Animals and plants do not use genes to self-replicate. It is the other way round. ‘We are robot vehicles blindly programmed to preserve the selfish molecules known as genes,’ he states. Thus the egg not only comes before the chicken, it runs the animal’s entire life. By Richard Dawkins, The Selfish Gene
Telegraph.co.uk, by Roger Highfield — Genetic instructions. passed down over the generations, are shaping our inheritance. Genes may well have been scrambling our DNA since the dawn of life, some four billion years ago
Genes will do whatever it takes to duplicate themselves and survive, even if the result is infanticide, murderous queens or a vicious battle of the sexes. Roger Highfield examines new evidence that reinforces Richard Dawkins’ 30-year-old vision of ruthless DNA
“We are survival machines – robot vehicles blindly programmed to preserve the selfish molecules known as genes. This is a truth which still fills me with astonishment” – Richard Dawkins, The Selfish Gene
Three decades after Richard Dawkins revolutionized our understanding of living things with The Selfish Gene, evidence has accumulated to back his cold-eyed vision of how bodies, families and society are shaped by the simple “duplicate me” message in our genetic instructions.
His book, which has sold more than a million copies, did not mean to imply that genes have actual motives, only that their effects can be described as if they do: the genes that get passed on to the next generation are the ones whose consequences serve their own interests, not necessarily those of the societies or even the organisms in which they find themselves. We are merely vehicles to help replicate DNA, according to the Oxford University biologist.
A Cambridge University team reported the consequences for meerkats, those loveable stars of natural history films, a day or two before Prof Dawkins marked the 30th birthday of his book last week, with a packed Darwin@LSE event with Ian McEwan, Dan Dennett, Matt Ridley, Sir John Krebs and Melvyn Bragg at the London School of Economics.
A meerkat group is closely related and this is why they look out for each other. But the image of caring creatures standing on endless sentry duty to protect their pups and family does not quite tell the full story, according to an eight-year study carried out on the Kuruman River Reserve by Dr Andrew Young and Prof Tim Clutton-Brock.
In the case of guarding against predators, the “selfish” actions of genes lead to unselfish actions. But food is so scarce that the matriarch tries to monopolize reproduction in the group so only her genes are passed on. When she becomes pregnant she evicts subordinate females and kills their young to maintain control.
When her pups are born, the subordinates will return and even help the dominant female with the babysitting: she is a close relative and by looking after the young, they are helping to spread some of their genes, too. But the Cambridge team reported that in the cases when a subordinate female does become pregnant, she, too, resorts to infanticide – killing the pups of subordinate sisters and of matriarchs – to boost the chances that her own litter will have enough food to thrive and that even more of her genes pass to the next generation.
Despite the females being closely related, and thus sharing genes, meerkat society appears to be riven by internal conflict, with close parallels to those of social insects such as bees or ants, where infanticide – in the form of egg- and larva-eating – and tactical power struggles are also common, even though colonies and hives are populated by closely-related individuals.
“The meerkat findings show a remarkable similarity to recent work we have done in Dolichovespula sylvestris wasps in Britain,” said Prof Francis Ratnieks of the University of Sheffield, where he studied the wasps with Dr Tom Wenseleers and colleagues.
The nests consist of colonies of 50-100 wasps with several females that lay eggs, one being the queen and a few workers. The females kill each other’s eggs and lay their own eggs in the cells: however, egg-laying workers only kill each other’s eggs, while the queen kills eggs laid by the workers. “What we have in both meerkats and the wasps is competition among breeding females for rearing resources manifested in the killing of eggs or infanticide,” said Prof Ratnieks.
This is one way, when resources are limited (as they always are), that genes increase the chance that they will be passed on. Selfish genes also explain why co-breeding sister acorn woodpeckers, which lay in the same nest, throw each other’s eggs out to increase their contribution to the communal brood. And they reveal why female worker ants prefer to raise young queens, rather than males, to skew the sex ratio of some insect societies.
This genetic gender battle has had a bizarre outcome in the case of the “little fire ant”, Wasmannia auropunctata. As with other ants, queens combine genes from male sperm with their own, to produce female worker ants, which are sterile. However, when it comes to the next generation of queens, this species has evolved a remarkable trick – to maximize the transmission of their own genes, queens actually clone themselves, rather than incorporating DNA from the male’s sperm.
