from the clearing-the-air dept.
As the world knows, we face an emerging virus threat in the Wuhan coronavirus (2019-nCoV) outbreak. The problem is, right now there are several important things that we don't know about the situation. The mortality rate, the ease of human-human transmission, the rate of mutation of the virus (and how many strains we might be dealing with – all of these need more clarity. Unfortunately, we've already gone past the MERS outbreak in severity (which until now was the most recent new coronavirus to make the jump into humans). If we're fortunate, though, we'll still have something that will be worrisome, but not as bad as (say) the usual flu numbers (many people don't realize that influenza kills tens of thousands of people in the US each year). The worst case, though, is something like 1918, and we really, really don't need that.
[Ed note: The linked story is by Derek Lowe who writes a "commentary on drug discovery and the pharma industry". He is perhaps best known for his "Things I Won't Work With" blog entries which are as hilarious as they are... eye opening. I have found him to be a no-nonsense writer who "tells things as they are", holding no punches. The whole story is worth reading as he clearly explains what a coronavirus is, about the current one that reportedly originated in Wuhan, China, what could be done about it, how long that would likely take, and what can be done for those who have already been infected. --martyb]
Previous Stories Referencing Derek Lowe:
Machine Learning Comes to Biochemistry
Ignition! The Funniest, Most Accessible Book on Rocket Science is Being Reissued
Another Failed Alzheimer's Disease Therapy
Marathon Pharmaceuticals is Part of the Problem
Lobbying Results in FDA Approval for Controversial Drug
"Right to Try" New Experimental Medicine and the Value of Experts
Cancer Hazard vs. Risk - Glyphosate
A Terrific Paper on the Problems of Drug Discovery
Things I Won't Work With
Derek Lowe keeps a blog, that alone wouldn't be news worthy but his blog is the home of Things I Won't Work With, a fascinating look at chemicals so noxious, so volatile that even the names will make amateur chemists flinch.
Such things as:
Everyone knows hydrogen peroxide, HOOH. And if you know it, you also know that it's well-behaved in dilute solution, and progressively less so as it gets concentrated. The 30% solution will go to work immediately bleaching you out if you are so careless as to spill some on you, and the 70% solution, which I haven't seen in years, provides an occasion to break out the chain-mail gloves.
When we last checked in with the Klapötke lab at Munich, it was to highlight their accomplishments in the field of nitrotetrazole oxides. Never forget, the biggest accomplishment in such work is not blowing out the lab windows.
And a hard core it is! This stuff was first prepared in Germany in 1932 by Ruff and Menzel, who must have been likely lads indeed, because it's not like people didn't respect fluorine back then. No, elemental fluorine has commanded respect since well before anyone managed to isolate it, a process that took a good fifty years to work out in the 1800s. (The list of people who were blown up or poisoned while trying to do so is impressive). And that's at room temperature.
Has anyone here had to work with any of these?
Derek Lowe brings us a paper on the problems in drug discovery
Here's a really interesting paper from consultants Jack Scannell and Jim Bosley in PLoS ONE, on the productivity crisis in drug discovery. Several things distinguish it: for one, it's not just another "whither the drug industry" think piece, of which we have plenty already. This one get[s] quantitative, attempting to figure out what the real problems are and to what degree each contribute.
As they finish up by saying, we have to realize what the "domains of validity" are for our models. Newtonian physics is a tremendously accurate model until you start looking at very small particles, or around very strong gravitational fields, or at things with speeds approaching that of light. Similarly, in drug discovery, we have areas that where our models (in vitro and in vivo) are fairly predictive and areas where they really aren't. We all know this, qualitatively, but it's time for everyone to understand just what a big deal it really is, and how hard it is to overcome. Thinking in these terms could make us value more the data that directly reflect on predictive value and model validity (read the paper for more on this).
Be sure to read the comments at the end of Dr Lowe's article.
For those who may not recognize the name, this is the Derek Lowe who is author of: Things I Won't Work With and Things I'm Glad I Don't Do. He has a gift for writing that conveys complicated concepts in a very readable and entertaining fashion.
