Graham writes ...
The real identity of what was thought to be a rather uninteresting nearby star was revealed in an article in Nature Astronomy on 19 February. The star, which is labelled J0529-4351, was first catalogued in a Southern Sky Survey dating back to 1980 (the rather uninteresting name is derived from the object’s celestial coordinates). Also, more recently, automated analysis by ESA’s Gaia spacecraft catalogued it as a star. The lead author of the article in Nature, Christian Wolf, is based at the Australian National University (ANU), and it was his team that first recognised the star’s true identity as a quasar last year, using the ANU’s 2.3 metre telescope at Siding Springs Observatory. As an aside, there is a relatively local link with this telescope, as it was once housed at Herstmonceux, Sussex as part of the Royal Greenwich Observatory. The true nature of the ‘star’ was further confirmed using the European Southern Observatory’s Very Large Telescope in Northern Chile. You can see the ANU’s press release here.
So, what’s a quasar you might ask? A quasar (standing for ‘quasi-stellar object’) is an extremely luminous active galactic nucleus. When first discovered in the 1960s, these star-like objects were known by their red-shift to be very distant from Earth, which meant that they were very energetic and extremely compact emitters of electromagnetic radiation. At that time, the nature of such an object with these characteristics was a subject for speculation. However, over time, we have discovered that super-massive black holes at the centre of galaxies are ubiquitous throughout the Universe. Indeed, we have one at the centre of our own Milky Way galaxy with a mass of 4 million Suns, just 27,000 light years away. So, when we observe a quasar, the light has taken billions of years to reach us, and we are seeing them as they were in the early Universe when galaxies were forming. In those early structures, ample gas and matter debris was available to feed the forming black holes, creating compact objects with a prodigious energy output.
And this is what J0529-4351 turned out to be. This object’s distance was estimated to be 12 billion light years (a red-shift of z = 4), with a mass of approximately 17 billion Suns, hence dwarfing our Milky Way black hole. As black holes feed on the surrounding available material (gas, dust, stars, etc.) they form an encircling accretion disk, in which the debris whirlpools into the centre. Velocities of material objects in this disk approach that of light speed, and the emission from the quasar radiates principally from this spiralling disk. The accretion disk of J0529-4351 is roughly 7 light years in diameter, with the central blackhole consuming just over one solar mass per day. This gives the object an intrinsic brightness of around 500 trillion Suns, making it the brightest known object in the Universe. Hopefully, like me, you are awed at the characteristics of this monstrous black hole that provided this amazing light show 12 billion years ago!
Apologies that this month’s blog is shorter than usual, mainly because of preparation work required for next month’s conference at Lee Abbey, Devon, UK (see information on the home page). For those booked in, we are really looking forward to meeting you all next month!
John has also been busy posting other item(s) of interest on our ‘Big Bang to Biology’ Facebook page.
John writes …
A century (nearly) of antibiotics
It is one of those things that ‘every school pupil knows’: Alexander Fleming discovered penicillin in 1928. At the time, he thought that his discovery had no practical application. However, in 1939, a team at Oxford, led by Howard Florey, started to work on purification and storage of penicillin and having done that, conducted trials on animals followed by clinical trials with human patients. The work led to its use amongst Allied troops in the World War II and, after the war, in more general medical practice. Its detailed structure was worked out by Dorothy Hodgkin, also at Oxford, in 1945 and that led to the development of a range of synthetic modified penicillins which are more effective than the natural molecule.
This leads us to think about penicillin’s mode of action: it works mainly by disrupting the synthesis of the bacterial cell wall which may in turn lead to the autolysis (self-destruction) of the cell. Other antibiotics have since been developed which target other aspects of bacterial metabolism. In my own research on genes, I have used rifampicin which inhibits the transcription (copying) of genes into messenger RNA (the working copy of a gene) and chloramphenicol which prevents the use of messenger RNA in the synthesis of proteins (1). However, antibiotics in the penicillin family are by far the most widely used (but see next section).
But there’s a problem
Bacteria can be grouped according to whether they are ‘Gram-positive’ or ‘Gram-negative’. Hans Christian Gram was a Danish bacteriologist who developed a technique for staining bacterial cells – the Gram stain. Species which retain the stain, giving them a purple colour, are Gram-positive; species which do not retain the stain are Gram-negative. We now know that this difference is caused by differences in the cell’s outer layers. Gram-positive bacteria have a double-layered cell membrane (the plasma-membrane), surrounded by a thick cell wall; Gram-negative bacteria also have a double-layered plasma-membrane which is surrounded by a thinner cell wall and then another double-layered membrane.
It is this structure that prevents the stain from entering the cells and which also leads to antibiotics in the penicillin family being totally or partially ineffective. Like many molecular biologists, I have used non-pathogenic strains of a Gram-negative bacterium, Escherichia coli (E .coli). It is the bacterial model used in research and has also been used to ‘look after’ genes which were destined for use in genetic modification. By contrast, pathogenic strains of this species can cause diarrhoea (‘coli’ indicates one of its habitats – the colon) while more seriously, some Gram-negative bacteria may cause pneumonia and sepsis. As already indicated, penicillin derivatives are mostly ineffective against Gram-negative bacteria and some of the effective antibiotics which have been developed have quite serious side effects.
And an even bigger problem
It is a truth universally acknowledged that an organism better adapted to an environment will be more successful than one that is less well adapted. This is of course a slightly ‘Austenesque’ way of talking about natural selection. Suppose then, that antibiotics are so widely used in medical, veterinary, or agricultural settings that they effectively become part of the environment in which bacteria live. Initially there will be a small number of bacteria that, for a number of reasons, are resistant to antibiotics. For example, some are able to de-activate a particular antibiotic and some can block the uptake of an antibiotic. Whatever the reason for the resistance, these resistant bacteria will clearly do better than the non-resistant members of the same species. The resistance genes will be passed on in cell division and the resistant forms will come to dominate the population, especially in locations and setting where antibiotics are widely used. And that, dear reader, is exactly what has happened. Antibiotic resistance is now widespread especially in Gram-negative, disease-causing bacteria, as is seen in the WHO priority list of 12 bacterial species/groups about which there is concern: nine of these are Gram-negative. The situation, already an emergency, is now regarded as critical in respect of three Gram-negative bacteria. Thinking about this from a Christian perspective, we might say that antibiotics are gifts available from God’s creation but humankind has not used those gifts wisely.
But there is hope
The growing awareness of resistance has catalysed a greatly increased effort in searching for new antibiotics. There are many thousands of organisms ‘out there’ remaining to be discovered, as is evident from a recent announcement from Kew about newly described plant and fungal species. It is equally likely that there is naturally occurring therapeutic chemicals, including antibiotics, also remaining to be discovered, perhaps even in recently described species (remembering that penicillin is synthesised by a fungus). There are also thousands of candidate-compounds that can be made in the lab. Concerted, systematic, computer-aided high throughput searches are beginning to yield results and several promising compounds have been found (2). Nevertheless, no new antibiotics that are effective against Gram-negative bacteria have been brought into medical or veterinary practice for over 50 years. However, things may be about to change.
On January 4th, a headline on the BBC website stated ‘New antibiotic compound very exciting, expert says’ (3). The Guardian newspaper followed this with ‘Scientists hail new antibiotic that can kill drug-resistant bacteria.’ (4) The antibiotic is called Zosurabalpin and it was discovered in a high throughput screening programme (as mentioned earlier) that evaluated the potential of a large number of synthetic (lab-manufactured) candidate-compounds. In chemical terminology Zosurabalpin is a tethered macrocyclic peptide, an interesting and quite complex molecule. However, its most exciting features are firstly its target organisms and secondly its mode of action. Both of these are mentioned in the news articles that I have referred to and there is a much fuller account in the original research paper in Nature (5).
Referring back to the WHO chart, we can see that one of the ‘critical’ antibiotic-resistant bacteria is Carbapenem-resistant Acinetobacter baumannii (known colloquially as Crab). Carbapenem is one of the few antibiotics available for treating infections of Gram-negative bacteria but this bacterial species has evolved resistance against it (as described above). This means that it is very difficult to treat pneumonia or sepsis caused by Crab. The effectiveness of Zosurabalpin against this organism is indeed very exciting. Further, I find real beauty in its mode of action in that it targets a feature that makes a Gram-negative bacterium what it is. One of the key components of the outer membrane is a complex molecule called a lipopolysaccharide, built of sugars and fats. The antibiotic disrupts the transport of the lipopolysaccharide from the cell to the outer membrane which in turn leads to the death of the cell.
