Discussing viruses in Napoleon's backyard

I just returned from Ajaccio (pronounced Ajak-cio) on the western coast of the island of Corsica, a French territory in the Mediterranean Sea, which is actually closer to Italy than it is to France. Besides being an extremely beautiful locale, its claim to fame is being the birthplace of Napoleon Bonaparte.

The purpose of this trip was to attend a meeting of the International Consortium on Antivirals (http://www.icav-citav.ca/), "a not-for-profit drug development organization dedicated to the discovery and development of anti-viral therapies for neglected and emerging diseases." This was a small "by invitation" conference with scientists from various parts of the world who discussed emerging viruses, neglected diseases and strategies to fight them over 3 days.

Most of the group traveled from Marseille to Ajaccio (map on left), an overnight journey on the ship Napoleon Bonaparte. I flew from Delhi to Paris, on to Ajaccio to land at the (you guessed it right) Napoleon Bonaparte airport. Ajaccio, the capital city of Corsica is at the northern end of Ajaccio Bay (map on right). The conference was in Ajaccio, but we stayed at a resort called Coralia Club across the Bay at Porticcio (map on right), about 20 km by road or a 15 minute ferry ride across the Bay.

Ajaccio Bay is beautiful with hills lining it all along. It makes for a perfect setting to watch the sunset, and if you can get up early enough in the morning when the moon is full, it offers a spectacular sight. The pictures below show various moods across Ajaccio Bay, from Ajaccio and Porticcio.

Corsica is the fourth largest island in the Mediterranean Sea, with a coastline of over 1000 km and a population of only around 250,000. Large parts of the island are Nature Reserves, which includes rare breeding sites for sea eagles and protection for other endangered species. Corsica has been inhabited continuously since the Mesolithic Age and over time acquired an indigenous population that has influenced Mediterranean history. It became part of the Roman Empire, and was claimed by the Repulics of Pisa and Genoa. The Genoese took possession in 1347 and governed till 1729, briefly being taken by the French in 1553. The Corsican Independence Movement began in 1729 and 26 years later, in 1755 an independent Corsican Republic was formed under the leadership of Pasquale Paoli, which remained sovereign till 1768. In 1764, Corsica was secretly purchased by the French from the Republic of Genoa. Following a  brief civil war in 1768-69, Corsica was incorporated into France in 1770.

Napoleon Bonaparte (Nabulione Buonaparte) was born in 1769 in the house of Charles-Marie Buonaparte, an attorney and secretary to Pasquale Paoli. The modest 4-storey home is now a museum in the heart of Ajaccio, not far from the central piazza, the cathedral and the Town Hall.

The central piazza has a statue of Napoleon on horseback surrounded by his four brothers. Napoleon's presence is all over this town in the form of statues, streets and lanes.

Travel to the northern point of Ajaccio Bay and you come across some interesting sights. At lands end the coast is rocky and the Sanguinaires archipelago is visible with its Genoese tower, which was used to sight pirates and warn the inland population by lighting fires. Similar towers can also be found inland to relay the message through smoke and drums.

Another very interesting and unique sight towards the northern end of Ajaccio Bay is the Cemetery. It is unique because unlike other cemeteries with graves, this one has small chapels, each for an individual or many times even for a family.

While strolling through the Cemetery, I captured an interesting view with the chapels in the foreground and modern apartments in the background. I call this "Apartments for the Dead and Living".

The beauty of this place is awesome. I forget I was actually here to discuss viruses, viral diseases and research on drugs against them. So, back to the science.

The Conference was held at the Palais des Congres, which overlooks the Ajaccio Port. The first session presented an innovative model for funding drug development research. This included adding a small tax on international travel, which has so far raised over $500 million to finance access to medicines in developing countries.

The session "HIV - Present and Future Challenges" discussed various aspects of HIV vaccines, including recent success of the ALVAC-AIDSVAX prime-boost vaccine combination (which I covered in an earlier blog; Sept 24), and the failed Merck vaccine trial last year. Discussions also  focused on the host response to HIV infection and ways to modulate the host to contain infection.

The session "Dengue - An integrated model for arthropod-borne viral disease control" was dominated by an elegant and comprehensive talk by Eva Harris from UC-Berkeley. Eva's efforts from the bench to bedside in dengue research, her reach in impoverished and under-developed scientific communities, and her efforts to make them part of the solution are truly inspiring. Various other lectures and discussions focused on new drug targets in dengue and other flavi viruses. The community seems to be coming together for drug design and testing that requires coordination between virologists, structural biologists, bioinformatics experts, organic chemists, industry and clinical trials experts.

