Ebola Updates: Still no reason to panic

Another big headline at the NYTimes: A Second Healthcare worker in Dallas has tested positive for ebola.

Is anyone shocked?  Please raise your hand where I can see you.

Didn’t think so.

Update: So, now we find that the second nurse who was infected was on a plane from Cleveland to Dallas the day before she reported symptoms.  Ahhh, now here is where Americans should start to get concerned.  Americans get around.  That is, it’s  relatively easy to jump on a plane for a weekend getaway, though why anyone would want to go to Cleveland is beyond me.  Sorry about that, Cleveland.  And Pittsburgh is only a few hours from Cleveland by car.  Nevertheless, there is still no reason to panic, though the CDC seems to think the passengers on that flight need to be tracked down. The nurse landed in Dallas-Ft. Worth on Monday night at 8:16pm and reported symptoms on Tuesday. That is a very tight timeframe so passengers probably have more of a reason to be concerned but not panicked. But the bigger problem is that it will be harder to keep ebola in Texas if infection rates blossom.

Reminder: Back in May, I went to a user group meeting in Cambridge, MA where I met several researchers who had just come back from a visit to the CDC.  They reported that the budget cuts had demoralized the CDC and researchers there sometimes didn’t know who they reported to or who was in their group.  That’s not a slight on the CDC.  It has been a world renowned institution but if you starve it for funds, it is going to have problems.  If you do it over a period of 14 years, it’s going to have BIG problems.

I’m copying a few comments I made in a previous thread on the latest ebola news.

On the CNN report about the Nurses Union that is speaking out for the Dallas health care workers, Katiebird may be posting on this later once she has tracked down some information.  These are just my uninformed, idle speculations to the news that Texas Health Presby Hospital may have put its employees and others at risk:

I read that CNN article late last night and I was shocked but not surprised, if that makes any sense. Shocked because the hospital was caught so unprepared and was really botching it. But unsurprised because it made a lot of sense in how the infection was spread to this nurse. No health care worker in their right mind wouldn’t take the utmost precautions given the media frenzy over ebola.

I could only conclude that the hospital itself was at fault for being caught off guard and, probably, considering cost over treatment protocol. After all, who was going to pay to isolate Thomas Duncan? Rick Perry turned down medicaid expansion and the Texas legislature has severely cut back on state board of health offices. Laissez faire apparently means anything goes when it comes to profiting off of health care and Duncan was a money sink.

The 90 minutes gap where Duncan was with other patients before he was isolated may have referred to the emergency room. Here’s my best guess: The ambulance dumps Duncan off at the ER with a barf bag. He has to sit there with other sick patients while calls are being made to the hospital administrative staff to decide how to admit him. He’s a foreign visitor, not even an immigrant, with no health insurance, dumped on Texas Health Presby Hospital. He doesn’t qualify for Obamacare, there’s no medicaid for him either because, hellloooo, Americans, especially those living in the south, don’t want to pay for the health care needs of foreigners. Are there funds set aside in Texas to manage a highly infectious disease like ebola? Are you kidding?? Decisions, decisions. The hospital might have thought of transferring him elsewhere but I’m betting the other facilities said they were no better able to care for him. It’s your problem.
Damn, Duncan could wipe out the profit for the entire year, what with the isolation and ruining ventilation and dialysis equipment, not to mention how to get rid of hazardous waste.

So, he sat in the ER for 90 minutes, vomiting and sweating all over the chairs and gurneys, before the hospital decides it doesn’t have a choice anymore and has to take him. Who knew how many people came in contact with him while he was shedding billions of viruses? Poor Nina Pham probably did what she was instructed to do with very little CDC oversight.

On the ebola forum symposium held yesterday at the Johns Hopkins School of Public Health that was held yesterday:

Peter Jahrling showed all of the possible drug treatments in the pipeline. It’s a joke. No, seriously. ZMapp looks like the best bet but the company can only make about 20 doses in its next batch. It’s not their fault. They’re just overwhelmed by the scale and logistics.

A couple of vaccines are being tested in the field. And they have to have a control group so 1/3 of the participants are getting Hepititis C vaccine. It can’t be helped but the participants must know that some of these people are going to die. There’s no way around it. That’s the way science is done. And these vaccines are not in anyway ready for FDA approval.

Other treatments are even less ready. Interferon actually makes the infection worse. There’s an interesting research topic. What is it about the cell signaling that makes interferon treatment worse? Then there are a couple of “drugs”. Honestly, I think biologists are analyzing the high throughput data. They think any hit is a drug. The compounds presented may have some efficacy (probably in the millimolar range from the looks of them) but they’re not very bioavailable and the toxicity could be a major problem.
So, in short, we’re pretty much screwed if we can’t get West Africa back under control and the infection spreads.

