Blog – What's in our genes

Gene Therapy for Hunter’s Disease

The complex molecules which make up our cells are in a state of perpetual turnover: new ones are being made and old ones broken down and recycled. This recycling is carried out by lysosomes, tiny structures within each of our cells. Lysosomes contain some 50 different degrading enzymes, each one breaking down a different set of large molecules.

There are around 70 rare inherited diseases caused by mutations affecting these lysosomal enzymes. One such is Hunter’s disease. This a very rare, affecting around one in every 100,000 newborn boys.

Hunter’s disease is caused by a rare faulty gene located on the X chromosome. Women, having two X chromosomes, are protected from this disease. Should one of their X chromosomes carry this mutant gene, in all likelihood their other X chromosome will carry a normal working version of this gene. This single working gene will be sufficient to spare them any symptoms. So they will be healthy carriers of the faulty gene. But males have only a single X chromosome, so there is a 1 in 2 chance that any son of a carrier mother will inherit the faulty gene and have Hunter’s.

The gene in question, IDS, encodes one of the enzymes which breaks down complex carbohydrate molecules that are present in every tissue. In the absence of a working version of this enzyme, these molecules accumulate and perturb cell functions. All body tissues are affected, but the most serious symptoms develop in the brain. Hunter’s boys are born apparently healthy but within a few months start to show abnormalities, including movement problems, a loss of skills and intellectual impairment. Their lives are short.

A number of treatments for Hunter’s have been developed including bone marrow transplantation and injection of replacement IDS enzyme, but these have limited effect on the serious neurological consequences.

It has just been announced that a 3 year-old boy, Oliver Chu, has been treated by a new experimental gene therapy at the Royal Manchester Children’s Hospital in the UK.

Stem cells from Oliver’s bone marrow have been isolated and treated with an artificial virus which has delivered a working copy of the gene into them. On re-infusion back into Oliver, these cells have repopulated his bone marrow and given rise to mature white blood cells. Such cells then travel around his body taking the functioning enzyme to all his tissues.

One year on, the treatment is working and Oliver is developing normally. Another four Hunter’s boys have been recruited into this experimental trail.

It is early days, but this new gene therapy is bringing great hope to the affected families.

27th November 2025

A Gene Therapy for Huntington’s Disease

Huntington’s disease is a rare but particularly horrible genetic condition. It occurs at an incidence of around 100 people in every million for those with European ancestry, but is much rarer in those of Asian and African descent.

People with Huntington’s disease develop normally but typically in their 30s to 50s develop clumsiness due difficulties in control their movements. There is then a progressive neurodegeneration causing emotional and behavioural changes, memory loss, cognitive decline, immobility, difficulties in swallowing, and eventually, dementia and premature death.

The late emergence of the disease means that by the time a diagnosis is made, patients are likely to have become parents, and there is a 50% chance they will have passed the mutant gene responsible for this condition to any child they have, girl or boy. So a long shadow is cast over affected families.

Now some hope is at last being offered to these families. An initial trial using a genetically engineered virus has shown highly promising results. A team of researchers at University College London has developed this virus to block the production of the faulty protein encoded by the mutant gene. Treatment requires the precise injection of this virus into affected regions deep in the brain. This is not a cure but it shows a dramatic slowing of disease progression, offering many years more of productive and independent life.

The mutation causing Huntington’s disease involves a particular mechanism. At some point deep in human history the gene involved developed a repeat sequence of three bases within the DNA of the gene. Using the conventional one letter code to represent these bases, they are C, A and G, making the triplet CAG. Within the Huntington’s disease gene we find this repeated many times in tandem:-

– C A G C A G C A G C A G C A G C A G –

Most people have between 6 and 27 such CAG repeats at a particular site in the gene involved and they will be free of the disease. But when the DNA is repaired or copied, by mechanisms which are not entirely clear, additional CAG copies may be added to this sequence. Now it becomes hazardous:

People with 27 to 35 repeats are unlikely to suffer, but may have children who do.
More than 36 repeats is likely to confer the disease, with severity increasing with the number.

Around 10% of Huntington’s cases have no family history of the disease, as they arise from a new expansion mutation arising between the generations.

Huntington’s is not the only disease arising from this repeat expansion mechanism. Some 20 others are known, each arising from similar mutations in different genes. These are all rare disease, but it shows that our human DNA is not as stable as we might hope.

30th September 2025

Preventing Mitochondrial Genetic Diseases.

The human genome comprises some 20,000 genes encoded on the DNA stored in the nucleus of each of our cells. But this is not quite the whole story. There are 37 genes encoded in small pieces of DNA found in tiny cell bodies called mitochondria. Each cell contains a number of mitochondria. These consume oxygen to perform the biochemical reactions which generate the energy to drive cellular processes. So this tiny number of genes are essential for the normal functioning of the body, particularly in the nervous system and heart which have high energy demands.

This mitochondrial DNA can be affected by mutations which result in congenital diseases. Cases are rare, around 1 in every 5,000 births, but there can be major impacts on the development of children, in the most severe cases causing serious disability and early death.

When the fertilisation of an egg takes place, the mitochondria in the father’s sperm are all destroyed, so our mitochondrial DNA comes exclusively from our mothers. This means that mitochondrial DNA diseases are inherited solely down the female line of affected families. Most women carrying such mutations have a mix of normal mitochondria and mutated mitochondria, and in generally having 20% of normal mitochondria is sufficient to stave off disease. But when their eggs develop there are unknown random selection processes taking place which reset the proportion of normal to mutated mitochondrial. This means that when such women wish to become mothers, they face a terrible dilemma. Their children may be severe affected, or alternatively they may be fortunate enough to be spared the disease themselves, although they will still be carriers of the mutations to subsequent generations.