The sessions on "Emerging Viruses" started with  an entertaining but highly informative talk by Ernst Gould from Oxford University. Ernie's appearance and mannerisms reminded me of one of the comedians on the very funny TV show "Whose Line Is It Anyway". Various other speakers dealt with drug design efforts against hepatitis C virus, influenza virus, and more generic approaches to broadly active drugs against positive- or negtive-stranded RNA viruses. Predictably, pandemic flu viruses dominated the discussions.

This is definitely one of the best meetings that I have attended in a long time. Besides the beautiful surroundings, the science was good, discussions were intense but friendly and informal, the organization was superb, and there were just enough people to make it scientifically interesting yet personal.

One advantage of meeting in a small place is that even scientists get noticed. The Mayor of Ajaccio organized a reception for us in the Town Hall. We passed through a ceremonial Guard of Honour and were welcomed and addressed by the Mayor himself in the richly decorated Napoleon Bonaparte room.

The ICAV recognizes the state of scientific research and the pharmaceutical industry in India, and expressed interest in starting an India Consortium. A few MOUs were signed between ICAV and Indian institutions. We return energized from this conference and hope to get more Indian colleagues involved in this unique effort. We also hope to organize the 2011 ICAV Annual Conference somewhere in India.

I would like to personally thank  the organizers for inviting me and a few other colleagues from India. Jeremy and Michel are the brains behind ICAV; Rajan and Christine did all the logistics. Thank you everyone for a wonderful and stimulating meeting.

I hope to see you all in Montreal next year.

Agra - a Photo Essay

Agra is the architectural garden of the Moghuls. The Moghul rule was most powerful and prosperous during the reigns of Akbar, Jahangir and Shahjahan, all having governed from Agra till Shahjahan built a new capital in Delhi (Shahjahanabad). This power and prosperity shows in the architecture of Agra.

The Agra Fort is one of the largest in India and was the seat of this power. The entrance is over a moat and through a long incline with fortified walls to repel any enemy force trying to gain access.

The Fort shows a progression of styles from  the rugged power of its ramparts and outer walls to the ornate carvings on its columns. Its 16 different palaces span three rulers and a variety of designs - from Akbar's heavy reliance of Rajput building style to Shahjehan's finesse in marble and motifs. The Diwan-e-Khas (Hall of Private Audience) is small and ornate, while the Diwan-e-Aam (Hall of Public Audience) is large, columnar and symmetrical.

Agra is home to some important Mughal tombs and I will present these on a progressing time scale.

Akbar's tomb is at Sikandra, about 10 km from Agra on the road to Delhi. When I last visited it over 10 years ago, it was still a small sleepy village. Today, there are traffic jams on the road right in front of Akbar's magnificent tomb. He built is during his reign and it shows in the richness of design, the jalis (screens) and the motifs. The gate to enter the tomb is impressive. The tomb itself shows the influence of Hindu/Rajput architecture on early Mughal tombs in India, mixed with a typical Mughal layout with the tomb in the middle of a square garden.

Not far from Akbar's tomb is the tomb of his wife Mariam Zamani, the Rajput princess Jodha. Unlike the Emperor's tomb, it is hard to find and you will miss it unless you really look for it. It is about 1 km upstream (towards Delhi), on the opposite side of the road. It is plain and uses an earlier 'baradari' to house the tomb. Makes sense as it was built not by a loving husband, but by a son who was by then the king, and much under the influence of his own wife - the powerful Nur Jehan.

Nur Jehan, wife of Jehangir, the fourth Mughal emperor is associated with one of the most beautiful tombs in Agra - the Itamadud-daulah Tomb, locally known as "Baby Taj". This is the tomb of her father, a Persian nobleman and minister in Jehangir's court. The tomb is small, set in the middle of a garden, with three gates and one pavilion by the river Yamuna.  

The inlay work, the motifs and the jalis (screens) on this tomb are just exquisite. Most tourists in a rush miss this tomb, on the other bank of Yamuna from the Fort and the Taj Mahal.

Further down from Itamadud-daulah's Tomb on the same bank of Yamuna is the delightful Mehtab Bagh, a garden developed recently, but one used by Shahjahan and the later Mughals to view the Taj Mahal on a moonlit night. At sundown, Mehtab Bagh offers a view of the Taj Mahal different from that seen by most tourists, and you dont have to jostle with the crowds.