Not that we have much to worry about here in the US. We don’t. But it’s not very reassuring to me that we are sooooo far behind in the drug discovery area on infectious diseases. Again, shocked but not surprised.

The symposium can be found here. Most of it is School of Public Health academics trying to one up each other on modeling the progress of the disease. It got to be too insidery and less informative after awhile. Jahrling’s presentation was more straightforward, to the point and alarming. If the general public truly understood what Jahrling’s presentation was saying, they’d never vote for another budget slashing Republican. Ebola is only one of a number of devastating infectious diseases that we are not prepared to deal with because we cut funding, blocked nominations, and let private industry, dominated by shareholders and billionaires, dictate the research and manage the pipeline portfolios. It’s baaaaad.

About quick and dirty drug design using publicly available ebola virus crystal structures and the funky vocabulary that goes with it, this is a little primer on what I was initially thinking and about some of the obstacles:

FASTA is a format for amino acid sequences. Every protein has a sequence of amino acids and they are all unique. Families of proteins are related to one another. You can perform an evolutionary trace on a single protein if the sequence of that protein over time has been determined. The FASTA sequence is stored in publicly available databases. The NIH allows access to these sequences for researchers and provides tools to search them. One of these search tools is called BLAST. It can do sequence alignments. So, if you have a fragment of a sequence or a new sequence, you can search the database to find the entire sequence or similar sequences. I used to use a related tool called BLASTp. That allows the user to find protein sequences that have been crystallized and are stored at the RCSB.

So, let’s say you have a protein that you know has mutated away from its original source. In this case, we are talking about the ebola viral proteins. The crystal protein I referred to last night was from a strain found in Zaire, in a place called named after a nurse called Mayinga. But the newest outbreak of ebola is located in West Africa and it is a different strain, therefore, different mutations in the amino acid sequence.

If you designed a drug based on the Zaire Mayinga strain, it may not be effective against the West Africa strain because the amino acid sequences may be different. But we can make a homology model of the new viral protein structure if we know where the new mutations are. It’s the next best thing to a experimentally determined crystal structure.

The questions to ask are: do all of the viral proteins mutate at the same rate? We would know by looking at the latest FASTA sequences and mapping them onto the structure. Can we identify a binding site? The protein I looked at yesterday processed RNA. I can make an educated guess as to where this occurs. But when it oligomerizes, that is, forms a new structure by self assembly, it has a couple of different binding sites. That is, the binding sites of each subunit to the subunits adjacent to it can also be targeted for drug design. I worked briefly on a different oligomer previously and it was possible to create a drug like entity called a paptamer by extracting a chunk of the secondary structure of the subunit and modifying it very slightly. This prevented the subunits from self assembly, or so the theory goes.

But in the ebola protein I looked at yesterday, the protein-protein interactions between subunits appeared to be dominated by beta sheets, which relate to one another along parallel and antiparallel strands. So, extracting a piece of this binding surface would be difficult if not impossible. Another, more complex and time consuming drug design process would need to be done. If it were just a matter of a helix, it might have been a different story. So, this viral protein target might not be amenable to quick and dirty drug design work and it might have to be abandoned for another ebola protein.

In any case, the FASTA sequence is very informative. It has likely been deposited at the NIH. They usually do that for Flu viruses and you can track mutations as they zip around the world. But I’m not sure we have the very latest info for ebola.

Ok, that was long.  I’m going to eat lunch.

 

 

Ebola Post: Request for papers

Given that the number of cases of ebola in Africa is rising exponentially, and given that ZMapp is not going to be available in sufficient quantities any time soon, is it possible to find/screen for a small drug entity or protein aptamer that would interfere with the oligomerization of ebola matrix proteins or inhibit the action of other ebola virus proteins?

I think the answer is yes.  The RCSB, the publicly available repository of protein structures, has over 40 ebola virus proteins, some deposited this year.  I have to assume that someone(s) is screening ACD or other compound databases with docking programs to find potential hits.  It would be great if those of us who used to do this type of work would also be able to contribute.

However, while the structures are available, and much work can be done just using the structures, the papers that are associated with them frequently are not.  The journals involved can charge up to $33/copy for each paper.  This cost is prohibitive for most independent researchers.  Come to think of it, so are the applications I used to use to dock libraries of compounds into structures.  But even with the limited public software, we could still get a lot done if we were able to read the papers for free.  Like I said, reading the structure papers is not absolutely necessary but it can be helpful.

