Ebola: Experimental drug ZMapp is '100% effective' in animal trials | Hacker News Reader

Ebola: Experimental drug ZMapp is '100% effective' in animal trials

bbc.co.uk

58 pointsrichardwigley47 comments

I'm surprised that so much of the coverage of ZMapp doesn't include the fact that the drug is produced in tobacco plants.

To me, this is the single most interesting and impressive fact. It's also likely the main reason why "the limited supplies will not help the 20,000 people predicted to be infected during the outbreak in West Africa." Scaling production of antibodies grown in plants can't possibly be straightforward.

DARPA thinks it's a scalable method, at least for producing flu vaccines:

"Accelerated Manufacture of Pharmaceuticals (AMP), companies in four states are building facilities where they can quickly produce vaccine-grade proteins grown in the cells of tobacco plants. Once they produce the proteins, the goal is for each company to scale up its process to produce 100 million doses of H1N1 flu vaccine per month."

http://www.defense.gov/News/NewsArticle.aspx?ID=61520

Right. It certainly seems like a much more scalable way to produce antibodies. It's just getting all the infrastructure in place that's going to be a challenge.

That article was from 2010. I hear this place is pretty impressive:

http://nctm.tamu.edu/facilities.html

It's actually not very scaleable. The yield is incredibly low. Processing plants is also difficult because you have to deal with a bunch of stupid stuff like tough cell walls, etc. I'm not even sure that the glycosylation patterns that tobacco puts on the antibodies are human-compatible (i.e. problems could occur if you try to use tobacco-derived antibody therapeutics in a patient more than once).

The choice to use tobacco was very likely a symptom of "if you have a hammer," common in biology and chemistry, where some tobacco researcher (tobacco is a well-studied model organism) wrote a convincing grant with a handful of accurate but marginal improvements over contemporary systems (in this case glycosylated vs. unglycosylated) that would enable commercialization, and downplayed some of the setbacks (low yield). Meanwhile other technical approaches have matured that are really good at tackling those problems but without the other setbacks... but just weren't awarded seed money.

DARPA is misinformed about a lot of things and has the money to afford being so especially if a few long shots work out.

Tobacco is not scaleable for rapid response because of the amount of time it takes to verify and grow a plant clone. The goal with pandemic flu is to get a rapid response vaccine kit for first responders, then to stage in higher-scaled vaccines. [1]

Ebola is similar. Unfortunately ZMAPP has this technical debt where their testing and validation is tied (understandable from a scientific and legalistic viewpoint but maybe not necessary the best outcome) to production in tobacco. There are better systems now, I'm thinking the new system called 'pichia glycoswitch'.

[1]http://stm.sciencemag.org/content/5/185/185ra68.short Disclaimer: i used to work for the VI and witnessed the researcher D. Gibson come in after the 'timed experiment', where he had a special fedex truck come in at 3am to pick up the package from his private residence; he joked that his neighbors must have thought he was dealing drugs. Although I generally dislike the scientific product coming out of the VI, this was one I had immense respect for.

It's about time tobacco paid us back in the health department.

I've seen it widely mentioned, but most of the commentary on it went along the lines of 'take that, health Nazis!', as if this was the culmination of a years-long effort by Smokers Against Ebola.

> as if this was the culmination of a years-long effort by Smokers Against Ebola.

In some ways it is though. Research using marijuana is currently illegal, even if it gets FDA approval. And if tobacco were similarly illegal, then this research also could have never happened.

It isn't produced in a commercial tobacco cultivar:

http://en.wikipedia.org/wiki/Nicotiana_benthamiana

I expect that they used it because it is a fairly robust species as much as anything else. I guess the nicotine doesn't really factor into the choice:

http://en.wikipedia.org/wiki/Pharming_%28genetics%29#Pharmin...

I agree that it's not straightforward, but there are lots of industrial processes that take as long as growing a plant. Scaling physical production is always a huge problem. There have been years where it was difficult to manufacture the flu vaccine in the required quantities, and I believe that generally involves incubating the vaccine in an egg.

The membrane cells of chicken eggs (the egg itself is of course one cell).