The outer layers of a Gram-negative bacterial cell in more detail, showing the inner membrane, the peptidoglycan cell wall and the outer membrane. The essential lipopolysaccharides mentioned in the text are labelled LPS. The new antibiotic targets the proteins that carry the LPS to their correct position. Diagram modified from original by European Molecular Biology Lab, Heidelberg.
Zosurabalpin has been used, with a high level of success, to treat pneumonia and sepsis caused by A. baumannii in mice. Further, trials with healthy human subjects did not reveal any problematic side-effects. The next phase of evaluation will be Phase 1 clinical trials, the start of a long process before the new antibiotic can be brought into clinical practice.
(1) For anyone interested in knowing more about how antibiotics work, there is a good description here: Action and resistance mechanisms of antibiotics: A Guide for Clinicians – PMC (nih.gov).
(2) As discussed here: Antibiotics in the clinical pipeline as of December 2022 | The Journal of Antibiotics (nature.com).
(3) New antibiotic compound very exciting, expert says – BBC News.
(4) Scientists hail new antibiotic that can kill drug-resistant bacteria | Infectious diseases | The Guardian.
(5) A novel antibiotic class targeting the lipopolysaccharide transporter | Nature.
Graham writes …
The Nobel Prize in Physics 2023 has been awarded jointly to Anne L’Huillier of Lund University in Sweden, Pierre Agostini of Ohio State University in the USA and Ferenc Krausz of the Ludwig Maximilian University in Munich, Germany, for their experimental work in generating attosecond pulses of light for the study, principally, of the dynamics of electrons in matter.
Effectively, the three university researchers have opened a new window on the Universe, and this will inevitably lead to new discoveries. Before we think about the applications of this newly-acquired technique, we need to explore the Nobel Laureates’ achievements in general terms.
Firstly it would be good to know, what is an attosecond (as)? It is a very short period of time, which can be expressed in variety of ways,
1 as = a billion, billionths of a second,
= 0.000 000 000 000 000 001 sec, or in ‘science-speak’,
= 10^-18 sec.
Whichever way you think of it, it is an unimaginably short period of time. Other observers reporting on this have pointed out that there are more attoseconds in one second than there are seconds of time since the Big Bang! I don’t know if that helps? In general terms, what the research has led to is the development of a ‘movie camera’ with a frame rate of the order of 10 million billion frames per second. Effectively this allows the capture of ‘slow-motion imagery’ of some of the fastest known physical phenomena, such as the movement of electrons within atoms. If we think about objects in the macroscopic world, generally things happen on timescales related to size. For example, the orbits of planets around the Sun take years, and the time it takes for a human being to run a mile is measured in minutes and seconds. Another macroscopic object that moves very rapidly is a humming bird. Or rather, while it hovers statically to consume plant nectar its wings need to flap around 70 times per second, which is once every 0.014 sec. Clearly if we had a movie camera with a frame rate of, say 25 per second then the bird’s wings would simply be a blur. To examine each wing beat in detail, to study how the bird achieves its steady hover, then a minimum of maybe 10 frames per flap would be required. So, something like, at least, 1,000 frames per second would be advised to allow an informative slow-motion movie of the bird’s physical movements.
If we now consider the quantum world of particles and atoms, movements such as the dance of electrons in atoms are near-instantaneous. In 1925, Werner Heisenberg (one of the pioneers of quantum mechanics, and the discoverer of the now famous uncertainty principle) was of a view that the orbital motion of an electron is unobservable. In one sense he was correct. As a wave-particle, an electron does not orbit the atom in the same way as planets orbit the Sun. Rather physicists understand them as electron clouds, or probability waves, which quantify the probability of an electron being observed at a particular place and time. However, the odds of an electron being here or there change at the attosecond timescale, so in principle our attosecond ‘movie camera’ can directly probe electron behaviour. I’m sure that Heisenberg would have been delighted to learn that he had underestimated the ingenuity of 21st Century physicists.
However, the ‘movie camera’ we have been discussing, is not a camera in the conventional sense. Instead a laser beam with attosecond period pulses is brought to bear on objects of interest (such as atoms within molecules, or electrons within atoms) to illuminate their frenzied movements. But how is this achieved?
L’Huillier team’s early work prepared the scene for attosecond physics. They discovered that a low frequency infra-red (heat radiation) laser beam passing through argon gas generated a set of additional high-energy “harmonics” – light waves whose frequencies are multiples of the input laser frequency. The idea of harmonics is a very familiar one in acoustics, and in particular those generated by musical instruments. The quality of sound that defines a particular instrument (its ‘timbre’) is determined by the combination of its fundamental frequency combined with its main harmonic frequencies. In music, the amplitude (or loudness) of the higher harmonics tends to decrease as the frequency increases, but one striking characteristic that L’Huillier found was that the amplitude of the higher harmonics in the laser light did not die down with rising frequency.
The next step was to try to understand this observed behaviour. L’Huillier’s team set about constructing a theoretical model of the process, which was published in 1994 (1). The basic idea is that the laser distorts the electric-field structure within the argon atom, which allows an electron to escape. This liberated electron then acquires energy in the laser field and when the electron is finally recaptured by the atom it gives away the acquired energy in the form of an emitted photon (particle of light). This released energy generates the higher frequency harmonic waveforms.
The next question was whether the light corresponding to the higher harmonic modes would interfere with each other to generate attosecond pulses? Interference is a commonly observed phenomenon, when two or more electromagnetic (or acoustic) wave forms are combined to generate a resultant wave in which the displacement is either reinforced or cancelled. This is illustrated in the diagram below. In this example, two wave trains with slightly differing frequencies are combined to produce the resultant waveform (this occurrence is called ‘beats’ in acoustics). Notice that the maximum outputs in the lower, combined wave train occur when the peaks in the original waves coincide, and similarly a minimum occurs when the peaks and troughs coincide to cancel each other out.
In the case of L’Huillier’s experiments, for interference to occur a kind of synchronisation between the emission of different atoms is required. If the atoms do not ‘collaborate’ with each other, then the output will be chaotic. In 1996 the team demonstrated theoretically that the atoms (remarkably) do indeed emit phased-matched light, allowing interference between the higher harmonics to occur, so opening the door to the prospect of attosecond physics. The image below illustrates the generation of attosecond pulses as a consequence of the interference between the various higher harmonic wave train outputs.
Over the subsequent years, physicists have exploited these detailed insights to generate attosecond pulses in the laboratory. In 2001, Agostini’s team produced a train of laser pulses, each around 250 as duration. In the same year, Krausz’s group used a different technique to generate single pulses, each of 650 as duration. Two years later, L’Huillier’s team pushed the envelope a little further to produce 170 as laser pulses.
So, the question arises, what can be done with this newly acquired ‘super-power’? Well in general it will allow physicists to study anything that changes over a period of 10s to 100s of attoseconds.
As discussed above, the first application was to try something that the physics community had long considered impossible – to see precisely what electrons are up to. In 1905 Albert Einstein was instrumental in spurring the early development of quantum mechanics with his explanation of the photoelectric effect. The photoelectric effect is essentially the emission of electrons from a material surface, as a result of shining a light on it. He later won the 1921 Nobel Prize in Physics for this, and it is remarkable that he did not receive this accolade for the development of the theory of general relativity, which could be considered to be his crowning achievement. Einstein’s explanation showed that light behaved, not only as a wave, by also as a particle (the photon). The key to understanding was that the numbers of photo electrons that were emitted from the surface was independent of the intensity of the light and but rather depended upon its frequency. This emission was considered to take place instantaneously, but Krausz’s team examined the process using attosecond pulses and could accurately time how long it took to liberate a photoelectron.
The developments I have described briefly in this post suggest a whole new array of potential applications, from the determination of the molecular composition of a sample for the purposes of medical diagnosis, to the development of super-fast switching devices that could speed up computer operation by orders of magnitude – thanks to three physicists and their collaborators who explored tiny glimpses of time.
(1) Theory of high-harmonic generation by low-frequency laser fields, M. Lewenstein, Ph. Balcou, M. Yu. Ivanov, Anne L’Huillier, and P. B. Corkum, Phys. Rev. Vol. A 49, p. 2117, 1994.
Greetings and blessings of the season to you all from John and Graham.
Please click on the picture.
(Graham's choir is singing this blessing from the pen of Philip Stopford this Christmas season).
Graham's December blog post on the 2023 Nobel Prize in Physics will be arriving soon ...
John writes ...
