Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

December 24th, 2009

Pandemic flu and disease

It’s been a busy couple weeks, and tomorrow we’re heading out for a week’s vacation. I don’t know what my internet access will be like, but probably not too good, so this might be the last Mystery Rays post for 2009.

Quick notes from a series of articles in New England Journal of Medicine on disease caused by the pandemic swine-origin influenza virus:

… the majority of those infected have a mild illness. The typical period during which the virus can be detected with the use of real-time RT-PCR is 6 days (whether or not fever is present). The duration of infection may be shortened if oseltamivir is administered1

I bolded the part about oseltamivir (Tamiflu) because of the recent controversy (see the Avian Flu Diary, here and here) about Tamiflu’s effectiveness.

But even though the pandemic is usually mild, several groups are at unusual risk:

2009 H1N1 influenza can cause severe illness and death in pregnant and postpartum women; regardless of the results of rapid antigen testing, prompt evaluation and antiviral treatment of influenza-like illness should be considered in such women. The high cause-specific maternal mortality rate suggests that 2009 H1N1 influenza may increase the 2009 maternal mortality ratio in the United States. 2

And:

Pandemic 2009 H1N1 influenza was associated with pediatric death rates that were 10 times the rates for seasonal influenza in previous years … Most deaths were caused by refractory hypoxemia in infants under 1 year of age (death rate, 7.6 per 100,000). 3

There’s an emerging sense that much of the young-person mortality associated with the pandemic flu4 is due fairly directly to the virus itself, rather than to subsequent bacterial infection.   That was probably not true for the 1918 influenza pandemic, where bacterial infections were a major part of the high mortality rates:

… bacterial infections, especially pneumococcal infections, were a major cause of influenza- associated pneumonia and death among both military personnel and civilians in 1918–1919. The distribution of pneumococcal serotypes shifted toward less invasive serotypes during that period as compared with the pre-1918 period, suggesting that the 1918 influenza virus increased host susceptibility to less-invasive pneumococci.5

And, as the authors note, underdeveloped countries may have higher mortality from the present pandemic, if there’s more risk of bacterial superinfection.


  1. Cao, B., Li, X., Mao, Y., Wang, J., Lu, H., Chen, Y., Liang, Z., Liang, L., Zhang, S., Zhang, B., Gu, L., Lu, L., Wang, D., Wang, C., & , . (2009). Clinical Features of the Initial Cases of 2009 Pandemic Influenza A (H1N1) Virus Infection in China New England Journal of Medicine, 361 (26), 2507-2517 DOI: 10.1056/NEJMoa0906612[]
  2. Janice K. Louie, Meileen Acosta, Denise J. Jamieson, Margaret A. Honein, & for the California Pandemic (H1N1) Working Group (2009). Severe 2009 H1N1 Influenza in Pregnant and Postpartum Women in California New England Journal of Medicine[]
  3. Romina Libster, & et al. (2009). Pediatric Hospitalizations Associated with 2009 Pandemic Influenza A (H1N1) in Argentina New England Journal of Medicine[]
  4. At least, in those places where autopsies have been consistently performed; which is biased against underdeveloped countries[]
  5. Chien, Y., Klugman, K., & Morens, D. (2009). Bacterial Pathogens and Death during the 1918 Influenza Pandemic New England Journal of Medicine, 361 (26), 2582-2583 DOI: 10.1056/NEJMc0908216[]
December 16th, 2009

On cancer genomes

Wellcome: Cigarette poster

We’re just dipping our toes into the oceans of information from large-scale genome sequencing. We’re at the point now where sequencing a human genome is, not routine, but not extraordinary. The most recent examples of this are two groups who sequenced the genome of a cancer (one group did a lung cancer, the other did a melanoma), and compared to the person’s normal cells. 1   This lets you see where the cancer cells are mutated.

How many mutations are there in a cancer? We already know that cancer is a multi-step process, involving probably at least 7 or 8 distinct stages. We also know that cancer cells have far more mutations than are needed for these minimals steps. How many is “more”?