A research team in Newcastle, UK, has just published a set of papers in the New England Journal of Medicine describing the early results of a method to allow affected families to escape this dismal fate.

This is an area of medical research which requires the utmost caution as any unforeseen side-effects might affect generations to come. This research remains unlawful in the USA, but in the UK a restricted regulatory approval was issued 10 years ago.

The team’s approach is based on in vitro fertilisation. Immediately after fertilisation has occurred, the new nucleus combining the mother’s and father’s DNA is removed from the egg to leave the mother’s mitochondria behind. It is then transferred to a newly activated donor egg, replacing the donor egg’s own nucleus. Now the embryo can develop with the support of the donor’s normal mitochondria.

The Newcastle team now report that 8 health babies have been born following this proceed. All have developed normally, the oldest now being 24 months old. 5 have no detectable mutant mitochondrial DNA. The other 3 do retain low levels of it, but well below those which risk disease. This will have arisen because of carry-over of the mother’s mitochondria during the transfer to the donor egg. The great success of this study to date offers real hope to the affected families.

23rd July 2025

A New Gene Therapy for an Inherited Cause of Blindness.

The concept of gene therapy, to treat diseases caused when people inherit a faulty gene, has now been around for half a century. Modern genetic technology is used to deliver a working copy of the particular gene, thereby tackling the root cause of the disease. There are over 5,000 diseases known to be caused by single faulty genes. Many of these are very rare, but this is not always the case, for example sickle cell anaemia and cystic fibrosis.

But the progress of gene therapy has been modest, with the list of those approved for routine use growing only slowly. A number of scientific challenges need to be overcome, not the least of which is inserting the working gene into the actual cells in the body where it is required.

The retina lining the back of the eyeball contains layers of cells critical for light perception and sight. The functioning of these delicate cells can be impaired in over 270 different single gene diseases. Fortunately these cells are readily accessible for the delivery of working copies of genes packaged into suitable artificial viruses. So several gene therapies to treat loss of sight are now available.

Recently a successful new gene therapy has been described by a large international research team centred on the UK National Institute for Health Research at Moorfields Eye Hospital in London. Congenital diseases causing loss of both types of light receptor cell in the retina affect some 3 in every 100,000 children at birth. At least 26 different faulty genes are known to cause such loss, but mutant variants of one gene, AIPL1, are responsible for 1 in 20 of these cases. Children lacking a functional AIPL1 gene have severely impaired vision at birth which then deteriorates rapidly.

The team delivered a working copy of AIPL1 into one eye of 4 children aged between 1 and 3 who had been diagnosed with this particular disease. 3-5 years later all four children were found to have markedly improved vision in the treated eye, whilst the untried eye deteriorated as expected. There were no serious side-effects.

This study paves the way for the development of this treatment for children with this specific form of congenital blindness, and hopefully it will soon become an approved gene therapy for this particular cause of blindness.

As the working gene is being targeted only to the retina, the treated children will still pass their faulty gene on to any offspring they might eventually have. Nonetheless the gift of sight to young children is a wonderful thing.

27th Feb 2025

Jumping Genes Are More Than Just Junk DNA.

Our genomes contain a remarkably high number of highly repetitive DNA sequences. These are called transposons because, even more surprisingly, they can occasionally copy themselves and get re-inserted at new positions in the chromosomes, even jumping across from one chromosome to another. This rare activity results in them being referred to as ‘jumping genes’.

Transposon repeats account for almost 50% of the human genome. Transposons are most likely the remnants of viruses which in our distant evolutionary history infected cells and somehow took up permanent residence in the DNA. In humans the most abundant transposon is a sequence called Alu. It is estimated that Alu first became integrated into early primate genomes some 65 million years ago, since when it has replicated many times over. In the human genome there are around a million copies of Alu, with the precise number and their positions within the chromosomes differing from one person to another. Alu and its variants make up around 10% of the human genome.

Transposon DNA has usually undergone heavy modification to render it inactive. So unlike our function genes they have no obvious role in gene activity, and have often been referred to as ‘junk DNA’. But such a dismissive term should be used with caution, as we often regard something as junk only because we can’t recognise its purpose and value.

If this repetitive DNA has no purpose, why has it persisted and even expanded throughout evolution? It represents a considerable burden of DNA that must be replicated every time a cell divides. Moreover it is not without hazard. Some cases of genetic diseases have been caused by a transposon jumping into the middle of a functional gene, disrupting its ability to produce the protein it encodes.

There are ideas that transposons may serve structural roles in the way that DNA is coiled up within our cells, or that they be raw material for future evolution. However a recent study published in the journal Science has established a clear function for some transposons.

The research team behind this paper were investigating how pregnant mothers produced the additional blood needed to support the growing foetus as well as their own body tissues. It had previously been shown that the female hormone estrogen plays a key role, but on studying the details of the control mechanism involved, the team made the unexpected discovery that a set of five transposons become highly active. This happened only within the cells in the spleen responsible for making the additional red blood cells. They further showed that this transposon activation is essential for the extra blood production, not just in pregnancy, but also after any substantial loss of blood.

This finding of a functional role for transposons raises the possibility that other transposons might have similar active roles during the growth of other tissues as the embryo develops. But it is certainly a major challenge to the questionable concept of ‘junk DNA’.

6th Nov 2024

A Key Susceptibility Gene in Inflammatory Bowel Disease.