Sickle-cell anaemia is a condition that occurs predominantly amongst people of Afro-Caribbean and Indian heritages. Eighty percent of cases occur in sub-Saharan Africa (see map) but we also note that, on a per capita basis, the Caribbean region has the second highest rate of occurrence (1). The name of the disease comes from the shape of the red blood cells which, instead of being round and squishy, are sickle-shaped and rather stiff. This means that they don’t travel so well through the smaller blood vessels which are thus prone to blockage, leading to a range of symptoms, including severe pain, as described in the NHS information page (2). Further, these aberrant red blood cells have a much shorter life in the body than normal red cells. This means that rates of cell production in the bone marrow may not keep up with the body’s needs, leading to anaemia.
The sickle-shape of the red blood cells is caused by change in the structure of the oxygen-carrying protein, haemoglobin. Intriguingly, at normal oxygen concentrations, the oxygen-carrying capacity of the mutant haemoglobin is only slightly affected. However, it is when the protein ‘discharges’ its cargo of oxygen in the tissues where it is needed, that the change in its structure has its effect. The globin molecules stick together leading to the changes in the red cells that I mentioned earlier.
At this point we need to remind ourselves firstly that the building blocks of protein are called amino acids and secondly that the order of the building blocks (‘bases’) in DNA ‘tells’ the cell which amino acids to insert into a growing protein (Chapter 5 in the book). The order of bases in the DNA is thus the genetic code in which a group of three bases (a codon) corresponds to a particular amino acid and it is interesting that the biochemistry of haemoglobin has a significant role in our knowledge of this. Firstly, thanks mainly to the work of Fred Sanger in Cambridge, it was already possible in the late 1950s to work out the order of amino acids in protein. Sanger was awarded the 1958 Nobel Prize for Chemistry in recognition this work. Thus, the amino sequences of normal and sickle-cell haemoglobin could be compared and by 1959, Vernon Ingram, an American scientist working in Cambridge, had shown that the two differed by just one amino acid. In sickle-cell haemoglobin, a molecule of glutamic acid is replaced by a molecule of valine (3). Secondly, it was not long after, in 1961, that scientists started to crack the genetic code, a task that was completed by 1966. Marshall Nirenberg and Gobind Khorana were awarded the 1968 Nobel Prize for their major roles in this achievement. This meant that the presence of valine instead of glutamic acid in sickle-cell haemoglobin could be ascribed to a mutation in DNA in which the codon GAG is replaced the codon GTG (we recall that we often refer to the bases in DNA just by their initials, A, C, G, T). In other words, a mutation which involved the change of just one base was responsible for the aberrant behaviour of the mutant haemoglobin.
GAG in DNA → Glutamic acid in protein
GTG in DNA → Valine in protein
This was the very first elucidation of a point mutation involving just one base which leads to the synthesis of a malfunctioning protein. It is worth reminding ourselves that this was achieved over a decade before Sanger (again!) published a method for sequencing DNA, a milestone which led to his receiving, in 1980, another Nobel Prize for Chemistry. Although other methods were developed at around the same time, the Sanger method was the first choice of most researchers, including me, from its arrival on the scene in 1977 until around 2010, when two much faster methods became widely adopted. In relation to sickle-cell disease, Sanger’s method was immediately used to sequence the normal and mutant globin genes, directly demonstrating the GAG to GTG change that had been deduced in previous research (as described above).
Back to the womb.
In the Bible, Nicodemus asked incredulously whether it was possible to return to his mother’s womb, with the strong implication that it was not (4). Of course, he was right. Here our figurative return to the womb involves looking at the haemoglobin circulating in the foetal blood stream. As in post-natal life, the haemoglobin has to pick up oxygen and deliver it round the body but from where does it get the oxygen? The only source available is the mother’s blood stream circulating through the placenta. The maternal and the foetal bloodstreams do not mix and so this oxygen capture occurs across cellular membranes. The transfer from the maternal to the foetal bloodstreams happens because foetal haemoglobin has a higher affinity (‘grabbing power’) for oxygen than maternal haemoglobin. It can therefore pull the oxygen from the mother’s bloodstream to the foetus’s bloodstream. If you find that hard to imagine, think of a magnet that has picked up some paper clips; if a stronger magnet is brought into the vicinity, it will ‘capture’ the paper clips from the weaker magnet (5).
At birth, a remarkable genetic event starts to occur: the gene encoding foetal haemoglobin is down-regulated by the activity of a repressor gene (known as BCL11A) and the gene encoding adult haemoglobin is switched on. By the time an infant is about six months old, the red cells contain, almost exclusively, adult haemoglobin although most of us continue to make a tiny amount of foetal haemoglobin (about 1% of the total) throughout life. Furthermore, when we look at that small amount of persistent foetal haemoglobin it is clear that it does not carry the sickle-cell mutation, even in people with sickle-cell disease.
Genome editing can cure sickle-cell disease.
The gene-switching phenomenon that I describe above immediately raises the possibility of reversing the switch as a route to curing sickle-cell disease. Indeed, over the past two to three years there have been reports of the success of trials using exactly this approach. The story of one patient, Jimi Olaghere, is told in this BBC article: Sickle cell: ‘The revolutionary gene-editing treatment that gave me new life’ – BBC News.
In practice, the procedure is quite complex but the principle is clear. A patient’s bone marrow stem cells (from which blood cells are produced) are removed. Genome editing is used to inactivate both the mutant adult haemoglobin gene and the repressor that normally switches off the foetal haemoglobin gene. The bone marrow stem cells are put back in the patient who then starts producing foetal haemoglobin. We need to say at this point that because foetal haemoglobin is better at grabbing oxygen than adult haemoglobin it is also less good at releasing it out in the body’s tissues. This is not a problem for a foetus whose oxygen demands are not great but for a child or adult, this probably means that activities with high oxygen demand, including many sports, may be difficult (although golf is clearly possible). Nevertheless, it is obvious from the testimonies of patients like Jimi Olaghere that their lives are so much better after the treatment than before, including being able to play golf without the sickle-cell-associated pain.
I started to compose this blog post on November 13th because I knew of the successful trials and I also learned that regulatory authorities in the USA, the EU and the UK were looking at the trials with a view to authorising the use of this gene-editing procedure in clinical practice. It was therefore very gratifying to turn on the BBC News on November 16th to hear that the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) had approved the procedure for treating both sickle-cell disease and thalassaemia (see below). This was also reported by several daily newspapers (6) and by New Scientist in its daily news (7).
As mentioned above, the MHRA has also authorised the gene-editing procedure for use in treating another inherited haemoglobin disorder, thalassaemia, a move that was warmly welcomed by the Cyprus-based Thalassaemia International Federation (8). The name of the disease comes from the Greek word for sea and the name of the sea goddess, Thalassa (Θάλασσα) in Greek mythology. This is because people living around the eastern Mediterranean exhibit some of the highest incidences of thalassaemia; in an earlier publication (9) I describe programmes in Cyprus aimed at reducing the incidence of the disease. The seriousness of thalassaemia depends on which mutation or mutations a person has but for people with the most serious versions, life can be very difficult. I do not have the space here to describe the genetics or the symptoms in any more detail (see references for further information). However, I do want to emphasise that the trials of the gene-editing procedure described above also involved thalassaemia patients and were equally successful.
A pause for thought.
Overall response to this development has been very positive and rightly so: it is a brilliant use of excellent science. However, I want to pause for a moment to refer back to the opening paragraph. Eighty percent of cases of sickle-cell disease occur in sub-Saharan Africa with high incidences also seen in India and in the Caribbean region. The gene-editing-based treatment is very expensive, although in the UK, the USA and western Europe it is considered that, in cold accounting terms, the cost of this treatment is less than the lifetime costs of dealing with the medical needs of someone with sickle-cell disease or thalassaemia. That may be so but we still need to ask whether the treatment can be made available to the low and middle-income countries where the need is greatest.
A look to the future.
In my blog post for December 2022, I mentioned that a very accurate form of genome editing called DNA base-editing had been used to treat a teenage girl who had T-cell acute lymphoblastic leukaemia. Given that sickle-cell disease is caused by single-base mutation, would it be possible to use base-editing to change the sickle-cell haemoglobin gene back to the normal haemoglobin gene, i.e., to change GTG back to GAG? Well, the answer is not quite. It has not been possible to change the T back to A but it is possible to change it to a C, giving the codon GCG which codes for the amino acid alanine (10). Although this is clearly not the ‘original’ glutamic acid, haemoglobin carrying this change works more or less normally, so perhaps base-editing may eventually become the treatment of choice.
(2) Sickle cell disease - NHS (www.nhs.uk)
(4) Holy Bible, John’s Gospel, Chapter 3, verse 4.
(5) I am grateful to Dr Mark Bryant for this analogy.
(6) For example, The Guardian UK medicines regulator approves gene therapy for two blood disorders | Gene editing | The Guardian.
