NIH opens the floodgates to creating super-viruses

Some scientists really want to earn their "mad scientist" label. Ever since Mary Shelley's Frankenstein, novelists and screenwriters have shown us the dangers of letting mad scientists pursue their dreams without any controls. Of course, those stories are fiction.

In the microbial world, though, technology has caught up with fiction. Scientists today can create viruses from scratch, as they've already done with the polio virus, back in 2002. Using the tools of modern genomics, virologists and microbiologists can make pathogens much, much more deadly. But would anyone really want to do this? The answer, it turns out, is yes.

A few years ago, some virologists had the clever idea of modifying the bird flu virus to make it more deadly to humans. What would it take, they wondered, to turn the bird flu into a human flu? They decided to give it a try, and they announced their plans to the world. Then, just a few months later, they published results showing that they had succeeded, at least partially, using a bird flu called H7N9.

That wasn't even their first try. Only a year earlier, they did the same thing using a different flu virus (H5N1). Both of these bird flu strains have killed people, but the wild-type version of the virus rarely infects humans. The scientists running these experiments aimed to create a strain that could get into humans much more easily.

Many scientists were mortified. 18 leading microbiologists and infectious disease experts, including Nobel laureate Sir Richard Roberts, formed the Cambridge Working Group to oppose efforts to create super-viruses in the lab. Hundreds of other scientists, including 3 more Nobel laureates, joined the group as charter members.

In response to the concerns raised by scientists and other public health experts, NIH announced a moratorium on these so-called "gain of function" (GOF) experiments, at least in the U.S. (The scientists leading the charge for GOF experiments were based primarily in The Netherlands, although they did get some funding from NIH.) The NIH convened an expert panel, the NSABB, who commissioned a 1,000-page report and then issued their own report, which was released in May of 2016.

The NSABB panel avoids taking very strong positions, but they do raise some alarms. Here's their definition of "research of concern," for example:

"...research that could generate a pathogen that is: 1) highly transmissible and likely capable of wide and uncontrollable spread in human populations; and 2) highly virulent and likely to cause significant morbidity and/or mortality in humans." 

This does not sound like a good idea! So what does the NSABB recommend? Well, this:

"Research proposals involving GOF research of concern ... should receive an additional, multidisciplinary review, prior to determining whether they are acceptable for funding."

I can't argue that research like this doesn't need "additional" review–but the wording here suggests that at least some experiments like this might be worth funding. Mad scientists must be rubbing their hands together in glee.

And finally, just last week NIH announced it will end the moratorium on gain-of-function research. (They made this announcement just a week before Christmas, when many people are probably not paying attention. Coincidence? Perhaps.) In his statement announcing the end of the moratorium, NIH Director Francis Collins wrote:

"I am confident that the thoughtful review process ... will help to facilitate the safe, secure, and responsible conduct of this type of research in a manner that maximizes the benefits to public health."

I am not so confident. Harvard's Marc Lipsitch, one of the leaders of the Cambridge Working Group, commented that "we don't need to do these dangerous experiments. Indeed there are many ways that can (and have) been used to answer the public health question with greater generality, little to no safety risk, and much lower cost."

But just in case there is some question, let's weigh the pluses and minuses, shall we?
Pluses:

• Creating novel pathogens might lead to insights in the basic biology of viruses and bacteria.
• Creating hard-to-kill pathogens might help us develop better anti-virals and anti-bacterials, although more effective strategies already exist.

Minuses:

• The viruses could accidentally escape, and millions of people could die.
• The viruses could get into the wrong hands, and millions of people could die.

I don't know about you, Dr. Collins, but I'm leaning towards banning such research permanently.

Research on artificially engineered flu strains expected to kill 2000 people per year

2,000 deaths expected for each year of research on how to turn avian flu into a more deadly virus. 

That’s the estimate in a new analysis by Harvard University’s Marc Lipsitch, professor and director of the Center for Communicable Disease Dynamics in the Harvard School of Public Health.

I heard Lipsitch present his results at an invitation-only hearing held at the National Academy of Sciences on December 15. The purpose of the two-day meeting, which was organized by the National Science Advisory Board for Biosecurity (NSABB), was to discuss the risks and benefits of “gain of function” research on viruses, especially the influenza virus.

What is gain-of-function (GOF) research? In this context, GOF means experiments designed to give a pathogen new powers, such as the ability to infect new species, or to jump from person to person more easily. Scientists have already conducted GOF experiments on the flu virus, and now they are considering other viruses including SARS and MERS.