Around one in every twenty people lives with a persistent autoimmune or inflammatory disease. Prominent amongst these are the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease. We lack highly effective treatments for these conditions, so managing them is difficult. Severe cases may even require the surgical removal of damaged parts of the bowel.

An authoritative research paper published this month by a large international team in the journal Nature has shed important new light on these diseases by identifying a particular gene variant which has a key role in causing them. It had been known previously that a specific region within Chromosome 21 could carry a genetic predisposition to developing such diseases. By employing a highly detailed study of the DNA within this region, the team identified the key gene sequence. Interestingly this is not a typical gene encoding a single protein. Rather, it is a regulatory genetic element called an enhancer, which increases the expression of another gene, ETS2.

The team then conducted detailed studies into the effects of ETS2 in human macrophages and monocytes in cell culture. These two cell types are central to the firing up of inflammatory responses, in the gut and elsewhere in the body. The team established that ETS2 promotes highly levels of pro-inflammatory activity.

So the mechanism which emerges here is that a relatively common gene variant carried on Chromosome 21 is able to enhance the activity of ETS2, which in turn orchestrates an over-active inflammatory response.

The challenge now will be to find drugs able to down-modulate this mechanism, but in a way which still allows its normal functioning, as we depend on a normal level of ETS2 signalling to protect our guts from potentially harmful infections.

12th June 2024

Circulating Tumour DNA: DNA in Blood Provides Genetic Clues in Cancer Treatment

Our DNA is essentially located within the central nucleus of our cells, but fragments of it leak out into the circulatory system. These can be detected by taking a small blood sample. Should cancer cells be present in the body, fragments of their DNA can also leak into the blood stream. These fragments from cancer cells are referred to as circulating tumour DNA, or ctDNA for short.

Cancer is basically a genetic disease in which dangerous mutations accumulate in body cells, causing them to divide continuously and escape the normal controls of cell growth. What is more, cancer cells can become genetically unstable, accumulating further mutations. In particular when a cancer becomes metastatic, throwing out secondary growths at distant sites in the body, the metastatic colonies usually harbour more mutations and grow more aggressively. They can also be difficult to detect.

These complexities in cancer pose a number of questions for the doctors treating it:-

is the treatment being used working?
which the various available cancer drugs is likely to be the most effective in a particular individual patient?
are further metastatic colonies developing?
is a patient who appears to be in remission actually remaining cancer free?

One way of addressing such questions is to use gene sequencing to analyse the patient’s ctDNA, to measure how much of it there is and to identify the particular cancer-driving mutations present. In this way a drug targeting the mutations found can be selected, and any new mutations can be identified.

Currently a great deal of research is going into working out the usefulness and reliability of such ctDNA analysis. Already a small but growing list ctDNA tests have received regulatory approval for use in particular cancers. It is very likely that more will follow.

Any advances which improve the treatment and monitoring of cancer patients is very welcome.

18th April 2024

How A Gene Risk Factor for Multiple Sclerosis Entered Europe

Multiple Sclerosis, MS, is a disease causing a range of symptoms including stiffness, partial paralysis and visual problems. It is caused by the patient’s immune system attacking the protective sheath surrounding nerve fibres, resulting in localised nerve damage. The disease often shows episodes of damage followed by slow recovery, or it can be progressive.

Globally around 2.5 million people have MS, but there is high prevalence in Scandinavia and some European countries including Italy and Germany. Here just over 1 in every 1,000 people can be affected.

MS develops in adulthood. The causes are unclear, and probably complex. Environmental factors are undoubtedly significant. For instance the widespread Epstein-Barr virus commonly infects us in childhood where it appears essential harmless. But people who are first infected with it as adults have a 30-fold increased risk of developing MS.

MS is not a straight-forward genetic disease: it is not inherited. But extensive analysis of the genomes of MS patients identified some 230 gene variants which are associated with the disease. Prominent among these is a variant of the HLA system which is a key component of immune responses. This variant is known by the code name HLA-DRB1*15:01. It is estimated to confer a 3-fold higher risk of MS on those who carry it. This is some 20% of the Northen European population, a much higher proportion than found in southern and western Europe.

So how did this relatively localised abundance of HLA-DRB1*15:01 arise? In a series of 4 papers recently published in the journal Nature, a large international team reported their extensive analyses of the genomes of ancient and medieval skeletons across Europe. This combined with archaeological evidence reveals that Europe was populated by 6 waves of different peoples migrating in from the east. One of these, animal herders from the Steppes, the Yamnaya people, carried the HLA-DRB1*15:01 gene variant. The Yamnaya contributed heavily to the gene pool of Northern Europe and Scandinavia. Moreover the frequency of HLA-DRB1*15:01 in these populations increased in the medieval period, most likely as it offered better resistance to waves of infectious diseases.

The thinking is therefore that the survival advantage of a powerful immune system also carries with it an increased risk of autoimmune diseases such as MS.

31st Jan 2024

First Approval for Use of Gene Editing for the Treatment of Haemoglobin Disorders

I previously blogged about the exciting development of the new technique of gene editing for the treatment of sickle cell disease (Gene Editing for the Treatment of Sickle Cell Disease. 1^st March 2022). In a world first, the UK Medicines Regulatory Agency has now approved this procedure. This approval also covers use in the related disease of β-thalassaemia.

Both conditions are inherited diseases affecting the production of the blood protein β-haemoglobin. They are comparatively common in people whose ancestry arose in the Mediterranean, Middle East, Africa or Asia. The explanation is that these regions, at least historically, where affected by malaria. Although the mutations causing sickle cell disease and β-thalassaemia are harmful under normal conditions, they do give some protection from malaria.