The Taj Mahal, the ultimate expression of love, was built by the fifth Mughal emporer Shahjahan for his wife, Mumtaz Mahal. The beauty, symmetry and presentation of this most famous Mughal tomb can only be experienced; it cannot be described. It is different from other Mughal tombs in that it is not in the centre of a garden, but at one end of it. The Taj Mahal is from an era in which Mughal power reached its pinnacle of power and prosperity, and this shows in its finesse. No more descriptions, just enjoy.

 

  

  

  

 

Swine Flu in India – Are we prepared?

This is festival time in India. The festivities for Ganesh chaturthi and Eid barely over, this weekend is the culmination of Vijaydashami, celebrated across India in various forms. Whether it is Dussehra, Dasara, Dashahara, Navaratri or Durgotdsav, the common theme is victory of good over evil. Large crowds gather every day in temples and puja pandals across India.

In times of a flu outbreak, this is a public health nightmare. This year’s Ravana is the microscopic influenza A H1N1 (2009) virus. Will the arrows of public health preparedness be able to slay this new age Ravana? This unlikely in India, if you listen to what experts have to say.

I wrote earlier about the 3.1% mortality among swine flu cases in India. The latest Ministry of Health and Family Welfare (MoHFW) release is for September 24, 2009; it reports 8979 cases and 277 deaths – 3.08% mortality.

Prof. T. Jacob John, unarguably India’s most prominent public health scientist, thinks this high mortality could be due to a selection bias – those with more severe illness are being tested. So, what has been India’s testing policy? A larger question is how has India dealt with this outbreak from a public health perspective.

An editorial in the August issue of the Indian Journal of Medical Research (IJMR) written by Prof. Jacob John and Prof. Jayaprakash Muliyil, provides a very frank and analytical assessment. It also provides sagacious advice to the Government on what it should and should not be doing.

The editorial can be read at http://www.icmr.nic.in/ijmr/2009/august/editorial1.pdf (I am grateful to the authors and the Editor, IJMR for their permission to post this link).

They say, and I quote – “At the request of the World Health Organization (WHO), many countries including India had made a detailed Pandemic Preparedness and Response Plan (PPRP). Many experts believed that India would, for the first time in our history, be well prepared to face an epidemic.-------- The events that took place in June, July and up to mid-August (as we write this) are still fresh in our memory. The expectation that India would face the pandemic with confidence and competence gradually gave way to disappointment and dismay. While the virus is reaching many places and spreading among the population, as anticipated, India does not have a public health infrastructure that could put into practice the PPRP”.

Prof. Jacob John agreed with my call in an earlier post and adds – “Science must guide policy. Policy must drive public health. So public health interventions must be evidence-based”.

Those who matter at the MoHFW and Indian Council of Medical Research will do well to read this editorial (which is in their own journal), and to ensure that policy is driven by science and not the other way around.

A Vaccine for AIDS

The human immunodeficiency virus (HIV), which causes AIDS, has been a difficult target for vaccine developers.

Vaccines are substances that mimic a pathogen to raise immunity in the host (human), which disables (neutralizes) and clears the pathogen from the body in the event of a natural infection.

Two types of immune responses are required for complete protection. These include humoral responses in which antibodies develop to neutralize extracellular pathogens, and cellular responses in which special cytotoxic cells are recruited to kill host cells that have become infected. An ideal mix of the two types of responses are required, and this mix is different for different pathogens.

The problem in the HIV field has been a poor understanding of the correlates of protection. In other words, we don't understand the quality and quantity of humoral and cellular responses that are required to prevent HIV infection. The problem is compounded by the extremely variable nature of HIV, which enables it to evade host immunity.

September 2009 has been a good month for HIV/AIDS vaccine efforts.

On Sept 3, a paper published in the journal Science, by a consortium of scientists led by the International AIDS Vaccine Initiative reported the discovery of two neutralizing antibodies, which target a potential Achilles heel on the virus surface. The discovery was the result of a global effort to search for antibodies in people who naturally control HIV infection. This is likely to provide important clues for engineering better vaccines. 

Good news was released today from a vaccine trial conducted jointly by the US Military HIV Research Program and the Thai Ministry of Public Health. This trial initiated in 2003 was a Phase III efficacy study of a prime-boost combination of two vaccine candidates - ALVAC, a bird pox virus carrying the HIV envelop protein (gp120) gene manufactured by Sanofi-Pasteur, and AIDSVAX, a recombinant form of gp120, manufactured by VaxGen (now Global Solutions for Infectious Diseases). Both of these candidate vaccines were earlier tested individually and found to have no efficacy.

The results released today showed a 31% efficacy for a prime-boost approach using these two vaccine candidates. Though the efficacy is not impressive, this is the first time a candidate AIDS vaccine has shown any level of protection in humans.

