Virus classification

• (unranked): Virus

• Realm: Riboviria

• Kingdom: Orthornavirae

• Phylum: Negarnaviricota

• Class: Monjiviricetes

• Order: Mononegavirales

• Family: Paramyxoviridae

• Genus: Henipavirus

• Species: Nipah henipavirus

Nipah virus, scientific name Nipah henipavirus, is a bat-borne virus that causes Nipah virus infection in humans and other animals, a disease with a high mortality rate. Numerous disease outbreaks caused by Nipah virus have occurred in South and Southeast Asia. Nipah virus belongs to the genus Henipavirus along with the Hendra virus, which has also caused disease outbreaks.

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Virology

Like other henipaviruses, the Nipah virus genome is a single (nonsegmented) negative-sense, single-stranded RNA of over 18 kb, which is substantially longer than that of other paramyxoviruses.^[1][2] The enveloped virus particles are variable in shape, and can be filamentous or spherical; they contain a helical nucleocapsid.^[1] Six structural proteins are generated: N (nucleocapsid), P (phosphoprotein), M (matrix), F (fusion), G (glycoprotein) and L (RNA polymerase). The P open reading frame also encodes three nonstructural proteins, C, V and W. There are two envelope glycoproteins. The G glycoprotein assembles as a tetramer to form the viral anti-receptor or attachment protein, which binds to the receptor on the host cell. The F glycoprotein forms a trimer, which mediates membrane fusion.^[1][2]

Tropism

Ephrins B2 and B3 have been identified as the main receptors for Nipah virus.^[1][2][3] Ephrin subtypes have a complex distribution of expression throughout the body, where the B3 is noted to have particularly high expression in some forebrain subregions.^[4]

Evolution

The most likely origin of this virus was in 1947 (95% credible interval: 1888–1988).^[5] There are two clades of this virus—one with its origin in 1995 (95% credible interval: 1985–2002) and a second with its origin in 1985 (95% credible interval: 1971–1996). The mutation rate was estimated to be 6.5 × 10⁻⁴ substitution/site/year (95% credible interval: 2.3 × 10⁻⁴ –1.18 × 10⁻³), similar to other RNA viruses.

Pteropus vampyrus (large flying fox), one of the natural reservoirs of Nipah virus

Geographic distribution

Nipah virus has been isolated from Lyle's flying fox (Pteropus lylei) in Cambodia^[6] and viral RNA found in urine and saliva from P. lylei and Horsfield's roundleaf bat (Hipposideros larvatus) in Thailand.^[7] Infective virus has also been isolated from environmental samples of bat urine and partially eaten fruit in Malaysia.^[8] Antibodies to henipaviruses have also been found in fruit bats in Madagascar (Pteropus rufus, Eidolon dupreanum)^[9] and Ghana (Eidolon helvum)^[10] indicating a wide geographic distribution of the viruses. No infection of humans or other species have been observed in Cambodia, Thailand or Africa as of May 2018.

History : Emergence

The first cases of Nipah virus infection were identified in 1998, when an outbreak of neurological and respiratory disease on pig farms in peninsular Malaysia caused 265 human cases, with 105 deaths.^[11][12][13] The virus itself was isolated the following year in 1999.^[14] This outbreak resulted in the culling of one million pigs. In Singapore, 11 cases, including one death, occurred in abattoir workers exposed to pigs imported from the affected Malaysian farms. The Nipah virus has been classified by the Centers for Disease Control and Prevention as a Category C agent.^[15] The name "Nipah" refers to the place, Sungai Nipah in Port Dickson, Negeri Sembilan, the source of the human case from which Nipah virus was first isolated.^[16][17] Nipah virus is one of several viruses identified by WHO as a likely cause of a future epidemic in a new plan developed after the Ebola epidemic for urgent research and development before and during an epidemic toward new diagnostic tests, vaccines and medicines.^[18][19]

The outbreak was originally mistaken for Japanese encephalitis, but physicians in the area noted that persons who had been vaccinated against Japanese encephalitis were not protected in the epidemic, and the number of cases among adults was unusual.^[20] Although these observations were recorded in the first month of the outbreak, the Ministry of Health failed to take them into account, and launched a nationwide campaign to educate people on the dangers of Japanese encephalitis and its vector, Culex mosquitoes.

Symptoms of infection from the Malaysian outbreak were primarily encephalitic in humans and respiratory in pigs. Later outbreaks have caused respiratory illness in humans, increasing the likelihood of human-to-human transmission and indicating the existence of more dangerous strains of the virus.

Based on seroprevalence data and virus isolations, the primary reservoir for Nipah virus was identified as Pteropid fruit bats, including Pteropus vampyrus (large flying fox), and Pteropus hypomelanus (small flying fox), both found in Malaysia.

Locations of henipavirus outbreaks (red stars–Hendra virus; blue stars–Nipah virus) and distribution of henipavirus flying fox reservoirs (red shading–Hendra virus; blue shading–Nipah virus)

The transmission of Nipah virus from flying foxes to pigs is thought to be due to an increasing overlap between bat habitats and piggeries in peninsular Malaysia. At the index farm, fruit orchards were in close proximity to the piggery, allowing the spillage of urine, faeces and partially eaten fruit onto the pigs.^[21] Retrospective studies demonstrate that viral spillover into pigs may have been occurring, undetected, in Malaysia since 1996.^[11] During 1998, viral spread was aided by the transfer of infected pigs to other farms, where new outbreaks occurred.

History : Outbreaks of disease

Main article: Nipah virus infection (includes list of outbreaks)

Nipah virus infection outbreaks have been reported in Malaysia, Singapore, Bangladesh and India. The highest mortality due to Nipah virus infection has occurred in Bangladesh, where outbreaks are typically seen in winter.^[22] Nipah virus first appeared in 1998, in peninsular Malaysia in pigs and pig farmers. By mid-1999, more than 265 human cases of encephalitis, including 105 deaths, had been reported in Malaysia, and 11 cases of either encephalitis or respiratory illness with one fatality were reported in Singapore.^[23] In 2001, Nipah virus was reported from Meherpur District, Bangladesh^[24][25] and Siliguri, India.^[24] The outbreak again appeared in 2003, 2004 and 2005 in Naogaon District, Manikganj District, Rajbari District, Faridpur District and Tangail District.^[25] In Bangladesh there were also outbreaks in subsequent years.^[26]

See also[edit]

• Viruses portal

• 1998–1999 Malaysia Nipah virus outbreak

• 2018 Nipah virus outbreak in Kerala

References[edit]

• ^

• Jump up to:

• ^{a b c d} Aditi, M. Shariff (2019). "Nipah virus infection: A review". Epidemiology and Infection. 147: E95. doi:10.1017/S0950268819000086.

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• ^{a b c} Moushimi Amaya, Christopher C. Broder (2020). "Vaccines to emerging viruses: Nipah and Hendra". Annual Review of Virology. 7: 447–473. doi:10.1146/annurev-virology-021920-113833.

• ^ Lee B, Ataman ZA; Ataman (2011). "Modes of paramyxovirus fusion: a Henipavirus perspective". Trends in Microbiology. 19 (8): 389–399. doi:10.1016/j.tim.2011.03.005. PMC 3264399. PMID 21511478.

• ^ Hruska, Martin; Dalva, Matthew B. (May 2012). "Ephrin regulation of synapse formation, function and plasticity". Molecular and Cellular Neurosciences. 50 (1): 35–44. doi:10.1016/j.mcn.2012.03.004. ISSN 1044-7431. PMC 3631567. PMID 22449939.

• ^ Lo Presti A, Cella E, Giovanetti M, Lai A, Angeletti S, Zehender G, Ciccozzi M (2015). "Origin and evolution of Nipah virus". J Med Virol. 88 (3): 380–388. doi:10.1002/jmv.24345. PMID 26252523.

• ^ Reynes JM, Counor D, Ong S (2005). "Nipah virus in Lyle's flying foxes, Cambodia". Emerging Infectious Diseases. 11 (7): 1042–7. doi:10.3201/eid1107.041350. PMC 3371782. PMID 16022778.

• ^ Wacharapluesadee S, Lumlertdacha B, Boongird K (2005). "Bat Nipah virus, Thailand". Emerging Infectious Diseases. 11 (12): 1949–51. doi:10.3201/eid1112.050613. PMC 3367639. PMID 16485487.

• ^ Chua KB, Koh CL, Hooi PS (2002). "Isolation of Nipah virus from Malaysian Island flying-foxes". Microbes and Infection. 4 (2): 145–51. doi:10.1016/S1286-4579(01)01522-2. PMID 11880045.

• ^ Lehlé C, Razafitrimo G, Razainirina J (2007). "Henipavirus and Tioman virus antibodies in pteropodid bats, Madagascar". Emerging Infectious Diseases. 13 (1): 159–61. doi:10.3201/eid1301.060791. PMC 2725826. PMID 17370536.