So, if there is anyone out there who has influence with PubMed, could you look into it?   Also, is anyone aware of a crowdsourcing effort to design drugs based on these structures?  Just give a shout out if you know of one.

One more thing: It would be very helpful to know the latest mutation data in FASTA format in case homology models need to be created on currently available crystal structures.  I see that the octamer was crystallized in 2002 and is from strain Zaire Mayinga.  If I’m not mistaken, the current epidemic is from a different strain. (though this protein may be more resistant to mutations?  Dunno.  Need to read the papers.)

Tuesday: Science, politics and niche theory

Update: I totally missed this.  The FCC is proposing new rules for broadband and wireless providers.  Depending on whether you have a landline method of delivery or wireless, your internet stream will be regulated differently.  This is particularly important because the world is going wireless so it could be a coup for the masters of the universe that want more control of content and how much you will pay for it.  They’re already gouging us.  Why make it easier for them to control what you can have and how fast?  We already lag Romania in terms of internet connection speed.  Romania.

According to the report “2010 Report of Internet Speeds in All 50 States” released recently by the Communications Workers of America (CWA):

“The report shows that the rate of increase in U.S. Internet connection speed is so slow, it will take the United States 60 years to catch up with current Internet speeds in South Korea, the country with the fastest Internet connections.”

It’s inexcusable that we’re going to let wireless companies off the hook and not make them invest in their infrastructure.  Allowing them two tiered data plans gives them exactly what they want: more money without having to lift a finger to improve their equipment.

ROMANIA.

Jeez, just twenty years ago, Ceaucescu was running the country, it was dark and dreary, there was nothing to buy there and babies in orphanages were dying from HIV infected blood transfusions.  Now, they have better internet access than we do.  I have an iPhone in central NJ and I still can’t get a signal in my office at work right in the heart of AT&T country.  How can lawmakers even contemplate this kind of change without requiring wireless companies to get with the program that the rest of the world enjoys?

Unbelievable.

Moving on…

Yesterday, I was perusing Derek Lowe’s pharma chem blog, In the Pipeline, and he had a post up called Politics in the Lab about a recent article in Slate with the weird title “Most Scientists in this Country are Democrats.  That’s a problem”.  I don’t know that’s a problem and I’m not sure it’s even true, but I’ll get to that below.

The chewy center of this article seems to be that until there are more Republican scientists, the field won’t be bipartisan enough to get its point across.  Huh?  The author states:

Yet, partisan politics aside, why should it matter that there are so few Republican scientists? After all, it’s the scientific facts that matter, and facts aren’t blue or red.

Well, that’s not quite right. Consider the case of climate change, of which beliefs are astonishingly polarized according to party affiliation and ideology. A March 2010 Gallup poll showed that 66 percent of Democrats(and 74 percent of liberals) say the effects of global warming are already occurring, as opposed to 31 percent of Republicans. Does that mean that Democrats are more than twice as likely to accept and understand the scientific truth of the matter? And that Republicans are dominated by scientifically illiterate yahoos and corporate shills willing to sacrifice the planet for short-term economic and political gain?

…

It doesn’t seem plausible that the dearth of Republican scientists has the same causes as the under-representation of women or minorities in science. I doubt that teachers are telling young Republicans that math is too hard for them, as they sometimes do with girls; or that socioeconomic factors are making it difficult for Republican students to succeed in science, as is the case for some ethnic minority groups. The idea of mentorship programs for Republican science students, or scholarship programs to attract Republican students to scientific fields, seems laughable, if delightfully ironic.

Yet there is clearly something going on that is as yet barely acknowledged, let alone understood. As a first step, leaders of the scientific community should be willing to investigate and discuss the issue. They will, of course, be loath to do so because it threatens their most cherished myths of a pure science insulated from dirty partisanship. In lieu of any real effort to understand and grapple with the politics of science, we can expect calls for more “science literacy” as public confidence begins to wane. But the issue here is legitimacy, not literacy. A democratic society needs Republican scientists.

Ahem.  I find this article truly disturbing for several reasons.  But let’s go back to YearlyKos2 in Chicago when Pharyngula of ScienceBlogs, presided over a panel on Science and the public or some silly title.  I was shocked by how arrogant and dismissive the panel was of the average American who didn’t believe in climate change and evolution.  Yeah, I know how incredibly frustrating it is to get family members to buy into evolution.  But I’ve made peace with the fact that if I describe the theory of natural selection well enough, they will accept it without having to go back to the beginnings of time to find out where God is in the picture.  It can be done.  You have to choose your battles.

