This is a scientific story that started from a polluted water stream in Kashmir to a new human virus, the remarkable discovery of Hepatitis E virus (HEV).

Scientific discoveries are often associated with sophisticated laboratories, advanced technologies, and large research teams. Yet some of the most important breakthroughs begin with a simple observation that something does not fit existing knowledge. The discovery of Hepatitis E virus (HEV) is one such story. It began not in a major research centre but in the villages of Kashmir, where an unusual epidemic challenged established medical thinking and eventually led to the identification of an entirely new human pathogen [1–3].

The story starts in the winter of 1978–79, when a massive epidemic of hepatitis swept through the Kashmir Valley. Thousands of people developed jaundice, and hundreds died. The epidemic was centred in the Baramulla-Sopore region and was eventually traced to contamination of the Ningli Nallah water supply system [1,4,5]. At the time, viral hepatitis was already a familiar disease. Hepatitis A and hepatitis B had been described, and physicians believed that most waterborne hepatitis outbreaks were caused by hepatitis A [6]. What unfolded in Kashmir, however, did not follow the established rules.

The epidemic possessed characteristics that immediately attracted the attention of gastroenterologist and physician-scientist Dr. Mohammad Sultan Khuroo. The pattern of disease was unusual. Waterborne hepatitis typically affects children because they are more likely to lack immunity. Yet in Kashmir, children were largely spared. Instead, the disease struck adults, particularly young adults. Even more striking was the disproportionate impact on women, especially pregnant women, among whom mortality was alarmingly high [1,4,7–9]. The epidemiological puzzle was impossible to ignore.

Without dedicated funding, institutional support, or a large investigative team, Khuroo embarked on what would become one of the most important field investigations in modern hepatology [2,3]. Using largely personal resources, he and his colleagues conducted an extensive door-to-door survey across affected communities. Every household was visited. Every suspected case was documented. The work was laborious, physically demanding, and conducted under conditions far removed from the sophisticated infrastructure commonly associated with major scientific discoveries [2].

What emerged from this investigation was a remarkably detailed picture of the epidemic. The disease was spreading through contaminated water. The attack rate differed from classical hepatitis A. The age distribution was different. The severity profile was different. Most importantly, the high mortality among pregnant women suggested a biological behaviour unlike that of any known hepatitis virus [1,4,7].

The next step was laboratory investigation.

Blood samples from affected individuals were tested for all known hepatitis viruses of the era. The results repeatedly returned negative. The disease was neither hepatitis A nor hepatitis B [1,10]. At a time when the concept of a new hepatitis virus was still speculative, Khuroo reached a bold conclusion. The epidemic appeared to be caused by an unknown enterically transmitted virus. He described the disease as “epidemic non-A, non-B hepatitis” and proposed that another hepatitis virus existed beyond those already recognised [1,11]. Such a claim was extraordinary in the late 1970s.

Scientific progress often advances through skepticism, and the reaction from many international experts was cautious [2,3]. Some investigators argued that the epidemic was simply hepatitis A and that available laboratory assays lacked sufficient sensitivity. Others questioned whether a new viral entity was necessary to explain the observations [2,12]. The burden of proof rested heavily on the investigators from Kashmir.

In 1980, Khuroo published the landmark epidemiological description of the epidemic in the American Journal of Medicine, one of the leading medical journals of the period [1]. The paper systematically documented the outbreak and presented evidence supporting the existence of a previously unrecognised hepatitis agent. The publication attracted international attention because it challenged prevailing assumptions about viral hepatitis [1–3].

The response from the global scientific community was mixed. While many researchers recognised the importance of the observations, others remained unconvinced [2,12]. Rather than relying on argument alone, Khuroo sought evidence. Large numbers of serum and stool samples collected during the epidemic were distributed to leading laboratories around the world, including institutions in the United States, Europe, and Japan [2,3]. These laboratories independently tested the specimens using their own methods and expertise. The results converged on the same conclusion.

The outbreak could not be explained by hepatitis A or hepatitis B. Independent analyses consistently supported the original findings from Kashmir [2,10,12]. By the early 1980s, international confidence in the existence of a new form of viral hepatitis was growing [2,13]. Yet proving the existence of a disease entity is different from identifying the causative virus.

The challenge now shifted from epidemiology to virology. One of the most dramatic chapters in the story emerged from an unexpected setting: the Soviet-Afghan war. During the conflict, large numbers of Soviet soldiers stationed in Afghanistan developed hepatitis [14]. Concerned by the scale of the problem, Soviet authorities initiated investigations into its cause. Among the scientists involved was virologist Dr. Mikhail Balayan [14,15].