These two disease cause a great deal of suffering. Current treatment options for both conditions are limited and cannot fully protect from long term complications, so patients face shortened life expectances.

The new gene editing treatment uses the recently developed editing tool CRISPR which enables pin-point changes to be made in a single gene. The discovery of CRISPR was awarded a Nobel Prize in 2020.

The licenced treatment, called Casgevy, involves taking a sample of the patient’s own bone marrow stem cells, and modifying them by CRISPR. The patient’s remaining bone marrow cells are then depleted, and the gene edited cells are returned. The patient is likely to need a hospital stay of a month in a protected ward while the modified bone marrow regenerates to full activity. It is therefore not an easy treatment, nor does it come cheap. But set against it are the considerable costs of the current management and treatment of these conditions. Since it is only bone marrow cells which receive the gene editing, the edit will not be passed on to any children the patients may have after treatment.

Casgevy takes a subtle approach to tackling these diseases because it does not target the faulty β-haemoglobin gene directly. Instead it targets a controlling gene called BCL11A. In adults the β-haemoglobin chain is a major component of haemoglobin, the oxygen carrying protein. But in the foetus a further chain, γ, is found in its place: there is a γ to β switch at birth. It has long been known that those few individuals with sickle cell disease or β-thalassaemia who persist in producingγ beyond birth are spared the worst effects of these diseases. Some years ago it was discovered that the γ to β switch is controlled by the BCL11A gene. Casgevy disrupts BCL11A to block the switch away from γ, allowing its production to continue. thereby ameliorating the effects of the faulty β gene.

Of the 70 or so patients treated by Casgevy and followed up for a 12 month period, over 90% were free of disease episodes and had no need for additional treatment. This apparent cure represents a step change in their clinical management. They will continue to be monitored to find out how long these cures last. Also, although CRISPR is a very precise gene editing tool, does there remain a risk, however small, of it hitting the wrong target in the DNA? Given the marked benefits of Casgevy for these patients it seems a risk worth taking, but due to the extreme novelty of this approach, this needs to be monitored this carefully.

Following this first approval for the medical use of CRISPR can we look forward to more approvals for its use in other genetic diseases?

29th Nov 2023

Long Covid – a Predisposing Gene?

Although most people recover promptly and completely from Covid-19 infection, a significant number suffer long Covid, persistent and often very debilitating symptoms. This is an intractable problem as it is poorly understood and lacks really effective treatments. One issue is that long Covid is probably not a single disease entity, but a set of related conditions.

Modern gene technology has made it feasible to sequence the entire genomes of large numbers of individuals. Computer searches can then compare the genomes of sufferers from a particular disease to those of a healthy control group. The implication here is that any genetic variants which are over-represented in the disease group are likely to have a role in predisposing people to that disease. This provides clues as to how the disease might develop, and how it might be treated.

To apply this approach to the study of Covid-19, an international collaboration of researchers called the COVID-19 Host Genetics Initiative (HGI) has been set up. They have been studying various aspects of Covid-19 infection including long Covid. In a recent publication, yet to be independently reviewed, a group within the HGI has announced that a particular variant of a single gene called FOXP4 is significantly over-represented in long Covid patients.

Although the computerised searches employed by the researchers scanned across the entire genome in an unbiased manner, it is perhaps not surprising that the link to they found was to the gene FOXP4. This gene is known to be active in various sites in the body including the lung, the obvious target organ in Covid-19, but also in some cells of the immune system. It is a member of a family of regulatory genes that control cell activity.

The same variant of FOXP4 is already known to be a risk factor for developing severe Covid-19, and such severe disease is known to be in turn a risk factor for developing long Covid. Nonetheless, the researches estimated this did not explain fully its strong link with long Covid. So FOXP4 is likely to promote long Covid in other ways too.

This new finding suggests a focus for those wanting to understand better this long-term health problem for both individual sufferers and our public health services. A first step will be to determine precisely how the specific FOXP4 variant identified here differs in activity from other variants of this gene.

20^th July 2023

©CC Rider

Gene Therapy for the Devastating Disease of MLD.

A little girl called Teddi has become the first recipient of a novel gene therapy provided by the UK’s National Health Service. Teddi was born with the inherited disease of MLD (or in full, metachromatic leukodystrophy) because she lacks a critical enzyme.

MLD is a very rare genetic condition affecting around 1 in 100,000 babies, but it is typical of a large number of equally rare diseases called the ‘inborn errors of metabolism’. Each of these diseases is caused by the lack of a different enzyme and they arise from faulty genes.

We all carry about half a dozen faulty genes in our individual genomes, but we are protected from such diseases by having two copies of each gene, one inherited from each of our parents. If we inherit a single faulty gene copy, the other working copy still produces sufficient levels of the enzyme or protein it encodes to provide for good health.

Genetic disease strikes when both parents have one good copy and one faulty copy of the same gene. They themselves will be quite healthy and unaware of any risk to their potential children. Unfortunately there is a 1 in 4 random chance that any child of theirs will inherit two faulty copies, and will therefore be unable to make the corresponding enzyme.

This was the case with Teddi’s parents, and they had the bad luck that their elder daughter, Nala, was born with MLD. As is often the case in such diseases, the babies are born normal, because they have used the mother’s metabolism as a life support system. After birth, it takes a few months for the metabolic consequences of the disease to emerge. In the case of MLD the missing enzyme is important in recycling a class of metabolic products called sulfatides. These then accumulate inside cells, particularly those essential for protecting nerve fibres, not just in the brain but around the entire body. The protective cells are gradually killed off by the accumulating sulfatides, and the now unprotected nerves become damaged.

