Bird Flu, Indian Reverse Engineers and Mangosteens, Oh My!

I sometimes hang out at Brad DeLong’s blog, where apparently Razib thought I was a dude. Yesterday DeLong wrote a Cipla's Chief, Yusu Hamiedpost about Tamiflu, the Roche patented drug which is the one of the only plausible defenses against the dreaded Avian influenza or Asian Bird Flu. DeLong was mostly concerned with the domestic policy and economic ramifications of nationalizing a patent in times of emergency and stockpiling a drug ahead of time, but as with Sepia Mutiny, the comments can be most educational–and that’s how I found out that clever Cipla is at its Robin Hood reverse engineering tricks again. Bird flu is, of course, a global issue:

Cipla, an Indian producer of generic drugs, is preparing to become an alternative producer of oseltamivir phosphate, an antiviral drug better known by the brand name Tamiflu.Cipla plans to offer Tamiflu in the Indian market and in 49 less-developed countries where the company already sells AIDS treatments, Hamied says. The legality of the introduction in India, where pharmaceutical patents started to be recognized this year, is uncertain.

Hamied says he will withdraw Tamiflu from the Indian market if Roche’s patent is recognized.  (Link.)

A Roche spokesman, Terry Hurley, said that the company ”fully intends to remain the sole manufacturer of Tamiflu.” . .Making the drug involves 10 complex steps, he said, and the company believes that it’ll take another company ”two to three years, starting from scratch,” to produce it. Hamied dismissed that claim, saying that he initially thought it would be too hard but that his scientists had finished reverse-engineering the drug in his laboratories two weeks ago. He said he could have small commercial quantities available as early as January 2006. Asked if he thought Hamied was making an idle boast, Hurley declined to comment. Hamied said he would sell generic Tamiflu ”at a humanitarian price” in developing nations and not aim at the US or European market. ”God forbid the avian flu should strike India,” he said. ”There is no line of defense.” (Link.)

What does this have to do with mangosteens? I’m glad you asked!

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 DeLong commenter DuckedApe pointed out an Independent article (original link, readable copy) about how Tamiflu has a key raw ingredient that is primarily available in large quantities from a species of Chinese star anise:

But the herb has a vital function as the source of shikimic acid from which the drug Tamiflu is made, the only defence the world currently has against the threatened flu pandemic. . . .Yesterday it emerged that a shortage of star anise is one of the key reasons why countries including Britain cannot obtain enough Tamiflu to protect their populations. The herb from which Tamiflu is made is grown in four provinces in China and “huge quantities” of its seeds are needed, according to the Swiss pharmaceutical manufacturer Roche. It is harvested by local farmers between March and May, purified and the shikimic acid extracted at the start of a 10-stage manufacturing process which takes a year. Only star anise grown in the four provinces of China is suitable for manufacture into Tamiflu and 90 per cent of the harvest is already used by Roche. (Link.)

Hamied is aware of the problem: .

But Cipla has neither produced the drug in large quantities nor is able to predict whether its price will be much lower than Roche’s “You must understand one thing: Our synthesis starts from shikimic acid, and it’s not native to India, so we must get it from outside,” Cipla Chairman and Managing Director Yusuf K. Hamied says. (Link.)

Once you have the shikimic acid, the process to make Tamiflu is extremely complex and even involves an explosive step similar to one in AZT manufacturing. It seems that what Cipla has reverse engineered is this post shikimic acid process. Roche has developed a “fermentation route” to manufacturing the shikimic acid, and it seems that Cipla has not yet reverse engineered that. It makes sense that harvesting the raw material might be cheaper than synthesizing or even growing it in vats of E. Coli.* So I got to wondering–what other plants even contain shikimic acid? (I’m, uh, taking Roche’s word for it that “only” the star anise which Roche happens to have a lock on could possibly be useful.) 