When I last looked at this, during the swine flu pandemic, companies typically get 3 doses of antigen per egg.

And this is a very slow process for new strains, first a seed culture has to be created by serious specialists that will both grow well in eggs (can be hard for avian flu...) and expresses the correct surface antigens.

Much better approaches like this company's https://en.wikipedia.org/wiki/Protein_Sciences are desperately needed if a killer flu is someday brewed (this tends to happen in an animal that is simultaneously infected with two strains of flu, so it's not mutation per se).

In this NYT article:

http://www.nytimes.com/2014/08/30/world/africa/study-says-zm...

It mentions that all 3 control group animals died.

Does anyone know why the control group is so small compared to the test group of 18?

I would hazard a guess that we know Ebola to be pretty close to 100% lethal, and if you know that three out of three control animals died, then the virus is "working" and there's no need to sacrifice many more animals.

Exactly. The control group is there to, for example, make sure your culture of Ebola is really that, viable and so on. If they didn't get sick, let alone die, you'd know your experimental group results were invalid.

Monkeys are also very expensive animals to do research on, and no one likes to kill them, or at least we don't tend to have the same sentiments about mice and rats.

It looks like the 18 animals were actually sub-divided into at least three test groups. One test group got the drug after 3 days after exposure, one at 4 days and one at 5 days. So the number of animals in each sub-group is closer to the control.

It wouldn't surprise me if there were actually six test groups of three animals each (perhaps divided by both day-of-treatment and something else like drug amount), thus matching the control. But the article doesn't actually imply that.

why we still test effectiveness on animals when there are several thousands of people who has no downside and only upside for the drug to be tested on them? Ethics? It would be a strange ethics that had worked only until an American needed the cure. Something isn't right that this drug got out of shadow only when there was a need to cure an American. I mean, of course, thanks God, that i have real chance of soon becoming an American too :)

"And two out of seven people given the drug, have later died from the disease."

Sounds like they're already doing precisely that.

http://mobile.nytimes.com/2014/08/13/world/africa/ebola.html

The first four paragraphs describe what happened: different decisions were made by different doctors, and the drug did not "get out of the shadow only when there was a need to cure an American".

>different decisions were made by different doctors

that is exactly my point. It is a discernible trait of the system level behavior with many different people involved.

http://scientiasalon.wordpress.com/2014/08/14/on-the-science... (related HN discussion: https://news.ycombinator.com/item?id=8189528)

The second paragraph does a good job of summing up ethical concerns related to this particular outbreak (standard ethical concerns also apply):

"The first two patients to be treated were Americans. Prior to this came the old (and historically justified) fear of testing potentially dangerous new treatments on vulnerable populations in developing countries rather than on privileged first world patients. The first ever treatment was not given to an African doctor because of this concern [1]. After Westerners were treated, complaints rose about giving infected Westerners access to a new drug while infected Africans went without. These two concerns are obviously mutually exclusive. People are concerned, they are just not sure about what, sometimes even voicing both concerns in the same article [2]."

One would hope that African doctors would be reasonably capable of assessing the risks and benefits of taking experimental new treatments themselves. I seem to recall the trials that people have been concerned about involved large-scale testing on poorly-educated members of the general population. (Also, I think that kind of testing still happens even now!)

Treating an ebola patient is complicated.

Treating an ebola patient who has a bunch of weird side effects caused by an experimental drug makes a sub-optimal situation much worse.

> ..makes a sub-optimal situation much worse.

I guess the OP's point was how much more sub-optimal can the situation get if the alternative to not trying the experimental drug is the death of the patient.

The alternative is a about a 40% chance of survival without the drug. With the drug, maybe it will be higher, but maybe it will be lower. We don't actually know (though this new trial is very encouraging).

A bad drug could also cause suffering beyond what Ebola causes: even if the patient was going to die anyway, it could make their death even more painful.

I guess that's when you hope you're not in the US, and get someone to inject you with a fatal dose of morphine.

if walking dead and zombie movies taught us anything, it's that things can get a whole lot more sub-optimal.

