Field of Science

Resistance is inevitable

Today’s Washington Post has an article by David Brown reporting on an alarming upsurge in the number of cases of tuberculosis that are resistant to some or all known antibiotics. The headline is that 5% of TB cases are now drug resistant, but the substance is much more alarming. In some regions of the former Soviet Union, drug-resistant TB accounts for 20% of cases, and the true rates might be even higher. These TB strains are not only drug resistant, but deadly: as David Brown reports, the death rate in untreated cases is “close to 100 percent.” 100% mortality is truly frightening.

Why should we worry about this? Well, there are (at least) two reasons:
1. Spread is inevitable. The countries of the former Soviet Union, where these new TB strains are spreading, are no longer isolated from the rest of the world. Humans travel freely among all countries now. And tuberculosis doesn’t make everyone sick – some people can carry it without knowing that they have it. A major TB outbreak could pop up anywhere before we even realize that a carrier has been spreading the disease.

2. Resistance is inevitable. The Borg on Star Trek: TNG liked to warn their targets, “resistance is futile.” In the world of infectious diseases, though, we have a different saying, thanks to Mark Crislip of Quackcast: resistance is inevitable. What that means is that whenever we come up with a new drug, the bacteria or viruses will inevitably develop resistance to it. For the bacteria, resistance is not futile – it’s an extremely effective way to survive. Multi-drug resistant (MDR) TB, which is resistant to the two most commonly used drugs, rifampin and isonizid, is spreading rapidly. Even worse, a new strain of “extremely” drug-resistant (XDR) TB is resistant to those two drugs plus two others, leaving basically no effective means of treatment.

I was surprised to read in Brown’s article that Mario Raviglione, the head of the WHO’s tuberculosis department said that the rate of multi-drug resistant infections “wouldn’t go over 10 percent.” I guess he’s much more optimistic than I am. I wouldn't be surprised if the rate went to 50% or even higher. Whenever we get a new drug, we use it – of course. But when we use it, we begin the evolutionary process of selection in favor of drug-resistant strains. Unless you can make sure that every patient is completely cured – an unrealistic goal – then some amount of resistance will begin to emerge.

In the 19th and early 20th centuries, TB was a scourge of all civilized countries. Countless millions, including many famous authors and artists, died of TB (including Balzac, the Bronte sisters, Camus, Kafka, Keats, Thomas Wolfe, and many more). Most of us probably assume that era will never return – but it might. What can we do to prevent it? We need better surveillance of the TB strains now spreading, and even more urgently, we need new drugs. I think that our government(s) should develop these drugs, rather than leaving it to the whims of private companies, but that puts me in a rather small minority here in the U.S. Our best hope for new drugs right now is probably the Gates Foundation, which has made combating TB and malaria its top two priorities. In a much smaller way, everyone can do their part by warning others against the mis-use and overuse of antibiotics. We can’t stop the spread of drug resistance, but at least we can slow it down.

Lament from a flu outsider

Dear CDC,
Oh, if only you wouldn’t spurn me. Don’t you know we both want the same thing? Like you, I want the flu vaccine to work. I want everyone to get their flu shots. I know I’m an outsider, but maybe you could at least listen to my ideas? Is it my fondness for sequencing over serotyping? Or maybe my insistence that you should share all your sequencing data? Why not invite everyone to the party? It’d be much more fun. And think of all the flu viruses we could keep out.
The news this week has been filled with reports of a new flu outbreak around the country. My own university has reported over 400 cases, the worst flu season in many years. Those of you who’ve followed this blog may remember that I predicted this would happen in a November blog post. Part of me wanted to be wrong – I didn’t want a bad flu season – but it turns out I was right.

The CDC had a press conference on Friday (15 February) acknowledging that the vaccine was a bust, but they didn’t explain why they’d chosen an old strain of H3N2 (from 2005!) for inclusion in the vaccine. As I explained in November, they already knew it was a bad choice – or they should have – last year.

So what is happening out there? Well, from the CDC website we can see results from the week of Feb 3-9 (the most recent data they have) summarized in this figure:
The red cases are H3N2, which are clearly dominant. The blue cases are H1N1 (the vaccine works against that strain!), and the yellow are influenza A but not typed as H3 or H1 – most of these are probably H3N2 as well.

The raw numbers for the season tell an even more compelling story of vaccine failure. Out of 65 H3N2 viruses that the CDC has genotyped, only 9 (14%) matched the vaccine strain. The remaining 91% are a new strain, for which the vaccine either limited or zero efficacy. (The CDC doesn't say when those 9 cases appeared, but I'm betting they were early in the season.) A newer, 2007 strain, which they have decided to put into the vaccine for the Southern hemisphere for the 2008 season, should provide far better protection. (The flu season down under occurs in their winter – our summer – so it peaks 6 months after ours, and they can use a newer vaccine.) We’ll get the newer strain in our vaccine next year too, assuming the FDA agrees when they meet next week to decide. Unfortunately it’s too late for this year.