Eye-straining KosmicJourney.com listed it in the leaves of our familiar rice plant, but I’m a sucker for .gov databases and when I found Dr. Duke’s Phytochemical and Ethnobotanical Database at ARS-GRIN.gov** I was thrilled to see what plants came up for Shikimik Acid. It seems that small amounts are available from prickly pears, the leaves of the mastic tree, and India’s own haritaki fruit. The motherlode of a possible 700,000 ppm, however, comes from the leaves of one Mammea americana:

Mammea Americana: Mangosteen's Long Lost South American CousinBotanically, it is identified as Mammea americana L., of the family Guttiferae, and therefore related to the mangosteen, q.v. Among alternative names in English are mammee, mammee apple, St. Domingo apricot and South American apricot. . . .The ripe flesh is appetizingly fragrant and, in the best varieties, pleasantly subacid, resembling the apricot or red raspberry in flavor.. . The mamey is native to the West Indies and northern South America. . It has been nurtured as a specimen in English greenhouses since 1735. It grows well in Bermuda and is quite commonly cultivated in the Bahama Islands and the Greater and Lesser Antilles. (Link.)

 

Go Fighting Mangosteens!In other words, it’s the mangosteen’s long lost Latin American cousin! Mangosteen was previously noted by Abhi as the South Asian Queen of Fruits, and fellow guest-blogger ADS had previously directed my attention to the Fighting Mangosteens! At some point we wondered idly if the tough looking fruit was drinking a glass of its own brethren. I hope it’s not a glass of its Carribean cousins. I am rather charmed by a vision of this tough desi fruit affectionately greeting its relation at the airport, albeit with an Italian accent: Mammea Americana!

Ahem, back to your regularly scheduled seriousness–the issue of patents, profits, and drug manufacturing has long been entangled with the subcontinent. About a year ago I blogged about the Institute for OneWorldHealth, a non-profit working to develop a drug to treat Black Fever Leishmaniasis, which kills 200,000 every year in India, Nepal, and parts of Africa. Quite a controversy has raged over the patenting of the traditional use of neem as a fungicide, especially given WTO pressure on other nations to conform to U.S. Patent law. Indeed, controversy is still simmering over the pharmaceutical implications of patenting the human genome. (Hat tip, Rhinocrisy.) The concentration of drug profitability in the developed world contrasts painfully with the concentration of tropical diseases in the developing world, and some have proposed that an Open Source model be used in drug development. Check it out, O Brilliant Mutineers.

I’d like to reiterate that the shikimik acid is only a starting ingredient, so that chewing tons of haritaki is unlikely to to be a good substitute for Tamiflu in case of Avian flu infection. Also, Razib’s blogmate ScottM says that Avian flu isn’t that worrisome.

*Could the hive mind help me figure out if this Roche method is the same as this Michigan State patent on biocatalytic synthesis of shikimic acid, United States Patent 661 3552?

**Chaucer, anybody?

25 thoughts on “Bird Flu, Indian Reverse Engineers and Mangosteens, Oh My!

  1. My head’s spinning after reading this — you’ve lost me. Saheli, or anyone else out there — have you read any stories/commentary about avian flu that a total layperson like me can understand? I hear the word ‘pandemic’ thrown around a lot, and frankly, I’m a little spooked.

    Does this bird flu really have the potential of becoming a huge global problem if it mutates into something else?, If so — related to your post — will Tamiflu or other vaccines be available to to the general public? What’s the US government’s response to this beyond the published research? I’ll try not to freak out, thanks.

  2. timepass, dont freak out. While it is true that avian flu can spread wide enough to cause a pandemic, I do not think it will cause as many deaths as is feared. People ( media, press, experts) point to the 1918 pandemic and how it wiped out between 20-40 million people. However, it is important to remember, People who perish ,do so to secondarily acquired bacterial super infections. Or to simplify further, when a person gets Influenza , his/her immune system is not strong enough to combat the bacteria which are ubiquitous, and these bacterial infections are responsible for the subsequent complications leading to death. One thing to remember: in 1918 there were NO antibiotics to combat bacterial infections, we have plenty of those, in large quantities and ability to overcome different strains of bacterial infection. Moreover, the general health of the at-risk population, namely the elderly and the children is definitely much better than in 1918. Levels of hygiene, nourishment are also much much better, expcially in the developed world (US).

    Remember the SARS epidemic. It was supposed to wipe out half the population too. That did not happen and partly the reasons are the same as I mentioned above. The Virus maybe different, the approach will remain the same when we combat it. Saheli, great job compiling the post.