More details on the antibody discovery and the vaccine trial are available from the following sources:
International AIDS Vaccine Initiative: http//www.iavi.org
US Military HIV Research Program: http://www.hivresearch.org/
Science magazine:  http://www.sciencemag.org/cgi/rapidpdf/1178746

Swine Flu in India

The last situation update from WHO puts the number of positive cases worldwide at over 296,471 with at least 3486 deaths (http://www.who.int/csr/don/2009_09_18/en/index.html).

India's Ministry of Health and Family Welfare (MoHFW) puts out daily updates on the swine flu situation in the country (http://mohfw.nic.in/press_releases_on_swine_flu.htm). The updates started on August 1, 2009, by which time there were already 534 positive cases but no deaths. The first death, a 14-year old schoolgirl from Pune, was reported on August 3, 2009. Since that time, the number of positive cases have gone up steadily. As I write this, the last MoHFW update from September 21, 2009 reports that samples from 35,148 persons have been tested across the country, 8153 (23 .1%) have been found positive and 257 persons have died as a result of this infection.

The mortality rate in India stands at 3.1%, compared to a global average of 1.1%. What is the reason for this higher mortality in India? We don't know as there is no epidemiological analysis available. The reasons could be
(a) virological - increased virulence of the virus circulating here,
(b) host genetics - maybe Indians are genetically predisposed to get more severe disease
(c) environment -  poor healthcare infrastructure, late reporting of cases, selection bias with only severe cases being tested, etc.
It could also be an interesting mixture of all of the above.

The point is - unless we look at these issues systematically, we will not know.

I have made a graph on the situation in India based on MoHFW updates. The plot shows positive cases and deaths every 5 days from the start of updates (Aug 1, 2009) for the first 50 days of reporting.

 

It is quite clear from the graph that the outbreak in India is growing at a steady rate. Since early in the outbreak, the number of cases have gone up  at the same rate. The pink line in the graph has a constant slope. Curiously, the death curve shows a hint of biphasic nature to it. The death rate seems to be picking up lately. After running almost parallel with the positive cases curve for some time, the death curve has now intersected it.  Will it continue its upward spiral? In the absence of any analysis or models, only time will tell.

India has done well in gearing up resources to put testing in place. Scientists and technicians involved in testing for swine flu have done an admirable job. They have used all the resources at their command to test quickly and have adhered to quality.

But this is only half the job done. We should be analyzing this outbreak. The Indian Council of Medical Research (ICMR; http://www.icmr.nic.in/), whose mandate is medical research, should be driving this. We have a National Institute of Epidemiology, an ICMR institute in Chennai (http://www.icmr.nic.in/pinstitute/nie.htm). What are those guys doing? What are the public health experts at the  Public Health Foundation of India (http://www.phfi.org/) doing? The PHFI website has H1N1 flu advice (http://www.phfi.org/h1n1flu/index.html), but no analysis.

It is the same case with virological analysis. No genomic data is available on the virus circulating in India. The Influenza Virus Resource uploads genomic data in the public domain on a daily basis. See http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html. There is no data in the public domain from India. And it is truly shameful.

Is the virus in India showing genomic signatures of increased virulence? How many mutations will it take to make it highly virulent? Are we beginning to see the H274Y mutation in the NA protein, which is reported to be associated with Oseltamivir (Tamiflu) resistance? WE DON'T KNOW.

Should we not have science drive policy? Where is the science? It is time for ICMR, PHFI, Ministry of Health, Ministry of Science and the scientific and biomedical research community at large to ask these questions.

In India, our flu season is just beginning. Wake up.

Swine Flu - a triumph for science

Influenza pandemics happen about three times in a century. At least this is what 20th century history teaches us. There was the big Spanish Flu of 1918 (which did'nt really start from Spain), which infected an estimated third of the human population at that time and killed 40 to 50 million people. Then, there were the Asian Flu of 1957 and the Hong Kong Flu of 1968, each killing an estimated 1 million persons each.

Historically we were due for another big one. Is this the one? The swine flu (again a misnomer) started in Mexico around March of this year and has gone around the world, prompting WHO to raise its alert to Level 6, the first time in over 30 years. As of September 6, 2009, this disease has infected over 277,000 persons and killed at least 3200 (see http://www.who.int/csr/don/2009_09_11/en/index.html). If you believe that in infectious diseases you only see the tip of the iceberg, there are many more infections and deaths that have gone unrecorded. And we are just getting into the flu season in the Northern hemisphere.