A genetic analysis by Dr Denis Fournier of the Free University of Brussels in Belgium showed that the male ants have evolved their own counter-tactic to ensure that their genes still get passed on: they have found a way to eliminate the female genetic contribution to a fertilized egg, thereby producing a male clone, too.
The battles between genes go deeper than between groups, families and individuals. They go on within our bodies too. We inherit two copies of each gene, one from each parent. However, for some genes, we use the copy from only one parent because of a process called imprinting. Prof David Haig of Harvard University argues that imprinting arose because of the battle between the genes of mother and father: both want to pass on their genes to their offspring, but the genes inherited from the mother and the father are in conflict over how much of her resources the mother should devote to the fetus. In essence, maternally-inherited genes have a greater interest in the survival of the mother than those from the father.
The father wants his offspring to grow big. This will provide his offspring – and his genes – with an enhanced chance of survival and use up the mother’s resources so they won’t be wasted on another man’s offspring. Women, on the other hand, want to provide resources for the growing child, but within reason – they need to retain some resources to ensure their own survival and their potential to pass on more of their genes in future children. The result, Prof Haig says, is an arms race, with paternal genes beefing up the offspring and maternal genes counter-attacking to hold growth in check.
Look closely at the human genetic code and you will find it swarming with selfish genes. The existence of supposed junk DNA that provides no obvious benefit to our bodies, which was once a puzzle, is easily explained with their help. These genetic parasites, “duplicate me” instructions that have been passed down over the generations, are shaping our inheritance.
With meaningless names such as Lines, Sines, Ltr retrotransposons, and DNA transposons, these parasites make up a significant fraction of our genetic code, representing 13, 20, eight and three per cent respectively, according to Dr Tim Hubbard of the Wellcome Trust Sanger Institute, near Cambridge. Some, like Lines, code for protein machinery that inserts new Lines in our genetic recipe.
Others, notably those called Alus, take advantage of the protein machinery produced by the Lines to reproduce. According to Dr Hubbard, “Here we have one kind of selfish DNA feeding off another selfish DNA.” Indeed, selfish genes may well have been scrambling our DNA since the dawn of life, some four billion years ago
DETECTIVE Dr. James M. Musser, second from right, put DNA sequencing to work in a Houston case involving lethal bacteria that looked like anthrax. The culprit turned out to be a closely related strain of Bacillus.
Photo: Michael Stravato for The New York Times
The New York Times, By GINA KOLATA, August/September 2011 —
It was Tuesday evening, June 7. A frightening outbreak of food-borne bacteria was killing dozens of people in Germany and sickening hundreds. And the five doctors having dinner at Da Marco Cucina e Vino, a restaurant in Houston, could not stop talking about it.
What would they do if something like that happened in Houston? Suppose a patient came in, dying of a rapidly progressing infection of unknown origin? How could they figure out the cause and prevent an epidemic? They talked for hours, finally agreeing on a strategy.
That night one of the doctors, James M. Musser, chairman of pathology and genomic medicine at the Methodist Hospital System, heard from a worried resident. A patient had just died from what looked like inhalation anthrax. What should she do?
“I said, ‘I know precisely what to do,’ ” Dr. Musser said. “ ‘We just spent three hours talking about it.’ ”
The questions were: Was it anthrax? If so, was it a genetically engineered bioterrorism strain, or a strain that normally lives in the soil? How dangerous was it?
And the answers, Dr. Musser realized, could come very quickly from newly available technology that would allow investigators to determine the entire genome sequence of the suspect micro-organism.
It is the start of a new age in microbiology, Dr. Musser and others say. And the sort of molecular epidemiology he and his colleagues wanted to do is only a small part of it. New methods of quickly sequencing entire microbial genomes are revolutionizing the field.
The first bacterial genome was sequenced in 1995 — a triumph at the time, requiring 13 months of work. Today researchers can sequence the DNA that constitutes a micro-organism’s genome in a few days or even, with the latest equipment, a day. (Analyzing it takes a bit longer, though.) They can simultaneously get sequences of all the microbes on a tooth or in saliva or in a sample of sewage. And the cost has dropped to about $1,000 per genome, from more than $1 million.