(7) Casgevy: Sickle cell CRISPR 'cure' is the start of a revolution in medicine | New Scientist.
(8) TIF applauds new thalassaemia therapy | Cyprus Mail (cyprus-mail.com).
(9) Bryant JA & La Velle L (2019) Introduction to Bioethics (2nd edition), Wiley, Chichester, pp. 122-123.
(10) Gene editing shows promise as sickle cell therapy — Harvard Gazette.
Graham writes ...
The James Webb Space Telescope has been in the news again with a reported claim that it has detected evidence of life on an exoplanet located at a distance of about 120 light years from Earth. The media reports are somewhat exaggerated however, suggesting that the James Webb has triumphed again with a momentous breakthrough. But the truth is much less clear cut, and I thought it helpful to have a more objective look at the story to determine the veracity of the claims. Before considering this instance, it is useful, and hopefully fascinating, to review the methodology that the JWST uses to determine the composition of the atmospheres of planets outside our own solar system.
First of all, its worth noting that it is very common for stars, in general, to possess a planetary system, and there is a large and growing catalogue of so-called exoplanets. If we think about our own planet, the depth of the atmosphere is relatively very small, being about 1.5% of the radius of the planet – and only about one tenth of this estimate corresponds to the that part of the atmosphere which is dense enough to support life. So the target of study – the atmosphere of an exoplanet – is generally very small, especially when examined remotely at such large distances. As we have mentioned in previous posts, the JWST is optimised to operate in the infra-red (IR) part of the electromagnetic spectrum, and we have discussed why this is beneficial. However, it turns out that this characteristic is also useful when investigating exoplanet atmospheres. To do this the JWST uses spectroscopy, which is simply the science of measuring the intensity of light at different wavelengths. The ‘graphical representations’ of these measurements are called spectra, and they are the key to unlocking the composition of exoplanet atmospheres. Typically, a spectrum is an array of rainbow colours, but if you capture the spectrum of, say, a star, it will also have discreet dark features called absorption lines. As the light passes through the star’s atmosphere on its way to Earth, the various elements (hydrogen, helium, etc) absorb the light at specific wavelengths, and a particular set of such lines reveals the presence of a particular element in the star’s atmosphere.
Coming back to thinking about the composition of exoplanetary atmospheres, why is IR spectroscopy such a powerful tool? It is at IR wavelengths that molecules in the atmospheres of exoplanets have the most spectral features. In particular, IR spectroscopy is especially effective in detecting molecules that are associated with life, such as water vapour, carbon dioxide, and methane. The detection of these molecules can provide evidence of habitable conditions on exoplanets and even of life itself.
So how does the JWST capture a tell-tale spectrum of the atmosphere of a distant exoplanet? The process requires that the planet transits its star at some point in the planet’s orbit. A transit occurs when the planet is between the star and the Earth, and the planet moves slowly across the disk of the star. Prior to the transit, a spectrum is taken of the star, Spectrum (star). When the planet begins its transit then the received light will have passed through the exoplanet’s atmosphere, as well as emanating from the star. A second spectrum is collected, which contains spectral features from the star and the atmosphere, Spectrum (star and planet). To acquire the spectral features of the atmosphere we difference the two,
Spectrum (planet’s atmosphere) = Spectrum (star and planet) – Spectrum (star).
Hopefully the accompanying diagram helps to appreciate the process.
Getting back to the specific claims about finding evidence of life, the exoplanet concerned is designated K2-18b. The star governing this planetary system, K2-18, is to found 124 light years away in the constellation of Leo. The star is a red dwarf, which is smaller and cooler than our Sun, so that K2-18b orbits at a much closer distance than we do around our Sun. The exoplanet orbit has a radius of about 21 million km, and a period (‘year’) of 33 Earth days. This places it in the habitable zone, where it receives about the same amount of energy from its star as we receive from ours.
The atmospheric composition of K2-18b was examined during two transits in January and June this year, and the results paint a picture of an ocean world with a hydrogen-dominated atmosphere. However, along with hydrogen, water vapour, carbon dioxide and methane, something else showed up called dimethyl sulphide (DMS) which caused a bit of a stir in the media. This is because the main primary and natural providers of DMS on Earth are marine bacteria and phytoplankton in our oceans. So, inevitably, it was heralded as the first detection of a ‘life signature’ on an exoplanet.
The JWST results suggest that DMS makes up about 0.0003% of K2-18b’s atmosphere, but unfortunately in the IR bandwidth used to obtain the results, DMS is degenerate with other atmospheric species – in particular, methane and carbon dioxide. This means that the ‘bump’ in the spectrum produced by DMS is coincident with the spectral features of the other gases, so introducing a difficult ambiguity into the analysis. Looking at the results shows that there is a 1 in 60’ish chance that the detection of DMS is a statistical fluke. So, the conclusion that it is a marker for life is not secure.
Not to be put off by this, the scientists are planning more JWST observations of K2-18b using instruments that look at longer IR wavelengths where DMS absorbs more strongly and unambiguously. However, after due process, my guess is that those results will be another year or so away. I will bring you any further news as it develops …
John writes …
Earlier in the month, I was interested to note that both Nature, the UK’s leading science research journal and New Scientist, the UK’s leading popular science magazine, drew attention to an article about invasive species that had appeared in The New York Times (1).
What do we mean by invasion?
To start to answer this question I go back to the early and middle years of the 20th century and tell the story of three species of bird. The first is the Collared Dove. This originated in India but over several millennia had slowly spread west and became well established in Turkey and SE Europe. Then, in the early 1930s it started to spread north and west, reaching The Netherlands in 1947 and first breeding in Britain (in Norfolk) in 1956. From there it went on to rapidly colonise the whole country. By 1976 it was breeding in every county in the UK, including the Outer Hebrides and Shetland and is now a familiar inhabitant of parks and gardens.
The second bird is a sea bird, the Fulmar, which breeds on maritime cliffs. It is now widely distributed in the north Atlantic and sub-arctic regions but until the late 19th century, its only breeding colonies were in Iceland and on St Kilda, a remote archipelago of small islands 64 km west of the Outer Hebrides. However, in the 1870s, their range started to expand outwards from St Kilda and from Iceland. Fulmars first bred in Shetland in 1878 and then slowly moved south via Orkney, down both the east and west coasts of Britain. They first bred at Bempton in Yorkshire in 1922 and at Weybourne in north Norfolk in 1947.
The range extension included Ireland and Norway in Europe and westwards to Greenland and Canada. In Britain, the west coast and east coast expansions completed the circling of the British mainland by meeting on the south coast in the late 1970s. Since then, southern expansion has continued into northern France.
The third species is the Little Egret, a marshland bird in the Heron family. Until the 1950s, this was regarded as a species of southern Europe and north Africa which was very occasionally seen in Britain. However, it then began to extend its range north, breeding in southern Brittany for the first time in 1960 and in Normandy in 1993. By this time, it was seen more and more frequently along the coasts of southern Britain, especially in autumn (2) and the first recorded breeding was in Dorset in 1996 (and in Ireland in 1997). Little Egrets now breed all over lowland Britain and Ireland and disperse further north in autumn and winter.
These three birds give us clear pictures of ecological invasions. They have extended their range, become established in new areas and are now ‘part of the scenery’. In these cases, the invasions have not been harmful or detrimental to the newly occupied areas nor have any species already there been harmed or displaced. The invaders have been able to exploit previously under-exploited ecological niches and in doing so have increased the level of biodiversity in their new territories.
The ‘balance of nature’ is thus a dynamic balance. Increases and reductions in the areas occupied by species have occurred and continue to do so. Such changes are usually the result of changes in the physical environment or of changes in the biological environment that result from physical changes. At one end of the scale there have been very large physical changes. Consider for example the series of glacial and inter-glacial periods that have been occurring over the past 2.6 million years during the Quaternary Ice Age. The last glacial period ended ‘only’ about 11,700 years ago and during the current inter-glacial period there have been several less dramatic and more localised fluctuations in climate which had some effect on the distributions of living organisms (although obviously not as dramatic as those shifts resulting from alternating glacial and inter-glacial periods).
Having said all this, I need to add that there is no consensus about the reasons for the three dramatic extensions to breeding range that I described above. However, some more recent and currently less dramatic changes in the ranges and/or in migratory behaviour of some bird species are thought to be responses to climate change.
Introductions and invasions.