  • Over 20,000 mutations – 23,000 mutations in the lung cancer, 33,000 in the skin cancer.

Where did these mutations come from? What drives mutagenesis in a cancer cell?

  • Cigarettes and UV light. They can point out the typical kinds of mutagenesis for each and show that the lung cancer mutations are tobacco-induced, the skin cancer mutations are UV-induced.

How often do cigarettes cause mutations?

  • “… an average of one mutation for every 15 cigarettes smoked.”

(I question this figure, or rather, question whether the implied causation is that direct. But it’s not impossible, given their data.)  From an immunological viewpoint, the 20,000 mutations is interesting because it suggests that cancers should have lots of targets for the immune system. This was already pretty clear, but this helps nail it down.

(By the way, the poster at the top, like the research in question, comes from the Wellcome Trust Institute.)


  1. Pleasance, E., Stephens, P., O’Meara, S., McBride, D., Meynert, A., Jones, D., Lin, M., Beare, D., Lau, K., Greenman, C., Varela, I., Nik-Zainal, S., Davies, H., Ordoñez, G., Mudie, L., Latimer, C., Edkins, S., Stebbings, L., Chen, L., Jia, M., Leroy, C., Marshall, J., Menzies, A., Butler, A., Teague, J., Mangion, J., Sun, Y., McLaughlin, S., Peckham, H., Tsung, E., Costa, G., Lee, C., Minna, J., Gazdar, A., Birney, E., Rhodes, M., McKernan, K., Stratton, M., Futreal, P., & Campbell, P. (2009). A small-cell lung cancer genome with complex signatures of tobacco exposure Nature DOI: 10.1038/nature08629

    Pleasance, E., Cheetham, R., Stephens, P., McBride, D., Humphray, S., Greenman, C., Varela, I., Lin, M., Ordóñez, G., Bignell, G., Ye, K., Alipaz, J., Bauer, M., Beare, D., Butler, A., Carter, R., Chen, L., Cox, A., Edkins, S., Kokko-Gonzales, P., Gormley, N., Grocock, R., Haudenschild, C., Hims, M., James, T., Jia, M., Kingsbury, Z., Leroy, C., Marshall, J., Menzies, A., Mudie, L., Ning, Z., Royce, T., Schulz-Trieglaff, O., Spiridou, A., Stebbings, L., Szajkowski, L., Teague, J., Williamson, D., Chin, L., Ross, M., Campbell, P., Bentley, D., Futreal, P., & Stratton, M. (2009). A comprehensive catalogue of somatic mutations from a human cancer genome Nature DOI: 10.1038/nature08658 []

December 14th, 2009

Influenza before 1918, part II: 1872

In 1872, a pandemic influenza outbreak brought the US to its knees:

“The streets are almost deserted.” –Washington, D.C.

“A Sunday quiet prevails upon the streets.” –Springfield, OR

“The streets yesterday looked deserted.” –San Francisco, CA

“The street cars have stopped.” – Erie, PA 1

And yet, if you look at the mortality rates for influenza in 1872, it’s not a particularly impressive year — if anything, the influenza death rates were exceptionally low that year.  At least, they were low in humans.  1872 brought a pandemic equine influenza, laying low almost every horse in North America.

On the evening of October 21st only a few animals were affected, but on the morning of the 22d there was scarcely an animal of the equine species that was not affected.  Horses, mules, and even a zebra.  More than twenty thousand were suffering in different degrees. 2

An estimated 3-4% of the tens of thousands of horses in New York died. 2 But the deaths weren’t the biggest problem:

The actual money losses, in an epizootic of influenza, are more in the way of the loss of work and the complete stagnation of trade in all departments, than in the number of deaths.  Yet even in this sense it may prove more ruinous than would a disease having a less universal away though far more fatal to the animals attacked. 3

Without horses, business slammed to a halt; the mail didn’t run, groceries didn’t reach the cities, crops weren’t harvested or transported.  After a few weeks, most of the horses recovered and business followed, but the epizootic swept across the country1  (intensely tracked by the newspapers of the day, warning each city in turn that it was going to be attacked), finally fizzling out the following summer in British Columbia.