Why do you say there is no downside? As Jonathan Kaplan points out in the comments of the article Crito links to, Ebola is not 100% fatal and several drugs that have worked in animals have proven to have catastrophic effects when administered to humans (see e.g. TGN1412 [1]).

[1] - http://en.wikipedia.org/wiki/TGN1412

several drugs that have worked in animals have proven to have catastrophic effects when administered to humans

This is an argument for animal testing?

The argument for animal testing would be that several drugs have had catastrophic effects on animals, and would have had those same catastrophic effects on humans had we not tested first on animals.

Not all drugs effective for humans will be safe for animals, and not all drugs effective for animals will be safe for humans. Animal testing aims to operate in the middle-ground between the two, where things work similarly in both animals and humans.

Ya, too bad humans with terminal diseases can't give consent to receive experimental treatments. Better to forcibly test on a being that can't say "no".

Even if the established/widely accepted standards of ethics made human testing in lieu of any animal testing the clear ethical choice, it still would not be practical.

Think about it, how would you work on potential cures of ebola in the (several times many year long: http://en.wikipedia.org/wiki/List_of_Ebola_outbreaks) gaps between ebola outbreaks? Deliberately infect humans to be used as test subjects? Put all research on hold until the next outbreak came around?

You'd be able to find plenty of human test subjects for diseases like malaria or HIV, but for many diseases you would rapidly exhaust your supply of sick humans.

There are many practical things we do not do because they are unethical.

For example, bombing military forces using human shields as cover. Very practical, considered unethical and hence not practiced. (Same applies to the inverse, using civilians as shields.)

Eugenics, practiced to advance the human genome by artificial selection. Practical, not ethical!

During war, placing people of the same race as the enemy into concentration camps. Practical, no longer considered ethical, thankfully!

Testing drugs on the clinically insane and on criminals, or of humans of different races. Practical, not ethical.

Enslaving people of a different race to work plantations. Practical! No longer considered ethical!

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For testing between outbreaks, how about instead of your strawmen, we try infecting lab-grown specimens of non-sentient tissue with Ebola? This is the 21st century, we can grow entire organs [1]. Even barring that, tissue from organ donor cadavers can be used.

[1] http://www.telegraph.co.uk/science/science-news/10275996/The...

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And one more thing:

Deliberately infect humans to be used as test subjects?

Why do you see this as different/worse than deliberately infecting other primates?

Is it because they do not have advanced technology?

Is it because they do not speak our language?

Is it because they cannot resist us?

Is it because they are not chosen by your God?

Is it because they look different than you?

Is it because you have no social links with them?

Is it because, despite overwhelming scientific evidence to the contrary, you believe them not to be capable of thought and feeling?

Something else I haven't listed?

Everyone who downvotes me, I challenge you to answer this question. It's the least you can do if you don't doubt yourself.

Let me guess, you'd be opposing a cure to ebola even if it didn't involve animal testing because "Why do you think that it is okay to kill poor hapless ebola?"

> "Why do you see this as different/worse than deliberately infecting other primates? Is it because they do not have advanced technology?"

Sure, let's go with that one. Humans are able to research and eradicate diseases, but monkeys are not. Humans therefore have a greater inherent worth.

Go proselytize somewhere else.

> Sure, let's go with that one. Humans are able to research and eradicate diseases, but monkeys are not. Humans therefore have a greater inherent worth.

So would you agree with the statement that Westerners have greater inherent worth than Australian aboriginal adults? After all, they don't have the technology or knowledge to research and eradicate diseases.

How about vs. the Amish? They choose not to engage in such research.

How about a normal human adult vs. an invalid?

I'm curious where you draw the line.

> "Why do you think that it is okay to kill poor hapless ebola?"

> Go proselytize somewhere else.

I feel sorry for you, that you are both so easily offended and lacking in debate skills that your response is so childlike.

I was hoping you'd could provide a level-headed counterargument to mine, as I'm open to challenges to my worldview. Sadly it seems you're little more capable of checking your emotions than everyone else who downvoted because they disagree with me.

Because only humans are made in God's image. Therefore it's ethical to test drugs on enslaved non-human sentients incapable of acknowledging consent.

