When worlds collide: Wakefield, ethics, & where I live

The News of the Day is that the British Medical Journal has called Andrew Wakefield’s notorious and notoriously retracted vaccine-MMR study “fraud.” That’s something a lot of people had already figured out, but with the imprimatur of BMJ, I guess this makes it official.

Ah, it takes me back, though. To the time I dined with Andrew Wakefield. To that day that the Lancet issued its full retraction of that horrific, fraudulent trash heap of a paper.  To that satisfying few hours of schadenfreude when the GMC handed down its decision to strip him of his license. To my various other Andy sightings about town. To the real horrors of what he wrought when he did what he did to those children in that study.

I’ve posted a lot about Wakefield on my personal blog, and some of the posts have focused on my anger at his bastardization of science and my musings on how people might feel when they falsify data. They’ve included mapping what the enormity of the alleged conspiracy against him would have to be and breaking down with tongue firmly in cheek his plea to make his book of apologia a bestseller. There was the post that I swore would be My Last Word on Wakefield (it wasn’t).

Finally, there is what I taught my son today. We’re studying science–Science–and we were discussing the qualities that make one a good scientist. Sure, there’s curiosity. Creativity. And…there’s honesty. For that and that alone, I close with my defense of ethics in science, why ethics matter, and why I think someone who perpetrates this level of harm to public health ought to be somewhere away from his comfortable, ultra-expensive home just a stone’s throw from where I live. Preferably a quiet place, perhaps with four bare walls, a place where he can ponder the damages he’s wrought.

Roll over eggs…it’s time for (unrolled) tobacco leaves

Tobacco leaf infected with Tobacco Mosaic Virus. Courtesy of Clemson University - USDA Cooperative Extension Slide Series

Timeline, 2008: If you’ve ever been asked about allergy to egg products before receiving a flu vaccine, you have had a little encounter with the facts of vaccine making. Flu viruses to produce the vaccine are painstakingly grown in chicken eggs because eggs make perfect little incubators for the bugs.

So…many…eggs

There are problems—in addition to the allergy issue—that arise with this approach. First of all, growing viruses for a million vaccine doses usually means using a million fertilized, 11-day-old eggs. For the entire population of the United States, 300 million eggs would be required. Second, the process requires months of preparation, meaning a slow turnaround time for vaccines against a fast-moving, fast-changing disease. Last, if there is anything wrong with the eggs themselves, such as contamination, the whole process is a waste and crucial vaccines are lost.

The day may come when we can forget about eggs and turn to leaves. Plants can contract viral disease just like animals do. In fact, an oft-used virus in some research fields is the tobacco mosaic virus, which, as its name implies, infects tobacco plants. It gives a patchy look to the leaves of infected plants, and researchers use this feature to determine whether the virus has taken hold.

Bitter little avatars of evil used for good?

Tobacco plants themselves, bitter little avatars of evil for their role in the health-related effects of smoking, serve a useful purpose in genetic research and have now enhanced their approval ratings for their potential in vaccine production. Plants have caught the eye of vaccine researchers for quite a while because they’re cheaper and easier to work with than animal incubators. Using plants for quick-turnaround vaccine production has been a goal, but a few problems have hindered progress.

To use a plant to make a protein to make a vaccine, researchers must first get the gene for the protein into the plant. Previous techniques involved tedious and time-consuming processes for inserting the gene into the plant genome. Then, clock ticking, there was the wait for the plant to grow and make the protein. Add in the Byzantine process of obtaining federal approval to use a genetically modified plant, and you’ve got the opposite of “rapid” on your hands.

One solution to this problem would simply be to get the gene into the plant cell cytoplasm for immediate use. It’s possible but involves meticulously injecting a solution with the gene sequence into each leaf. Once the gene solution is in, the plant will transcribe it—copy it into mRNA—in the cell cytoplasm and then build the desired protein based on the mRNA code. But there has been no way to take hand injection to the large-scale production of proteins, including for vaccines.

Age-old vacuum suction =  high-tech high-throughput

To solve this problem, researchers turned to one of our oldest technologies: vacuum suction. They grew tobacco plants to maturity and then clipped off the leaves, which they submerged in a solution. The solution was spiked with a nasty bug, Agrobacterium tumefaciens, a pathogen responsible for the growth of galls, or tumors, on plants. Anyone working in agriculture fears this bacterium, a known destroyer of grapes, pitted fruit trees, and nut trees. But it does have one useful feature for this kind of work: It can insert bits of its DNA into plant cells. The researchers tricked A. tumefaciens into inserting another bit of DNA instead, the code for the protein they wanted to make.