Typically, the affected toddler may have begun walking and talking, but then gradually regresses into severe disability, becoming immobile, losing their sight, hearing, and all other sensory inputs.

Because MLD is very rare and beyond the expertise of most doctors, Nala already had severe neurological damage by the time her exact diagnosis was established. But this sad outcome alerted doctors to test Teddi early, to find that she too had MLD. This made the early intervention of the new gene therapy feasible before any damage occurred.

This gene therapy treatment is called Libmeldy. A sample of the stem cells from Teddi’s bone marrow was taken when she was 10 months old and infected with a harmless virus engineered to carry a working version of the faulty gene. Next Teddi was given powerful chemotherapy to eliminate all her remaining bone marrow stem cells. This potentially dangerous step is needed to ensure that when she receives back her genetically modified stem cells, they are not in competition with any uncorrected ones.

Her treated stem cells then took up residence in her bone marrow and populated her circulatory system with white blood cells expressing the previously missing enzyme. These travel around the body, breaking down the sulfatide, effectively curing her MLD.

Her prospects for a long and healthy life are now good. One boy given Libmeldy as part of its clinical trial some 10 years ago is now a healthy and active 12 year-old. In more general terms there is now hope that this type of treatment can be developed for other inborn errors of metabolism.

©CC Rider

20th Feb 2023

The Genetic Shadow of the Black Death

The Black Death was a highly infectious and usually fatal disease caused by the bacterium Yersinia pestis. The pandemic which raged across Northern Africa, Europe and the Middle East between 1345 and 1350 killed as much as 50% of the population. So did this massive and sudden death toll shape the human population? Did the survivors have favourable genes which they then passed on to subsequent generations?

These questions were addressed by a large team of human geneticists mostly based at the University of Chicago, in a study recently published in the journal Nature. The team started by studying DNA extracted from 360 skeletons buried either just before, during, or just after the Black Death plague. Most were exhumed from three graveyards in east London, close to the Tower of London and St. Paul’s Cathedral, but some were from equivalent burials in Denmark.

Searching for gene variants which abruptly increased in frequency at the time of the Black Death, they ended up with 4 clear examples, of which the strongest was a particular variant of the ERAP2 gene. The frequency of this variant in those surviving the Black death was double that in the population prior to the pandemic. So it would appear that this variant favoured survival.

The protein encoded by the ERAP2 gene is known to have a role in the immune response. There are two common variants of ERAP2. The variant associated with survival produces a full length, stable protein. The other variant produces a shorter protein which tends to be rapidly degraded within the cell.

To examine a role for ERAP2 in the response to Yersinia pestis, the team isolated immune cells from living donors with the different ERAP2 gene variants and infected them with the bacterium. Those cells with the full length, stable protein were better at killing the bacterium.

But the full length ERAP2 protein is not all good news. It is known to be a risk factor for developing an autoimmune condition called Crohn’s disease. This is a persistent inflammatory disease of the bowels and intestines, and it affects around 2 people in every thousand in Europe and North America. So it looks as if the price paid for improved survival from the Black Death, was a propensity to develop autoimmune disease.

Overall this study highlights a number of significant points:-

A pre-disposition to developing certain auto-immune conditions is likely to be an outcome of genes inherited from survivors of the Black Death.
The rapid increase at the time of the Black Death in the prevalence of a gene variant associated with resistance of bacterial infection shows Darwin’s theory of natural selection at work in human evolution.
For many genes, it is not a simple question ‘good gene’ variants and ‘bad gene’ variants. Rather there are gene variants which are favourable in some circumstances (such as during pandemics of bacterial disease), but unfavourable in others (propensity to develop autoimmune disease).
A powerful immune response is not always what you want.

27^th Oct 2022

A Nobel Prize for the Genetics of Human Evolution.

Congratulations to Professor Svante Pääbo for winning the 2022 Nobel Prize in Physiology and Medicine for his ground-breaking work on the genetics of human evolution. The Swedish born scientist, now at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, is not exactly a stranger to this Prize. His father, the biochemist Sune Bergström, was awarded a share of this award in 1982.

Prof. Pääbo’s work is on the sequencing of ancient DNA fragments obtained from the fossilised bones of early hominids. Over several years up to 2010, his team was able to assemble a complete genome sequence of Neanderthals. This could then be compared to the genome sequence of modern man, Homo sapiens. Surprisingly, several portions of the sequence were common to both, establishing that Neanderthals and Homo sapiens had interbred on more than one occasion. Cleary we can only speculate as to the circumstances of this genetic interflow. It does however overturn the previously established view that as Homo sapiens migrated out of Africa it had progressively displaced Neanderthals from Europe and Asia as it colonised these regions. This new genetic evidence shows instead that these two early hominids, at least for a time, must have lived side by side.

Another big surprise to come out of Pääbo’s work, was that when his team sequenced the DNA they extracted from a hominid finger bone found in the Denisova Cave in southern Siberia, it was neither Neanderthal nor sapiens. In other words, they had discovered a previously unknown extinct hominid branch, which is has been called the Denisovans. Even now, few physical remains of Denisovans have been found, but there is evidence for them being in Tibet, and arguably elsewhere too.

There is further evidence of hominid interbreeding, between Neanderthals and Denisovans. Indeed Pääbo’s team, on analysing the DNA from one bone fragment showed it was from a woman, which they nicknamed Denny, who had a Denisovan Father and a Neanderthal mother.