• ^ Hayman DT, et al. (2008). Montgomery JM (ed.). "Evidence of henipavirus infection in West African fruit bats". PLOS ONE. 3 (7): 2739. Bibcode:2008PLoSO...3.2739H. doi:10.1371/journal.pone.0002739. PMC 2453319. PMID 18648649.

• ^

• Jump up to:

• ^{a b} Field, H; Young, P; Yob, JM; Mills, J; Hall, L; MacKenzie, J (2001). "The natural history of Hendra and Nipah viruses". Microbes and Infection. 3 (4): 307–14. doi:10.1016/S1286-4579(01)01384-3. PMID 11334748.

• ^ Centers for Disease Control and Prevention (CDC) (30 April 1999). "Update: outbreak of Nipah virus—Malaysia and Singapore, 1999". Morbidity and Mortality Weekly Report. 48 (16): 335–7. PMID 10366143.

• ^ Lai-Meng Looi; Kaw-Bing Chua (2007). "Lessons from the Nipah virus outbreak in Malaysia" (PDF). The Malaysian Journal of Pathology. 29 (2): 63–67. Archived(PDF) from the original on 30 August 2019.

• ^ "Nipah Virus (NiV) CDC". www.cdc.gov. CDC. Archived from the original on 16 December 2017. Retrieved 21 May 2018.

• ^ Bioterrorism Agents/Diseases. bt.cdc.gov

• ^ Siva SR, Chong HT, Tan CT (2009). "Ten year clinical and serological outcomes of Nipah virus infection" (PDF). Neurology Asia. 14: 53–58.

• ^ "Spillover – Zika, Ebola & Beyond". pbs.org. PBS. 3 August 2016. Retrieved 4 August 2016.

• ^ Kieny, Marie-Paule. "After Ebola, a Blueprint Emerges to Jump-Start R&D". Scientific American Blog Network. Retrieved 13 December 2016.

• ^ "LIST OF PATHOGENS". World Health Organization. Retrieved 13 December 2016.

• ^ "Dobbs and the viral encephalitis outbreak".. Archived thread from the Malaysian Doctors Only BBS Archived 18 April 2006 at the Wayback Machine

• ^ Chua KB, Chua BH, Wang CW (2002). "Anthropogenic deforestation, El Niño and the emergence of Nipah virus in Malaysia". The Malaysian Journal of Pathology. 24 (1): 15–21. PMID 16329551.

• ^ Chadha MS, Comer JA, Lowe L, Rota PA, Rollin PE, Bellini WJ, et al. (February 2006). "Nipah virus-associated encephalitis outbreak, Siliguri, India". Emerging Infectious Diseases. 12 (2): 235–40. doi:10.3201/eid1202.051247. PMC 3373078. PMID 16494748.

• ^ Eaton BT, Broder CC, Middleton D, Wang LF (January 2006). "Hendra and Nipah viruses: different and dangerous". Nature Reviews. Microbiology. 4 (1): 23–35. doi:10.1038/nrmicro1323. PMC 7097447. PMID 16357858. S2CID 24764543.

• ^

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• ^{a b} Chadha MS, Comer JA, Lowe L, Rota PA, Rollin PE, Bellini WJ, et al. (February 2006). "Nipah virus-associated encephalitis outbreak, Siliguri, India". Emerging Infectious Diseases. 12 (2): 235–40. doi:10.3201/eid1202.051247. PMC 3373078. PMID 16494748.

• ^

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• ^{a b} Hsu VP, Hossain MJ, Parashar UD, Ali MM, Ksiazek TG, Kuzmin I, et al. (December 2004). "Nipah virus encephalitis reemergence, Bangladesh". Emerging Infectious Diseases. 10 (12): 2082–7. doi:10.3201/eid1012.040701. PMC 3323384. PMID 15663842.

• ^ "Nipah virus outbreaks in the WHO South-East Asia Region". South-East Asia Regional Office. WHO. Archived from the original on 23 May 2018. Retrieved 23 May2018.

External links

• Current status of Nipah (virus encephalitis) worldwide at OIE. WAHID Interface - OIE World Animal Health Information Database

• Nipah virus – CSIRO

• Enserink M (February 2009). "Virus's Achilles' Heel Revealed". Science Now. AAAS. Archived from the original on 22 February 2009.

1998–1999 Malaysia Nipah virus outbreak

The first site of the virus in Ipoh in 1998 and later occurrence to other places with the virus extent in blue while Hendra virus in red, both belong to the Paramyxoviridae family.

The 1998–1999 Nipah virus outbreak areas in West Malaysia, blue is the origin source of the virus while the red are further affected areas.

Disease

Nipah virus infection

Virus strain

Nipah virus

First outbreak

Ipoh, Perak

Index case

September 1998

Confirmed cases

265

Deaths

105

The 1998–1999 Malaysia Nipah virus outbreak was a Nipah virus outbreak occurred from September 1998 to May 1999 in the states of Perak, Negeri Sembilan and Selangor in Malaysia. A total of 265 cases of acute encephalitis with 105 deaths caused by the virus were reported in the three states throughout the outbreak.^[1] The Malaysian health authorities at the first thought Japanese encephalitis (JE) was the cause of infection which hampered the deployment of effective measures to prevent the spread before being finally identified by a local virologist from the Faculty of Medicine, University of Malaya that it was a newly discovered agent named Nipah virus (NiV). The disease was as deadly as the Ebola virus disease (EVD), but attacked the brain system instead of the blood vessels.^[1][2] University of Malaya's Faculty of Medicine and the University of Malaya Medical Centre played a major role in serving as a major referral centre for the outbreak, treating majority of the Nipah patients and was instrumental in isolating the novel virus and researched on its features.

This emerging diseases where it caused major losses to both animal and human lives, affecting livestock trade and created a significant setback to the swine sector of the animal industry in Malaysia.^[3] The country also became the origin of the virus where it had no more cases since 1999 but further outbreaks continue to occur in Bangladesh and India.^[4][5]

[...]

Background[edit]

The virus firstly struck pig-farms in the suburb of Ipoh in Perak with the occurrence of respiratory illness and encephalitis among the pigs where it is firstly thought to be caused by Japanese encephalitis (JE) due to 4 serum samples from 28 infected humans in the area tested positive for JE-specific Immunoglobulin M (IgM) which is also confirmed by the findings of World Health Organization (WHO) Collaborating Centre for Tropical Disease at the Nagasaki University.^[1] A total of 15 infected people died during the ensuing outbreak before the virus began to spread into Sikamat, Nipah River Village and Pelandok Hill in Negeri Sembilan when farmers affected by the control measures began to sell their infected pigs to these areas.^[1] This resulted 180 patients infected by the virus and 89 deaths. With further movement of the infected pigs, more cases emerged from around Sepang District and Sungai Buloh in Selangor with 11 cases and 1 death reported among abattoir workers in Singapore who had handled the infected pigs imported from Malaysia.^[1]

Authorities response and further investigation[edit]

Since the cause was firstly wrongly identified, early control measures such as mosquito foggings and vaccination of pigs against JE were deployed to the affected area which proved to be ineffective since more cases emerged despite the early measures.^[1] With the increasing deaths reported from the outbreak, this caused nationwide fear from the public and the near collapse of local pig-farming industry.^[1] Most healthcare workers who were taking care of their infected patients had been convinced that the outbreak was not caused by JE since the disease affected more adults than children, including those who had been vaccinated earlier against JE.^[1] Through further autopsies on the deceased, the findings were inconsistent from the earlier results where they suggest it may come from another agent.^[1] This was supported with several reasons such as all of the infected victims had direct physical contacts with pigs and all of the infected pigs had developed severe symptoms of barking cough before dying.^[1] Despite the evidence gathered from autopsies results with new findings among local researchers, the federal government especially the health authorities insisted that it was solely caused by JE which delayed further appropriate action taken for the outbreak control.^[1]

Identification of the source of infection[edit]

In early March 1999, a local medical virologist at the University of Malaya named Dr Chua Kaw Beng finally found the root cause of the infection.^[2] Through his findings, the infection was indeed caused by a new agent named Nipah virus (NiV), taken from the investigation area name of Nipah River Village (Malay: Kampung Sungai Nipah),^[6] where it is still unknown to available science records at the time.^[1][7] The virus origin is identified from a native fruit bat species.^[8] Together with the Hendra virus (HeV), the novel virus is subsequently recognised as a new genus, Henipavirus (Hendra + Nipah) in the Paramyxoviridae family.^[1] He found that NiV and HeV shared enough epitopes for HeV antigens to be used in a prototype serological test for NiV antibodies which helped in the subsequent screening and diagnosis of NiV infection.^[1] Following the findings, widespread surveillance of pig populations together with the culling of over a million pigs was undertaken and the last human fatality occurred on 27 May 1999.^[1] The outbreak in neighbouring Singapore also ended with immediate prohibition of pigs importation to the country and their subsequent closure of abattoirs.^[1] The virus discovery received the attention from the American Centers for Disease Control and Prevention (CDC), Commonwealth Scientific and Industrial Research Organisation (CSIRO) and Singapore General Hospital (SGH) who giving swift assistance towards the characterisation of the virus and the development of surveillance and control measures.^[1]