[The WHO] and the Food and Agriculture Organization have come out with a statement that glyphosate is "unlikely to pose a carcinogenic risk in humans". And this only a year after another UN agency, the International Agency for Research on Cancer, stated what looks like the exact opposite, that it could "probably" be a cause of cancer in humans. Later on last year, the European Food Safety Authority said that glyphosate is "unlikely to pose a carcinogenic hazard".
[...] the difference is that the IARC is looking at the question from a "Is there any possible way, under any conditions at all, that glyphosate could be a carcinogen?", while the FAO and WHO are giving an answer to the questions "Is glyphosate actually causing cancer in people?"
[...] "Risk", technically speaking, refers to your chances of being harmed under real-world conditions, while "hazard" refers to the potential for harm.
Under real-world conditions, eating a normal amount of bacon raise your risk of colorectal cancer by an amount too small to consider. But it does appear to be raising it by a reproducible, measurable amount, and therefore bacon (and other processed meats) are in the IARC's category 1.
[...] It's important to note that some hypothetical substance that reproducibly, in human studies, gives anyone cancer every single time they touch it would also be in category 1, the same as a hypothetical substance that reproducibly, in human studies, raises a person's risk of cancer by one millionth of a per cent. Same category. These categories are not arranged by relative risk – they're arranged by how good the evidence is. Glyphosate is in category 2A, which means that there is evidence from animal studies, but limited/insufficient evidence from humans as of yet.
[...] So yes, by the standards of the available evidence, glyphosate is in the same cancer hazard category as working the night shift, or working as a hairdresser.
TFA is interesting and worth a read, especially for its use of a shark analogy explaining the difference between risk and hazard.
Link: Glyphosate And Cancer By Derek Lowe
Additional Wired link: Does Monsanto's Roundup Herbicide Cause Cancer or Not? The Controversy, Explained
At what point should an experimental drug be made available for anyone to try it?
[...] "Right To Try" law [allows] a therapy to be prescribed after it's passed Phase I and is under active investigation in Phase II. [...] Insurance companies are not required to pay for these, it should be noted, nor are drug companies required to offer access.
The big underlying question here is "Who gets to make the decisions?" Right-to-try advocates would say that the patients themselves should be making those calls (presumably with some advice from their physicians). Others would say no, we need an FDA, some sort of regulatory authority to make sure that the therapies people are choosing from are actually worth choosing. Another argument is that the underlying medical and clinical issues are complex enough to make some sort of expert review worthwhile, and that we can't necessarily expect "informed consent" to always be informed enough under some of the more wide-open proposals.
[...] The Limits of Expertise
Past that, though, you run into the folks who aren't even bothering to appeal to experts at all, because they simply don't trust them much and don't believe what they have to say. Here, too, we have gradations. If we're talking about the Poincaré Conjecture, to pick an issue on one end of the scale, the only people that will be of much use while discussing the details of Grigori Pearlman's proof of it will be those who have devoted serious time to the study of topology. No one who is not comfortable dropping the phrase "Riemannian manifold" into their conversational flow can really have a seat at that table. Even world-renowned prize-winning scientists from many other fields are not going to able to pull up a chair.
Dr. Lowe breaks these types of questions into "Matter for Experts", "Just Plain Facts", "Flat-Out Unknowable", and "Matters of Opinion" and the relative value of expertise for each.
Background on "Right To Try" laws:
Eteplirsen received approval for use as a Duchenne muscular dystrophy therapy despite the FDA review team concluding that the treatment was unlikely to show any benefit for patients.
Dr. Janet Woodcock's (Director of the Center for Drug Evaluation and Research) decision was heavily influenced by the "parading diseased children in front of the cameras" and was made before the FDA's review team completed their analysis.
Part of Dr. Woodcock's rational for approval included the stock price of Sarepta (the pharmaceutical company responsible for eteplirsen):
She opined that Sarepta in particular "needed to be capitalized." She noted that [Sarepta's] stock went down after the AC meeting and went up after FDA sent the June 3, 2016 letter. Dr. Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and the other similar drugs in its pipeline.