The natural invasions described above contrast markedly with the situation described in the New York Times feature: the author writes that ‘over the last few centuries’, humans have deliberately or accidentally introduced 37,000 species to areas outside their natural ranges. Nearly 10% of these are considered harmful and it is these harmful introduced species that are termed ‘invasive’. But actually, human-caused animal introductions go back further than the last few centuries. For example, rabbits were introduced to Britain by the Romans, probably from Spain and there is evidence of their being used both as ‘ornamental’ pets and as food. It is not clear when the species became established in the wild in Britain although the best-supported view is that this started to occur in the 13th century. What is clear is that rabbits are now found throughout Britain, with the rather curious exceptions of Rùm in the Inner Hebrides and the Isles of Scilly.
The introduction of rabbits to Britain is probably representative of a slow trickle of introductions as human populations moved across Europe but the rate surely started to increase as the world was explored, colonised and exploited by various European nations. The rate increased still further with, for example, the widespread collection of exotic plants and animals which gathered pace in the 18th and 19th centuries. And alongside the carefully garnered specimens for zoo or garden, there were doubtless species that in one way or another came along for the ride, just as in previous centuries, European explorers and colonisers accidentally took rats into lands where they had never previously occurred.
Further, as international trade and travel has increased since Victorian times – and indeed is still increasing – so the possibility of introductions has also increased and is still increasing (current rate is about 200 per year). Even so, the number of 37,000, quoted above, seems difficult to comprehend, although I do not any way doubt the reliability of the data (provided by the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, IPBES). Further, as mentioned above, nearly 10% of these introduced species cause harm of some sort in their new environment. This may be harm to nature because of negative interactions with native species or because of damage to the environment; it may be damage to agriculture or other aspects of food systems or it may be harm to human health. Taken together, it is estimated that these harmful introductions ‘are causing more than $423 billion in estimated losses to the global economy every year’ (3).
Some examples of harmful introductions.
It is clearly not possible to discuss all 3500+ species whose introductions have been harmful so I am going to present a selection, mainly relevant to Britain, that give examples of different levels and types of harm.
There are several species of rhododendron but only one, Rhododendron ponticum (Common Rhododendron) is considered invasive. Its native distribution is bi-modal with one population around the Black Sea and the other on the Iberian peninsula. These are actually fragments of its much wider distribution, including the British Isles, prior to the last glaciation. It has thus failed to re-colonise its former range after the retreat of the ice and our post-glacial eco-systems have developed without it. In the 1760s it was deliberately introduced to Britain and in the late 18th and early 19th centuries was widely sold by the growing nursery trade both as a hardy ornamental shrub and as cover for game birds. However, it is now regarded as an invasive species: it has covered wide areas in the western highlands of Scotland, parts of Wales and in heathlands of southern England. In all these regions, rhododendrons can quickly and effectively blanket wide areas, to the exclusion of most other plant species and to the detriment of general biodiversity.
This plant is also listed as an invasive non-native species but its invasiveness is more localised than that of rhododendron. Its native range is the Mediterranean region. It was introduced into Britain as an ornamental garden plant in 1806 and was valued for its winter flowering (December to March) and the fragrance of the flowers. Only male plants were introduced and thus the species cannot produce seeds in this country. However, it spreads via vigorous underground rhizomes and can grow from fragments of those rhizomes. Nevertheless, it is not clear how this species became established in the wild, first recorded in Middlesex in 1835: were some unwanted plants/rhizome fragments thrown out? Once established, it quickly covers the ground with its large leaves smothering or shading out nearly all other species. In the two locations that I know where it is growing in the wild, the area covered is increasing year by year. Interestingly, at least one national park authority has a specific policy to control and/or exterminate winter heliotrope while the Royal Horticultural Society has published advice about controlling it when it is grown as a garden plant.
Himalayan Balsam (also known in some cultures as Kiss-me-on-the mountain).
As the name implies this plant originates from the Himalayan region of Asia. It was introduced to Britain in 1839 by Dr John Forbes Royle, Professor of Medicine at Kings College, London (who also introduced giant hogweed and Japanese knotweed!). The balsam was promoted as an easy-to-cultivate garden plant with attractive and very fragrant flowers. In common with other members of the balsam family, including ‘Busy Lizzie’, widely grown as a summer bedding plant, Himalayan Balsam has explosive seed pods which can scatter seeds several metres from the parent plant. It is no surprise then that the plant became established in the wild and by 1850 was already spreading along river-banks in several parts of England. Its vigorous growth out-competes other plants while its heady scent and abundant nectar production may be so attractive to pollinators that other species are ignored. Further, the explosive seed distribution means that spread has been quite rapid. It now occurs across most of the UK and in addition to its out-competing other species, it is also regarded as an agent of river-bank erosion.
This species has been very much in the news this and last year. The main concern is that it is a serious predator of bees, including honey bees, so serious in fact that relatively small numbers of hornets can make serious inroads into the population of an apiary, even wiping it out completely in the worst cases. So why would anyone want to introduce this species? Answer: they wouldn’t. Asian hornets arrived in France by accident in 2004, in boxes of pottery imported from China. From there it has spread to all the countries that have a border with France. Indeed, as the map at the head of this article shows, ideal conditions exist for the Asian hornet across much of Europe. It was first noted in Britain in 2016 and since then there have been 58 sightings, nearly all in southern England (4); 53 of the sightings have included nests, all of which have been destroyed. The highest number of sightings has been in this year, with 35 up to the first week of September. By contrast, there is no evidence that Asian hornets are established in Ireland.
Those who follow me on Facebook or X (formerly Twitter) will know of my encounters with the Box-tree Moth. There has been a major outbreak this year in the Exeter area, with box hedges and bushes being almost completely defoliated by the moth’s caterpillars. At the time of writing, the adults are the most frequently sighted moth species in our area. Box-tree Moth is native to China, Japan, Korea, India, far-east Russia and Taiwan; there are several natural predators in these regions; these keep the moth in check and so damage to box bushes and trees is also kept in check. However, in Europe there are no natural predators and thus a ‘good’ year for the moth can be a very bad year for box. Looking at the pattern of colonisation in Europe it appears that it has been introduced more than once, almost certainly arriving on box plants imported from its native area, as is proposed for its arrival in Britain in 2007 (5). Like the Asian hornet then, its introduction was accidental but it has left us with a significant ecological problem to deal with.
The cane toad is surely the best-known example of deliberate introductions that have gone very badly wrong. As we discuss this, we need to dispel from our minds any notions of toads based on the familiar common toad. Cane toads are, as toads go, enormous, weighing up to 13 kg; they also secrete toxins so that their skin is poisonous to many animals; the tadpoles are also very toxic. Cane toads are native to Central America and parts of South America and have also been introduced to a several islands in the Caribbean. It is a predator of insect pests that feed on and damage sugar cane. It was this feature that led in 1936 to its introduction into Queensland, Australia where it was hoped that it would offer some degree of protection to the sugar cane crop. However, as one commentator stated, ‘The toads failed at controlling insects, but they turned out to be remarkably successful at reproducing and spreading themselves.’ They have spread from Queensland to other Australian states; they have no predators in Australia (in their native regions, predators have evolved that can deal with the toxins). They eat almost anything which means that they are a threat to several small animal species firstly because they compete for food and secondly because the toads eat those animals themselves. The population of cane toads in Australia is now estimated at 200 million and growing and they are regarded as one of the worst invasive species in the world.
Grey Squirrel (also known as the Eastern Grey Squirrel).
Many of us enjoy seeing grey squirrels; they are cute, they are inventive and clever and they often amuse us. But wait a moment – and aiming now specifically at British readers of this blog – these agile mammals that we like to see are not the native squirrels of the British Isles. The native squirrel is the red squirrel which has, over many parts of the UK, been displaced by its larger, more aggressive relative. Grey squirrels imported from the USA were introduced into the grounds of stately homes and large parks from around 1826 right through to 1929. It was from these introduced populations that the grey squirrel spread into all English counties – although it was not until the mid-1980s that they reached Cumbria and the most distant parts of Cornwall. This is an invasion that has been happening during the lifetime of many of our readers. But what is the problem? The problem is that in expanding its range, the grey squirrel has displaced the native red squirrel which is now confined to the margins of its previous range. I need to say that there are several factors that have contributed to this decline but that the grey squirrel is certainly a major one. The grey is more aggressive than the red which is important in that they often compete for the same foods and the grey also seems to be more fertile. Further, the grey squirrel carries a virus which is lethal to the red squirrel. Thus, overall, the introduction of a species to add interest to a stately home or to a large area of parkland has had a significant effect on ecosystems.
As I stated at the beginning, ecosystems are in a state of dynamic balance with some degree of self-regulation. We need to think about this before taking any action that may interfere with that dynamic balance. And also, in view of the ways in which Asian hornet and Box-tree Moths arrived, check incoming packages very carefully!
All images are credited to John Bryant unless stated otherwise.