EDIT: Very curious whether the downvoters (a) don't get the sarcasm, (b) get the sarcasm and are offended that I question their religious tenets, (c) think animal testing is justifiable beyond reproach, (d) disagree that monkeys are sentient, (e) think that monkeys consent to testing, or (f) just don't like how I worded things.

opponents of animal testing in particular or anthropocentrism (like in "humans are the top of the God's creation and the Earth is given to humans into their dominion to be [ab]used as they wish") in general don't fair well on this much more conservative than one might expect site.

Ya, unfortunately, humans don't react well when you question their worldview.

Does anyone know why the WHO reporting frequency seems to be irregular? Recently it seems to be timed with the release of defensibly bad versus downright scary figures. https://en.wikipedia.org/wiki/2014_West_Africa_Ebola_virus_o...

I would suspect that reporting figures to the WHO, which I'll add is not providing a whole lot of help, is a rather low priority to these countries.

Plus the way this epidemic is playing out in the 3 major countries makes the figures altogether iffy (Nigeria is an obvious exception, with one index case caught quickly).

It's interesting to me that people are working on a cure for Ebola yet no one is deeply interested in working on new antibiotics. Ebola is a scary disease yet rare (across the entire planet) so there doesn't seem to be a lot of monetary reason to invest in it. Antibiotic resistance is far more widespread. I guess I don't always understand how the pharmaceutical industry decides what to look at.

I don't know if Ebola qualifies, but there are 'orphan drug' laws in many places that help pay for the development of medicine to treat rare diseases or conditions.

> Ebola is a scary disease yet rare (across the entire planet) so there doesn't seem to be a lot of monetary reason to invest in it. Antibiotic resistance is far more widespread.

All true, but once one understands the microbiology, it becomes obvious why drug companies are giving up on antibiotics. It's perfectly rational behavior -- no matter what antibiotics we invent, the microbes will evolve resistance to them in a short time. That's been the history of antibiotics until now, and there's no reason to expect the future to be any different -- if anything, it will probably become worse.

http://www.pbs.org/wgbh/pages/frontline/health-science-techn...

Title: "Dr. Arjun Srinivasan: We’ve Reached 'The End of Antibiotics, Period'"

Ebola has been around for decades, and this is an experimental drug. The fact is that interest in experimental drugs for Ebola has only cropped up recently, so this doesn't really prove any point about interest in antibiotics.

New antibiotics are in the works all the time. We are currently in an arms race with infections; I recall reading that new antibiotics are expected to last for only 10 years, and future antibiotics are going to last even less time (before resistance develops)

Why doesn't it get more press? I don't know for sure, but it is:

- Ongoing, which makes for bad news

- Kind of depressing, because we are slowly losing the battle

- Feels a little bit hopeless, because foolish choices by individuals accelerate the development of resistance, and inventing new antibiotics doesn't fix that fundamental problem

Yeah, it is depressing in the UK - the usage of antibiotics on colds (i.e. of no value to most people with colds) has increased 40% this century even with a campaign to limit usage.

I've personally spoken to a couple of GPs/Docs and they said after a few hours of people coming in and asking they get tired and give in.

Between that and farms using them like M&Ms (smarties ;-) ) on the cattle it seems like people are taking a precious resource and throwing it on the floor.

http://www.bbc.co.uk/news/health-28648785

The treatment in question (Zmapp) are heavily funded supported by various DoD entities. Weaponized ebola (along with smallpox) were always something of a bogey-man that received perhaps outsized attention from various sources.

Secondly, if it weren't for this outbreak, all of these treatments and vaccines would likely sit around in clinical trial hell for quite a while.

Cynically speaking, since clinical trials are so risky and expensive, its best if the developers can off-load some of that risk and expense. Picking something like Ebola, surviving on government funding (because its seen as strategic), and waiting for an emergency to allow you to skip a lot of red tape, and get dollops of support, isn't really a terrible choice.

Oh, and antibiotics are hard. For an overview of the current state of antibiotic development, you can take a look here:

http://www.pewtrusts.org/en/research-and-analysis/issue-brie...

Note that 43 drugs are in the pipeline.

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