In a recent review, Dr. David A. Relman, a professor of medicine, microbiology and immunology at Stanford, wrote that researchers had published 1,554 complete bacterial genome sequences and were working on 4,800 more. They have sequences of 2,675 virus species, and within those species they have sequences for tens of thousands of strains — 40,000 strains of flu viruses, more than 300,000 strains of H.I.V., for example.
With rapid genome sequencing, “we are able to look at the master blueprint of a microbe,” Dr. Relman said in a telephone interview. It is “like being given the operating manual for your car after you have been trying to trouble-shoot a problem with it for some time.”
Dr. Matthew K. Waldor of Harvard Medical School said the new technology “is changing all aspects of microbiology — it’s just transformative.”
One group is starting to develop what it calls disease weather maps. The idea is to get swabs or samples from sewage treatment plants or places like subways or hospitals and quickly sequence the genomes of all the micro-organisms. That will tell them exactly what bacteria and viruses are present and how prevalent they are.
With those tools, investigators can create a kind of weather map of disease patterns. And they can take precautions against ones that are starting to emerge — flu or food-borne diseases or SARS, for example, or antibiotic-resistant strains of bacteria in a hospital.
Others are sequencing bacterial genomes to find where diseases originated. To study the Black Death, which swept Europe in the 14th century, researchers compared genomes of today’s bubonic plague bacteria, which are slightly different in different countries. Working backward, they were able to create a family tree that placed the microbe’s origin in China, 2,600 to 2,800 years ago.
Still others, including Dr. Relman, are examining the vast sea of micro-organisms that live peacefully on and in the human body. He finds, for example, that the bacteria in saliva are different from those on teeth and that the bacteria on one tooth are different from those on adjacent teeth. Those mouth bacteria, researchers say, hold clues to tooth decay and gum disease, two of the most common human infections.
A Real-World Test
For Dr. Musser and his colleagues, the real-world test of what they could do came on that June evening.
The patient was a 39-year-old man who lived about 75 miles from Houston in a relatively rural area. He had been welding at home when, suddenly, he could not catch his breath. He began coughing up blood and vomiting. He had a headache and pain in his upper abdomen and chest.
In the emergency room, his blood pressure was dangerously low and his heart was beating fast. Doctors gave him an IV antibiotic and rushed him to Methodist Hospital in Houston. He arrived on Saturday night, June 4. Despite heroic efforts, he died two and a half days later, on Tuesday morning.
Now it was Tuesday night. On autopsy, the cause looked for all the world like anthrax, in the same unusual form — so-called inhalation anthrax — that terrified the nation in 2001. Even before the man died, researchers had been suspicious; washings from his lungs were teeming with the rod-shaped bacteria characteristic of anthrax. Investigators grew the bacteria in the lab, noticing that the colonies looked like piles of ground glass, typical of anthrax but also other Bacillus microbes.
“We knew we had to get this solved in a hurry,” Dr. Musser said. “We had to know precisely what we were dealing with. That’s when we put into play a plan to sequence the genome.”
A few days later they had their answer. The bacteria were not anthrax, but were closely related. They were a different strain of Bacillus: cereus rather than anthracis.
The bacteria had many of the same toxin genes as anthrax bacteria but had only one of the four viruses that inhabit anthrax bacteria and contribute to their toxicity. And they lacked a miniature chromosome — a plasmid — found in anthrax bacteria that also carries toxin genes.
The conclusion was that the lethal bacteria were naturally occurring and, though closely related to anthrax, not usually as dangerous. So why did this man get so ill?
He was a welder, Dr. Musser noted, and welders are unusually susceptible to lung infections, perhaps because their lungs are chronically irritated by fine metal particles. So his fatal illness was most likely due to a confluence of events: welding, living in a rural area where the bacteria lived in the soil and happening to breathe in this toxin-containing species of bacteria.
Dr. Waldor and his colleagues asked a slightly different question when Haiti was swept by cholera after last year’s earthquake. Cholera had not been seen in Haiti for more than a century. Why the sudden epidemic?
The scientists quickly sequenced the genome of the bacteria in Haiti and compared them with known cholera strains from around the world. It turned out that the Haitian strain was different from cholera bacteria in Latin America and Africa, but was identical to those in South Asia.
