Musings on science, photography, and design

In ecology, measurements of abundance made along a transect are often represented on kite diagrams. Essentially, these are line graphs, in whch each line is translated vertically so that it does not overlap the others, and reflected in its x-axis. The space between the reflections is then shaded.

Unfortunately, these are awkward to draw by hand. They are frequently plotted on graph paper in its landscape orientation, requiring that several sheets be stuck together in order to represent the full set of measurements. This is messy, and results in a low information density. Consequently, it is desirable to produce kite diagrams with a computer, rather than ruler and pen. Some suitable software exists, but mostly as plugins for Excel (EasyStats, Merlin), a proprietary software package with a long history of computational errors and inadequacies.

I therefore wrote my own program to draw kite diagrams. It accepts the name of a CSV file as its only argument. The first line of this file is a header specifying the labels to print at each tick on the x-axis. Subsequent lines consist of a species name, then list of measurements. Output is written to a file as postscript.

Example input file:

0,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80
Sea pink, 0,0,0,0,3,0,0,6,6,3,0,0,8,22,0,0,0
Sea lavendar,0,0,0,0,0,0,0,4,0,0,30,0,16,16,17,0,0
Saltmarsh grass,0,0,0,0,0,15,0,0,0,0,50,100,49,50,83,100,0
Glasswort,10,0,35,5,0,40,8,4,0,0,20,0,11,1,0,0,0
Sea plantain,0,0,0,0,0,0,0,0,38,0,0,0,0,0,0,0,0
Sea Purslane,0,1,4,77,0,27,52,0,0,0,0,0,12,11,0,0,0
Sea rush,0,0,0,0,0,18,38,34,6,0,0,0,0,0,0,0,0
Sea couch,0,0,0,0,52,0,0,0,0,0,0,0,0,0,0,0,0
Cord Grass,22,0,5,0,0,0,0,0,0,0,0,0,0,0,0,0,0

Becomes:

The perl script can be downloaded here. After downloading, change the extension from .txt to .pl .

Arrows have been used to communicate an enormous variety of different concepts. They can represent almost any relation between two objects (or sets of objects). For clarity, when different relations must be shown in close proximity to one another, they are depicted by visually distinct arrows; over time many specific styles of arrow have acquired particular meanings.

These meanings are often idiomatic to a particular field: the curly arrows that indicate electron movement, or the double arrows showing that a reaction stops at equilibrium rather than going to completion, are not used outside of chemistry. The US military uses a large set of arrows (at least 30) to depict specific troop movements and attacks in their tactical mission graphics. Chemists use fewer: I have tabulated some of the most commonly used below.

Some arrows have very different meanings in different contexts: in mathematics, the double arrow represents logical implication (`if X is true, then Y must be true too’); in chemistry, it is the retrosynthetic arrow, (`X can be produced from Y’).

A few arrows do not represent relationships, but things themselves. For example, an arrow may represent a vector (such as a force or velocity) in a diagram.

It is often said that humans are losing the battle against disease. I disagree. Our opportunities are ongoing, progress continues, and we are winning the battle. The efforts of human to control infection have a long history, though in the past they were often ineffective. Early efforts control the plague failed, because they were based on the flawed belief that it was caused by a ‘bad air’ or miasma, rather than recognising that it was caused by an infectious agent transmitted by fleas carried by rats. However, after the acceptance of the germ-theory of disease, many effective interventions were developed. Lister’s use of carbonic acid to reduce infections during surgery set a precedent for the sterilization of surgical theatres and instruments, which has undoubtably saved countless lives.

There are many cases in which epidemics have been ended by careful interventions, such as cleaning water in areas where water-bourne infections are occurring (however, the popular belief that John Snow ended London’s 1854 cholera epidemic by disabling the Broad street pump is false; the epidemic was already drawing to a close). Other infections have been only partially controlled: no ‘treatment’ has been developed for HIV/AIDS, but Anti-Retroviral Therapy can extend life (and reduce infectiousness), Post-Exposure Prophylaxis can help prevent those exposed to HIV by needle-stick injuries from developing the disease, and the latex condom provides an effective barrier to its transmission via sexual intercourse.