FDA Commissioner Dr. Robert Califf, Acting Chief Scientist Dr. Luciana Borio, and Dr. Ellis Unger, the Director of the Office of Drug Evaluation, all opposed the approval but Dr. Califf declined to overrule Dr. Woodcock's decision.
Dr. Unger argued that the approval was unethical and counterproductive:
By allowing the marketing of an ineffective drug, essentially a scientifically elegant placebo, thousands of patients and their families would be given false hope in exchange for hardship and risk.
Dr. Borio argues:
Granting accelerated approval here on the basis of the data submitted could make matters worse for patients with no existing meaningful therapies — both by discouraging others from developing effective therapies for DMD and by encouraging other developers to seek approval for serious conditions before they have invested the time and research necessary to establish whether a product is likely to confer clinical benefit.
[...] [Sarepta] has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study 201/202147 –which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings.
Dr. Derek Lowe, from In The Pipeline, agrees with Dr. Unger and Dr. Borio that the drug is "unlikely to provide much benefit, and is reasonably likely to provide none at all" and that the drug "may well be [$300,000 per year] worth of placebo".
Note: Bold was added by the submitter.
Dr. Derek Lowe, from In the Pipeline, writes:
So since drug pricing and FDA regulations are so much in the news, it would seem like the perfect time for a small company to game the system for big profits, right? That's apparently what Marathon Pharmaceuticals believes. They just got approval for deflazacort, a steroid, as a treatment for Duchenne Muscular Dystrophy.
[...] So what's not to like? Well, this drug has been around since the early 1990s. Marathon most certainly did not invent it. Nor did they think of applying it to DMD patients – the biggest clinical trial of the drug for that indication was done over twenty years ago, by someone else. DMD patients in the US were already taking the (unapproved) drug by importing it from Canada. Marathon just dug through the data again and ran a trial in 29 patients themselves, from what I can see. I should note that this is not any sort of cure, nor does it address the underlying pathology of the disease. The steroid treatment makes muscle strength in DMD patients stronger – barely. But even for that benefit, US patients will now have to get it from Marathon at something like 50 to 100 times the former price.
[...] So while I defend the FDA's function of making it tough on new drugs (making them prove safety and efficacy), I cannot stand how loose they are with old generic compounds. The agency hands out extremely valuable rewards like lollipops in these cases – a priority review voucher can be sold for hundreds of millions of dollars
[...] And they're also allowing the likes of Marathon to make the rest of the drug industry look like greedy sociopaths. Marathon, Catalyst, T*ring and all the rest of the people who are pulling these tricks have the word "Pharmaceuticals" in their name, but they are not drug companies. They discover nothing. They do no research. They take virtually no risks. They exist only to play legal games and watch the money roll in.
[...] As for the FDA, the agency probably can't change this on its own, though, even if it wants to – Congress has to act to give them the authority to deny market exclusivity or priority review vouchers under some conditions. Either that, or we should rethink these incentives entirely, because they are (clearly) too easy to exploit for fast bucks.
Also at ArsTechnica.
Dr. Derek Lowe, from In the Pipeline, writes about another disappointing failure to treat Alzheimer's Disease:
Merck announced last night that the first Phase III trial of their beta-secretase (BACE) inhibitor verubecestat was stopped because of futility. The monitoring committee, after looking over the data so far (the trial's been running since 2012) concluded that there was no real chance of seeing efficacy.
[...] The list of Alzheimer's clinical failures is impressive, but the list of failures to clinically validate the amyloid hypothesis is even more so.