So the researchers concluded that the earthquake was indirectly responsible for the epidemic. Many relief workers who came to Haiti lived in South Asia, where cholera was endemic. “One or more of these individuals likely brought cholera to Haiti,” Dr. Waldor said.
Charting Disease Maps
One of Dr. Waldor’s collaborators in that study, Eric Schadt, wants to take the idea of molecular forensics one step further. Dr. Schadt, the chairman of genetics at Mount Sinai School of Medicine and chief scientific officer of Pacific Biosciences, wants to make disease weather maps.
He began with pilot studies, first in his company’s offices. For several months, the company analyzed the genomes of microbes on surfaces, like desks and computers and handles on toilets. As the flu season began, the surfaces began containing more and more of the predominant flu strain until, at the height of the flu season, every surface had the flu viruses. The most contaminated surface? The control switches for projectors in the conference rooms. “Everybody touches them and they never get cleaned,” Dr. Schadt said.
He also swabbed his own house and discovered, to his dismay, that his refrigerator handle was always contaminated with microbes that live on poultry and pork. The reason, he realized, is that people take meats out of the refrigerator, make sandwiches, and then open the refrigerator door to return the meat without washing their hands.
“I’ve been washing my hands a lot more now,” Dr. Schadt said.
The most interesting pilot study, he says, was the analyses of sewage.
“If you want to cast as broad a net as possible, sewage is pretty great,” Dr. Schadt said. “Everybody contributes to it every day.”
To his surprise, he saw not only disease-causing microbes but also microbes that live in specific foods, like chicken or peppers or tomatoes.
“I said, ‘Wow, this is like public health epidemiology,’ ” he said. “We could start assessing the dietary composition of a region and correlate it with health.”
Dr. Relman, meanwhile, is focusing on the vast bulk of microbes that live peacefully in or on the human body. There are far more bacterial genes than human genes in the body, he notes. One study that looked at stool samples from 124 healthy Europeans found an average of 536,122 unique genes in each sample, and 99.1 percent were from bacteria.
Bacterial genes help with digestion, sometimes in unexpected ways. One recent study found that bacteria in the guts of many Japanese people — but not in the North Americans tested as control — have a gene for an enzyme to break down a type of seaweed that wraps sushi. The gut bacteria apparently picked up the gene from marine bacteria that live on this red algae seaweed in the ocean.
But if these vast communities of microbes are as important as researchers think they are for maintaining health, Dr. Relman asked, what happens when people take antibiotics? Do the microbial communities that were in the gut recover?
Using rapid genome sequencing of all the microbes in fecal samples, he found that they did return, but that the microbial community was not exactly as it was before antibiotics disturbed it. And if a person takes the same antibiotic a second time, as late as six months after the first dose, the microbes take longer to come back and the community is deranged even more.
Now he and his colleagues are looking at babies, taking skin, saliva and tooth swabs at birth and during the first two years of life, a time when the structure of the microbe communities in the body is being established.
“We wait for the babies to be exposed to antibiotics — it doesn’t take that long,” Dr. Relman said. The goal, he says, is to assess the effects on the babies’ microbes, especially when babies get repeated doses of antibiotics that are not really necessary.
“Everything comes with a cost,” he said. “The problem is finding the right balance. As clinicians, we have not been looking at the cost to the health of our microbial ecosystems.”
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of
Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
MedPageToday.com, September 7, 2011, by Charles Bankhead — Sleep-time blood pressure topped awake-time pressure as a predictor of cardiovascular risk in patients with and without hypertension, according to data from a large, prospective, cohort study.
Every 5-mm decrease in sleep-time systolic blood pressure was associated with a 17% reduction in cardiovascular risk during a median follow up of 5.6 years.
Asleep systolic blood pressure remained an independent predictor of cardiovascular event-free survival after adjustment for ambulatory blood pressure parameters, as reported in the September 6 issue of the Journal of the American College of Cardiology.
“The sleep-time blood pressure mean is the most significant prognostic marker of cardiovascular morbidity and mortality,” Ramón C. Hermida, PhD, of the University of Vigo in Spain, and co-authors wrote.
“Most importantly, the progressive decrease in asleep blood pressure, a novel therapeutic target that requires proper patient evaluation by ambulatory monitoring, was the most significant predictor of event-free survival,” they wrote.