(1) Manuela Andrioni, Invasive Species Are Costing the Global Economy Billions, Study Finds, The New York Times, 4 September 2023.
(2) On one autumn afternoon in the early 1990s I counted 34 in a flock on the Exe estuary marshes.
(3) Data from IPBES: IPBES Invasive Alien Species Assessment: Summary for Policymakers | Zenodo.
(4) Asian hornet sightings recorded since 2016 - GOV.UK (www.gov.uk).
(5) The Box-Tree Moth Cydalima Perspectalis (2019) (rhs.org.uk).
Graham writes ...
Since the James Webb Space Telescope (JWST) started doing the business, there has been a deluge of rather dubious reports on social media about a variety of crises in cosmology. For example, there have been statements that the telescope has proven that the Big Bang didn’t happen, that the Universe is twice as old as we thought it was, that the very early massive galaxies that JWST has observed are physically impossible, and so on! First, let me reassure you that these ‘stories’ are not true. When we look at the details, it’s clear that this amounts to rumour-mongering or ‘false news’! That’s not to say that the status quo – the standard model of cosmology – is sacrosanct. I’m sure that the new space observatory will make observations that will genuinely challenge our current models. This is not a bad thing. It’s just the way that science works. The new instrument provides a means to modify and enhance our current understanding, and hopefully allow us to learn lots of new physics!
However, having said all that, there is a genuine ‘crisis’ in cosmology at the moment which demands attention, and this is the topic for this month’s blog post. It concerns the value of an important parameter which describes the expansion of the Universe called Hubble’s constant, which is usually denoted by Ho (H subscript zero). This is named after Edwin Hubble, the astronomer who first experimentally confirmed that the Universe is expanding. The currently accepted value of Ho is approximately
70 km/sec per Megaparsec.
As discussed in the book (1) (pp. 57-59), Hubble discovered that distant galaxies were all moving away from us, and the further away they were the faster they were receding. This is convincing evidence that the Universe, as a whole, is expanding (1) (Figure 3.4). To understand the value of Ho above, we need to look at the standard units that are used to express it. I think we are all familiar with km/sec (kilometres per second) as a measure of speed, in this case the speed of recession of a distant galaxy. But what about the Megaparsec (Mpc for short) bit?
A parsec (parallax second) is a measure of distance, and the ‘second’ refers to an angle rather than a second of time. If you take a degree (angle) and divide it by 60 you get a minute of arc. If you then divide the minute by 60 you get a second of arc. So a second of arc is a tiny angle, being one 3,600th of a degree. To understand how this relates to astronomical distances we need to think about parallax. There is a simple way to illustrate what this is. If you hold a finger up in front of your eyes, and then look at it alternatively with one eye and then the other, your finger will appear to move its position relative to the background. Furthermore, it will appear to change its position more when your finger is close to your face, than when it is further away. Keeping this simple observation in mind, the same principle of parallax can be applied to measuring the distance to nearby stars. The diagram below illustrates the idea.
If you observe the position of a star from opposite sides of the Earth’s orbit around the Sun it will appear to move relative to the background of distant stars. When the parallax angle P (shown in the diagram) takes the value of one second of arc, then trigonometry says that the star is 1 parsec away, which is about 3.26 light years. So, getting back to Hubble’s constant, Ho says that the speed of recession of galaxies increases by 70 km/sec for every Megaparsec they are distant, where a Megaparsec = a million parsecs = 3,260,000 light years. Therefore to determine the current value of Ho, you can observe a number of galaxies to estimate their distance and rate of recession and plot them on a graph as shown below. The slope of the resulting plot will give the value of Ho. Hubble was the first to do this in the 1920s, and his estimate was around 500 km/sec per Megaparsec – some way off, but still a remarkable achievement given the technology available at that time.
However, having been somewhat distracted by the units in which Ho is expressed, what is the issue that I introduced in my second paragraph? There are currently two independent ways of measuring the value of Ho. The first of these, sometimes referred to as the ‘local distance ladder’ (LDL) method, is essentially the process we have already described. We establish an observational campaign where we measure the distances and rates of recession of many galaxies, spread across a large range of distances, to estimate the ‘slope of the plotted curve’ as described above.
However, this is not as easy as it sounds – measuring huge distances to remote objects in the Universe is problematic. To do this, astronomers rely on something called the ‘local distance ladder’, as mentioned above. The metaphor of a ladder is very apt as the method of determining cosmological distances involves a number of techniques or ‘rungs’. The lower rungs represent methods to determine distances to relatively close objects, and as you climb the ladder the methods are applicable to determining larger and larger distances. The accuracy of each rung is reliant upon the accuracy of the rungs below. For example, the first rung may be parallax (accurate out to distances of 100s of light years), the second rung may be using cepheid variable stars (1) (p. 58) (good for distances of 10s of millions of light years), and so on. The majority of these techniques involve something called ‘standard candles’. These are astronomical bodies or events that have a known absolute brightness, such as cepheid variable stars and Type Ia supernovae (the latter can be used out to a distance of about a billion light years). The idea is that if you know their actual brightness, and you measure their apparent brightness as seen from Earth, you can easily estimate their distance. This summary is a rather simplified account of the LDL method, but hopefully you get the idea.
The second method to estimate the value of Ho employs a more indirect technique using the measurements of the cosmic microwave background (CMB). As discussed in the book (1) (pp. 60-62) and in the May 2023 blog post, the CMB is a source of radio noise spread uniformly across the sky, that was discovered in the 1960s. At that time, it was soon realised that this was the ‘afterglow’ the Big Bang. Initially this was very high energy, short wavelength radiation in the intense heat of the early Universe, but with the subsequent cosmic expansion, its wavelength has been stretched so that it current resides in the microwave part of the electromagnetic spectrum. The characteristics of this radio noise has been extensive studied by a number of balloon and spacecraft missions, and the most accurate data we have was acquired by the ESA Planck spacecraft, named in honour of the physicist Max Planck who was a pioneer in the development of quantum mechanics. The map of the radiation produced by the Plank spacecraft is shown below. The temperature of the radiation is now very low, about 2.7 K (2), and the variations shown are very small – at the millidegree level (3). The red areas are the slightly warmer regions and the blue slightly cooler.
To estimate the value of Ho based on using the CMB data, cosmologists use what they refer to as the Λ-CMD (Lambda-CMD) model of the Universe – this is what I have called ‘the standard model of cosmology’ in the book (1) (pp. 63 – 67, 71 – 76). This model assumes that Einstein’s general relativity is ‘correct’ and that our Universe is homogenous and isotropic (the same everywhere and in all directions) at cosmological scales. It also assumes that our Universe is geometrically flat and that it contains a mysterious entity labelled dark matter that interacts gravitationally, but otherwise weakly, with normal matter (CDM stands for ‘cold dark matter’). It also supposes that there’s another constituent called dark energy (that’s the Λ bit, Λ being Einstein’s cosmological constant (1) (pp. 55, 56)), which maintains a constant energy density as the Universe expands. So, how do we get to a value of Hubble’s constant from all this? We start with the CMB temperature map, which corresponds to an epoch about 380,000 years after the Big Bang. The blue (cooler and higher density) fluctuations represent the structure which will seed, through the action of gravity, the development of the large-scale structure of stars and galaxies that we see today. The idea is that using the CMB data as the initial conditions, the Λ-CMD model is evolved forward using computer simulation to the present epoch. This is done many times while varying various parameters, until the best fit to the Universe we observe today is achieved. This allows us to determine a ‘best fit value’ for H0 which is what we refer to as the CMB value.
Now, we get to the crunch – what exactly is the so-called ‘crisis in cosmology’? The issue is illustrated in the diagram below, which charts the value of Ho using the two methods from the year 2000 to the present day from various studies. The points show the estimated value of Ho and the vertical bars show the extent of the ±1σ errors in these values. It can be seen that the two methods were showing reasonable agreement with each other, within the bounds of error, until around 2013. However, thereafter the more accurate estimates have diverged from one another. The statistics say that there is a 1 in 3.5 million chance that this situation is a statistical fluke – in other words there is confidence at the 5σ level that the divergence is real. Approximate current values of Ho using the two methods are:
Ho = 73.0 km/sec per Mpc (LDL), Ho = 67.5 km/sec per Mpc (CMB).
This is quite a considerable difference, which influences the resulting model of the Universe. For example, mathematicians among my readers will notice that the inverse of Ho has units of time, and in fact this give a rough measure of the age of the Universe. Our best estimate of the age of the Universe currently is around 13.8 billion years, and the approximation, based on the inverse of Ho, for the LDL method is 13.4 billion years, and that for the CMB method 14.5 billion years. So, roughly a billion years difference in the age estimate between the two methods. So, what can we deduce from all this? Well, put succinctly:
Either (1) the LDL method for estimating cosmic distances is flawed,
Or (2) our best model of the Universe (the Λ-CMD model) is wrong.