Equine influenza map, 1872


  1. Adoniram B. Judson, MD (1873). History and Course of the Epizootic Among Horses Upon the North American Continent in 1872-1873. Public Health Papers and Reports. American Public Health Association. Hurd and Houghton, New York, 88-109[][]
  2. Annual report of the Department of Health of the State of New Jersey. By The New Jersey State Dept. of Health, 1877 (“Epizootic influenza”, p. 160)  [][]
  3. Text book of veterinary medicine, Volume IV.  By James Law, F.R.C.V.S.  1906 []
December 9th, 2009

Are flu vaccines effective in the elderly?

Influenza vaccine

There’s been a fair bit of discussion online about the new study in the British Medical Journal1  throwing doubt on Tamiflu’s effectiveness against influenza.  (If you haven’t already seen this, see the Avian Flu Diary for an excellent summary of the situation, and an update here.2 Also see the CDC’s recommendations for antivirals here.)

There’s a new paper3 that takes a similar skeptical look at the effectiveness of influenza vaccines in the elderly (I emphasize, the question is how well the vaccines work in the elderly; as far as I know there’s general agreement that the flu vaccines work reasonably well in younger people and children).  It’s long been agreed that flu vaccines don’t work as well in elderly people as they do in the young.  This is a real concern, because it’s also generally agreed that seasonal influenza takes its greatest toll on people over 65 years or so. 4

However, while it’s been agreed that flu vaccines don’t work as well in the elderly, this new paper suggests the situation is even worse than we thought; and in fact the vaccine may hardly work at all (in the elderly!).  The authors argue that the apparent benefits of vaccination, as previously detected, aren’t real; they’re the result of bias in vaccination.  That is, it’s not the people who are vaccinated don’t die of flu; rather, people who aren’t going to die of flu, are the ones who get vaccinated. Correlation is not causation:

Because persons who are most likely to die are less likely to receive the vaccine, vaccination appears to be associated with a much lower chance of dying; thus, the “effectiveness” of the vaccine is in great part due to the selection of healthier individuals for vaccination, rather than due to true effectiveness of the vaccine.3

They offer a number of possible reasons for this bias — perhaps the most frail people don’t get to vaccine clinics; perhaps doctors try harder to have their most energetic patients vaccinated; perhaps those people on the verge of death don’t want further intervention.  I don’t have the statistical chops to critique their analysis in detail, but from what I do follow it seems well supported.  I’d like to see more work on this, because it obviously has huge, huge implications for vaccination policy and vaccination research.

We hope this knowledge will stimulate research into better vaccines for elderly patients (perhaps by use of higher doses or adjuvants) and will lend more weight to the importance of vaccinating schoolchildren to prevent disease in the rest of the population.3

Even if this suggestion eventually doesn’t hold up, it’s a really important message: Always be skeptical.

By the way, I and my family got the H1N1 vaccine last night (even though I read this article last week some time), so I’m walking the walk as well as talking the talk.


  1. Jefferson, T., Jones, M., Doshi, P., & Del Mar, C. (2009). Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ, 339 (dec07 2) DOI: 10.1136/bmj.b5106
    Also see the editorial:
    Godlee, F., & Clarke, M. (2009). Why don’t we have all the evidence on oseltamivir? BMJ, 339 (dec08 3) DOI: 10.1136/bmj.b5351[]
  2. And if you’re not reading AFD already, why aren’t you?[]
  3. Baxter, R., Lee, J., & Fireman, B. (2009). Evidence of Bias in Studies of Influenza Vaccine Effectiveness in Elderly Patients The Journal of Infectious Diseases DOI: 10.1086/649568[][][]
  4. The biggest difference between this H1N1 pandemic influenza this year and seasonal flu is in the age groups at risk.  Normally, seasonal influenza causes death almost entirely in the older people.  This year, older people are relatively, though not absolutely, not being killed by influenza, while younger people are.  So while it’s true that the mortality rate due to the new swine-origin influenza virus isn’t really higher than usual, and may even be lower, that mortality is clustered in an unfamiliar group — young people, and children, who normally are at essentially no risk of flu-caused death.[]
December 8th, 2009