Here’s a proposal to the CDC: release all the sequence data you have from this year’s strains right away, and put it in GenBank. And release any other data you use to pick the strains that go in the vaccine – and do this every year. Then everyone can look at it and double-check your decision about which strain should go in next year’s vaccine. Sure, it might be annoying to have other scientists checking your work. But wouldn’t it be great if researchers – including students – all over the world could look at the flu data and make their own predictions about what strain would dominate next season? The science would only get better.

A stealth attempt to sneak creationism into a peer-reviewed journal

Here’s a strategy I’ve not seen before from the creationism movement. Today I encountered an article in the well-respected journal Proteomics titled “Mitochondria, the missing link between body and soul: Proteomic prospective evidence.” by M. Warda and J. Han. Despite the strange title (what do mitochondria have to do with the soul?), the article appears primarily to be a detailed review of the function of mitochondrial genes and how the proteins interact between the mitochondrion, other organelles, and the nucleus. The article hasn’t yet appeared in print – like many articles, it has been e-published ahead of print and will appear later in the hardcopy edition of the journal. (Thanks to Andrew McArthur for alerting me to this.)

The only hint of something controversial is the statement in the abstract that they will present evidence to “disprove the endosymbiotic hypothesis of mitochondrial evolution that is replaced in this work by a more realistic alternative.” This is a little unusual because review articles usually discuss the literature and sometimes produce summaries, but don’t usually disprove hypotheses or present new work.

So what is this “more realistic alternative”? First, a very brief explanation of what the endosymbiotic hypothesis is: the mitochondrion is a small organelle present in almost all eukaryotic cells (the cells of all organisms that have a nucleus). This category of living things ranges from single-celled creatures like yeast and fungi all the way up to plants and animals. Mitochondria are often called the “energy factories” of cells, and they have their own genome. It’s a small genome, but it contains many essential genes that cells need. Virtually all evolutionary biologists agree that the mitochondrian was originally a free-living bacterium, and that the predecessor to all eukaryotic cells engulfed it about 2 billion years ago. The ancestral mitochondrion then became an endosymbiont: a cell living inside our cells in a mutually beneficial relationship. This theory was first proposed over a century ago, and recent decades have seen a huge amount of evidence accumulate to support it.

Warda and Han don’t disprove the endosymbiotic hypothesis at all. Instead, they make an argument that the coordination between the mitochondrial proteins and those of the nucleus is so complex, and so well orchestrated, that it just can’t be explained by the endosymbiotic model. Then they come out with this stunning assertion:
“Alternatively, instead of sinking into a swamp of endless debates about the evolution of mitochondria, it is better to come up with a unified assumption…. More logically, the points that show proteomics overlapping between different forms of life are more likely to be interpreted as a reflection of a single common fingerprint initiated by a mighty creator than relying on a single cell that is, in a doubtful way, surprisingly originating all other kinds of life.”
A “mighty creator”? In other words, “god did it.” It was quite a shock to see this in a scientific article. This statement, buried as it is in the middle of a long, technical review, very likely slipped past the peer reviewers. (I can’t imagine any decent scientist accepting the article otherwise.) This is basically the same argument that creationists and “intelligent design” proponents have been making for years: that certain processes are just too complicated to have evolved naturally.

Does the article contain any more creationist assertions? Well no, it just jumps back into review mode and continues like that until the end, until the very last paragraph. There, Warda and Han have one more surprise for us. They say that “many controversial questions still need to be answered, e.g., how signaling molecules … precisely translocate from or to mitochondria in a matter of milliseconds while crossing a huge ocean of soluble and insoluble barriers.” Okay, but then they go to say “we still need to know the secret behind this disciplined organized wisdom. We realize so far that mitochondria could be the link between the body and this preserved wisdom of the soul devoted to guaranteeing life.” What the heck does that mean? The mitochondrion as the “wisdom of the soul”?! That’s just nonsense.

Warda and Han have inserted blatant creationist conclusions – not justified in any way in their article – into a peer-reviewed article in a highly respected journal. This is a (clever) stealth attempt to get creationism into the literature. The title of this article should have warned the reviewers, but apparently not enough. If the article appears unchallenged, creationists can point to it and say that creationism is now supported in the scientific literature!

I have already contacted the Editor-in-Chief of the journal Proteomics, and he is looking into this already. Warda and Han’s home institutions (Inje University in Korea and Cairo University in Egypt) and departments should be very concerned about how this paper makes them look, but chances are they don’t even know about it. Since the paper hasn’t appeared yet in hardcopy, maybe there is still time to remove the unscientific nonsense. I hope so.