Aftermath[edit]

Until 2010s, the pig farming ban on Pelandok Hill was still in force to prevent the recurrence of the outbreak despite some people had quietly restarted the business after being instigated by community leaders.^[9] Most of the surviving pig farmers have turned to palm oil and Artocarpus integer (cempedak) cultivation.^[10] Since the virus has been named Nipah from the sample taken in Nipah River Village of Pelandok Hill, the latter area has become synonyms with the deadly virus.^[11]

Memorials[edit]

In 2018, the outbreak are being memorialised in a newly constructed museum named Nipah River Time Tunnel Museum in the Nipah River Village with several of the surviving victims stories have been filmed in a documentary which will be featured at the museum.^[10]

See also[edit]

• Paramyxoviridae

• Asia portal

• Biology portal

• Malaysia portal

• Medicine portal

• Viruses portal

Further reading[edit]

• Yob, J. M.; Field, H.; Rashdi, A. M.; Morrissy, C.; van der Heide, B.; Rota, P.; bin Adzhar, A.; White, J.; Daniels, P.; Jamaluddin, A.; Ksiazek, T. (2001). "Nipah virus infection in bats (order Chiroptera) in peninsular Malaysia". Emerging Infectious Diseases. 7 (3): 439–441. doi:10.3201/eid0703.010312. PMC 2631791. PMID 11384522.

• Lam, Sai Kit; Chua, Kaw Bing (2002). "Nipah Virus Encephalitis Outbreak in Malaysia". Clinical Infectious Diseases. 34 (2): S48–S51. doi:10.1086/338818. PMID 11938496 – via Oxford Academic.

• Lam, S. K. (2003). "Nipah virus--a potential agent of bioterrorism?". Department of Medical Microbiology, Faculty of Medicine, University of Malaya. 57 (1–2): 113–9. doi:10.1016/s0166-3542(02)00204-8. PMID 12615307 – via National Center for Biotechnology Information.

• Hughes, James M.; Wilson, Mary E.; Luby, Stephen P.; Gurley, Emily S.; Hossain, M. Jahangir (2009). "Transmission of Human Infection with Nipah Virus". Clinical Infectious Diseases. 49 (11): 1743–1748. doi:10.1086/647951. PMC 2784122. PMID 19886791 – via Oxford Academic.

• Banerjee, Sayantan; Gupta, Nitin; Kodan, Parul; Mittal, Ankit; Ray, Yogiraj; Nischal, Neeraj; Soneja, Manish; Biswas, Ashutosh; Wig, Naveet (2019). "Nipah virus disease: A rare and intractable disease". Intractable and Rare Diseases Research. 8 (1): 1–8. doi:10.5582/irdr.2018.01130. PMC 6409114. PMID 30881850 – via National Center for Biotechnology Information.

• Mazzola, Laura T.; Kelly-Cirino, Cassandra (2019). "Diagnostics for Nipah virus: a zoonotic pathogen endemic to Southeast Asia". The BMJ. 4 (2): e001118. doi:10.1136/bmjgh-2018-001118. PMC 6361328. PMID 30815286.

References[edit]

• ^

• Jump up to:

• ^{a b c d e f g h i j k l m n o p q} Looi, Lai-Meng; Chua, Kaw-Bing (2007). "Lessons from the Nipah virus outbreak in Malaysia" (PDF). The Malaysian Journal of Pathology. Department of Pathology, University of Malaya and National Public Health Laboratory of the Ministry of Health, Malaysia. 29 (2): 63–67. Archived (PDF) from the original on 30 August 2019.

• ^

• Jump up to:

• ^{a b} Doucleff, Michaeleen; Greenhalgh, Jane (25 February 2017). "A Taste For Pork Helped A Deadly Virus Jump To Humans". NPR. Retrieved 30 August 2019. The disease was as deadly as Ebola, but instead of attacking blood vessels, it attacked the brain. Young men would be healthy one day, the next day their brains would swell up. They couldn't walk or talk. They'd become comatose and some of them became paralysed. Yet the Malaysian government told people not to worry, it said the disease was coming from mosquitoes and it had it under control because it was spraying for mosquitoes. Both C. T. Tan and Kaw Bing Chua thought the government was wrong and there was one big clue: No Muslims were getting sick, mosquitoes don't care which religion you practice so if the disease was coming from mosquitoes, you would have Muslims, Hindus and Christians getting sick. But only Chinese Malaysians were catching the disease — and even more specifically, only Chinese farmers raising pigs. As you know, Muslims don't handle pigs.

• ^ "Manual on the Diagnosis of Nipah Virus Infection in Animals" (PDF). RAP Publication. Food and Agriculture Organization: v [11/90]. 2002. Archived (PDF) from the original on 30 August 2019.

• ^ Ang, Brenda S. P.; Lim, Tchoyoson C. C.; Wang, Linfa (2018). "Nipah Virus Infection". Journal of Clinical Microbiology. 56 (6): e01875-17. doi:10.1128/JCM.01875-17. PMC 5971524. PMID 29643201 – via American Society for Microbiology.

• ^ "Nipah virus". World Health Organization. 30 May 2018. Retrieved 30 August 2019.

• ^ "Nipah Virus Infection" (PDF). World Health Organization. Archived (PDF) from the original on 30 August 2019. The virus is named after the Malaysian village where it was first discovered. This virus along with Hendra virus comprises a new genus designated Henipavirus in the subfamily Paramyxovirinae.

• ^ "Nipah Virus (NiV)". Centers for Disease Control and Prevention. 20 March 2014. Retrieved 30 August 2019.

• ^ Enserink, Martin (2000). "Malaysian Researchers Trace Nipah Virus Outbreak to Bats". Science. 289 (5479): 518–9. doi:10.1126/science.289.5479.518. PMID 10939954 – via American Association for the Advancement of Science.

• ^ Singh, Sarban (3 July 2014). "1998 ban on pig farming in Bukit Pelanduk still in force". The Star. Retrieved 31 August 2019.

• ^

• Jump up to:

• ^{a b} Yong, Yimie (14 April 2018). "Nipah virus outbreak memorialised in museum". The Star. Retrieved 31 August 2019.

• ^ Yi, Chang (27 May 2018). "Bukit Pelandok revisited". The Borneo Post. Retrieved 31 August 2019.

Smallpox, the ancient disease, was eradicated 20 years ago. Smallpox, the virus, is on death row, frozen in two highly protected laboratories in the United States and Russia. Like lawyers filing last-minute briefs, American scientists have come up with new arguments for reprieve.

Yesterday, with the backing of Russia and other governments, the World Health Organization formally bowed to their wishes and granted the virus yet another stay. In keeping with action taken last week, the United Nations subagency in Geneva said it would appoint another committee to study the arguments and help decide the virus's fate. It has now been put off until June 2002.

By then, the Geneva-based organization hopes, the committee may have figured out whether there is any reason to keep stocks on hand.

For example, research using the virus might yield drugs against the disease, or improved vaccines to prevent it. These would be of no use, in effect, unless some rogue nation unleashed hidden stores of smallpox virus in a biological terror attack, a prospect no longer regarded as outlandish. Or use of new techniques might decipher some of smallpox's distinctive features, providing clues to help fight other diseases.

Ordinarily, such broad research goals would attract little attention until they produced important findings. But there is nothing ordinary about smallpox. It was one of the deadliest scourges, killing one in three victims, peasants and monarchs alike. The virus, known as variola, usually left survivors with deep, pitting scars on the face and body, and often blinded them.

Smallpox was the first disease prevented by a vaccine, one developed by Edward Jenner in 1798, and it was the first and only disease to be wiped out, by the World Health Organization in 1979. Variola lives only in people. After epidemiologists tracked down the last cases and focused vaccinations on areas where they occurred, they broke the human-to-human chain of infection. The virus came to a dead end. Only the research stocks remained. Few opposed the health organization's proposal that they be destroyed, in what would be the first deliberate extinction of a life form.

But attitudes began to change in recent years when a shocked world learned that Russia had secretly stockpiled tons of smallpox virus and manipulated it for use as a possible weapon. During that period, Moscow supported the disease's eradication. North Korea and other countries are believed to have clandestine supplies of smallpox virus as well.

Until Russia's duplicity and secret stores were exposed, scientists elsewhere had virtually abandoned smallpox research largely because the disease was gone.

Scientists are the people most knowledgeable about smallpox and presumably have the most at stake in the decision. Astonishingly, with rare exception, scientists have had little to say about the proposed action.

''The sense was that it was out of our hands, that it was a done deal between W.H.O. and the C.D.C.,'' said Dr. Ronald Luftig of Louisiana State University, referring to the World Health Organization and the Centers for Disease Control and Prevention in Atlanta. Dr. Luftig is an official of the American Society for Virology and American Society for Microbiology, both of which officially support destruction of variola.