Although Neanderthals and Denisovans became extinct, some of their genes survive in modern human populations. In people whose ancestry orginates in Europe and Asia, up to 6% of their genome is Neanderthal in origin. Pääbo and his team suggest this inheritance has consequences, by demonstrating that a small cluster of Neanderthal genes located on chromosome 3 is a risk factor for the development of severe Covid-19 infections. Some 16% of Europeans and 50% of south Asians carry at least one copy of the Neanderthal versions of these genes.

Denisovan genes contribute to modern populations in south east Asia including the aboriginal peoples of Oceania. The Denisovan variant of the gene EPAS1, which aids the body’s response to limited oxygen availability, is common in Tibetans. It is thought to be an adaption to living at high altitude.

These insights into the unexpectedly complex origins of modern man provided by Prof. Pääbo’s study of genomes could never have been obtained by conventional archaeology or palaeontology. He has provided an accessible account of his research in his 2014 autobiographical book ‘Neanderthal Man: In Search of Lost Genomes’.

12^th Oct 2022

Did a tiny change in a single gene drive the evolution of modern humans?

For a period of perhaps 500,000 years modern humans lived alongside earlier hominids, in particular Neanderthals. But by some 50,000 years ago, the other hominids had disappeared leaving just us, Homo sapiens, to take over the planet.

Quite what happened here we will never know, but genome sequencing is providing some intriguing insights. The genomes of modern humans can now be compared with those obtained from archaeological bone fragments of early hominid remains. Amongst other findings, this shows rather surprisingly, that Homo sapiens interbred with their hominid cousins on multiple occasions across Europe and Asia. In fact Neanderthals contribute around 2% of the DNA of those modern human populations which arose outside Africa.

A high quality Neanderthal genome sequence was obtained from a fossilised toe bone excavated from a cave in Siberia. This showed only a modest set of changes from the genomes of modern humans. These changes would have affected the structures of just 85 of the many thousands of different proteins that humans produce.

Fossilised skeletons show that Neanderthals were shorter and stockier than we are. But evidence from the tools and art left behind suggest that early Homo sapiens were the more skilful and imaginative. The consensus is that despite being less physically powerful, they were the more cunning hunter-gathers, and so out-competed the Neanderthals.

Measurements of fossilised skulls show that the overall brain size of Neanderthals was the same as that of modern humans. These fossils leave no record of the brain structure, but the conjecture is that the neocortex is better developed in Homo sapiens. The neocortex is the brain region responsible for higher cognitive activities, involved in attention, thought, perception and memory.

Of the 85 genes found to differ between Neanderthals and modern humans, 5 are associated with the development of the neocortex. One these genes, active in the developing human neocortex, is called TKTL1. This was the subject of a recent paper in the journal Science, published by a team of researchers based in Dresden and Leipzig, Germany. The TKTL1 gene of Homo sapiens produces a protein over 550 amino acids long. A tiny change in the gene causes it to differ by just a single amino acid from the equivalent protein produced by the Neanderthal TKTL1 gene. Amongst their findings, the team showed that the introduction of the Homo sapiens TKTL1 gene into a simple cell culture system of developing human brain increased the number of cells destined to become nerve cells. By contrast, introduction of the Neanderthal version of the gene did not.

The authors propose that the tiny difference between the Neanderthal and modern human version of the TKTL1 may have driven the development of a more advanced human neocortex. Could small gene changes such as this have been responsible for ultimate dominance of Homo sapiens?

©CC Rider

28^th Sept 2022

Gene Editing for the Treatment of Sickle Cell Disease

The recently developed technique of gene editing now enables us to make targeted changes within single genes. Any such edits will be life-long alterations of an individual’s DNA, and so this approach must be used with great caution. Nonetheless we are starting to see the first applications of gene editing to treat inherited diseases arising from faulty genes.

Amongst the most widespread of such diseases are those affecting for the red blood cell protein, haemoglobin. The most common of these is sickle cell disease. Globally, each year some 300,000 people are born with this inherited disease and they will have to live with this painful disease which can have serious debilitating consequences.

The faulty gene causing sickle cell disease persists in various populations in spite its harmful effects because it offers some protection from malaria. Many countries, from the Mediterranean through the Middle East and into much of Africa and Asia, once had high levels malaria. So people whose families originated from these regions can carry this faulty gene.

In sickle cell disease, the haemoglobin produced is less stable than the normal form. When it is destabilised it distorts the red blood cells it is packed in to. These then change from their normal rounded structure into a flattened and curved shape, reminiscent of the blade of a sickle, hence the name of the disease.

When the circulatory system is stressed, for instance during periods of intense cold, the amount of red blood cell sickling increases, and the distorted red blood cells can jam together and block small blood vessels. This causes intense pain, and can result in damage to the tissue normally supplied with oxygen by the blood vessels involved. Sickle cell patients will suffer periodic episodes of this throughout their lives.

Haemoglobin is the major protein of red blood cells and is responsible for carrying oxygen from the lungs around the body, and it has been studied intensively. Over 60 years ago, a biochemist called Vernon Ingram found that sickle cell disease arises from just a single aminoacid change in one of the two protein chains which make up the major form of adult haemoglobin.

This scientific breakthrough has until now not provided much benefit for patients. Treatments have largely been limited to pain killers and drugs aimed at stabilising their haemoglobin. Although new treatments have been introduced, they tend to be limited and less than satisfactory. Most do not address the route cause of the disease.