[...] Beta-secretase inhibitors have failed in the clinic. Gamma-secretase inhibitors have failed in the clinic. Anti-amyloid antibodies have failed in the clinic. Everything has failed in the clinic. You can make excuses and find reasons – wrong patients, wrong compound, wrong pharmacokinetics, wrong dose, but after a while, you wonder if perhaps there might not be something a bit off with our understanding of the disease. Remember, every time one of these therapies comes around, it builds on the failures before it. Better and better attempts are made – I mean, verubecestat seems to be a pretty good compound, from the preclinical drug discovery perspective. It's surely the best swing anyone's taken at beta-secretase (and there have been many). But it just flat out did not work.
The good news about this study is that it adds to the evidence that the amyloid hypothesis of Alzheimer's Disease is a blind alley and that the presence of amyloid plaques is simply correlative and not causative. As more data comes in from the study, I hope that the evidence will be conclusive enough that more effort will be spent on pursuing other therapeutic targets.
It's rare that the forthcoming publishing of a book fills me with excitement and anticipation. Doubly rare when said book has been out of print for decades. Elon Musk may have popularized the term RUD (Rapid Unscheduled Disassembly), but his experiences can barely hold a candle to the tales told by John D Clark, author of Ignition! An Informal History of Liquid Rocket Propellants. Read on for the scoop from Ars Technica:
Often hilarious, always informative, this history of rocket science is a must-read.
It's rare that a book about as high-minded and serious a topic as rocket science manages to be both highly informative and laugh-out-loud funny. But if there's a better way to describe John Clark's Ignition!, I've yet to discover it. A cult classic among chemists, many of the rest of us discovered the book via one of Derek Lowe's tales of hilariously scary chemicals.
[...] Rutgers University Press has decided to dust it off and reissue it. From May it will finally be possible to put a physical copy on one's bookshelf. And honestly, if you've got any interest in chemistry—particularly the branch of it involving violent, energetic, and occasionally explosive reactions—it's a book you need to read.
Ignition! is a history of liquid rocket propellants, but it's also a history of cold war and the space race, told from a particular point of view. Clark was the chief chemist at a rocket lab in New Jersey, operated first by the US Navy, then US Army. He was a central figure in what was a relatively small field, one with a definite purpose. This wasn't science just for science's sake, but a quest to find new oxidizers and fuels for rocket engines, to make better missiles or space probes.
The propellants being asked for would have to be liquids throughout a range of temperatures, and preferably completely innocuous and easily stored until reacting violently together upon combination. However, if you guessed that many of the chemicals suitable for energetic reactions in a rocket often tend to react energetically in many other situations—often with no provocation at all—Clark's tales of "catastrophic self-disassembly" might not be entirely surprising.
Pricing ranges from $24.95 to $95.00 with pre-orders being accepted now. A PDF is available on February 14th; other formats and a reduced-price PDF is available on May 15th.
Read on for a sample passage from Chapter 6 of Ignition!:
Every two years, hundreds of scientists enter a global competition. Tackling a biological puzzle they call "the protein folding problem," they try to predict the three-dimensional shape of proteins in the human body. No one knows how to solve the problem. Even the winners only chip away at it. But a solution could streamline the way scientists create new medicines and fight disease.
Mohammed AlQuraishi, a biologist who has dedicated his career to this kind of research, flew in early December to Cancun, Mexico, where academics were gathering to discuss the results of the latest contest. As he checked into his hotel, a five-star resort on the Caribbean, he was consumed by melancholy. The contest, the Critical Assessment of Structure Prediction, was not won by academics. It was won by DeepMind, the artificial intelligence lab owned by Google's parent company. "I was surprised and deflated," said Dr. AlQuraishi, a researcher at Harvard Medical School. "They were way out in front of everyone else."
[...] "It is not that machines are going to replace chemists," said Derek Lowe, a longtime drug discovery researcher and the author of In the Pipeline, a widely read blog dedicated to drug discovery. "It's that the chemists who use machines will replace those that don't."
After the conference in Cancun, Dr. AlQuraishi described his experience in a blog post. The melancholy he felt after losing to DeepMind gave way to what he called "a more rational assessment of the value of scientific progress." But he strongly criticized big pharmaceutical companies like Merck and Novartis, as well as his academic community, for not keeping pace.