  3. SP

    Remember the SARS epidemic.

    me! me! pick me!! I know. I was there.
    Seriously, I was hoping someone would bring it up because I was so damn proud of my city, the way we handled it… especially in light of how disaster has been handled in other situations around the globe.
    The disease was checked not because of some medical gymnastics or heroics but through a grassroots campaign for risk mitigation and disease containment. This is something to be proud of. This point has been echoed in other blogs – knowledge and processes are the biggest tool in loss prevention – and in my opinion needs a community effort to be effective.
    I’m so proud. I’m so proud. It’s 6 pm. me thinks I will go run like a llama or an emu.

  4. saheli, that was scott, not me who posted that. my opinions are mixed, but probably a lot less empirically informed than the typical person who is into this topic (i have some theoretical hunches based on how evolution works in regards to lethality of pathogens and what not).

  5. saheli – thats some good stuff

    I think the bigger issue here is how governments and companies handle such knowledge and combat diseases. This whole thing with Roche not releasing its patent has set up a storm of discussions, and i do think that either pharmas need to co-operate or the government needs to intervene. If only the pharmas and the various reserach institutions co-operated, do you think we would have had a cure for half the diseases currently uncurable?

    And for its worth – go cipla!

  6. this is too funny.. i posted my favorite fruit mangoosteen on my blog today… weird… had dinner with a friend from the CDC who works on the avian flu… have no fear, she doesn’t think it’s coming to america… i trust her.. i think people are just freaking out unncessarily…

    p.s. mangoosteens ROCK!

  7. Saheli, if someone is able to figure out whether that patent matches the Roche method, I will applaud them and you!

    Though I don’t want in any way to be an alarmist, I do want to point out that the 1918 influenza affected the 18-35 population more than the young/old. In addition, the fast-progressing cases of 1918/Spanish influenza involved mortality tied directly into viruses (virus-consolidation in lungs, etc), not bacteria. So, it’s not as simple as dismissing the new virus based on our current standards of medical care.

    SARS was well-contained not only because of current standards of medical care, but mostly because there was a fast-response to its identification- as dhavaak so aptly pointed out. The reservoir (palm civet cats) were immediately quarantined, and there was heightened monitoring for SARS in Asia. That seems the most important thing to remember about containment of viruses, and the best news about avian influenza- we know about it now, and we’re watching for it.

  8. What kind of a climate does Chinese star anise need? I’m sure entreprenuers must have known about the oppurtunity why hasnt any one else jumped on it?

  9. I was listening to NPR about an hour ago and I heard Roche was thinking of allowing other drug companies limited Tamiflu production rights in order to bypass a WTO rule that allows contries to override patent laws to prevent a public health crisis…

    here is an article saying the same…

  10. Couple of points.

    1) Avian bird flu is not pandemic. There is no indication it is about to become pandemic either. In fact, the WHO has suggested that it is being over-hyped. Human to human transmission has still not been effectively established.

    2) Roche had previously agreed to provide the drug for free if necessary to 3rd world nations.

    3) Point #2 is essentially useless because, as it turns out, the virus is becoming resistant to Tamiflu. This has been made event recently in the Asian countries (esp Vietnam). By the time there is, God forbid, human to human transmission, expect Tamiflu to be a completely ineffective therapeutic regimen.

  11. Razib, thanks, I fixed the post but then had to run.

    timepass–sorry!!! Perhaps I got carried away by the Fighting Steen Spirit. To summarize–TamiFlu is a drug for treating the flu, and is one of the few agents that can treat the Avian Flu, or Asian Bird Flu. Flu generally develops in a seasonal cycle from birds to pigs to humans (one reason why the new flu usually develops in China is the dense concentration of all three), and for some reason that’s unclear to me, flu that jumps straight from birds to humans is often worse–and currently such a strain is infecting bird populations all over Asia and has already killed some people. No vaccine exists for it, so the few drugs like Tamiflu and Relenza are even more critical should this virus start to really spread. Of course, whether or not we need to worry about it spreading–or whether or not it’s that dangerous–is up for debate/discovery. It does share some genetic similarities with the Spanish Influenza of 1918, but the significance of the similiarities is not well understood. Basically, people are worried, but I can’t tell you how much you should worry–I don’t know myself!