But the potential use of hidden stores of virus as a weapon are changing that picture. First, the release of the virus among the world's largely unvaccinated population could kill millions of people. Second, the Clinton Administration's pledge to spend millions of dollars on bioterrorism defenses makes smallpox research a potential source of money for interested scientists.

Scientists in the United States, Russia and elsewhere have begun to debate, often bitterly, why W.H.O. should insist on destroying a virus that might still exist secretly in other countries.

A crucial point in the debate is that irrevocable destruction of the virus would deprive future generations of the opportunity to use new knowledge and research tools to solve the many mysteries of smallpox, and thereby unravel mysteries of other ailments as well.

''Everyone can envision situations in which you might want to take the virus from the freezer,'' said Dr. Harold E. Varmus, who heads the National Institutes of Health.

Dr. Clarence J. Peters, an international leader in virology who works with smallpox and other lethal viruses at the Centers for Disease Control, said, ''I have been on both sides of the argument at different times.''

But several factors make variola studies difficult.

One is that such work must take place in a laboratory with the highest biosecurity standards. Scientists must wear a protective spacesuit, isolating them from the laboratory. They wear gloves that increase the difficulty of handling small vials. The air they breathe is filtered. On leaving the laboratory, they must take two showers, the first with a disinfectant. The aim is to protect themselves and the community.

''It's a nuisance to do experiments in that environment,'' said Dr. Frank Fenner of Canberra, Australia, a top expert on the pox family of viruses and a leader in the eradication effort.

There are few high security laboratories, and W.H.O. wants work on smallpox to be limited to two sites: the C.D.C. in Atlanta and Russia's State Research Center of Virology and Technology, better known as Vector.

Competition among scientists for time in the Atlanta laboratory is intense. Investigations of other deadly viruses, like the newly discovered Nipah virus, which has recently killed more than 100 people in Malaysia, have highest priority.

Responding to a W.H.O. request, scientists will soon pull variola from a freezer at the centers in Atlanta for the first time in four years, said Dr. Brian W. J. Mahy, who oversees the agency's smallpox work. For about a month they will grow the virus, inactivate it with radiation, and prepare viral proteins that might be used in standard laboratories to develop more rapid tests to help doctors detect smallpox, since so few have ever seen it.

Experts who favor destroying variola say that most important research questions about smallpox could be answered from work conducted in less secure laboratories. Such work would involve different viruses belonging to the pox family that affect monkeys, camels and other species.

The most compelling reason for keeping variola is to discover potentially lifesaving drugs in case the virus ever reappears, either naturally or as an act of war or terrorism. A report on these research needs, issued in March by the Institute of Medicine, the medical arm of the National Academy of Sciences, was pivotal in President Clinton's decision to reverse course and advocate retaining the virus.

Few potential anti-variola drugs exist, and scientists are handicapped in developing new ones because the virus naturally infects only humans and so there is no animal model for drug tests. ''That's where we are stuck with smallpox,'' Dr. Mahy said.

Nevertheless, Food and Drug Administration approval of 20 antiviral drugs in the last 10 years offers hope of eventually discovering other drugs that would be effective against variola, said Dr. Martin S. Hirsch, a virologist at Harvard University who is a member of the Institute of Medicine committee.

Variola is one of the biggest viruses, with about 200 genes compared with 9 for the AIDS virus and 3 for the Rift Valley fever virus. Thus variola offers many targets for drugs.

Dr. Mahy said C.D.C. scientists were looking at new ways to develop potential anti-variola drugs.

Dr. Stanley Falkow of Stanford University, a former president of the American Society for Microbiology, said ''epidemic diseases of humans are quite recent in the evolutionary sense because human populations were not big enough to sustain epidemics until about 5,000 years ago, and we don't know'' how best to study them now.

Among smallpox's many unusual features is that a different virus is used to prevent it. Most vaccines are derived from weakened or killed strains of the same virus that they prevent.

Only two other diseases are fought with vaccines derived from different viruses. One is a new rotavirus vaccine made from a monkey strain to protect humans against the diarrheal illness. Veterinarians use a vaccine prepared from turkey herpes virus to protect chickens against Marek's disease, which is caused by a different herpes virus.

If scientists understood the small differences in genetic makeup between smallpox and the vaccinia viruses that protect against it, smallpox might serve as a model to develop immunizations for diseases, like dengue fever and AIDS, for which vaccines are needed.

The eradication of smallpox documents the effectiveness of the standard vaccine, but the remaining supplies are dwindling as many vials lose potency. If scientists tried to replace the vaccine with a safer one, particularly for people with immune deficiencies from AIDS or treatment for cancer, live variola might be needed for such research, said the Institute of Medicine committee, which was headed by Dr. Charles C. J. Carpenter of Brown University.

But Dr. Donald A. Henderson, who led the smallpox eradication program, said lack of human cases and an animal model made it impossible to test safety and effectiveness of new drugs and vaccines against variola. ''One could never be certain that they were protective until actually used,'' said Dr. Henderson, a former deputy White House science adviser.

• NOTE : "Donald A Henderson .. Henderson served as Chief of the CDC virus disease surveillance programs from 1960 to 1965, working closely with epidemiologist Alexander Langmuir. Du "

• https://en.wikipedia.org/wiki/Donald_Henderson

• https://en.wikipedia.org/wiki/Alexander_Langmuir

Also, scientists know very little about what makes some viruses more virulent than others. Dr. Varmus of N.I.H. and Dr. Anthony S. Fauci, who heads the National Institute of Allergy and Infectious Diseases, expressed hope that future studies of variola's genes and the way the virus kills cells would help unravel mysteries about the more general nature of why many infectious agents harm humans.

Scientists can use newer techniques to make mutations in viruses in the laboratory to study the effects of different genes in new ways.

In advocating retention of variola, Dr. Varmus said that as scientists learned more about how viruses harmed humans, the virus that was such a scourge ''ought to be available for study if we had an important experiment to test.''

At W.H.O.'s request, Russian and American scientists mapped the complete DNA sequences of three strains of variola. W.H.O. believed that such information would be a sufficient knowledge base for future research and for comparing viruses released by terrorists or somehow emerging from nature.

But a number of scientists challenged that view, saying that sequences alone could not determine a virus's vulnerability to a drug.

Speaking of the unpredictability of research, Dr. Fauci said, ''You might never take the virus from the freezer, but at least you have it.''

HONG KONG— The European Union sought Tuesday to prevent its growing food scandal from turning into a trade dispute with Asia as countries across the region imposed or extended bans on the import of European food.

South Korean officials in Brussels received complaints from France and the Netherlands that Seoul's ban on pork from the two countries was "draconian," according to an Agence France-Presse report citing the South Korean news agency Yonhap.

Although Belgium is the source of the food scare in Europe, animal feed from Belgium containing a cancer-causing chemical, dioxin, may have been used in several other European countries.

"In this case the proof in the pudding is not in eating it, but in testing it," said Etienne Reuter, head of the office of the European Commission in Hong Kong. "But if there's a doubt, one has to accept that people take these measures to protect their consumers.

"I certainly would not wish to see this in terms of a trade war. You have to see this uniquely in terms of protecting the consumer and restoring confidence."

he list of places in Asia banning products grew Tuesday as Taiwan suspended imports of 77 kinds of Belgian egg, dairy and meat-based farm products.

The Philippines banned all poultry, beef and pork products from Belgium, the Netherlands, France and Germany, and Thailand said it had banned Belgian meat, poultry and dairy products as of Monday. Malaysia, South Korea, Hong Kong and Singapore have already announced bans on various European food imports.

Part of what is making the bans on European food so sweeping is the dearth of information coming out of Belgium about the possible extent of the contamination, a source of considerable tension within the European Community.

As stores in Hong Kong moved to clear their shelves of six brands of European infant formula, a Hong Kong government spokesman said the ban "was taken as a precautionary measure and mothers do not have to be over anxious," but that "it will be safer to avoid these milk formulas until clarification and assurance can be obtained" from the countries concerned.

For some Asian countries, the bans have a considerable impact, but not critical to maintaining sufficient food supplies. In Hong Kong, which has now extended the ban on pork and poultry to include beef and dairy products from Belgium, the Netherlands, France and Germany, the import restrictions will affect 30 percent of the baby formula market, 18 percent of the market for fresh eggs, and 10 percent for poultry, according to European Community figures.

Food scares are nothing new to Asia. The Belgian scandal has led to the worst one in Europe since the bovine spongiform encephalopathy — or "mad cow"— crisis over British beef in 1996, but since that time Asia has had several of its own food crises at least as serious as the one in Europe.

This year, Malaysia has slaughtered more than 900,000 pigs to contain outbreaks of two viruses, Japanese encephalitis and Nipah.

Alarmed at what the Clinton Administration views as the growing threat of biological terrorism to America's food supply, the Agriculture Department is seeking money to turn the Plum Island Animal Disease Center, one mile off Long Island, into a top security laboratory where some of the most dangerous diseases known to man or beast can be studied.