What prompted the NSABB hearing was the series of experiments by researchers in the U.S. and the Netherlands designed to transform avian influenza (or “bird flu”) into a human-transmissible virus. These novel, lab-created flu strains have the potential to cause a worldwide pandemic. When virologists Ron Fouchier and Yoshi Kawaoka first published their experiments two years ago, the public, the press, and many members of the scientific community (including me; see here and here) expressed serious alarm. After a brief hiatus, though, the experiments continued. 

In mid-October, the U.S. government announced a “pause” in gain-of-function experiments, which has Fouchier, Kawaoka, and their colleagues very upset.

At the NSABB meeting in December, the vast majority of panelists were influenza researchers defending GOF research, arguing that it could lead to valuable insights about the flu. As a group, they seem to have convinced themselves that everything is fine, and they want to tell the rest of us that there’s nothing to worry about. Prof. Lipsitch (and a couple of other speakers) stood out as a voice of reason. He was one of the very few scientists who took a hard look at the risks and also pointed out alternative, low-risk methods for answering the same scientific questions.

Lipsitch conducted a careful risk analysis (something apparently not even considered by Fouchier and Kawaoka) looking at the chances of a virus escaping a lab, of such a virus causing further infections, the likely number of fatalities, and more. It turns out that the scientific community has excellent data quantifying all the key variables involved, as Lipsitch documented. He and his colleague Tom Inglesby just published these figures, with supporting data, in the journal mBio.

Using conservative estimates, many of them provided by influenza researchers themselves, Lipsitch calculated that for each year of gain-of-function research on pandemic viruses, we can expect at least 2,000 fatalities worldwide. And that’s only the low end: at the other extreme, this estimate rises to 1.4 million fatalities per year.

Lipsitch also described many other ways to study and defeat influenza, all of them with little or no risk, which he’s published in the journal PLoS Medicine. His point is that even if we accept the supposed benefits of GOF research, there are far less risky ways to obtain those same benefits.

One of the most ironic–or outrageous–claims of the pro-GOF scientists is that these experiments will help us predict future pandemic flu strains, and even help us design a vaccine in advance of outbreaks. The irony is that this year, the seasonal flu vaccine is a poor match to the strains that are circulating. This vaccine was chosen only 9 months ago, based on extensive surveillance of circulating flu strains, demonstrating how difficult it is to predict even the regular seasonal flu. As a result, we’re having a very bad flu season this year (aside: it's still worth getting the flu vaccine).

During the discussion at the NSABB meeting, an audience members observed that the claims of Fouchier, Kawaoka, and other pro-GOF scientists is hubris. She pointed out that not only are they claiming that they can predict future outbreaks–which no one has ever done accurately–but that we should invest billions of dollars stockpiling specially-designed vaccines based on their predictions. (This was indeed suggested by one of the presenters.) 

2000 deaths per year. And that’s only the direct risk: what about the risk from publishing these experiments? What happens when we provide instructions on how to build deadly biowarfare agents to anyone with an internet connection? Indeed, “gain of function” research on pandemic pathogens is really biowarfare research, which supposedly ended after the Cold War.

I’m a huge supporter of biomedical research and of NIH in general. NIH research has yielded tremendous benefits to the public health, as I’ve written before. We don’t need to overreact by cutting medical research in general, but we can make the “pause” in gain-of-function research permanent. There are far better things to do with our research funds. If you want to register your concerns, write to the NSABB at nsabb@od.nih.gov and tell them to recommend a permanent halt to gain-of-function research on pathogenic viruses.

Why Google Flu is a failure: the hubris of big data

It seemed like such a good idea at the time.

People with the flu (the influenza virus, that is) will probably go online to find out how to treat it, or to search for other information about the flu. So Google decided to track such behavior, hoping it might be able to predict flu outbreaks even faster than traditional health authorities such as the Centers for Disease Control (CDC).

Instead, as the authors of a new article in Science explain, we got "big data hubris."  David Lazer and colleagues explain that:

“Big data hubris” is the often implicit assumption that big data are a substitute for, rather than a supplement to, traditional data collection and analysis.

The folks at Google figured that, with all their massive data, they could outsmart anyone.

The problem is that most people don't know what "the flu" is, and relying on Google searches by people who may be utterly ignorant about the flu does not produce useful information. Or to put it another way, a huge collection of misinformation cannot produce a small gem of true information. Like it or not, a big pile of dreck can only produce more dreck. GIGO, as they say.

Google's scientist first announced Google Flu in a Nature article in 2009. With what now seems to be a textbook definition of hubris, they wrote:

"...we can accurately estimate the current level of weekly influenza activity in each region of the United States, with a reporting lag of about one day."

They obtained this remarkable accuracy entirely from analyzing Google searches. Impressive - if true.