    So, with this backdrop of worry, people are wondering how much Tamiflu they can get. Now, drug companies have patents which give them legally allowed/legally enforcable monopolies, and a monopoly is pretty useless if you can’t use it to artificially hold supply down, thereby keeping price up. People are concerned that that is what Roche is doing–domestically, some economists and public health experts are calling for the “nationalization” of the Tamiflu patent, while in India Cipla is basically asking for a cheap and local license/threatening to circumvent it (depending on how you read the negotiations). Roche says that it will increase production but also says that the problem is not its monopoly, but the finite supply of star anise and the necessary shikimic acid that comes from the star anise, and Cipla agrees that this is a problem. I was sort of idly wondering where else you can find shikimic acid at all, and was tickled by the Mangosteen connection. I also wanted to point that many people have been proposing other models for drug development–nonprofit and opensource–recognizing that the patent&monopolize method doesn’t acknowledge incentives for research and innovation than simply profit. These alternative models are particularly interesting to tropical and developing countries, where the need for drugs may far outstrip the ability to pay for them as they are currently produced.

    See, not nearly as exciting when you put it that way. ;-)

    dhavaak Toronto is, indeed, an impressive city. :-) And this, my friend, this deserves a t-shirt:

    It’s 6 pm. me thinks I will go run like a llama or an emu.

    brimful I’m not worried about Avian flu in particular, I’m worried about our general public health system, so as you point out, past successes with SARS might not mean much with bird flu. Today it’s bird flu, tomorrow it might be resistant tuberculosis or who knows what else. Maybe Janak is right, and this bird flu won’t matter. We just don’t have a very robust network, I feel.

    Janak I was surprised that anything works, at all, after the fact of infection. Pity that the resistance is already developing. I’m not surprised that Roche is caving in, it doesn’t want bad PR, and if the shikimic acid really is a bottle neck, it won’t matter much anyway.

    OYBBB, you wrote, “do you think we would have had a cure for half the diseases currently uncurable?” that seems rather optimistic to me. But I don’t see how it could possibly hurt.

  12. saheli, i appreciate you increasing the geek-quotient on this weblog btw :) feel less like a stranger in a strange land…. (no offense to abhi and manish, u 2 are rather nerdy, but i feel comfortable only in majoritarian preponderance, not equitable representation).

  13. have you read any stories/commentary about avian flu that a total layperson like me can understand? I hear the word ‘pandemic’ thrown around a lot, and frankly, I’m a little spooked.

    timepass: I was in a similar situation, until I got hold of Jon Stewart’s pithy take from his Daily show(via BoingBoing – 10MB). One word: Hilarious. Chk out that whacky Bushism midway through the video… therez loads of gyaan for us :)

    ps: cicax, you’ll need Quicktime to play that file :-)

  14. Saheli, thanks for that. Very nicely explained. I had started to imagine a Hitchcockian doomsday scenario where scary virus-ridden birds attack innocent people while they’re fighting over Tamiflu shots outside the local pharmacy. No, I’m not paranoid at all!

    Now I’m going to check out Suhail’s link and laugh it all off.

  15. Great post, Saheli, food for thought, huh?

    Roche only has assigned patents for chemical synthesis of shikimic acid. They must have bought out someone else’s patent for the “fermentation process”. In addition to your find, I found this one from the Ajinomoto Company. Both use the same basic principle of introducing certain genes into bacteria to enable them to produce large quantities of shikimic acid or its precursor. So I conclude that Roche’s patent is one of these, or one using the same principle. I’m not a patent expert, but I imagine that Cipla could try to patent a new method of manufacture by using a different bacterium/different genes to generate a different shikimic acid precursor. But even thats moot if Roche’s patent for the end product (Tamiflu) is upheld in Indian courts.

  16. I’m not worried about Avian flu in particular, I’m worried about our general public health system, so as you point out, past successes with SARS might not mean much with bird flu. Today it’s bird flu, tomorrow it might be resistant tuberculosis or who knows what else. Maybe Janak is right, and this bird flu won’t matter. We just don’t have a very robust network, I feel.

    I can tell you that after listening to California’s officials talk about the public health infrastructure over the last few days, it’s not looking so great. Cuts in funding having taken quite a toll on public health. I keep hoping that news of avian flu will disappear… not so much luck in that department.

  17. so just FYI, almost EVERY plant makes shikimic acid — it’s a precursor to the amino acids tyrosine and phenylalanine, and your garden variety E.Coli makes shikimic acid, too. The big problem is not production, but isolation. Star Anise happens to make a LOT of shikimic acid, in a form that’s easy to extract (press seeds, and freebase).

