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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.

 

 

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Freaky Weird Prescience (Ebola Post)

Well, it’s not looking good on the ebola front.  We still don’t know why the nurse in Dallas has ebola despite all of her precautions but I’m still not panicking.  My relatives in Houston are probably safe, though what did they say during the Black Death?  Run fast, go far, stay long?  Ok, that’s not really funny and is only encouraging a kind of hysteria that isn’t helpful.  Two ebola patients in Texas does not an epidemic make.  Then again, it’s Texas.

Nevertheless, there is a some speculation that the virus has become more virulent.  Peter Jahrling of the National Institute of Allergy and Infectious Diseases says this may be due to the increased viral load in infected individuals:

You’re seeing all these patients getting infected, so people think there must be aerosol spread. Certainly, it’s very clear that people who are in close contact with patients are getting a very high incidence of disease and not all of that can be explained by preparation of bodies for burial and all the standard stuff. But if you are to assume that the differences in virus load detected in the blood are reflected by differences in virus load spread by body secretions, then maybe it’s a simple quantitative difference. There’s just more virus.

Jahrling says that HIV was actually a hotter disease, primarily because carriers weren’t obvious and were able to spread the disease easily.  It also helped that HIV attacks cells in the immune system, which prevents a vigorous response.  But it’s a little hard to make this argument when comparing it to ebola.  HIV is a long, slow death and we now have drug cocktails to treat it.  Ebola is quick, excruciating, bloody and the lethality is alarming, especially because the treatment options are so few.

Which brings me to the next bit of bad news.  Frances Collins of the NIH says we might have had a vaccine for ebola except our politicians, with anti-governmental fervor, cut funding to those very institutions that might have helped to develop one.  I’d heard from researchers I met in Cambridge who had recently been to the CDC that morale was pretty low and disorganization was high.  Then, I lived through the summer of sequester when university research groups lost a sizable chunk of their funding as grants became more and more unattainable.  Layoffs quickly ensued.

One of the reasons I have been reluctant to pursue a job in research is because the money isn’t there anymore and I’m really sick of layoffs.  And let me make it clear that while scientists like to get paid fairly for the work they do, they don’t work for the money, for the most part.  They just like the work.  It can be frustrating and maddening and discoveries take a long time.  But it is also intensely rewarding in a way that money isn’t.  That’s not to say that we don’t have our own caloric requirements and shelter needs.  Also, no one likes to be exploited.  But bankers and Jack Welch types don’t understand the nature of science or the vast majority of people who do it for what is turning out to be a vanishing living.  But I digress.

The problem is that the patent cliff spooked pharma shareholders and they abandoned American research in search of get-rich-quick schemes and foreign research that isn’t ready for prime time.  At the same time, rabidly anti-government Republicans, abetted by complacent Democrats, have been slashing research budgets.

This is not the same America that we had in the post World War II days.  This is an infrastructure that is rapidly being gutted.  If you have any doubt of how bad things are, consider that Mapp Pharmaceuticals is virtually the only company on the planet with a possible treatment for ebola (we won’t know how the GSK vaccine is doing for awhile yet) and it is a small company in San Diego facing a logistical nightmare.  How does it grow the monoclonal antibodies and purify them on a scale to meet the urgent need of thousands of patients around the world?  Where is the CDC/NIH/Private Industry SWAT team that can get this off the ground?  We are asking this company to do the impossible on a massive scale in such a way that would attract every class action lawyer in the country if there wasn’t a health care emergency.

But it’s even worse than that.  As Collins says, ebola is only the tip of the iceberg.  The vast majority of us will not die of ebola.  We’re going to suffer from other maladies that no one is studying right now.   The funding is low on antibiotics, certain central nervous system disorders, heart disease, etc.  Companies just stopped working on these diseases because the research was expensive and shareholders didn’t think the profits were high enough.

All of this is happening when there is a revolution in biology.  The most ironic aspect of this problem is that thousands of trained researchers have been sidelined right at the same time that there is more than enough work to keep every one of them extremely busy for the rest of their lives.  There’s a profound disconnect between the people who are experienced enough to do the work and the funding mechanisms, either private or public, that will allow it to get done.

I see a lot of fuming on the ebola twitter feed about how scientists should just step up and get it done.  We’re all going to be saved by scientists.  How this is going to happen without funding is anybody’s guess.  It takes money to buy the equipment and reagents and research the papers and feed these scientists who everyone seems to think are going to be self-sacrificing for the betterment of mankind and to save their asses from some exotic African disease.  But as soon as the crisis is over, will we go back to chain sawing through the NIH budget?

From what I can see, neither private industry or our political leaders are taking the threat seriously.  So, I stand by my earlier prediction.  It’s going to take a plague to focus the nation’s attention on our crumbling research infrastructure.  It might as well be ebola.