in Singapore, it quickly spread to Hong Kong in April and the United States by summer. The estimated number of deaths was 1.1 million worldwide and 116,000 in the United States. The rapid development of a vaccine and the availability of antibiotics limited to some extent the spread and death toll.

L/ The first antiviral drug (Idoxuridine) was approved in 1963.

M/ The Hong Kong flu of 1968 infected 500,000 people in two weeks and then quickly spread throughout Southeast Asia and reached the United States within months, transported by soldiers returning from Vietnam. It is suspected that the 1968 virus evolved from the strain of influenza that caused the 1957 pandemic such that many exposed to the 1957 virus retained immunity against the 1968 virus. The pandemic killed between one and four million people globally.

N/ In 1993, the first study demonstrating mRNA vaccination in mice was published.

O/ Between 2019 and 2020, it is estimated that flu vaccines prevented about 7.5 million illnesses, 3.7 million doctor visits, 105,000 hospital stays, and 6,300 deaths in the U.S. alone.

Today's understanding of influenza reveals a virus that is both ancient and perpetually new. Each year's strain is a novel composition, like a musician riffing on an age-old melody. The virus's genius lies in its imperfection: it makes mistakes when reproducing, and these very mistakes ensure its survival. While our immune systems learn to recognize one version, the virus has already moved on, donning new molecular disguises.

The contemporary fight against influenza might seem more sophisticated than our ancestors' star-based theories or medicinal whiskey, but in many ways, we remain as vulnerable as ever. Despite our advances in surveillance, vaccination, and treatment, the flu still kills between 290,000 and 650,000 people globally each year. The virus continues to write its history through us, teaching harsh lessons about the limits of human ingenuity and the persistence of natural forces.

As we face new viral threats in the 21st century, the history of influenza offers both warning and wisdom. It reminds us that our battle with infectious disease is not so much a war to be won as a dance to be mastered—an endless waltz with an ever-changing partner who never tires and never forgets a step.

– Geoffrey W. Smith



First Five
First Five is our curated list of articles, studies, and publications for the month.

1/ Regular flossing may lower risk of stroke from blood clots, irregular heartbeats
People who regularly floss their teeth (one or more times per week) may lower their risk of stroke caused by a blood clot traveling from the heart and a stroke associated with an irregular heartbeat such as atrial fibrillation (AFib). Read more here >

2/ Unbundling the university
“An extended essay attempting to synthesize the current zeitgeist around universities, our research ecosystem, and technological stagnation; to argue that at least part of the solution is to unbundle the societal roles the university has taken on; and to suggest some concrete actions.” Read more here >

3/ Is it okay?
“How do you make a language model? Goes like this: erect a trellis of code, then allow the real program to grow, its development guided by a grueling training process, fueled by reams of text, mostly scraped from the internet. Now. I want to take a moment to think together about a question with no remaining practical importance, but persistent moral urgency: Is that okay?” Read more here >

4/ The end of programming as we know it
“There’s a lot of chatter in the media that software developers will soon lose their jobs to AI. I don’t buy it.” Read more here >

5/ Why your earbud batteries don’t last
Engineers took on the well-known battery challenge of degradation in a real-world technology that many of us use daily: wireless earbuds. Read more here >



Did you Know?
In this section of our newsletter, we seek to demystify common terms and practices in our work as investors.

Issued and outstanding shares vs. fully diluted shares
Outstanding shares represent the total number of shares that are currently issued and held by shareholders, including founders, employees, and investors. These are the shares that are already in circulation. Fully diluted shares include not only the outstanding shares but also all potential shares that could be created or issued in the future. This includes options, warrants, and convertible securities (like convertible notes or preferred stock that can be converted into common shares). The fully diluted share count is used to give a more comprehensive picture of the company's ownership, assuming all possible conversions and exercises of securities.

Venture capital investors often pay attention to fully diluted shares to understand the potential impact of future equity issuances (such as stock options for employees) on their ownership percentage. It helps them assess the potential dilution of their ownership stake over time.

– Haiming Chen & Dylan Henderson

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