Malaria and mosquitoes: Not 1908, not Cuba

A couple of days ago I posted this map of malaria in the USA. It got picked up by Grant Jacobs, who made some interesting and useful comments, and that in turn got picked up by someone who posted it to boingboing.net.  Unfortunately, whoever wrote it up for boingboing tried to add some value by offering a couple of points on the history of malaria, both of which were wrong. 1 In particular, he claimed that “It wasn’t until 1908 that a Cuban doctor made the connection with mosquitoes”.  To set the record straight:

RECENT researches by Surgeon Major Ronald Ross have shown that the mosquito may be the host of parasites of the type of that which causes human malaria. Ross has distinctly proved that malaria can be acquired by the bite of a mosquito, and the results of his observations have a direct bearing on the propagation of the disease in man. Dr P. Manson describes the investigations in a paper in the British Medical Journal, and sums them up as follows: –The observation tend to the conclusion that the malaria parasite is for the most part a parasite of insects; that it is only an accidental and occasional visitor to man; that not all mosquitos are capable of subserving it; that particular species of malaria parasites demand particular species of mosquitos; that in this circumstance we have at least a partial explanation of the apparent vagaries of the distribution of the varieties of malaria. When the whole story has been completed, as it surely will be at no distant date, in virtue of the new knowledge thus acquired we shall be able to indicate a prophylaxis for malaria of a practical character, and one which may enable the European to live in climates now rendered deadly by this pest.

Nature, Sept. 1898.  p. 523

The earliest probable reference I can find2 is from 1896:
The Goulstonian Lectures on the Life History of the Malaria Germ Outside the Human Body. P. Manson. The British Medical Journal, 1896

Update: I just realized what the boingboing.net poster had in mind with his comment that “It wasn’t until 1908 that a Cuban doctor made the connection with mosquitoes”: He was thinking about yellow fever, a virus rather than a parasite. Here and there about the web it’s suggested that yellow fever was shown to be mosquito-borne, in 1908, by a Cuban doctor, Carlos Finlay.  Unfortunately that’s also not correct; it probably was originally a typo somewhere that got spread around.

Finlay (who was, I believe, American, though he worked in Cuba) originally published his observations in 18813 and then in English in 18891886.4  His theory wasn’t immediately accepted, but by 1900 it was confirmed by a medical commission that included the famous Walter Reed.


  1. Also, he didn’t credit me, which is probably for the best, since my pathetic hosting would have undoubtedly crashed[]
  2. I haven’t read the text of this yet[]
  3. C. Finlay. El mosquito hipoteticamente considerado como agente de trasmislon de la flebre amarllla. An. de la Real Academia de ciencias med. … de la Habana, vol. 18, pp. 147-169 (Aug 14 1881) []
  4. C. Finlay. Yellow Fever, its transmission by means of the Culex mosquito. Am. Journ. Med. Sci. vol. 92, pp. 395-409 (1886) []
December 7th, 2009

Influenza before 1918

The huge 1918 influenza pandemic, caused by the great-grandfather of today’s swine-origin pandemic H1N1, wasn’t the first time influenza was seen in people — not by a couple of thousand years. 1 Seasonal flu was around before it, just as it has been since; and epidemics and pandemics regularly swept through the world before 1918.

The charts below, published in 1921,2 show  completely modern-looking patterns of influenza.