The Agriculture Department already operates here at Plum Island, just across Gardiners Bay from the wealthy Hamptons, a laboratory where such dreaded foreign animal diseases as foot-and-mouth and African swine fever are examined. But the department is seeking $75 million this year and $140 million over the next two years to upgrade the center to handle even more dangerous animal diseases that can affect humans.

While there are four civilian and military laboratories in America equipped to study such diseases -- technically known as Biosafety Level Four facilities -- their work is focused on germs that primarily affect humans, not domestic animals or plants.

[...]

Plum Island, which was once operated by the United States Army Chemical Corps, was designated as an animal-disease research center and transferred to the Agriculture Department in the early 1950's. It is already what scientists call an agricultural ''Biosafety Level Three'' center, which means that its containment areas, which hold germs dangerous to animals, have filtered air, sealed doors and negative air pressure that prevents germs from leaking out of the labs. Liquid waste is decontaminated.

All who enter the labs wear white lab coats and slippers. After leaving the containment areas, they are required to shower, shampoo their hair, scrub their nails and rinse their mouths, since lethal germs can live in human throats and infect animals up to two days later. To stop viruses or microbes from escaping to the mainland, no clothing or articles, even eyeglasses, are permitted to leave the labs without being soaked in disinfectant, said Dr. Alfonso Torres, the deputy administrator of the Agriculture Department's Veterinary Services Division and former director of the center, who conducted this reporter on a tour.

[...]

Moving to the next level of bio safety would require that scientists working with dangerous pathogens wear the protective decontaminated suits portrayed in movies like ''Outbreak,'' and breathe only filtered air pumped into their hoods. Such precautions would allow scientists to work with even more dangerous animal pathogens that can affect humans, like the Hendra virus, which afflicts horses, and the Nipah pig virus, named for the Malaysian village in which it was first isolated this year. The virus has already killed more than 100 people.

''We intend to work closely with local officials and community groups to allay any concerns about safety,'' said Dr. Horn, who acknowledges that Plum Island has long been shrouded in mystery and plagued by what he and Dr. Torres call unfounded rumors and fears.

The 850-acre island was opened to news organizations only in 1992 in response to concerns about safety at the center. In 1995, the Department of Agriculture was fined $111,000 for illegally storing hazardous chemicals here. Since then, the agency has changed the contractor who operates the island, and there have been no violations.

The extent of the threat posed by agro-terrorism remains in dispute, even within the Clinton Administration. Some scientists and terrorism analysts argue that there is little reason to believe that terrorists would attack American agriculture or livestock.

But intelligence reports increasingly conclude that several countries, including Iraq, have developed germs to attack the food supplies of their adversaries. And senior American officials now believe that an outbreak of screwworm, a parasite that afflicts animals and people, was spread deliberately 14 years ago in Mexico less than 50 miles from the Texas border by workers who were employed in a screwworm eradication program and feared the loss of their jobs.

[...]

Fueled by growing concern about the proliferation of such expertise and such dangerous germs, President Clinton ordered the Government last year to prepare defenses against germ and other unconventional attacks on the nation's plants and animals. In January, Dr. Horn recruited four former Pentagon intelligence analysts and terrorism experts to form the Agricultural Research Services' first unit to evaluate such threats. In April, the White House formally included the Agriculture Department in the group of agencies that meet regularly under National Security Council aegis to weigh plans to deter or respond to unconventional terrorism, a $2.8 billion effort.

[...] Senator Pat Roberts, Republican of Kansas, who is chairman of the Senate Armed Services Subcommittee on Emerging Threats and Capabilities, plans to hold hearings on agro-terrorism in October that will explore the Administration's plans for Plum Island. [...]

[...]

As the federal Agriculture Department considers whether to seek congressional approval to make the 45-year-old Plum Island center the only government laboratory in the country to study extremely virulent animal diseases that can also kill humans, questions of safety and security are suddenly looming large.

The department and its highest-ranking experts have said that an animal disease center with labs that have the highest security rating, biosafety level four, are an absolute necessity for combating viruses that could attack cattle, pigs, sheep and other domestic herds, with the potential to devastate the country's $90 billion livestock industry.

Some of the diseases -- the kind scientists call zoonotic -- can also spread to humans with lethal effects, making them a double threat if they were used in a bioterrorist assault.

Fears of bioterrorism prompted the Clinton Administration to direct the Agricultural Department and other agencies to take steps to protect the country, and changes at Plum island could be part of the response.

Because Plum Island is now rated at biosafety level three for studying foreign animal viruses, the department has made no secret that the island is its first choice for the level four labs.

As the wheels begin turning, critics are already questioning the wisdom of importing viruses for which there are no known cures to an island off crowded Long Island and 95 miles from Manhattan.

[...]

In a spacious conference room, Wilda Martinez, the area director for the Animal Research Service, one of two Agriculture Department agencies at Plum Island, extended a welcome but minced no words.

Recent news reports, she said, have been inaccurate in their details, and have blurred the reasons the level four labs are needed. ''Bioterrorism aside,'' she said, ''it is apparent that the protection afforded by ocean barriers and geographic separation will no longer prevent the introduction of foreign animal diseases.''

Dr. Alfonso Torres, a native of Colombia and the deputy administrator of the Animal and Plant Health Inspection Service, the other Agriculture Department agency at Plum Island, followed with a slide lecture intended to leave no doubt about the importance of the lab in protecting agriculture, the county's largest industry.

[Dr. Peter Keith Murray (born 1946)], the director of the Animal Research Service national animal disease center in Ames, Iowa, said Plum Island was already equipped to protect the public from exposure from even so dangerous a virus as the Nipah virus. That virus, hitherto unknown, spread among domestic swine in Malaysia, and then to farmers and farm workers. More than 250 people died and millions of swine were slaughtered to eradicate the outbreak, he said.

[Dr. Peter Keith Murray (born 1946)], a former head of what is now the world's only level four animal disease lab near the Australian city of Geelong, said the Nipah virus could be studied now in level three labs at Plum Island without endangering the public because lab safety systems would prevent the virus from ''escaping into the environment.''

But safety level three was ''not good enough,'' he said, to protect the laboratory's staff of 14 research scientists and more than 160 other employees, and therein lay the need for the upgrade to level four.

Researchers and others working with viruses in level four labs wear so-called ''space suits'' that are connected to external air supplies. The suits are not required in level three labs.

[Dr. Peter Keith Murray (born 1946)] and others said the need for the level four labs had been urgent and obvious for some time. ''Nobody is sure why, and there's a lot of speculation, but we are encountering more and more of these new diseases over the past 15 years,'' said Dr. Murray, citing the Nipah virus and mad cow disease in England as examples.

''Frankly, given the nature of emerging threats from around the world and here at home, it is very clear that U.S.D.A. must have access to BSL4 facilities,'' he said. ''We're all here today because of the talk Plum Island might be that site.''

[...]

On the tour Carmen Farrugia, a lab employee involved with shipping and receiving, demonstrated how viruses are shipped. First, a small amount of virus contained in a small vial was placed in a slightly larger vial with absorbent material, which in turn was placed in another container with more absorbent material.

The container was then packed in a box with a hard plastic liner, and capped with a spongelike material and often with dry ice. The box, she said, was designed to withstand a fall of 27 feet. The boxes, which bear labels warning of an infectious substance inside, are shipped by air.

''This gets shipped like cargo, like you were sending a package to grandma or something,'' Ms. Farrugia said.

In this way, viruses collected from other parts of the world were transported to Kennedy International Airport, where they are met by couriers with cell phones, decontamination kits and training in cleanup. The couriers then drove east on the Long Island Expressway ''except when there are traffic jams,'' Ms. Farrugia said, eventually taking Route 25 down the North Fork to Orient Point; the packages then traveled by boat to Plum Island.

Dr. Michael Kiley, the Animal Research Service safety officer at the lab, said the packages were designed to withstand a plane crash. Dr. Kiley also said that other government agencies, including the Federal Bureau of Investigation, would be involved in assuring shipment and lab security if Plum Island was upgraded to a level four center.

[...]

In an unmarked warehouse in the middle of a wheat field in central Ohio, a hulking 300-pound pig lies on her back, her legs tethered to a crude iron gurney in a bare, well-lighted room. The animal has been sedated into a light state of sleep, and the pale pink expanse of her belly rises and falls rhythmically with each breath. A young man in green hospital garb has just sliced a six-inch incision between the sow's nipples; now he pokes around her innards with latex-gloved hands.

The pig on the table is pregnant. The young man, a veterinary technician named Bruce Close, is about to remove her newly fertilized eggs. At 26, Close is an old hand at pig surgery; he has performed this operation more than 600 times in the two years he has been employed by Nextran, the Princeton, N.J., biotechnology company that runs this warehouse as a breeding center. This, however, is no ordinary pig farm. For the past decade, Nextran has been locked in a high-stakes race to build the perfect pig: an animal with human genes, whose organs can be transplanted into people. In the medical lexicon, this is known as xenotransplantation, and it has been an elusive dream of scientists for nearly 100 years.