To get the solution close to the cells, the investigators had to get past air bubbles, and that’s where the vacuum came in. They placed the submerged leaves into a vacuum chamber and flipped a switch, and the activated chamber sucked all the air out of the leaves. When the vacuum was turned off, the solution flowed into the now-empty chambers of the leaf, allowing the A. tumefaciens-spiked solution to bathe the plant cells. After 4 days and a few basic protein-extraction steps, the research team had its protein batch. According to the team lead, “any protein” could be made using this process, opening up almost unlimited possibilities and applications for this approach.

Vaccines…or combating bioterrorism?

The technology has come far enough that a US company has taken steps toward manufacturing vaccines using tobacco leaves.  And it appears that the applications go beyond vaccines, as one news story has noted…the tobacco plants might also be used to produce antidotes to common agents of bioterrorism.

Microbes redirect our best-laid plans

Greeks at War (pottery from the British Museum; photo courtesy of Wikimedia Commons)

The madness of King George

Timeline, 2006: It’s not that unusual for disease to alter the course of history–or, history as humans intended it to be. Some scholars believe, for example, that the intransigence of King George III of England arose from his affliction with porphyria, a heritable metabolic disorder that can manifest as a mental problem, with symptoms that include irrational intractability. But it’s rarer for a disease to shift the balance of power so entirely that one nation gains the upper hand over another. Yet that appears to be what happened to the city-state of Athens just before the Peloponnesian Wars of around 430 B.C. The upshot of the wave of disease and the wars was that Sparta conquered Athens in 404 B.C.

Spartans had a little microbial assistance

Sparta may have owed its big win to a small bacterium, Salmonella enterica enterica serovar Typhi, the microbe responsible for typhoid fever. A plague swept across Athens from 430 to 426 B.C., having traveled from Ethiopia to Egypt and Libya before alighting in the Greek city and destroying up to a third of its population. In addition, it brought to a close what became known as the Golden Age of Pericles, a time when Athens produced some of its most amazing and widely recognized art, artists, and philosophers, including Aeschylus, Socrates, the Parthenon, and Sophocles. Pericles was a statesman who oversaw the rebuilding of Athens following the Greek win in the Persian Wars, and he guided the city-state to a more democratic form of rule and away from the dictatorships of the previous regimes. In the process, the city flourished in art and architecture.

And then along came the plague. The Greek historian Thucydides, who chronicled the Peloponnesian Wars, left behind such a detailed account of the plague, its symptoms, and what happened to its victims, that intrigued medical detectives have ever since debated about what might have caused it. Thucydides, himself a plague survivor, vividly described the sudden fever, redness of the eyes, hemorrhaging, painful chest and cough, stomach distress, and diarrhea that ultimately led to death in so many cases. He also mentioned pustules and ulcers of the skin and the loss of toes and fingers in survivors. This litany of symptoms produced many candidate causes, including bubonic plague, anthrax, smallpox, measles, and typhoid fever.

Construction crews yet again uncover something interesting

In the mid-1980s, a construction crew was busy digging a hole for a subway station in the city of Kerameikos when they uncovered a mass burial site. Unlike other Greek burial sites, this one bore marks of hasty and haphazard burials, and the few artefacts that accompanied the bones dated it to the time of the plague that destroyed Athens. Researchers were able to harvest some teeth from the site and analyze the tooth pulp, which retains a history of the infections a person has suffered. They examined DNA sequences from the pulp for matches with suggested microbial agents of the plague, and finally found a match with the typhoid bacterium.

Typhoid Mary: Intent on cooking, ended up killing

One discrepancy between the disease pattern of typhoid fever and that described by Thucydides is the rapidity of onset the Greek historian detailed. Today, typhoid fever, which still infects millions of people worldwide, takes longer to develop in an infected individual, and sometimes never develops at all. People who bear the virus but don’t become ill themselves are “carriers.”

Perhaps the most famous carrier was Typhoid Mary, Mary Mallon, a cook in New York City at the beginning of the 20th century. It is believed that she infected hundreds of people, with about 50 known cases and a handful of deaths being directly associated with her. Typhoid Mary was told not to work as a cook any longer or she would be quarantined, but she simply disappeared for awhile and then turned up under a different name, still working as a cook. After another outbreak was traced to her, she was kept in quarantine for 23 years until she died.

Bisphenol A: multisystem effects

These bottles were produced without BPA in response to concerns about the chemical. Photo via Creative Commons, attributed to Alicia Vorhees, thesoftlanding

Are endocrine disruptors stealing our future?