So far this virus appears to be mild. It has killed about 1% of infected people, many of whom had underlying problems such as asthma, diabetes, hypertension and obesity. Yes, obesity! Thats a new one positively identified for this virus. But will it remain mild? No one knows. History tells us otherwise.

The 'Spanish flu' started as a mild infection in the summer of 1918, spread rapidly and the virus got a lot of chance to mutate. By November of 1918, the flu season in the Northern hemisphere, it became highly virulent and killed with disdain. We are into a similar situation with this one. It has already gone around the world, including Australia and South America (Southern hemisphere) in their flu season, and is getting a lot of chance to transmit and mutate. Health agencies are already preparing for the 'second wave'. See
http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html

Are we then sitting ducks? Or pigs to be more appropriate for this one! Not really. Health systems are much better prepared to handle these emergencies today than they were 90 years ago. The agent for Spanish flu took over 11 years to identify. The 'swine flu' virus was identified in days.

This virus, technically called Influenza A H1N1 (2009), is a triple reassortant. Scientists have traced its 8 different gene segments to influenza viruses that have circulated in humans, birds and pigs (see: Garten et al, Science vol 325, pages 197-201; July 10, 2009). The cartoon below illustrates the lineage of different gene segments in this new virus.
The surface proteins of the virus - the hemeagglutinin (H1) and the neuraminidase (N1), are both of swine origin. This makes the virus new to the human population, not recognized by our immune system. This is obvious from the efficient manner in which it is transmitting between humans.

Every adversity has a lesson. The lesson here is how investments in biomedical science are paying up in unexpected ways. It took just days to identify this virus and weeks to come up with its origins. This is truly the power of molecular biology, built up over years with the Human Genome Project as a very visible high point. Many have criticized that megaproject, but consider that it enabled the development of technology, which is making all this possible. When SARS came around in 2003, the sequencing of its genome was also undertaken in facilities set up for the HGP. Chinese scientists sequenced the SARS virus genome in a facility built to sequence the rice genome! That is a great off-target effect and a lesson for science funders and planners.

Every day dozens of swine flu sequences are being uploaded in public databases (http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html). Many scientific journals, normally driven by commercial interests, have made swine flu papers "open access". This uninhibited access to knowledge and the power of internet is bringing the technical prowess of big science closer to where it matters - the hot zone.

Are we really making use of this knowledge in my hot zone - India? Stay tuned.

Ten days in Turkey - Part 10

Time to go home

Time to say goodbye to this lovely city. We spent the morning having a lazy breakfast, soaking the last views of Sultanahmet Camii from our hotel’s terrace.

As I reflect back on this trip, it could not have turned out any better. We had cherished this trip for a long time. Over almost two decades my interaction with Turkish students who trained with me in Delhi has been a pleasant one. We have become friends for life. Their warmth is genuine and that comes from the warmth you feel everywhere in this beautiful country. Our hosts, their extended families (the network of cousins), the staff at Ararat Hotel, the masseurs at the hamam, the shopkeepers at the Bazaar, the Turkish professor and his students at the conference, were all warm and interesting in many ways. The sights notwithstanding, it is they who made this trip memorable.

The writer Elif Shafak, whose novel The Bastard of Istanbul is both widely read and despised for insulting Turkishness, writes – “Like a pendulum, Istanbul swings obstinately between cosmopolitanism and nationalism, memory and amnesia — between a weighty past we can never fully shed, much as we like to try, and a hopeful future we can only run after but never quite grab hold of. Istanbul is the stepchild of the modern, secular Turkish Republic. But it still embodies remnants of a multicultural imperial legacy that don't quite match the founding myths of a supposedly homogeneous nation-state”.

There is so much common between Turks and Indians in their approach to life, their hospitality and the huzun they feel by not being in control of things. The muslims of India have historical attachments to Turkey with the Khilafat movement and its leaders being an integral part of our own struggle for independence. It was especially memorable for me as a muslim to see important religious relics at the Topkapi Palace, which one only has only read about. Being a muslim capital for over 700 years and never to have been conquered by the army of a different faith, the Islamic monuments and treasures are especially well preserved here. This is unlike Delhi, which was probably richer than Istanbul at the peak of the Mughal Empire, but was subsequently plundered by the British rulers.

Turkey, I hope you stay that way, even when you are part of the European Community. You aspire to be European, but you are more Asian in your approach to life, your values, your hospitality and your huzun.

Thank you Turkey. Thank you Bursa, Konya, Istanbul and all the lovely people we met in the last ten days. I hope to be back another day. Inshallah.