Today, despite fears that pig-to-human transplants could unleash a deadly new virus, the dream is closer than ever to reality. In August, a long-awaited safety study conducted by Nextran's chief competitor, Imutran Ltd., of Cambridge, England, found no evidence of active infection in 160 people who had been treated with pig tissue for a variety of conditions. The findings come as the companies are laying the groundwork to begin testing transplanted organs in people. Sometime within the next few years, and possibly as soon as the end of next year, either the British or the Americans will grab the brass ring: approval from a regulatory agency, either the United States Food and Drug Administration or its equivalent in Britain, to perform the world's first animal-to-human transplant using a heart or a kidney from a genetically engineered pig.

Nobody expects cross-species transplants to be successful overnight. But with time, xenotransplantation could solve the most pressing crisis in medicine -- the organ shortage. It could also make the companies very rich. Unlike human organs, which are donated, pig organs will be sold, and in a climate in which demand far outstrips supply, the seller will name the price. By greatly expanding the donor pool, pigs could make transplants possible for tens of thousands of people who, because of the current rationing system, never even make the list, not to mention those in some Asian nations, where taking organs from the dead is culturally taboo. Imagine a therapy as revolutionary as penicillin and as lucrative as Viagra rolled into one.

In Ohio, Bruce Close is working toward that day. Moving quickly and in silence, he tears at layers of pig fat until he can feel the pig's uterus. Gently, he extracts the slippery pink-and-purple mass, palpating it until his fingers reach a cluster of 10 blood-rich pustules -- the ovulation points.'' Each contains a single egg so recently joined with a sperm, through artificial insemination, that it has not yet divided from one cell into two. This is the optimal moment for creating ''transgenic'' piglets -- animals that, at least in a genetic sense, look ever so slightly like people.

It is a bizarre, almost creepy sight, this big, fat pig upside down on an operating table, her head dangling backward over a bucket in case she vomits, her insides splayed out on a blue-paper surgical drape as a scientist rearranges the DNA of her unborn young. In a moment, the animal's eggs will be flushed out of the ovaries, collected in a tiny vial and smeared onto a glass slide; then a ''microinjectionist'' will examine them under a high-powered microscope and, with a needle finer than a strand of hair, insert a single human gene into each.

Later this afternoon, Close will return to the operating room to implant the growing embryos into a foster mother sow. In roughly 114 days, if all goes as Nextran hopes, she will deliver a litter that includes at least one transgenic piglet. Yet if Close sees anything Frankensteinian in this, he does not admit it. ''What I'm doing right now,'' he says, ''may someday save people's lives.''

Across the Atlantic Ocean, at an undisclosed location in the English countryside, Imutran is running its own transgenic pig farm. Like Nextran, which was purchased several years ago by Baxter International, one of the world's largest medical-products manufacturers, Imutran is owned by a drug-industry powerhouse, the Swiss-based Novartis Pharma AG, a company with three times the annual revenue and nearly seven times the research budget that Baxter has. While Nextran has been testing its pig hearts and kidneys in baboons, Imutran has been running tests in monkeys and baboons, and reporting longer survival times. Like Nextran, Imutran is facing mounting criticism as it moves closer to testing its organs in people.

Animal rights advocates, predictably, lament the fate of the poor pigs that will be used as spare-parts factories, a charge the companies shrug off by pointing to refrigerators stuffed with bacon and pork chops. What they cannot shrug off, however, are the very real safety concerns. The Campaign for Responsible Transplantation, a coalition of scientists and public-health professionals, has asked for a ban on cross-species transplant research. And one prominent xenotransplant expert, Dr. Fritz Bach, of Harvard University, who is a paid consultant to Novartis, has called for a national commission to study the risks.

And so the companies are proceeding quietly, insisting that there is no rush to the clinic. ''I don't believe that there is a race in the sense of, 'Oh, let's be first,''' says David White, Imutran's chief scientist. Says John S. Logan, Nextran's scientific director, ''What we all want to be is the first to be successful.''

But there is a race, and in science, as in life, being first counts. ''Clearly,'' says Jeffrey L. Platt, a transplant immunologist at the Mayo Clinic, in Rochester, Minn., ''there is a competition between the two companies to enter the clinical arena.'' The first ''whole organ'' xenotransplant will attract intense press coverage, giving whoever conducts it free publicity, not to mention a spot in the medical history books. And if being first means earning the confidence of regulators and the public, then being first may well be tantamount to being successful.

Platt, for one, says that if xenotransplants could be made as safe and effective as human transplants, they would replace them. ''Metaphorically speaking,'' he says, ''it will be like the automobile repair industry. Nobody makes much effort to rebuild parts, because it is cheaper and better for your car to have a brand-new part.''

If it sounds like science pushing itself to the edge of science fiction, it is. And like all good science-fiction stories, this one has the potential to end in disaster.

It is not easy to find ''the pig farm,'' as Nextran obliquely calls its breeding warehouse. The building sits at the end of a long gravel road on a slight knoll in the middle of a 200-acre lot in the little farming hamlet of Albany, Ohio. There are no signs outside, which is by design. ''We're not big on signs,'' Logan, the Nextran scientist, explains. On the rare occasion when uninvited guests drop in with nosy questions, a supervisor dismisses them with a simple, if less than completely truthful, explanation: ''We breed pigs.''

With a shock of auburn hair draped across his forehead, and a reddish-brown beard covering his chin, Logan, 44, looks more like a lumberjack than a microbiologist. Born in Scotland, he still speaks with a strong accent after nearly two decades in this country, and he has the impatient manner of someone who is always hurrying to catch the next train. Where White, the Imutran scientist, is a master of public relations and charm, Logan is cautious and reserved. He is confident enough never to confess to being the underdog, but not cocky enough to make any grand predictions about success. ''When we get to the day when we are sitting here and it really works,'' he says, ''that's the day pronouncements will be worthwhile. That's the day you have to drive for. And that's what keeps me going.''

Outsiders are rarely allowed at the Nextran farm. The company line is that visitors are dangerous for the pigs; nobody sees the animals without showering first and donning company-issued, disinfected clothing, plus a surgical mask and gloves. But the policy, which includes a ban on photography, also suits Nextran's penchant for privacy, so as not to rile up animal rights advocates and antibiotech groups that oppose its work. The Nextran warehouse looks more like a pig dormitory than a pig farm, with animals housed in various rooms that run along dimly lighted, narrow corridors. There is no mud. The water is tested several times a week. The pigs are strict vegetarians; meat poses the risk of bovine spongiform encephalopathy, mad cow disease.

On this particular morning, as is the case two or three mornings each week, the miracle of birth has come to the Ohio farm. In the farrowing room, where expectant sows are kept, more than two dozen newborn piglets scamper about in their stalls, their skin a translucent pink, their umbilical cords still dangling from their bellies. In 24 hours, the piglets will be tagged and numbered, and a Nextran animal handler will snip off a tiny bit of their tails; the snippets will be shipped to the company's laboratory in Princeton, where their genetic makeup will be analyzed to see if they contain the crucial gene, or in certain cases two genes, that Nextran believes will trick the human immune system into accepting pig organs.

The breeding process is ''horribly inefficient,'' Logan says. Typically, 20 pigs are born from every 100 gene-altered eggs, but only one is transgenic. The 19 less fortunate animals meet an untimely demise. So while there is something peculiarly endearing about the sight of these little pink critters, rooting for their first taste of mother's milk, Logan has no idea at this point if the animals are of any use to him. When I ask him what he sees, expecting perhaps some philosophical answer about the wonders of molecular biology, or the future health of mankind, he replies: ''I see a bunch of little pigs. That's all I see.''

At a time when biological tinkering has invaded every aspect of modern life, the sight of swine with human DNA should probably not seem alarming. Still, it is difficult to look at Nextran's pigs without wondering if there is an element of hubris to Logan's work, if porcine-people aren't better left to Greek mythology, or at least George Orwell, than to modern medicine. Clearly, in 1999, some pigs really are more equal than others.

Harold Vanderpool, a medical ethicist at the University of Texas Medical Branch, in Galveston, has a term for the visceral reaction these pigs evoke. ''I call it 'the gag factor,''' he says. ''We are thinking across a barrier that should never be crossed.'' And in point of fact, there may be a very good reason -- the viruses -- it should not be. Pigs have become the animal of choice in xenotransplant research for a variety of reasons. They are plentiful, and they breed easily. They are physiologically similar enough to humans. And pigs and people have lived side by side, in relative health and harmony, for centuries. Virologists say most disease-causing germs can be eliminated through careful selection and breeding. But over the past two years, they have focused their attention on one obscure organism that cannot be bred out, the porcine endogenous retrovirus, abbreviated in the medical literature as PERV.