Endocrine-disrupting compounds are chemicals in the environment—usually compounds that we have introduced—that can alter normal hormone signaling processes. Often, exposure to these compounds has little immediate effect in adult animals, but it can have big effects on organisms during sensitive developmental periods, like embryogenesis. During embryonic development in vertebrates, steroid hormones govern many processes, and the fetal hormone environment is usually carefully calibrated to ensure that these processes go forward normally.

Tiny amounts, big changes

But many compounds disrupt these processes, knocking them off track and resulting in development that is unusual or abnormal. For example, male alligators exposed in the egg to these compounds—which often persist in fatty tissues or yolk—emerge with serious penile abnormalities that can affect their ability to reproduce. The banned pesticide DDT is probably one of the best-known of these compounds, and exposure to it or its metabolites has been shown to disrupt hormone signaling to the point of altering sex development completely.

When we think of hormones, we often think of puberty, the time when hormones seem to govern our every move. When we think of estrogen, we probably think “female” because estrogen has historically been considered the “female” hormone. What you might not know is that estrogen, which is made in the ovaries, is also made in our brains during embryonic development. In mammals, appropriate male development appears to require neural estrogen synthesis. When estrogen synthesis in embryonic mammals is blocked, the males that develop do not exhibit typical male behaviors when they reach reproductive maturity.

Bisphenol A: ubiquitous chemical

Among the compounds that have been identified as endocrine disruptors is bisphenol A (BPA). In the United States, we produce about 2 billion pounds of BPA a year. Previous studies have demonstrated that BPA can disrupt thyroid signaling to the point of affecting the thyroid’s role in appropriate brain development. In addition, BPA has been linked to feminization of reptiles. Some scientists were aware of BPA’s hormone-activity potential as far back as the early twentieth century.

But because no one took that knowledge or its potential seriously—the field of endocrine disruptors is relatively young—BPA has found its way into almost every aspect of our lives. It is in the dental sealants we put on our teeth to keep the cavities at bay. It is in the lining that coats the insides of food cans to keep the metal from rusting. It is in the hard plastic that we use for baby bottles and teething rings. And it can leach from these products into the food that we eat. BPA is found at high levels in some pregnant women, and it appears to accumulate in higher concentrations around the umbilical cord and in the fetal amniotic fluid.

BPA and effects on the developing brain

Work from Yale and from researchers in Japan also points to some potentially serious effects on the brain. Part of the role of estrogen in brain development is facilitating synaptic connections in a crucial brain area called the hippocampus. The hippocampus is the center where neurons organize that will later be activated to produce sex-appropriate activity in vertebrates. It is also the area of the brain involved in the formation and retention of memory.

The researchers found that small doses of BPA—doses that fall within EPA-approved levels for exposure—can inhibit hippocampal synaptic formation in rats, counteracting the effect of estrogen. That BPA is an estrogen inhibitor could be serious for our brains if the results translate into human effects. As we age and our endogenous estrogen levels decrease, for example, the hippocampus suffers and our memory does, too. If BPA sets this process in motion even earlier, hippocampal—and thus, memory—decline may occur even earlier.

Rodents, monkeys, and people–oh, my

A recent report in Environmental Health Perspectives concludes that rodents, rhesus monkeys, and people all exhibit similar pharmacokinetics with BPA and that exposures may be far greater than previously calculated. Other recent studies suggest effects on sugar metabolism related to diabetes, an association with polycystic ovarian syndrome in rats, and a relationship to the development of asthma in a mouse model.

Crazy cat lady may have microbe to blame

Toxoplasma gondii is the cat-borne parasite responsible for causing toxoplasmosis and a host of other problems in humans. This close relative of the malaria-causing protozoan may drive human behavior and immunity, in addition to causing acute illness and devastating birth defects. Recent research points to a single gene underlying this parasite’s virulence in the human host. It’s scary yet fascinating to think that a single gene from a single organism could have such dramatic effects on our species.

Warning pregnant women away from litter boxes

Because T. gondii infection can result in serious fetal defects, many pregnant women have heard of toxoplasmosis, an illness that often goes unnoticed in the afflicted person. Pregnant women are warned away from cat litter boxes and even away from gardening because contact with cat feces can mean contact with the parasite. T. gondii spends the sexual part of its life cycle in cats, but for its asexual life, it can parasitize a number of hosts, from pigs to lambs to mice to people. People also can acquire the infection from eating undercooked meat or drinking contaminated water. In some countries, like Brazil, up to 60% of the population has been exposed to T. gondii; in the United States, about 33% of people tested have antibodies to the parasite, indicating past infection.