Note the 1890/91 pandemic of “Russian flu”: 3

Within the space of a few weeks in 1890 this disease prostrated hundreds of thousands in Europe and America, enormously increasing the death rate, and leaving many of its surviving victims in a condition of pronounced debility for many months.  For a time it closed factories and workshops, it checked business, and obstructed the prosecution of many enterprises. 4

Influenza - England and Wales, 1845 (Vaughn)

But also note the classic seasonal peaks before and after 1890:

Influenza - Massachusetts, 1887 (Vaughn)

In spite of all we’ve learned about influenza since 1845, we haven’t been able to do much to change its patterns.


  1. Stephen Dando-Collins, in “Caesar’s Legion: The Epic Saga of Julius Caesar’s Elite Tenth Legion and the Armies of Rome“, cites claims that influenza kept many of Julius Caesar’s legions from sailing to his assistance during his civil war with Pompey the Great, in 49 BC[]
  2. Warren T. Vaughn (1921). Influenza: An Epidemiologic Study The American Journal of Hygiene Monographic Series[]
  3. So-called in Western Europe; but the Russians called it “Siberian Fever”, and Siberians called it “Chinese Distemper”.  It supposedly originated in Bokhara, in present-day Uzbekistan, according to Encyclopaedia Medica, Volume V. By Chalmers Watson. New York, Longmans, Green, & co. 1900 []
  4. The Cottage Physician. For Individual and Family Use.  King-Richardson Publishing Co., Springfield, MA 1897[]
December 5th, 2009

Malaria in the USA, 1870

From the Library of Congress “Digital History” collection. (Click for a larger version)

Malaria in the USA, 1870

The legend shows increasing shades of red as

<100 per 10,000 deaths from all causes
100:250
250:350
550:900
900:1400
1400

December 3rd, 2009

Gone in 60 (milli)seconds

Gone in 60 (milli)seconds

Intracellular proteins have to be degraded, more or less at the same rate as new proteins are produced (or the cell would eventually burst). On the other hand, you can’t go about degrading proteins willy-nilly.  There are vast and complex systems for identifying proteins that should be destroyed, tagging them, and then moving them into a controlled destruction chamber.

The most important of these systems is the ubiquitin-proteasome degradation pathway.  Proteins that are destined for destruction are tagged with a chain of ubiquitin molecules.1  There are multiple steps in this pathway, in which ubiquitin is prepared for tagging, target proteins are identified, and ubiquitin is transferred from the activating components to the targeted protein.

Target proteins are destroyed when a chain of ubiquitin molecules (head to tail) are attached to them. An unanswered question has been how this works. Is the ubiquitin chain formed first, and then transferred to the target en bloc? Or are single ubiquitin transferred one at a time, sequentially, first to the target protein and then to the previously-attached ubiquitins?  The problem has been that the process goes so fast that it’s been hard to distinguish between the possibilities.

Now, in a gorgeous series of experiments, Pierce et al2 were able to watch ubiquitination happening over fractions of a second:

… we performed our single-encounter reactions on a quench flow apparatus that allowed us to take measurements on a timescale ranging from 10 ms to 30 s2

And the answer looks pretty clear: Ubiquitins are transferred sequentially, not en bloc.

Even at this timescale, though, they weren’t able to catch the very first event — the transfer of the first ubiquitin to the target.  That happens, apparently, in less than 10-20 milliseconds.  They also draw the conclusion that target tagging is critically dependent on the kinetics of ubiquitin chain elongation (as you’d expect) which are governed by ubiquitin off-rates, and this mode of regulation is probably a billion years old.

Pierce et al (2009) Fig. 3d: Ubiquitin addtion

Figure 3d: Kinetics of ubiquitin addition and elongation2(Click for a larger version)


  1. Ubiquitin being a small, abundant protein[]
  2. Pierce, N., Kleiger, G., Shan, S., & Deshaies, R. (2009). Detection of sequential polyubiquitylation on a millisecond timescale Nature, 462 (7273), 615-619 DOI: 10.1038/nature08595[][][]
December 2nd, 2009

What causes antigenic drift?