    The Roche fermentation method (AFAIK licenced from John Frost – http://www.frostchemlab.com) involves “plumbing” E Coli’s shikimic acid synthesis by removing key bottlenecks and feedback responses in the bacteria. It is slightly less economical to make shikimate than to buy it; and until now, Roche has maintained the fermenters solely as economic leverage against China.

  18. Just an update on Shikimic acid sources – Roche could be in big poo-poo if they think they have the source cornered on commercial production. The article pasted below is from the “Globe and Mail”, Toronto. Canada on Dec. 24, 2006.:


    Your used Christmas tree might save you from a bird flu pandemic.

    As governments around the world scramble to stockpile the antiviral Tamiflu, generic drug maker Biolyse Pharma Corp. plans to begin next month making shikimic acid, the main ingredient in the manufacture of oseltamivir, commonly known as Tamiflu, from the needles of discarded Christmas trees.

    Tamiflu, as almost everybody knows by now, treats seasonal influenza and is also being championed as a first line of defence against a possible pandemic outbreak of bird flu, which has been devastating chicken populations across Southeast Asia and parts of Europe.

    So far, the H5N1 virus, which usually strikes people in close contact with diseased fowl or their droppings, has infected an estimated 130 people, killing 70. The worry is that H5N1 will undergo a genetic mutation with a human seasonal influenza virus, morphing into a deadly strain that could jump between people like the common cold.

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    After being rejected as a Tamiflu supplier by Swiss drug maker F. Hoffmann-La Roche Ltd., which has a monopoly grip on the manufacture of the drug, Biolyse turned its sights to making shikimik acid.

    The reason: the price of shikimik acid has soared to more than $500 (U.S.) a kilogram from $45 in the past 12 months on shortages of Tamiflu and skyrocketing demand.

    Biolyse specializes in extracting chemicals from plants and biomaterials at its plant in St. Catharines, Ont., and now makes a generic version of the cancer drug paclitaxel from yew trees.

    “Our research has shown that 2-to-3 per cent of the biomass from various pine, spruce and fir trees is extractible shikimic acid,” Biolyse principal Claude Mercure said yesterday.

    As the process moves to the commercial stage from the laboratory, he said the company is aiming to eventually produce one-to-three tons of shikimic acid a month.

    To get started, next month it will receive some 500,000 Christmas trees to be donated by Toronto-based Gro-Bark, a forestry recycling company.

    Most shikimic acid is now extracted from star anise, the fruit of a slow-growing evergreen in China, which is harvested for several months each year. That’s why Roche’s production of Tamiflu takes about 12 months and there isn’t nearly enough of the drug to go around for government stockpiling.

    “What makes our process more viable is the fact that the particular species of pine, spruce and fir that we are working with are far more abundant than the seedlings of star anise,” said John Fulton, Biolyse’s vice-president for new product development.

    Mr. Mercure said Biolyse has no plans to make Tamiflu unless Ottawa grants compulsory licences under the Patent Act in a national emergency. In such a case, he said the company could produce the drug in five weeks.

    In countries where Roche’s patents on Tamiflu aren’t recognized, like the Philippines and Thailand, he said Biolyse is in discussions to sell shikimic acid and provide technical assistance so the drug can be manufactured for use in that country.

  19. Does any one know what is the expected yield when isolating shikimic acid from pine needles? is shikimic acid can be sold freely?

    Thanks

  20. I have come late. Three quick questions: a) is interest in sourcing shikimic acid still alive, b) what is the current demand in the global market (high,medium or low) and c) would some one believe and be interested if I said that we have identified a couple of alternate plant sources for shikimic acid. These accumulate levels comparable or sometimes higher than star anise. They accumulate it in the leaves and sufficiently high plant biomass is available. Any immediate takers on the last point please ?

  21. Uma Shankar, I was only ephemerally a biologist. But I strongly suggest that you patent whatever you have discovered down the ground- like taxol from yew trees and then found your own drug company. Ok, it might just be a fantasy. Just don’t freely give anything to, say, Roche. Knowledge is power, n’est-ce pas?

  22. But the million dollar question is how does one patent or protect a species (an organism) that has been discovered to have say the highest so far documented quantity of a metabolite such as shikimic acid ? I understand only process patents are possible, which is of now help here. Alternatively we will have to resort to modifying the species by some plant improvement program (say simple mutation/selection) and then apply for a patent for the said material.