What’s frustrating to me is that there are a lot of Democrats who are just as irrational and gullible.  Their fears and misunderstandins are just different- nuclear energy, genetically modified seeds, colony collapse, thimerosol in innoculations (that absolutely do not cause autism).  I’ve argued with many of them to no avail.  They are as resistent to facts as creationists.  It has been particularly frustrating when it comes to pharmaceutical science where many people on the left, and you dear reader may be one of them, are convinced that the researchers are cold, heartless, profit driven monsters who are either making nothing but “Me too!” drugs or don’t care if they make poisons that only serve to treat some manufactured quality of life problem or they get all their ideas from government sponsored labs and don’t contribute anything.  They just take, take, take and never give back.  Admit it.  That’s what some of you think, right?  (If I were you, I’d ask myself who benefits from that perception?)  But I don’t really want to go there right now.  That’s not my point.

Here’s my point: Not everyone is cut out to be a scientist.  That’s why people don’t go into the field.  It means studying lots of math, wrapping your head around stuff like quantum theory (which isn’t necessarily impossibly hard to understand but it is very, very weird) and spending hours in a lab hunched over smelly chemicals and microscopes.  Some people take their required science courses in high school, get a passing grade and move on.  And that’s fine.  The world needs writers and mechanics and accountants and elementary ed teachers too.  It’s not that the field is too hard.  If you are diligent and motivated enough, you can learn anything.  But some people just aren’t passionate about science. If it’s not your  niche, that’s OK.

But if that’s the case, please don’t pontificate on science.  I don’t care if you’re right or left.  Just don’t.  You sound uninformed to those of us who do it for a living.  Like most Americans, Democrats find it just as hard to assess risk and can be just as gullible when it comes to evaluating the merits of a science article in the New York Times.  That kind of analytical ability comes with time and from reading a lot of papers.  There are even some bloggers who I love in most every respect except when they go off on a science jag.  Then they quickly lose their mojo and I just have to walk away shaking my head.  And I don’t think that the labs are teeming with Democrats.  There may be a slight tilt that way but there are just as many Republicans in the lab as Democrats.  Most people I know are independents.  In my humble opinion, Democrats are born that way; Republicans evolve.  And when Republican scientists evolve, they become management, which may mean that they are finding their own niches.

Now, don’t go away mad.  I’m not saying that Democratic bloggers should never discuss science.  And I’m not saying scientists are knowledgeable about every field.  We’re not.  Gawd knows I struggle every day to understand new science.  Things remain a mystery until you beat your head on the bench long enough.  What I am saying is that if it isn’t your cup of tea, proceed with caution.  If you *are* interested in a particular area of science or science issue du jour, you owe it to yourself to read up on the subject in the way that any scientist would.  Dig into it by learning all you can from people in the field before you pop off some opinion. Learn to evaluate data (BTW, the nomination of Obama during the 2008 primary season should put to rest the notion that Democrats are better at evaluating evidence. Really, there’s nothing to crow about there guys.).  

Now, where can you get information about science?  First, if you have an eReader of any kind, you can find free text books in just about any subject.  Second, our government does an outstanding job providing resources to the public through such sites as PubMed and PubChem where you can find abstracts and links to scientific literature, entire genomes, sequences, chemical structures and their properties, etc. The abstracts are free, the actual articles may not be.  You can purchase access to full articles through several services at nominal cost. There are tools like BLAST to compare nucleic acid and protein sequences, a database repository of protein structures in the RCSB, and lots of other sites of open source information in easy to use interfaces.  Some of them come with java viewers so that you can rotate molecules of interest.  If you wanted to start your own pharma, be a real entrepeneur, like the Republicans are always advocating, there’s plenty of free stuff online to use.  This is real time, up to date information, free to the public from the NIH and other government funded sources. We share our information with the world and the world with us.  That’s the way we advance science.  The sites belong to us, courtesy of us, the US taxpayer, and it’s one of the most valuable things we do.  Third, there are some popular blogs and podcasts out there where new science is covered in detail but also explained thoroughly for the non-science type.  I recommend the Naked Scientists from Cambridge University in the UK.  Their podcasts are challenging but fun and they will not talk down to you.

If there is one thing you can do for science this year, it’s advocate for the continuation of these valuable online tools.

One more thing:  Derek linked to a survey from the Pew Foundation on the public view of science.  You can test your scientific knowledge and get your score compared to the rest of the country by taking this online quiz.  I scored a 100%.  Nyah-nyah!