More remarkably, some diseases (most notably smallpox) have been completely eradicated due to vaccination programs. Unfortunately, such programs are not universally successful: efforts to produce a effacious vaccine against HIV/AIDs have thus far failed; efforts to eradicate polio have stalled, and whilst it has been removed from most countries, there are still a few in which it remains stubbornly endemic. Public concern about vaccine safety hinder such programs—these concerns often lack a solid evidential basis, and occur not only in Africa, but also in the UK, as illustrated by the media hype surrounding Andrew Wakefield’s suggestion that the MMR vaccine could cause autism.

Alexander Fleming’s discovery of penicillin’s antibiotic effect (and the subsequent work of Florey and Chain) led to the first effective chemotherapeutic treatment for those suffering from bacterial disease. The class of antibiotics that includes penicillin (the beta-lactams) now has dozens of members, and many other classes have been developed. Unfortunately, the over-use of antibiotics imposed a selection pressure that led to the development of resistance in many organisms. There are many mechanisms by which resistance may occur, including production of enzymes that metabolize the antibiotic (such as beta-lactamases, which break open the beta-lactam ring), and pumps that remove them from bacterial cells. This is particularly concerning given the facility with which bacteria can exchange genetic material. At present, the most prevalent diseases caused by drug-resistant pathogens are multi-drug-resistant tuberculosis and Methicillin Resistance Stapylococcus Aureas (MRSA). A study, published last year in the journal Science, found that many common soil bacteria were able not only to survive at high concentrations of antibiotics, but also to use them as a nutrient-source¹. As many of these bacteria are similar to pathogens, this is highly concerning. Nonetheless, there has been progress: it has been shown that using two beta-lactams in combination can be effective in killing drug-resistant-TB²: one of the beta-lactams is broken down very slowly, and effectively acts as a beta-lactamase inhibitor. Conveniently, both drugs are already in use, avoiding both regulatory hurdles in the licensing process, and difficulties in synthesis scale-up.

As antibiotic resistance has increased, development of new antibiotic classes has slowed. This is due partly to the fact that low-hanging fruit has been exhausted, and there are few easy targets remaining for new drugs to hit. There are also economic reasons: only a single course of antibiotics is prescribed at a time, but whilst a patient is put on some other types of drug (eg. statins) they will likely continue taking it for the rest of their lives. For these two reasons, antibiotic development is expensive, and does not result in high revenues. Nonetheless, there has been some progress: two new drugs with the potential for use as anti-tuberculosis agents have been recently described in the literature: one, a imidazole, acts by causing the formation of NO. This occurs only in infected cells, avoiding damage to healthy host cells, as it is dependent on an enzyme produced by the TB pathogen³

However, there is increasing awareness that drugs need not actually kill pathogens in order to cure a patient: rather, it may be sufficient to the expression of virulence factors. A recent paper in Science described a drug that prevented cholera bacteria from producing cholera toxin, and thus also from causing symptoms. At the same time, pilus formation was impaired, hindering entrance to cells of the intestinal epithelium. As the bacterium is not being killed by the drug, there is likely to be a weaker pressure driving selection for resistance. Similar approaches may be found to be useful against other pathogens⁴.

In future, administering antibodies may have a greater role in treating infection. The approach was pioneered by Pasteur, who used transplants of blood form a succession of animals (including a rabbit and a horse) to treat a boy who had been infected with rabies by a dog-bite. As it is harder to demonstrate the indistinguishability of two complex proteins than it would be for a conventional small-molecule medicine, there is a higher regulatory barrier to the production of ‘generic’ biologics. The manufacturer of a biologic therapeutic agent may thus enjoy a monopoly maintained not only by intellectual property law, but also regulatory & safety law, making the development of biologics commercially appealing . Antibodies are used to treat some diseases (the most widely known is probably Hercepetin, which is used in some cases of breast cancer). In the last few months, researchers have been able to produce a modified version of Herceptin with affinity for a second antigen: this is the first example of antibodies with high affinities for two different biomolecules⁵. A team at Scripps research institute have produced an antibody that binds to the ‘tail’ of one of influenza’s surface proteins (hemagglutinin), a region which mutates more slowly that the ‘head’⁶. This targeting of a more stable epitope could allow the development of `flu vaccines that do not have to be re-formulated every-year as the result of epitope mutation/serotypic-shift. It could also, perhaps, allow the stockpiling of antibodies that could be administered directly to infected persons.