Ironically, just a few months after announcing Google Flu, the world was hit with the 2009 swine flu pandemic, caused by a novel strain of H1N1 influenza. Google Flu missed it.

The failures have continued. As Lazer et al. show in their Science study, Google Flu was wrong for 100 out of 108 weeks since August 2011.

One problem is that Google's scientists have never revealed what search terms they actually use to track the flu. A paper they published in 2011 declares that Google Flu does a great job. The official Google blog last October makes it appear that they do an almost perfect job predicting the flu for previous years.

Haven't these guys been paying attention? It's easy to predict the past. Does anyone remember the University of Colorado professors who had a model that correctly predicted every election since 1980? In August 2012, they confidently announced that their model showed Mitt Romney winning in a landslide. Hmm.

Flu cases this year, which are dominated by H1N1.

A bigger problem with Google Flu, though, is that most people who think they have "the flu" do not. The vast majority of doctors' office visits for flu-like symptoms turn out to be other viruses. CDC tracks these visits under "influenza-like illness" because so many turn out to be something else. To illustrate, the CDC reports that in the most recent week for which data is available, only 8.8% of specimens tested positive for influenza.

When 80-90% of people visiting the doctor for "flu" don't really have it, you can hardly expect their internet searches to be a reliable source of information.

Google Flu is still there, and you can still look at its predictions, even though we know they are wrong. I recommend the CDC website instead, which is based on actual data about the influenza virus collected from actual patients. Big data can be great, but not when it's bad data.

Scientists are creating a dangerous flu strain, just to prove they can

In an outrageous display of chutzpah, a group of flu researchers led by Ron Fouchier of Erasmus Medical Center in the Netherlands announced today, in a letter to the journal Nature, that they were planning to engineer the new H7N9 avian flu strain to give it new, possibly much more deadly capabilities.  Fouchier is the same scientist who, two years ago, adapted the highly pathogenic H5N1 flu strain so that it could be passed from human to human, which it cannot do in its natural form.  The resulting outcry delayed publication of his paper, but it eventually did appear.

Now they want to do the same thing, and much more, with the new H7N9 influenza virus, which has killed 43 people in China to date, and which epidemiologists are tracking with great concern.

They should track Fouchier and his lab instead.

Wait a second, protests Fouchier.  He promises that

"All experiments proposed by influenza investigators are subject to review by institutional biosafety committees. The committees include experts in the fields of infectious disease, immunology, biosafety, molecular biology and public health; also, members of the public represent views from outside the research community."

Sorry, but I'm not reassured.  Fouchier's group wants to do this research because it's all they know how to do - and, I suspect, because they enjoy the publicity.  Despite their claims that the research is vital to our understanding of the flu, none of their past work, including their work on H5N1, has changed our ability to respond to a pandemic.  As flu expert Michael Osterholm said in a report by the Associated Press:

"H5N1 surveillance is as haphazard today as it was two years ago. Should we do the work if it's not actually going to make a difference?"

Precisely.  Fouchier and his colleagues can't do surveillance, nor do they work on vaccine development.  They have laboratories where they can engineer the flu virus to make new strains, so that's what they want to do. Two years after their controversial H5N1 experiments, they haven't contributed to any improvement in our ability to control a pandemic, nor have they shown how to develop a better flu vaccine.  The benefits of creating a deadly new H7N9 virus are marginal, at best.

What about the risk? As reported in the Daily Mail, Fouchier and his colleague Yoshihiro Kawaoka themselves said

"H7N9's pandemic risk would rise 'exponentially' if it gained the ability to spread more easily among people."

Really?  And from this they conclude that it's a good idea to engineer a virus that can do exactly that - spread more easily among people? Are we supposed to take this risk because of some theoretical benefit from a vague "better understanding" of how mutations in the virus change its pathogenicity?

Although Fouchier is in Rotterdam, the NIH funds part of his work through the National Institute of Allergies and Infectious Diseases (NIAID).  Dr. Anthony Fauci, the head of NIAID, offered the reassurance that a special panel will review this H7N9 project, and

"If the risk is felt to be too high by this outside review, they will recommend it won't be done and we won't fund it."

Despite this additional oversight, I remain skeptical. These special panels tend to include other scientists who are very sympathetic with the work they're reviewing, as was demonstrated two years ago when the H5N1 work was published despite the grave concerns expressed by many outside the field.  I predict they will approve Fouchier and Kawaoka's experiments.

Here's a thought: put me on the panel: I've published multiple research papers on the influenza virus (including this paper in Nature and this paper on H5N1 avian flu), so I think it's fair to say I'm qualified.  But somehow I doubt they will do that.