Numerous studies have examined specific aspects of 24-hour blood pressure to gain insight into cardiovascular risk, and potential preventive measures to reduce the risk. Several studies have shown a relationship between blunted blood pressure reduction during sleep and an increased risk of cardiovascular events, the authors noted.
Most previous studies had relied on a single blood pressure measurement to determine differences in cardiovascular risk over time. Hermida and colleagues sought to examine the relationship between changes in circadian blood pressure profile and cardiovascular risk.
The study involved patients with normal blood pressure, untreated hypertension, or treatment-resistant hypertension. The latter was defined as persistent hypertension despite compliance with three blood pressure medications.
Patients with untreated hypertension were randomized to bedtime or awakening dosing for each allowed antihypertensive drug. If a patient did not achieve adequate blood pressure control after three months of monotherapy, additional drugs could be added in keeping with current clinical practice.
Patients with treatment-resistant hypertension were randomized to substitute a new drug for one of their existing medications or to switch dosing for one medication from daytime to bedtime.
At enrollment and before each follow-up visit, patients’ blood pressure was assessed by automatic blood pressure monitors for 48 hours. Measures were obtained every 20 minutes from 7 a.m. to 11 p.m. and every 30 minutes the rest of the time.
Patients who had at least a 10% decline in sleep-time systolic blood pressure were classified as dippers. Nondippers were defined as patients with a relative decline in sleep-time systolic blood pressure of less than 10%.
Investigators estimated each patient’s cardiovascular risk on the basis of the baseline ambulatory blood pressure evaluation and changes in any measured blood pressure parameter during follow-up.
The study’s primary endpoints were:
The final analysis included 1,718 men and 1,626 women whose age at enrollment averaged 52.6. Investigators documented 331 first events:
Comparing patients with and without events, the authors found that patients with events had a significantly higher baseline 48-hour mean systolic blood pressure (137.2 versus 126.4 mmHg, P<0.001) but not diastolic blood pressure.
The largest blood pressure difference between groups was mean asleep systolic blood pressure, which was 133.5 mmHg in patients with events and 117.3 mmHg in patients who were event-free (P<0.001). Awake mean systolic blood pressure also was higher in patients who had cardiovascular events (139.2 versus 130.5 mmHg, P<0.001).
Sleep-time decline in systolic blood pressure averaged 4.2% in patients who had clinical events and 10.1% in those who did not (P<0.001). Asleep diastolic pressure declined by an average of 9.4% in patients with an event compared with 15.3% in patients who did not have events (P<0.001).
The authors found that 72.5% of patients with clinical events were nondippers as compared with 46% of patients who were event-free (P<0.001). A greater increase in sleep-time decline of systolic blood pressure was associated with a 25% reduction in the hazard for cardiovascular events (95% CI 0.67-0.84) and a similar effect was seen for major events.
Multivariate analysis showed that a higher mean sleep-time systolic blood pressure was associated with a hazard ratio of 1.52 for cardiovascular events (95% CI 1.40-1.66). The HR increased to 1.72 for major cardiovascular events (95% CI 1.49-1.99). No other variable assessed had as great an impact on cardiovascular events.
Dating back more than 20 years, the clinical implications associated with sleep-time blood pressure decline (dippers versus nondippers) has held up to scrutiny in studies that have consistently shown higher risk in dippers, Alan H. Gradman, MD, wrote in an accompanying editorial.
“The implications of these findings for clinical practice are substantial,” wrote Gradman, who is from Temple University in Philadelphia. “A strong case can be made to accept the conclusion of the authors that bedtime administration of at least some portion of the antihypertensive regimen of the patient should become the default standard.”
“The mere suggestion that cardiovascular event rates in patients with hypertension can be reduced by more than 50% with a zero-cost strategy of giving existing medications at bedtime rather than in the morning is nothing short of revolutionary,” he added.
Primary source: Journal of the American College of Cardiology
Hermida RC, et al “Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk” J Am Coll Cardiol 2011; 58: 1165-1173.
Additional source: Journal of the American College of Cardiology
Gradman AH “Sleep-time blood pressure: A validated therapeutic target” J Am Coll Cardiol 2011; 58: 1176-1175.