[For those who might not be aware, the Derek Lowe mentioned above is the author of the Things I Won't Work With blog. If you want to read about things that burn, go BOOM, or otherwise wreak havoc you'd be hard pressed to find a more entertaining source. --martyb]
Multiple Soylentils have submitted stories regarding the 2019-nCoV coronavirus which is believed to have originated in the city of Wuhan, China in December 2019. Rather than have a smattering of stories appear on the site, they have been gathered here in one story. Read on if you are interested; otherwise another story will be along presently.
Even though it has only been a short while since our last round-up there are 22 separate stories merged into this round-up. Many report duplicate news but, nevertheless, we have tried to distill the important elements of each submission.
Firstly, there is some confusion regarding the actual names that are reported for the virus, the disease that it causes, and names frequently seen in media reporting. From https://www.nature.com/articles/s41564-020-0695-z:
The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2.
In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
There is much more information at the link provided.
Secondly, as this is a fusion of stories received over the last week or so take all quoted figures of casualties as possibly out-of-date. At the time of merging these stories (12 Mar 20) there have been 127,863 confirmed cases world-wide resulting in 4,717 deaths. 68,309 people have already recovered with the remainder either in self-imposed or advisory isolation, in basic hospital care and a relatively small number in critical care. The pandemic has affected 116 countries/regions. Source: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6 - a graphical display produced by Johns Hopkins University (JHU).
Many countries have taken emergency measures to restrict travel or large gatherings of people. As this is a very fluid situation we suggest you refer to the media of any specific country in which you have an interest. President Trump has banned transatlantic air travel from countries in mainland Europe to the USA from Friday 2020-03-13 at 23:59 (no timezone stated) for a period initially of 30 days, and air travel within Europe is also significantly disrupted.
The new coronavirus has been declared a global emergency by the World Health Organization, as the outbreak continues to spread outside China.
"The main reason for this declaration is not what is happening in China but what is happening in other countries," said WHO chief Tedros Adhanom Ghebreyesus.
The concern is that it could spread to countries with weaker health systems.
Chicago health officials have reported the first US case of human-to-human transmission of the deadly coronavirus.
The new patient is the spouse of a Chicago woman who carried the infection back from Wuhan, China, the US Centers for Disease Control said on Thursday.
The discovery marks the second report of the virus in Illinois and the sixth confirmed case in the US.
This paper provides early estimates of 2019-nCoV epidemiological parameters: Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions (open, DOI: 10.1101/2020.01.23.20018549) (DX)
Used model does not offer much grounds for optimism.
China Reports 3rd Death, Nearly 140 New Cases of Coronavirus
China Confirms Human-To-Human Transmission of New Coronavirus; CDC Confirms First US Case
Coronavirus: Millions Quarantined in Wuhan City
China Battles Coronavirus Outbreak: All the Latest Updates
In The Pipeline: Coronavirus
Plague Inc. Maker: Don't use our Game for Coronavirus Modeling
This story is a roundup of several virus stories that were submitted over the past few days. This is a changing story, so some of what is posted below may have changed since the time of their originally being published.
What's in a name? One significant change is what the names are for everything. There is the question of what to call the actual virus and then what to call it when someone is infected.
Virus: The virus by itself is now officially referred to as SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). It was formerly known as 2019-nCoV (2019 novel coronavirus).
Disease: Those who have been infected by this virus are said to have a disease. The name of the disease is coronavirus disease (COVID-19) which is also known as 2019-nCoV acute respiratory disease.
More details are available on Wikipedia.
The six submitted stories are presented below.
NIH Official Says Coronavirus 'on the Verge' of Becoming Global Pandemic Unless Containment Improves
Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, told CBS's "Face The Nation" that multiple person-to-person transmissions need to occur in multiple countries in order to reach the pandemic threshold.
[...] "Technically speaking, the [World Health Organization] wouldn't be calling this a global pandemic. But it certainly is on the verge of that happening reasonably soon unless containment is more successful than it is right now," he said.