Link between parasite and schizophrenia

The “crazy cat lady” has practically become a social stereotype in the United States and other countries, conjuring the image of a woman who lives with 25 cats and talks to herself a lot. But researchers investigating schizophrenia have actually identified a potential link between people who are exposed to Toxoplasma infection and the manifestations of schizophrenia; for example, several studies have identified higher levels of antibodies to the parasite in people with schizophrenia, and infection with Toxoplasma can cause damage to brain cells that is similar to the damage seen in patients with schizophrenia. Toxoplasmosis can also sometimes lead to symptoms of psychosis.

The fact is that most people don’t know they have toxoplasmosis because they have healthy immune systems. In people with compromised immunity, however, such as those with HIV, T. gondii can precipitate an extreme form of dementia that eventually kills them. The dementia is so severe that the sufferer eventually becomes completely unaware of his or her surroundings and lapses into a coma. The bug, however, also can affect the central nervous system in healthy people and is also linked to severe eye problems even in patients who are not immunocompromised. One researcher has claimed that infection with the parasite makes men dumber and women act like “sex kittens.”

ROP18: Watch out for this one

There are different strains of T. gondii, and investigators have noted that the Type 1 strain is most closely associated with disease. Studies of T. gondii, which has a genome with about 6000 genes, have pinpointed the virulence capacity of the strain to a single gene, dubbed ROP18. This gene encodes a kinase, one of a huge class of cell signaling proteins that add phosphates to molecules. Typically in cell signaling, kinases exist in a series, phosphorylating the next protein in the pathway, which helps maintain regulation of the signaling. The most virulent T. gondii strains have a form of the gene that differs from that carried by benign strains. Researchers speculate that this kinase interferes with a cell’s normal signaling, hijacking it for its own purposes, including growth and reproduction. The good news is that because kinases are so important in cell signaling, pharmaceutical companies have developed libraries of molecules that inhibit specific kinases, so one potential path to preventing toxoplasmosis is to discover an inhibitor of ROP18.

Rats get a little nutty from it, too

Not only has this parasite been linked to the ability to alter human behavior, but it also appears to alter rodent behavior in ways that favor its own reproduction. For example, rodents exposed to toxoplasma via cat feces actually become more likely to hang out near cat urine. If a cat eats the infected animal, the toxoplasmosis bug can then move into the sexual phase of its life cycle in the cat.

Rats are fast, cheap TB detectors

An unpredictable killer continues to kill

Can you name the disease that killed Chopin, Keats, Descartes, Kafka, Florence Nightingale, Eleanor Roosevelt and 200 million more people in the last 100 years? It’s tuberculosis, formerly known as “consumption,” and now known as TB. The tuberculosis bacterium, Mycobacterium tuberculosis, is an airborne pathogen that can be passed on from people with active cases of TB and usually settles in the lungs, where it can flourish and cause infection. It is possible to have what is known as “latent TB,” a situation in which you harbor the bacteria, but do not manifest the disease and are not contagious. Worldwide, World Health Organization predicts that the numbers of people who die from TB will climb to 8 million by 2015.

Experts agree that generally, when TB is caught early and treated, it is curable. But with millions of people suffering from it—including people with suppressed immune systems, such as those with HIV infections—detecting every case of TB is a tough job. Current methods require three saliva samples taken over a two-day period to be prepped on a slide, stained, and examined by a trained technician for the presence of TB bacteria. A good technician can analyze about 20 samples per day; for the 8 million people who may have TB in 2015, it would take 1200 technicians working 365 days to identify them all. One thing desperately needed in nations without the funding for technicians is a fast, accurate, low-tech way to analyze samples for the presence of TB.

Bacteria, explosives…whatever

Enter the rat. Bart J.C. Weetjens, who is not a rat, but a scientist working for Apopo, a Belgian company based in Tanzania, had one of those “chance favors the prepared mind” moments. He realized that the Dutch word for tuberculosis, tering, means something along the lines of “that’s starting to smell like tar.” Given that traditional Chinese medicine includes using smell to diagnose TB, Weetjens concluded that a trained animal might be able to detect TB, much in the way a bomb-sniffing dog detects explosives. It just so happened that Weetjens’ company had already trained a native African giant pouched rat, Cricetomys gambianus, to use its olfactory faculties to sniff out land mines. Weetjens decided simply to substitute TB bacteria for explosives.

The rats were uniquely qualified for the job. Unlike most nocturnal predators, these animals have very small eyes, indicating a strong reliance on olfactory and aural senses. During the day, they seem blind, sniffing the air rather than looking around. They can grow as large as a cat, are omnivorous, easily tamed and trained, and great breeders; a single female can produce 10 litters of up to four young each year. Weetjens took his idea to the World Bank, which agreed to fund a complete study of the rats’ ability to sniff out TB.