The major form of haemoglobin is composed of two protein chains, α and β. The sickle cell gene mutation affects only the β, chain: the α chain remains completely normal. During gestation, the developing foetus mostly expresses a different form of haemoglobin, in which α is combined instead with a third type of chain, γ. This αγ combination binds oxygen slightly tighter than the adult αβ combination, so that oxygen is drawn from the mother’s blood into the foetal red blood cells, and then around the foetus’s growing body. Around birth, γ production is switched off and β starts to replace it. Since this replacement is never complete, a little αγ persists in the adult. This persistent αγ is known to protect sickle cell patients against the worst outcomes of the disease.

We now know that the switch from γ to β production involves a gene called BCL11A, and we also know how it works. Interfering with this switch, should result in less αβ haemoglobin being produced in the adult, and more αγ should persist. In the USA, trial treatments of sickle cell patients have used the precise technique of gene editing to inactivate a specific target site on the BCL11A gene. The results show the levels of αγ haemoglobin now produced is indeed raised, at the expense of the faulty αβ. Critically, in the few patients treated thus far, this effect has been sufficient to prevent further sickling attacks.

This outcome is not a true cure for sickle cell, as the fault in the β gene remains, but at last it is beginning to look as if this nasty disease can now be effectively treated. More trials of this gene editing therapy will be needed to judge whether it should be approved for routine use.

1st March 2022

Building the Body – HOX Genes

We start off our existence as a single fertilised cell, which as a result of several rounds of cell division becomes a simple ball of cells. How do we get from this to the fully formed, complex body of first a baby, then a child, and finally a fully grown adult? How do we develop a complex body plan with many different organs, all of which need to be the correct size and in the right place? Consider for instance our skeleton which has over 200 bones, many of which fit together in complex articulated joints that must have correctly attached muscles, tendons and ligaments to permit controlled movements.

Many different genes play a role in governing this development, but one important family of closely related genes are the HOX genes. These particular genes were first discovered by geneticists studying the development of the humble fruit fly. Their attention was drawn by bizarre mutations affecting the body plan, for example a leg which should be attached to the middle of the body sprouted in place of an antenna at the front of the head.

HOX genes are also found in animals. Like all mammals, humans have a total of 39 HOX genes, and these are again important in the development of the body plan. They are grouped together in four separate clusters on different chromosomes. Each cluster is a linear array of between 9 and 11 HOX genes.

In general, similar genes with related functions tend to be scattered around the DNA of our chromosomes in an apparently random manner, so that you can tell very little about the function of a gene from its location on a chromosome. The HOX genes are a standout exception to this.

In mammals the primary axis of development runs along the length of the body trunk, down the spine from the skull to the pelvic girdle, and in most species a tail. Remarkably the HOX genes are lined up in their arrays in precisely the order in which they function in this axis. So the first genes in the array govern the development of the vertebrae of the neck, just under the skull. Next are those responsible for the chest region with their attached ribs, then those governing the abdominal region, and then those controlling attachment of the pelvis and so on. It is thought that as the developing spine elongates downwards from the head end, a developmental clock progressively switchesonthe next HOX gene in the arrays in turn.

But the spinal axis is not the only developmental axis. Each of our limbs, arms and legs, has a developmental axis extending out from the attachment to the torso at shoulder/pelvic girdle, through the upper limb to elbow/knee joint, then the lower limb, wrist/ankle and eventually to the 5 digits (fingers/toes). HOX genes acting in the same sequence control these limb axes too.

We now know that in the fully formed adult body HOX genes retain their controlling activities. They are important in maintaining the body tissue structures and functions, amongst other things regulating the turnover of individual cells and their replacement by new ones. As such, their activities appear to become disorganised when these processes go wrong, which is what happens in cancer. So what started around a century ago as the study of genes in fruit fly development, through identifying the genes involved, is now leading to new insights into the abnormal body processes which give rise to cancer.

5^th Jan 2022

Gene Therapy for Babies with Severe Spinal Muscular Atrophy

A 5-month old baby boy called Arthur, diagnosed with the devastating condition of spinal muscular atrophy, has become the first patient to be treated in the United Kingdom by the National Health Service with a new gene therapy.

Spinal muscular atrophy, SMA for short, affects around 1 in every 10,000 births and is the result of mutations in a gene called SMN1. It is an inherited disease and babies born with it have mutations in both of their copies of the SMN1 gene. The absence of a functional SMN1 gene means they cannot make the corresponding protein.

Their parents will be healthy carriers with one normal SMN1 gene and one mutant copy, and it is this mutant copy which they will both have passed on to their affected child. In the parents, the single normal copy of the gene means that they are able to make the SMN protein in their cells, so they are unaffected. Around 1 in 50 of the population have a single SMN1 gene mutation and will be unaware of it, unless they have children with someone who also has such a mutation. Even then, their children have only a 1 in 4 risk of suffering from SMA. So nearly all the SMN1 gene mutation carriers in the population will be quite unaware of the danger to their children lurking in their mutated version of this genes. There is unlikely to be any family history of this condition amongst their relatives.

The affected children, lacking a normal functional SMN1 gene, are unable to make the SMN protein. Its absence causes the motor nerve cells emerging from their spinal columns to begin to die. These are the cells which control the movement of muscles, and as they die the muscles become progressively unresponsive and weaker. Babies with the most serious form of SMA face a short and limited existence. These babies are unable to sit up, and lose the ability to move their limbs and heads. Eventually the muscles needed for breathing begin to fail, and very sadly these children are unlikely to survive until their 3^rd birthdays.