Either way, it looks like this divergence in the estimates of Ho will provoke further experimental work to try to understand and resolve the issue. It is certainly the case that JWST’s greater angular resolution can aid in trying to resolve the crisis by investigating the various rungs of the LDL in unprecedented detail. At the time of writing there are various proposals for telescope time in the pipeline to look at this, and some observational campaigns underway. Alternatively, if the Λ-CMD model turns out to be flawed, it will be a shock, but then hopefully it will present an opportunity for scientists to learn lots of new physics. As always, things are not straight-forward and the ‘crisis’ may have far-reaching implications for our understanding of the Universe in which we live.
(1) Graham Swinerd and John Bryant, From the Big Bang to biology: where is God?, Kindle Direct Publishing, 2020.
(2) The Kelvin temperature scale is identical to the Celsius scale but with zero Kelvin at absolute zero (-273 degrees Celsius). Hence, for example, water freezes at +273 K and boils at +373 K.
(3) A millidegree is 1 thousandths of a degree.
John writes …
Cells and organelles
In order to comment on that headline, I need to start with a spot of cell biology. In all ‘eukaryotic’ organisms (i.e., all organisms except bacteria and archaea), cells contain within them several subcellular compartments or organelles. Two of these organelles, the mitochondrion (plural, mitochondria) and in plants, the chloroplast, contain a small number of genes, a reminder of their evolutionary past. These organelles were originally endosymbiotic within cells of the earliest eukaryotes. During subsequent evolution, the bulk of the endosymbionts’ genes have been taken over by the host’s main genome in the nucleus, leaving just a small proportion of their original genomes in the organelles. In mammals for example, the genes in the mitochondria make up about 0.0018 (0.18%) of the total number of genes.
When mitochondria go wrong
The main function of mitochondria is to convert the energy from food into a chemical energy currency called ATP. The average human cell makes and uses 150 million ATP molecules per day, emphasizing the absolutely key role that mitochondria play in the life of eukaryotes. This brings us back to mitochondrial genes. Although few in number, they are essential for mitochondrial function. Mutations in mitochondrial genes may lead to a lethal loss of mitochondrial function or may, in less severe cases, cause some impairment in function. During my time at the University of Exeter, I had direct contact with one such case. A very able student had elected to undertake his third-year research project with me and a colleague. However, towards the end of his second year his eyesight began to fail such that, by the start of his third year his vision was so impaired that a lab-based project was impossible. In a matter of a few months his eyesight had declined to about 15% of what he started with. The cause was a mitochondrial genetic mutation affecting the energising of the retina and hence causing impaired vision (2), a condition known as Leber hereditary optic neuropathy, symptoms of which typically appear in young adults. I need to say serious though it was for the student, this is one of milder diseases caused by mutations in a mitochondrial gene; many have much more serious effects (3), although I also need to say that diseases/syndromes based on mitochondrial genes are very rare.
Is it GM or isn’t it?
This brings us back to the BBC’s headline. Mitochondrial genes are only inherited from the mother. In fertilisation, the sperm delivers its full complement of nuclear genes to the egg cell but its mitochondria do not feature in the subsequent development of the embryo. In the early years of this century, scientists in several countries developed methods for replacing ‘faulty’ mitochondria in an egg cell or in a fertilised egg (one-cell embryo) with healthy mitochondria. This provides a way for a woman who knows she carries a mitochondrial mutation to avoid passing on that mutation to her offspring.
However, there is another issue to deal with here. The replacement of one set of mitochondrial genes with another is clearly an example of genetic modification (GM), albeit an unusual example. In the UK, the Human Fertilisation and Embryology Act, whilst allowing spare embryos to be used in experimental procedures involving GM, prohibited the implantation of GM embryos to start a pregnancy. This would include embryos with ‘swapped’ mitochondrial DNA (or embryos derived from egg cells with swapped mitochondrial DNA). In order to bring this procedure into clinical practice, the law had to be changed which duly happened in 2015. Prior to the debates that led to the change in law, pioneers of the technique gave several presentations to explain what was involved; indeed, I was privileged to attend one of those presentations addressed to the bioscience and medical science communities. It was during this time that some opposition to the technique became apparent and the phrases ‘three-parent IVF’ and ‘three-parent babies’ became widespread both among opponents of the procedure and in the print and broadcast media.
Should we, or shouldn’t we?
I will come back to the opposition in a moment but before that I want to ask whether our readers think that the use of the term ‘three-parent’ is justifiable. My friend, co-author and fellow-Christian, Linda la Velle and I discuss this on pages 52 to 54 of Introduction to Bioethics. In our view, the phrase is inaccurate and misleading and I was pleased to see that the recent BBC headline (in the title of this post) did not use it, even if the headline still conveyed slightly the wrong impression.
Returning to consider the opposition to the technique, there were some who believed that allowing it would open the gate to wider use of GM techniques with human embryos, leading to the possibility of ‘designer babies’. However, there were other reasons for opposition. Since its inception with the birth of Louise Brown in 1978, IVF has had its opponents who believe that it debases the moral status of the human embryo. According to their view, which I need to say, is not widely held (4), the one-cell human embryo should be granted the same moral status as a born human person, from the ‘moment of conception’. There can be no ‘spare’ embryos because that would be like saying there are spare people. This brings us to the two different techniques described in the recent BBC article.
How is it done?
As hinted at briefly already, there are two methods for removing faulty mitochondria and replacing them with fully functioning mitochondria, as shown in the HFEA diagram (below) reproduced by the BBC. In passing, I note that the ability to carry out these techniques owes a lot to what was learned during the development of mammalian cloning. In the first technique, an egg (5) is donated by a woman who has normal mitochondria. This egg is fertilised by IVF as is an egg from the prospective mother who is at risk of passing on faulty mitochondria. We now have two fertilised eggs/one-cell embryos. The nucleus (which contains most of the genes) is removed from the embryos derived from the donated egg and is replaced with the nucleus from the embryo with faulty mitochondria. Thus nuclear transfer has been achieved, setting up a ‘hybrid’ embryo (nucleus from the embryo with faulty mitochondria, ‘good’ mitochondria in the embryo derived from the donated egg). The embryo can then be grown on for two or three days before implantation into the prospective mother’s uterus, hopefully to start a pregnancy. However, readers will immediately realise that this method effectively involves destruction of a human one-cell embryo, raising again objections from those who hold the view that the early embryo has the same moral status as a person (see above).
This brings us to the second method. It again involves donation of an egg with healthy mitochondria but this is enucleated without being fertilised. Nuclear transfer from an egg of the prospective mother with faulty mitochondria then creates a ‘hybrid’ egg which is only then fertilised by IVF and cultured for a few days prior to implantation into the uterus of the prospective mother. The technique does not inherently involve destruction of a one-cell human embryo. However, since the procedure, including IVF, will be carried out with several eggs, there still remains the question of spare embryos, mentioned above. Further, since this technique leads to less success in establishing pregnancies than the first technique, it is likely not to be the technique of first choice in these situations.
So when was that, exactly?
The BBC report which stimulated me to write this blog talked of a ‘UK First’ but that cannot mean that the world’s first case was in the UK. There are well-documented reports from at least three different countries and going back to 2016, of babies born following use of nuclear transfer techniques. The headline must imply that this was the first case in the UK. However, following the change in the law (mentioned above), in 2017 the Human Fertilisation and Embryology Authority (HFEA) licensed the Newcastle Fertility Centre to carry out this procedure. It was predicted that the first nuclear transfer/mitochondrial donation baby would be born in 2018 (although we emphasise that because of the rarity of these mitochondrial gene disorders the number of births achieved by this route will be small). So, when was the first such baby actually born in the UK. The answer is that we do not know. The HFEA, which regulates the procedure, is very protective of patient anonymity and does not release specific information that might identify patients. All we know is that ‘fewer than five’ nuclear transfer/mitochondrial donation babies have been born and that the births have taken place between 2018 and early 2023 – so, in respect of the date of this ‘UK First’ we are none the wiser.
28 June 2023
(1) Baby born from three people’s DNA – BBC News.
(2) My colleague and I were able to offer him a computer-based project and the university’s special needs office provided all that he needed to complete his degree.
(3) See, for example: Mitochondrial DNA Common Mutation Syndromes, Children’s Hospital of Philadelphia – chop.edu.
(4) In Life in Our Hands (IVP, 2004) and Beyond Human? (Lion Hudson, 2012), I discuss the wide range of views on this topic among Christians.