HeroRats

Weetjens already reported preliminary results that indicate the rats may be a viable way to ID TB. The rats identified 77 percent of infected saliva samples, and 92 percent of cultured bacteria samples, with a false-positive (indicating bacteria where there were none) rate of 2 percent. The current human-based process has an accuracy rate of about 95 percent, but Weetjens figures that with several rats analyzing samples, the rats’ accuracy will match the humans’. According to Weetjens, the rats can analyze 126 samples in 20 minutes, making them a very cheap, fast diagnostic test. The analysis of 8 million samples that would have taken 1200 humans 365 days would take only two rats working the same period of time. The latest data indicate similar success rates.

Polio vaccine-related polio

Polio virus bits in vaccine rarely join forces with other viruses, become infectious

[Note: some of the links in this piece are to New England Journal of Medicine papers. NEJM does not make its content freely available, so unfortunately, unless you have academic or other access, you'd have to pay per view to read the information. I fervently support a world in which scientific data and information are freely available, but...money is money.]

Worldwide, billions of polio vaccine doses have been administered, stopping a disease scourge that before the vaccine killed people–mostly children–by the thousands in a horrible, suffocating death (see “A brief history of polio and its effects,” below). The polio vaccination campaign has been enormously successful, coming close to the edge of eradicating wild-type polio.

But, as with any huge success, there have been clear negatives. In a few countries–15, to be exact–there have been 14 outbreaks of polio that researchers have traced to the vaccines themselves.  The total number of such cases as of 2009 was 383. The viral pieces in the vaccine–designed to attract an immune response without causing disease–occasionally recombine with other viruses to form an active version of the pathogen. Some kinds of viruses–flu viruses come to mind–can be notoriously tricky and agile that way.

Existing vaccine can prevent vaccine-related polio

Odd as it sounds, the existing vaccines can help prevent the spread of this vaccine-related form of polio. The recombined vaccine-related version tends to break out in populations that are underimmunized against the wild virus, as happened in Nigeria. Nigeria suspended its polio vaccination program in 2003 because rumors began to circulate that the vaccine was an anti-Muslim tactic intended to cause infertility. In 2009, the country experienced an outbreak of vaccine-derived virus, with at least 278 children affected. Experts have found that the existing vaccine can act against either the wild virus or the vaccine-derived form, both of which have equally severe effects. In other words, vaccinated children won’t get either.

Goal is eradication of virus and need for vaccine

Having come so close to total eradication before wild-type-associated cases plateaued between 1000 and 2000 annually in the 21st century, global health officials hold out the hope for two primary goals. They hope to eradicate wild-type polio transmission through a complete vaccination program, which, in turn, will keep vaccine-derived forms from spreading. Once that goal is achieved, they will have reached the final target: no more need for a polio vaccine.

As Dr. Bruce Aylward, Director of the Global Polio Eradication Initiative at WHO, noted: “These new findings suggest that if (vaccine-derived polio viruses) are allowed to circulate for a long enough time, eventually they can regain a similar capacity to spread and paralyse as wild polioviruses. This means that they should be subject to the same outbreak response measures as wild polioviruses. These results also underscore the need to eventually stop all (oral polio vaccine) use in routine immunization programmes after wild polioviruses have been eradicated, to ensure that all children are protected from all possible risks of polio in future.”

If that sounds nutty, it’s been done. Until the early 1970s, the smallpox vaccination was considered a routine vaccination. But smallpox was eradicated, and most people born after the early ’70s have never had to have the vaccine.

A brief history of polio and its effects

I bring you the following history of polio, paraphrased from information I received from a physician friend of mine who works in critical care:

The original polio virus outbreaks occurred before the modern intensive care unit had been invented and before mechanical ventilators were widely available. In 1947-1948, the polio epidemic raged through Europe and the United States, with many thousands of patients dying a horrible death due to respiratory paralysis. Slow asphyxiation is one of the worst ways to die, which is precisely why they simulate suffocation in torture methods such as water boarding. The sensation is unendurable.

In the early twentieth-century polio epidemics, they put breathing tubes down the throats of patients who were asphyxiating due to the respiratory paralysis caused by the polio virus. Because ventilators were unavailable, armies of medical students provided the mechanical respiratory assist to the patients by hand-squeezing a bag which was connected to the breathing tube, over and over and over, 16 times a minute, 24 hours each day, which drove air in and out of the patients’ lungs.  Eventually the iron lung was developed and became widely implemented to manage polio outbreaks. The iron lung subsequently gave way to the modern ventilator, which is another story.

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