Hemagglutinin (HA) crystal structure
HA structure showing mutating amino acids1

Anyone who’s taken a virology class, and many who haven’t, know about “antigenic drift” and “antigenic shift”. These are usually used to explain influenza virus changes over time (although of course the same concepts apply to many other viruses). Antigenic shift refers to large, abrupt changes in the virus;2 antigenic drift refers to smaller changes. Antigenic shifts are associated with pandemic influenza, as the pre-existing immune responses to influenza from previous years aren’t protective any more (because the virus has shifted away from them). Antigenic drift doesn’t let the virus escape immune control altogether, but does give the virus an advantage in infecting people — presumably, people with strong responses are still protected, but those whose exposure was maybe a few years ago, or who happened to make a weaker antibody response, to the previous virus, would be susceptible to the new virus but protected against the original. Antigenic drift happens all the time, and new drifted variants of influenza take over every year or two, which is why we need new seasonal flu vaccines on a regular basis.

What drives antigenic drift? The simple answer is that it’s driven purely by immunity. According to this notion, viruses that are resistant to being neutralized by antibody are most able to replicate and transmit to new hosts. Jon Yewdell’s group, however, has just revisited antigenic drift,1 and propose a somewhat different model: Antigenic drift is the result of viruses cycling between immune and non-immune hosts, and it’s almost a side effect of the way the virus interacts with cells.  (Unusually for Jon, I don’t htink he coined any new and exciting acronyms for his new model.)

Model for antigenic drift
Model for antigenic drift selection (click for larger version)1

Normally, influenza virus doesn’t “want” to bind very strongly to its cellular target, 3 because then it’s harder for newly-formed viruses to escape from the cell (because it binds to the receptors on the way out, as well). But in the presence of neutralizing antibody, the virus needs to bind more strongly to the receptor to overcome the effects of antibody binding. Yewdell’s group argue that it’s this whip-saw effect that pushes long-term changes in antigenicity:

Thus, antigenic drift can be a by-product of Darwinian selection for mutations that optimize host cell receptor binding during influenza A virus transmission between immune (increased receptor binding) and naïve individuals (decreased receptor binding). 1

One difference between Jon’s model and the standard concept is that with the latter, you’d expect that there would be more antigenic drift as immunity increases among the population. Yewdell’s model, though, predicts that sequential passage through immune and non-immune individuals drives antigenic drift. This actually leads to an important prediction:

In our model, antigenic drift is accelerated by sequential passage of influenza A virus between immune and nonimmune individuals, which in the human population are nearly all children. Therefore, decreasing the naïve population size by increasing pediatric influenza A virus vaccination rates will likely slow antigenic drift and temporally extend the effectiveness of influenza vaccines.1

(My emphasis.)  They also point out that, because changes in antigenicity run in parallel with changes in receptor binding affinity, antigenic drift can itself could be pushing other changes in virus personality. That’s because the drift changes push changes in receptor binding, which in turn alters the cells to which the virus can interact; and changing the cells that the virus infects will inevitably change the nature of an infection as well. For example, does the virus best infect cells of the upper respiratory tract — leading to coughs and sniffles — or the lower respiratory tract — leading to pneumonia.


  1. Hensley, S., Das, S., Bailey, A., Schmidt, L., Hickman, H., Jayaraman, A., Viswanathan, K., Raman, R., Sasisekharan, R., Bennink, J., & Yewdell, J. (2009). Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift Science, 326 (5953), 734-736 DOI: 10.1126/science.1178258[][][][][]
  2. “Changes” here mean changes in the ways the immune system responds to the virus — hence, “antigenic” changes. In practice, the changes are antibody-based changes, although in principle antigenic shift and drift could also refer to T cell-based recognition.[]
  3. The influenza hemagglutinin, HA, protein binds to sialic acid on cells of the respiratory system.[]
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