Of all viruses, retroviruses are the most feared. They integrate their genetic code into the cells they infect, which means they multiply along with the cells. Retroviruses last for life. They are typically spread through blood or sexual contact, and they can lurk in the body for years, even decades, before causing any symptoms. ''It's like a ghost virus, a stealth virus,'' says Jonathan S. Allan, a virologist at the Southwest Foundation for Biomedical Research, in San Antonio. ''Once it splices itself into the host genome, it is virtually impossible to get it back out.''

If this scenario sounds familiar, it's because over the past two decades, another retrovirus, H.I.V., believed to have originated in apes, has cut a devastating swath around the world. Most scientists, Allan included, do not believe that xenotransplants will unleash the next AIDS epidemic. But no one, not even the companies, argues that the transplants will be risk-free. While there is thus far no evidence that PERV makes people sick, it can infect human cells in the test tube. And some experts theorize that the virus could mutate into a deadly form, as H.I.V. did, and then spread through sexual contact, infecting untold numbers before causing any symptoms. While the recent Imutran study is a comfort, it looked at only 160 patients, who had been treated in hospitals around the world and were later tracked down by Novartis. What will happen when people are getting xenotransplants by the tens of thousands?

The danger may not be limited to PERV. In January 1997, a pig farmer in Ipoh, a Malaysian village about 200 miles north of Kuala Lampur, became ill with what appeared to be encephalitis. The following year, 258 Malaysian pig farmers became sick; 101 of them died. It took until March of this year for the Centers for Disease Control and Prevention to identify the cause: a brand-new virus named Nipah.

This is a point that Allan, who serves on a panel of scientific experts convened by the Food and Drug Administration to plan for its first xenotransplant clinical trial, has made repeatedly. For all the focus on PERV, he says, there may be other viruses, about which much less is known, that in the end will pose a greater danger to the public health. To justify any human experiment, the scientists conducting it must show that the benefits to the patient outweigh the risk. But xenotransplants defy that calculation: the patient benefits while society takes the risk. ''The individual,'' Allan warns, ''can sign a consent form and say, 'I'll take the risk because I'm going to die anyway.' But that person is signing a consent form for the whole population, the whole human race.''

Still, there are good reasons to proceed. More than 62,000 Americans are now waiting to receive donated hearts, lungs, livers, kidneys and pancreases, according to the United Network for Organ Sharing. A new name is added to the list every 16 minutes, and every day 11 people die waiting. Increasing donations will not solve the problem; surgeons need young, healthy organs for transplants, so even if every dead person donated, there would still not be enough.

There is another reason, of course: money. In 1996, Salomon Brothers predicted that the global market for transgenic organs could reach $6 billion by the year 2010, a figure that explains why big pharmaceutical companies are involved. Novartis manufactures cyclosporine, an antirejection drug; the market for it would skyrocket if xenotransplants became common. Baxter's interest is self-preservation; it makes dialysis machines, which would be relegated to the medical junk heap if people with failing kidneys were given pig organs instead.

Hospitals and surgeons stand to gain as well. Transplants are expensive, and they make a good living for those who perform them. Three years ago, the Institute of Medicine calculated that if animal organs made it possible to offer a transplant to everyone in the United States who needed one, annual expenditures would rise to $20.3 billion, from $2.9 billion. Already, the Mayo Clinic has entered into what its director of heart and lung transplantation, Dr. Christopher McGregor, calls a ''strategic alliance'' with Nextran. McGregor is busy testing pig hearts in baboons, and the company has built a state-of-the-art breeding facility not far from the clinic so Mayo doctors can have a ready supply of pigs in the event that xenotransplantation takes off.

While the medical world is gearing up, so, too, is the Government. Donna E. Shalala, the Secretary of Health and Human Services, will soon appoint a special committee to advise her on medical, ethical and social issues surrounding xenotransplants. As the infrastructure grows, so does critics' frustration. The Campaign for Responsible Transplantation, the group pressing for a research ban, has lately been threatening to sue Shalala if she does not respond to its petition. ''The prospect of a global health pandemic doesn't seem to be concerning anybody,'' warns Alix Fano, the campaign's director. ''And the people that are voicing their concerns are either being silenced or ignored.''

For a freckle-faced 19-year-old named Robert Pennington, the issue is of more than academic interest. Exactly two years ago today, a Nextran pig saved his life. With a fake diamond stud in his left ear, a silver bracelet encircling his wrist and a scrawny tuft of reddish-brown hair decorating his chin, Pennington, clad in a black T-shirt and blue jeans, looks more like an up-and-coming rock star than someone who has been at the brink of death. The vast scar that creeps along his chest and abdomen, in the shape of an upside-down Y, tells a different story, one that began in the fall of 1997, in Garland, Tex., a suburb of Dallas where Pennington was reared by his paternal grandparents, Charlotte and Ray.

Pennington was working at a family-owned carpet store when he came down with what he thought was the flu. Three weeks later, still feeling poorly, he looked in the mirror and saw that the whites of his blue eyes had turned yellow. He went to a local medical clinic, where a doctor asked for a urine sample. When Pennington handed the cup back, he noticed the liquid inside was a coffee-colored brown.

The clinic doctor, mystified, sent him home with orders to come back in two weeks to see a specialist. Four days later, he was admitted to Baylor University Medical Center, in Dallas, with what Dr. Marlon Levy, a transplant surgeon there, describes as ''fulminate hepatic failure'' -- a sudden, overwhelming death of the liver. Without a transplant, Levy knew, the young man would be dead in a few days.

The liver's job is to clean toxins from the blood. When it stops working, ammonia and other poisons accumulate in the bloodstream and travel to the brain, which swells until the patient becomes comatose and dies. Within 24 hours of his arrival at Baylor, Pennington was showing signs of acute ammonia poisoning: hallucinations and aggression. At one point, nurses were forced to tie him to his bed. Charlotte Pennington, a gray-haired matronly woman with an abiding faith in God, was terrified. ''We were praying for him,'' she says. ''We told him to just rest and hold on to Jesus.''

Pennington was placed at the top of the transplant list, but there were no livers available. In the back of his mind, Levy was already weighing another option: a highly experimental procedure, ''extracorporeal perfusion,'' in which Pennington would be hooked up to a Nextran pig liver and his blood would be circulated through it. The idea was to use the pig liver outside the body as a bridge, in the hope that it would keep Pennington alive until a human liver could be found. The procedure had been approved by the F.D.A. for testing at Baylor. Pennington was the first candidate.

In the eight years he has been performing liver transplants at Baylor, Levy, a stocky man with slicked-down black hair and a boyish face, has watched more patients than he can remember die for lack of organs. Because of the liver's complex physiology, liver xenotransplants are a long way off; hearts or kidneys will probably be tested first. But the perfusion experiment offered Nextran a halfway step, a chance to see how the immune system responded when exposed to its organs. And it gave Levy a chance to help a patient. On Sept. 3, 1997, the first batch of Nextran pigs was trucked from Ohio to the Baylor campus.

On Oct. 2, Robert Pennington's condition took a turn for the worse. In a deep coma, and no longer able to eat or breathe on his own, he was placed on full life support. His grandmother remembers watching the sun go down that evening and wondering whether the boy she had reared practically from birth would be alive when it came up in the morning. That night at about 11, Levy called Charlotte Pennington, awakening her from a deep sleep for a hasty meeting in the intensive-care unit. They sat at Robert's bedside and talked about the pigs. In the blue spiral notebook in which she recorded her thoughts, Robert's frightened grandmother jotted these words: ''uncharted territory. Not done at Baylor before.'' Levy told her she would need to make a decision by 8 the next morning.

The following morning, a 15-week-old, 118-pound pig was readied for surgery in the simple brick building that houses Baylor's animal lab; while Levy removed the animal's liver, an anesthesiologist inserted a line of plastic tubing in Robert's neck. Later, a second line of tubing was inserted into his groin, and the two-pound pig liver, covered by a surgical towel, was brought to Robert's bedside. The perfusion officially began at 4:10 P.M.; Robert's blood was pumped first through a heater and an oxygenator, then through the liver and then back into his body, at the rate of two quarts per minute.

Levy could see right away that it was working. ''The liver had good color and texture,'' he says, ''and it was taking up oxygen from the bloodstream.'' It was still cleaning Robert's blood six and a half hours later when a human liver was found in Houston, 250 miles away. In her scrapbook, Charlotte Pennington keeps a snapshot of ''the pig that was sacrificed to save Robert,'' a Polaroid photograph given to her by one of Baylor's animal handlers, who had named the pig Sweetie Pie.

Three weeks later, the F.D.A. shut down the perfusion trial. A team of virologists in England, who had already reported that PERV could infect human cells in the test tube, had now documented two separate strains of the virus and discovered that the genes for both appeared in a wide variety of pigs, suggesting that it would be difficult to breed them out. ''We were very concerned,'' says Dr. Philip Noguchi, the F.D.A. official who oversees xenotransplant research. ''It was sufficiently worrisome that we felt it would be better to stop.''