Balayan became interested in reports emerging from Kashmir describing epidemic non-A, non-B hepatitis. Seeking definitive evidence, he undertook an extraordinary act of scientific self-experimentation. In a study that has since become part of virological history, he ingested material prepared from infected stool specimens. Weeks later, he developed hepatitis. Analysis of samples collected during his illness revealed virus-like particles associated with the disease [14,15]. His work provided some of the strongest evidence yet that a previously unknown virus existed.

At approximately the same time, investigators at the National Institutes of Health in the United States were pursuing experimental transmission studies. Researchers successfully transmitted the disease to non-human primates, further strengthening the case for a distinct viral agent [16–18]. The convergence of epidemiological, clinical, and experimental evidence increasingly pointed toward the same conclusion: the world was confronting a new hepatitis virus. Even then, the story was not finished.

Scientists could observe virus-like particles, yet obtaining sufficient viral material for definitive genetic characterisation proved difficult [17–19]. For years, the virus remained elusive. Researchers knew it existed, but they could not fully define its genetic identity. The search continued across laboratories in several countries.

Finally, advances in molecular biology enabled investigators to isolate and characterise the viral genome. The successful cloning and sequencing of the virus provided the definitive proof that researchers had been seeking for more than a decade [20–22]. The mysterious pathogen responsible for the Kashmir epidemic and numerous outbreaks elsewhere in the world was finally revealed. The question of nomenclature now arose.

Some observers suggested names linked to the place of discovery. Others proposed names honouring individual investigators. Khuroo advocated a different approach. Scientific nomenclature, he argued, should remain universal rather than geographic or personal [2,3]. Since the virus was associated with epidemic outbreaks, transmitted through the enteric route, and followed the already recognised hepatitis viruses A, B, C, and D, the designation “Hepatitis E” emerged as the logical choice [2,20]. The name endured.

Today, Hepatitis E is recognised as one of the most common causes of acute viral hepatitis globally [23–25]. The virus infects millions of people annually and remains a major public health concern across Asia, Africa, and other regions of the world [23–27]. What began as an unexplained outbreak in Kashmir has become a subject of global scientific and medical importance.

The discovery also transformed understanding of viral hepatitis. It demonstrated that established disease classifications are not immutable and that careful observation can reveal entirely new biological realities [2,3,24]. The recognition of Hepatitis E expanded the taxonomy of human hepatitis viruses and stimulated decades of research into viral evolution, transmission, pathogenesis, diagnostics, and prevention [23–30].

Beyond its scientific significance, the discovery offers a powerful lesson about the nature of research itself. The story of Hepatitis E was not driven initially by advanced technology. It was driven by curiosity, persistence, and rigorous observation [2,3]. The crucial breakthrough occurred when investigators recognised that the epidemic did not fit accepted explanations. Instead of forcing observations into existing categories, they allowed the evidence to challenge prevailing assumptions. Many landmark discoveries begin in precisely this way.

The Kashmir epidemic reminds us that science advances not only through sophisticated instruments but also through attentive minds willing to ask uncomfortable questions. A polluted stream in a remote corner of the Himalayas became the starting point for identifying a new human virus [1,4]. A door-to-door survey conducted with limited resources helped reshape global hepatology [2]. A local public health crisis evolved into an international scientific discovery.

More than four decades later, the legacy of that work continues to influence medicine worldwide [23–30]. The discovery of Hepatitis E stands as a testament to the power of epidemiology, the value of perseverance, and the enduring capacity of careful field science to transform our understanding of disease.

In an era increasingly defined by big data and high-throughput technologies, the origins of Hepatitis E offer a timely reminder: sometimes the most important scientific discoveries begin with a physician walking from house to house, listening carefully, recording meticulously, and refusing to ignore evidence that does not fit the textbook.

References 

1. Khuroo MS. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. Am J Med. 1980.

2. Khuroo MS. Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story. Viruses. 2023.

3. Balayan MS et al. Evidence for a virus in enterically transmitted non-A, non-B hepatitis obtained via self-experimentation. Intervirology. 1983.

4. Reyes GR et al. Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. Science. 1990.

5. Emerson SU, Purcell RH. Major reviews on HEV biology and discovery.

6. Aggarwal R. Epidemiology and global burden of hepatitis E.

7. Kamar N et al. Clinical Microbiology Reviews article on hepatitis E.

8. WHO Hepatitis E technical reports and fact sheets.

9. Khuroo MS and colleagues' subsequent papers on Kashmir outbreaks, pregnancy-associated mortality, and transmission.

10. Historical reviews documenting the evolution of HEV research from epidemiological observation to molecular characterization.