Surprisingly, gene therapy may be useful in treating not only genetic, but also infectious, diseases. The entry of HIV into white-blood cells is facilitated by a protein (CCR5) on its surface. A mutation (Delta-32) in this protein prevents HIV form binding to it, hindering infection. It was found that after a bone marrow transplant from a donor with the mutation, the recipient was able to come off anti-retrovirals, and has not since suffered viral rebound (the case was reported in the New England Journal of Medicine⁷). This is a promising result, but bone-marrow transplant procedures have an high morbidity and mortality. It would thus be desirable to bring about the change in blood-cell phenotype by gene therapy instead.

In conclusion, drug resistance is an increasing problem, and some vaccination programs have stalled (polio), whilst others have failed to get off the ground (HIV). However, there are now cures for many disease that were previously incurable, and new developments continue to be made. Many of these provide entire new paradigms for treatment, such as gene therapy (for HIV), carefully designed antibodies (for `flu), cleverer combination therapies (for TB), and inhibition of virulence factor formation (for cholera). Clearly, the battle is not lost—it still continues.

Capsaicin, and other closely related compounds (the capsainoids) are responsible for the heat of chillis. For some time, scientists have thought that Chillis produce capsacin in order to protect themselves from fungal infection. This hypothesis seems quite reasonable: after all, capsaicin has no obvious function in the plant, and so may have evolved to have an effect on other organisms, perhaps to protect the chillis from being eaten. Furthermore, Chillis are dependent on many animals to disperse their seeds, and any defense that developed against vertebrates would be likely to interfere with this, having a detrimental effect on the plant. In contrast, no microorganisms feeding on the chillis benefit them.

But the strongest evidence for this idea was presented in a paper in the Aug 19 2008 issue of Science ¹. The authors showed that fungal infections are indeed a major cause of damage to chillis, and that there is a correlation between number of insect bites in a particular fruit and the severity of subsequent fungal infections. The effect of additional insect bites is less significicant for peppers producing more capsaicin, which also contain less fungus, suggesting that capsaicin has a protective effect. To show that it was indeed capsaicin that was responsible for this difference, the scientists then grew fungus in two media, differing only in amount of capsaicin and dihydrocapsaicin – these compounds reduced fungal growth by 33%. Finally, they compared chillis growing across an area of 1,600 square kilometers in Bolivia. The scientists expected that in areas where chillis have more insect bites, they are exposed to the fungus more frequently, and will therefore be more likely to produce capsicin to protect themselves. And that is exactly what fieldwork found.

Not all chilis are equally hot, and their heat is compared with the Scoville Scale, developed by Wilbur Scoville. Each chilli pepper, or chilli sauce, can be given a score according to the number of times it must be diluted with water before its heat is no longer felt by a panel of taste-testers. The problem with this method is that it is time consuming, and the testers must be representative to the population. Some have tried to use more objective techniques from analytical chemistry, but initially had little success. High Performance Liquid Chromatography was tried, but its use was limited by its high cost. Last year, Richard Compton and his colleagues at Oxford University announced² that they had developed a technique for the voltammetric measurement of capsaicin concentration. In short, they placed electrodes into the sample, and measured how the current flowing between them varied as they changed the voltage across them. By repeating this several times, they could assign a Scoville score to the sample. This method is potentially much cheaper and more widely usable than existing methods.

The reason why capsaicin tastes hot is that it binds to a receptor called TRPV1 on specific nerve cells. This permits the entry of sodium or calcium ions into the cell, resulting in the transmission of an electrical signal to the brain. The opening of this recptor could have another application: the targeted entry of anesthetics. The local anesthetics currently used by dentists target all nerve cells in the mouth, not just the pain-causing nociceptors. Consequently, they make the mouth feel numb, and speech slurred, for hours after the operation. A study² conducted on rats by scientists in Massachusetts found that when an anaesthetic called QX-314 was applied after capsaicin, it would enter nociceptors through the TRPV1 channel, reducing pain, but have no effect on other nerve cells. Capsaicin has also be used alone as a local anaesthtic.

Some have suggested that people initially began eating chillis as medication, because of their anti-fungal properties. And as the paper by Compton observes they have “antioxidant power, in addition to anti-tumoral, anti-mutagenic, antibacterial and anticarcinogenic properties. . . protective effects against cholesterol and obesity”. Despite their usefulness in healing, they are also used to harm: many of the less-than-lethal pepper sprays used to disperse crowds or disable attackers contain capsainoids as their active ingredients.