• Note- 2003 , LA TImes : "Citing Illnesses, FDA Halts Gene Therapy Trials

• 2003-01-15-the-los-angeles-times-citing-illnesses-fda-halts-gene-therapy-trials.pdf

• https://www.latimes.com/archives/la-xpm-2003-jan-15-sci-gene15-story.html

• By THOMAS H. MAUGH II

• JAN. 15, 2003 12 AM PT

• TIMES STAFF WRITER

• The Food and Drug Administration on Tuesday suspended 27 gene therapy trials -- nearly half of those now underway in the United States -- after the agency learned that a second French child had developed leukemia after receiving the promising, yet highly experimental, treatment.

• The agency had halted three trials in October following the revelation that one child had developed the potentially fatal form of cancer. The suspension was broadened Tuesday “because of unanswered questions about what is going on,” said Dr. Philip Noguchi, in charge of gene therapy issues at the FDA."

The ''clinical hold,'' which applied not only to Nextran but also to a number of other companies using live pig tissue in experiments, was lifted once the companies developed tests to screen both pigs and patients for evidence of PERV. While the tests indicate that the Nextran and Imutran herds showed no evidence of active infection, Noguchi acknowledges that there are no guarantees. ''We can only give assurance to the sensitivity of the assay as it currently stands,'' he says, lapsing into the kind of technotalk that bureaucrats use when they don't want to sound alarmist. In plain English: the virus may well be there; current tests may not be sensitive enough to detect it. Robert Pennington still undergoes regular tests for PERV infection; so far all have been negative.

When most Americans think of animal-to-human transplants, they remember the ill-fated 1984 attempt by Dr. Leonard Bailey, a Loma Linda, Calif., surgeon, to put a baboon heart in a baby the world came to know only as Fae. Baby Fae died after 20 days, but hers was only the most publicized of a long string of xenotransplant failures, starting with the earliest animal-to-human organ transplants at the beginning of the century. By 1985, the year after Baby Fae got her heart, many doctors had concluded that animals and humans were simply too dissimilar for cross-species transplants to work. In the Journal of the American Medical Association, Bailey was condemned for having succumbed to ''wishful thinking.''

Microbiology changed all that. While Bailey was being ridiculed in the popular press, scientists were perfecting the creation of transgenic mice for the study of cancer. By the late 1980's, companies like Nextran and Imutran were trying to figure out how to use transgenic technology for commercial gain. Pigs as organ donors seemed an obvious choice, but first the companies would have to understand the genetic underpinnings of a process known as ''hyperacute rejection,'' in which the human immune system rejects animal organs minutes to hours after transplant. Most immunologists, including Platt, of the Mayo Clinic, believe that the human complement system, a collection of proteins that attack and destroy foreign cells, is responsible for hyperacute rejection. In the early 1990's, Platt, then at Duke University, teamed up with Logan to introduce genes to suppress these proteins. In 1995, in a study that turned the xenotransplant world on its head, they reported their results: Nextran's pig hearts survived for as long as 30 hours inside baboons. The problem of hyperacute rejection, it seemed, could be solved. In England, Imutran was proceeding on a similar track.

''There was an amazing amount of excitement in the field,'' White, of Imutran, says. ''Before that time, people measured the survival of organs transplanted from pigs to monkeys in minutes. And then you suddenly went from minutes to days. It doesn't seem very long, but it was an absolutely major breakthrough.''

White sensed early on that this was the stuff of which scientific legends are made. In 1995, he boldly predicted that human experiments would begin within two years, a prediction that generated a backlash in England and spawned a spate of ethics reviews. And though it did not come true, he is not shy about tooting his own horn. ''I always like to tell my story that the first transgenic pig was born in a stable on Christmas Eve,'' he says, only partly tongue-in-cheek. ''It's a slight stretch,'' he says, ''because, in fact, the first litter was born on the evening of the 23d but going over into midnight, on the 24th.'' He also had the presence of mind to give the animal a name: Astrid.

Nextran, on the other hand, gives its pigs numbers. ''They still tell that story?'' Logan asks, eyebrows raised. ''The day before Christmas Astrid story?'' He pauses a moment, then lets out a little sigh. ''Well,'' he says finally, ''I guess a good story endures.''

Today, four years after their big breakthrough in hyperacute rejection, the companies are trying to understand other forms of rejection that prevent their organs from surviving for more than a few months in baboons. Regulators will not approve human experiments until the companies can demonstrate longer survival times; Noguchi, of the F.D.A., says some experts have called for a minimum of six months. So far, Imutran has come closest; it has kept pig hearts alive in baboons for as long as 99 days, as opposed to 39 days for Nextran. The difference is a sore point between the companies. Logan says that Imutran is using antirejection drugs in such high doses that a patient could die from a weakened immune system. White says Logan is wrong. Both men, however, say one thing is clear: victory in this race will be dictated as much by progress in the laboratory as by regulatory politics and concerns about public health.

''There's an old story in science,'' Logan says, ''about climbing a hill. The question is, Once you get to the top of the hill, is it a whole series of mountains, or just this one hill? And you don't know until you get there. We are right at that stage, close to the top of the hill.

DUKE-NUS MEDICAL SCHOOL

Singapore, 09 December 2019 - The threat of infectious diseases, such as Nipah virus, spreading across borders has increased substantially as a result of the ease of global travel. Nipah virus experts and stakeholders gather at the first international conference to commemorate the 20th anniversary of the virus' discovery and to discuss innovative and effective solutions to combat the threat to global health security posed by Nipah virus.

Duke-NUS Medical School (Duke-NUS) and the Coalition for Epidemic Preparedness Innovations (CEPI) are co-hosting The Nipah Virus International Conference 2019 on December 9 and 10. The conference brings together Nipah experts and global health stakeholders to review past Nipah outbreaks, discuss the latest developments in diagnostics, vaccines and therapeutics, and foster greater international collaboration.

Guest-of-honour Dr Lam Pin Min, Senior Minister of State, Ministry of Transport and Ministry of Health, Singapore, will deliver the opening address. The conference guests include leaders and representatives from the Ministry of Health (Singapore), the World Health Organisation (WHO), Ministry of Health (Malaysia), the U.S. National Institutes of Health (NIH), Ministry of Social and Family Development (Singapore), Duke-NUS, CEPI, SingHealth and other key stakeholders from the healthcare and biomedical ecosystem in Singapore.

A growing threat to global health security

Nipah virus was first identified in 1999 during a large outbreak affecting Malaysia and Singapore. The virus is one of eight categories of diseases that the WHO has identified as epidemic threats in need of prioritisation. Over the past 20 years, the virus has continued to spread over thousands of kilometres to Bangladesh and India.

Nipah is a zoonotic virus, which means that it can be spread to humans from animals. It is spread primarily by bats (specifically Pteropus fruit bats) and pigs. It can also be transmitted through contaminated food and directly from person to person.

The virus causes severe disease, with recorded mortality rates in Malaysia, Bangladesh and India of between 40 and 90 percent. In 2001, the virus was detected in Bangladesh and since then, frequent outbreaks have occurred in the country. An outbreak in Kerala, India, in 2018 claimed 17 lives.

"There are currently no specific drugs or vaccines for Nipah virus infection, even though the WHO has identified Nipah as a priority disease for the WHO Research and Development Blueprint. Through the conference, we aim to stimulate dialogue between experts and stakeholders to bring about innovative and effective solutions to boost efforts in fighting Nipah virus," said Professor Wang Linfa, Director of Duke-NUS' Emerging Infectious Diseases Programme and Co-Chairman of the conference's organising committee.

With global travel being more prevalent than ever, infectious diseases, especially those that can be transmitted from animals to people, can be rapidly spread across borders. Therefore, it is crucial to strengthen outbreak preparedness and response against infectious diseases such as Nipah.

One of the ways the conference aims to achieve that is by facilitating interaction between clinicians, veterinarians, scientists and public health experts from the region and beyond. Discussions such as these would help enormously in the communication, cooperation and collaboration between animal and human public health agencies to ensure that Nipah never becomes a global pandemic.

"Outbreaks of Nipah virus have so far been confined to South and Southeast Asia, but the virus has serious epidemic potential, because Pteropus fruit bats that carry the virus are found throughout the tropics and sub-tropics, which are home to more than two billion people. Nipah virus can also be transmitted from person to person, so in theory it could spread into densely populated temperate areas too," said Richard Hatchett, CEO of CEPI.

"Twenty years have passed since its discovery, but the world is still not adequately equipped to tackle the global health threat posed by Nipah virus. This needs to change. Strengthening collaboration and knowledge sharing between Nipah virus experts, industry and key public-health stakeholders is crucial to the development of novel interventions against Nipah. As a co-host of the Nipah Virus International Conference 2019, CEPI is pleased to be able to foster such global collaboration," he added.

WHO and the National Institute of Allergy and Infectious Diseases, one of the U.S. National Institutes of Health, are also key sponsors of this conference.