(5) Although I use the singular for the sake of convenience, several donated and several maternal eggs are used in these procedures.
Graham writes …
This question has occupied cosmologists since the theory of cosmic inflation was first developed by Alan Guth in 1979, who realised that empty space could provide a mechanism to account for the expansion of the Universe.
In the theory it is assumed that a tiny volume of space-time in the early Universe – very much smaller than a proton – came to be in a ‘false vacuum’ state. Effectively, in this state space is permeated by a large, constant energy density. The effect of this so-called ‘inflaton field’ is to drive a rapid expansion of space-time for as long as the false vacuum state exists. I won’t go into the detail of how this happens here (1), but as a consequence the tiny nugget of space-time grows exponentially, before the energy density decays to acquire a ‘true vacuum’ state once again, bringing the inflationary period to an end. Theoretically, this expansion takes place between roughly 10 to the power -36 (10e-36) sec (2) and 10e-32 sec after the bang (ATB) – periods of time that makes the blink of an eye seem like an eternity. To generate a universe with the characteristics we observe today, the expansion factor must be of the order of 10e+30. To give an impression of what this degree of expansion means, if you expand a human egg cell by a factor of 10e+25, you get something about the size of the Milky Way galaxy! The diagram below helps, I think, to illustrate the time line of developments ATB. Clearly the horizontal time axis is not linear!
To me, the events of the inflation era seem extraordinary, prompting the question in the title of this post. However unlikely these events may seem, the cosmic inflation paradigm has been very successful in resolving problems which have dogged the ‘conventional’ theory of the big bang as originally proposed by Georges Lemaître in 1927 (3), for example, the horizon and flatness problems. A summary of these issues, and others, can be found here.
When we use Einstein’s field equations of general relativity, we make an assumption that on cosmic scales of billions of light years, the Universe is homogeneous and isotropic. In other words, it appears the same at all locations and in all directions. These simplifying symmetries are what allows us to use the mathematics to study the large-scale dynamics of the Universe. A nice analogy is to think of the Universe as a glass of water, and each entire galaxy as a molecule of H2O. In using the equations, we are examining the glass of water, and ignoring the small-scale molecules. However, cosmology at some point has to come to terms with the idea that when you examine the Universe at smaller scales you find clumpy structures like galaxies. And here we are faced with a conundrum.
The primary question addressed in this post is along the lines of ‘what is the origin of the inhomogeneities that led to the development of the clumpy structures like galaxies and stars that we observe today?’ Without these, clearly we would not be here to contemplate the issue. If we assume that cosmic inflation occurred, then the initial ‘fireball’ would be microscopically tiny. Its extreme temperature and energy density, just ATB but before the inflationary expansion, would be able to reach equilibrium smoothing out any variations. So, the question posed above becomes key. If the resulting density and temperature of the inflated universe was uniform, then how did galaxies form? Where did the necessary inhomogeneities come from? It is gratifying that the inflation theory offers progress in answering this question – indeed, remarkably, the initial non-uniformities that gave rise to galaxies and stars may have come from quantum mechanics!
This magnificent idea arises from the interplay between inflationary expansion and the quantum uncertainty principle. The uncertainty principle, originally proposed by Werner Heisenberg, says that there are always trade-offs in how precisely complementary physical quantities can be determined. The example most often quoted involves the position and speed of a sub-atomic particle. The more precisely its position is determined, the less precisely it speed can be determined (and the other way round). However, the principle can also be applied to fields. In this case, the more accurate the value of a field is determined, the less precisely the field’s rate of change can be established, at a given location. Hence, if the field’s rate of change cannot be precisely defined, then we are unable to determine the field’s value at a later (or earlier) time. At these microscopic scales the field’s value will undulate up or down at this or that rate. This results in the observed behaviour of quantum fields – their value undergoes a characteristic frenzied, random jitter, a characteristic often referred to as quantum fluctuations.
This takes us back then to the inflaton field that drives the dramatic inflationary expansion of the early Universe. In the discussion in the book (1), as the inflationary era is drawing to a close it is assumed that the energy of the field decreased and arrived at the true vacuum state at the same time at each location. However, the quantum fluctuations of the field’s value means that it reaches its the value of lowest energy at different places at slightly different times. Consequently, inflationary expansion shuts down at different locations at different moments, resulting in differing degrees of expansion at each location, giving rise to inhomogeneities. Hence, inflationary cosmology provides a natural mechanism for understanding how the small-scale nonuniformity responsible for clumpy structures like galaxies emerge in a Universe that on the largest scales is comprehensively homogeneous.
So quantum fluctuations in the very early Universe, magnified to cosmic size by inflation, become the seeds for the growth of structure in the Universe! But is all this just theoretical speculation, or can these early seeds be observed? The answer to this question is very much ‘yes!’. In 1964 two radio astronomers, Arno Penzias and Robert Wilson made a breakthrough discovery (serendipitously). The two radio astronomers detected a source of low energy radio noise spread uniformly across the sky, which they later realised was the afterglow of the Big Bang. This radiation, which became know as the cosmic microwave background (CMB), is essentially an imprint of the state of the Universe at around 380,000 years ATB (4). Initially the Universe was a tiny, but unimaginably hot and dense ‘fireball’, in which the constituents of ‘normal matter’ – protons, neutrons and electrons – were spawned. Initially electromagnetic (EM) radiation was scattered by its interaction with the charged particles so that the Universe was opaque. However, when the temperature decreased to about 3,000 degrees Celsius, atoms of neutral hydrogen were able to form, and the fog cleared. At this epoch, the EM radiation was released to propagate freely throughout the Universe. Since that time the Universe has expanded by a factor of about one thousand so that the radiation’s wavelength has correspondingly stretched, bringing it into the microwave part of the EM spectrum. It is this remnant radiation that we now call the CMB. It is no longer intensely hot, but now has an extremely low temperature of around 2.72 Kelvin (5). This radiation temperature is uniform across the sky, but there are small variations – in one part of the sky it may be 2.7249 Kelvin and at another 2.7251 Kelvin. So the radiation temperature is essentially uniform (the researchers call it isotropic), but with small variations as predicted by inflationary cosmology.
Maps of the temperature variations in the CMB have been made by a number of satellite missions with increasing accuracy. The most recent and most accurate was acquired by ESA’s Planck probe, named in honour of Max Planck, one of the pioneering scientists that developed the theory of quantum mechanics. The diagram below displays the primary results of the Planck mission, showing a colour coded map of the CMB temperature fluctuations across the sky. Note that these variations are small, amounting to differences at the millidegree level (6). This map may not look very impressive to the untrained eye, but it represents a treasure trove of information and data about the early Universe which has transformed cosmology from the theoretical science it used to be to a science based on a foundation of observational data.
The final icing on the cake is what happens when you carry out calculations based on the predictions of quantum mechanics that we discussed earlier. The details are not important here, but diagram 1 shows the prediction where the horizontal axis shows the angular separation of two points on the sky, and the vertical axis shows their temperature difference. In diagram 2 this prediction is compared with satellite observations and as you can see there is remarkable agreement!
This success has convinced many physicists of the validity of inflationary cosmology, but many remain to be convinced. Despite the remarkable success of the theory, the associated events that occurred 13.8 billion years ago seem to me to be extraordinary. And then, of course, there is also the issue of the origin and characteristics of the inflaton field that kicked it all off.
Despite all this, however, I am blown away by the notion that the 100 billion or more galaxies in our visible Universe may be ‘nothing but quantum mechanics writ large across the sky’, to quote Brian Greene (7)
(1) Graham Swinerd and John Bryant, From the Big Bang to Biology – where is God?, Kindle Direct Publishing, 2020, see Section 3.6 for more detail.
(2) In the website editor, I am unable to use the usual convention of employing superscripts to represent ‘10 to the power of 30’ for example. In the text I have used the notation 10e+30 to denote this.
(3) Georges Lemaître’s publication of 1927 appeared in a little-known Belgium journal. It was subsequently published in 1931 in a journal of the Royal Astronomical Society.
(4) Graham Swinerd and John Bryant, From the Big Bang to Biology: where is God?, Kindle Direct Publishing, 2020, pp. 60 – 63 for more details about the CMB.
(5) The Kelvin temperature scale is identical to the Celsius scale but with zero Kelvin at absolute zero (-273 degrees Celsius). Hence, for example, water freezes at +273 Kelvin and boils at +373 Kelvin.
(6) A millidegree is 1 thousandths of a degree.
(7) Brian Green, The Fabric of the Cosmos, Penguin Books, 2004, pp. 308-309.
John Bryant and Graham Swinerd comment on biology, physics and faith.