In 2019, the US Food and Drug Administration approved a gene therapy developed by Novartis for use in babies with severe SMA. Other jurisdictions have now followed suite. This involves infusing the children with a harmless virus modified to carry a normal copy of the SMN1 gene. Once these viruses have entered the baby’s cells, the SMN protein can be made, and the motor nerve cells will cease dying. Nearly all of the children in the clinical trials of this gene therapy have shown benefits, being able to breathe unaided at 14 months of age, and with a half of them able to sit independently at 18 months. Some treated children have reported even better responses. At present is too soon to be able to report the long-term outcomes of this treatment.

Now that we have an effective, if highly expensive treatment, it is important to diagnose SMA children as early as possible. Usually they are diagnosed at around 3 months of age onwards, when they fail to achieve the normal developmental milestones in mobility, such as reaching to grasp objects. The issue here is that once an affected child has been born, motor nerve cells are being lost steadily, and they cannot be replaced. A number of countries already use a genetic test to screen all babies at birth for SMA, and the pressure is now on for this to be adopted more widely, so as to maximise the benefits of this new gene therapy.

©CC Rider

2^nd Jun 2021

A Mutated Gene Which Causes Cancer

The adult human body is estimated to contain a total of 37 trillion cells. We have all arisen from a single fertilised cell by many rounds of cell division, giving firstly 2, then 4, then 8, then 16 cells and so forth. Once we have reached adult size, cell division is then tightly regulated to maintain the correct number of cells at the appropriate anatomical site. Any remaining cell division is balanced to only replace worn out or damaged cells. In cancer this tight regulation goes awry.

Cancer arises from damage to our DNA which results in a particular cell type undergoing continuous and uncontrolled cell division. In this way an excess of unnecessary and unwanted cells accumulates in the body. Over the last 50 years or so, cancer research has revealed that it is mutation in certain specific genes which drives the development of cancers. These genes are called oncogenes.

One instance of such genes are the set of three which carry the instructions to make normal variants of a protein called Ras. The Ras proteins act as signalling switches within our cells. Cells from time to time receive activating signals from within the body. When these become strong and prolonged, they can trigger the cell to start dividing and to become highly active. Ras has a role in transmitting such signals from the outside of the cell to its central nucleus, in which all our genes are stored.

Normally Ras flickers on and off according to these signals, as its structure is switched rapidly between active and inactive states, rather like a controlling circuit within a complex electronic device. However there are certain tiny errors, or mutations, which can occur within the Ras genes. Some of these then cause the Ras proteins they produce to be permanently locked into the ‘on’ state. If this happens, the signalling circuit which Ras participates in is permanently active and the cell is driven to undergo cell division without ceasing, producing more and more overactive cells.

Ras mutations are found in around one quarter of all human cancers, although the proportion varies greatly from one cancer type to another. For instance some 90% of pancreatic cancers contain mutations in a Ras gene, whereas other cancers show very little. With modern gene sequencing techniques, it is straight forward to find out whether the cancer in an individual patient has the Ras mutations, or not.

Cancer researchers are now trying to find ways of switching off excess Ras signalling in those cancers containing these mutations, but the challenge of being able to do this effectively and safely has so far proved elusive.

Ras is just one of several well-established oncogenes which can cause cancer when they are mutated.

©CC Rider

2^nd Feb 2021

Genes and Severe Covid-19

The Covid-19 virus has varying effects on different people. Many people experience no noticeable symptoms and their infections will only be revealed should they undergo a Covid-19 test. Others may experience just moderate symptoms which pass in a few days. However the real problem lies within the group of individuals who develop life-threatening respiratory disease. This is highly distressing and can even prove fatal, especially in the elderly, or those with pre-existing heart or lung conditions. Why is there such a very broad spectrum of response to Covid-19 infection? One interesting possibility is that disease severity may depend on the amount of virus someone is infected with. But another possibility is that some people have a genetic pre-disposition to respond badly to Covid-19.

It is this last possibility which has been investigated by a large international research group led by Dr J K Baillie in Edinburgh. This team scanned the entire genomes of 2244 patients who are in UK intensive care wards with severe Covid-19. They then performed computer searches which compared the frequency of gene variants within this group to those occurring amongst a large control group in the extensive UK genome database. They next verified their findings on a further group of 2415 severe Covid-19 patients. This work enabled them to identify 4 genome regions with particular gene variants found more often in the severe Covid-19 groups. To this another gene was added which does not have a variant DNA sequence, but which is expressed at higher levels in the Covid-19 sufferers compared to the normal population.

By knowing the individual genes involved in these variations it is possible to group them into two classes. One of these classes is involved in the very early responses to virus infection. Because such responses will have come into play several days before a patient develops severe Covid-19, there is little prospect that medical interventions here will be of benefit.

However the second class of genes control inflammatory responses, and it is dangerous over-reaction of on-going inflammatory responses in the lung which is the problem in severe Covid-19. Here there is hope that the new research has identified a new target suitable for clinical treatment. One gene in this second class is called Tyk2 (pronounced as tyke two) and this encodes an enzyme which drives prolonged inflammatory responses. The Tyk2 gene variant identified in severe Covid-19 causes too much Tyk2 enzyme to be produced. Excitingly, there is already a drug called baricitinib which is used to inhibit Tyk2 in the treatment of rheumatoid arthritis, another disease of excessive inflammation, in this instance in the joints rather than the lungs. Since baricitinib is already in clinical use, we already have a full knowledge of its safety profile and suitable dosage levels. Now we just need a clinical trial in severe Covid-19 to find out whether baricitinib does actually save lives and might speed the recovery of a patient who is in a very ill state in intensive care. If it does, it will not only provide a huge benefit, but it will also become a great example of how advanced genetics can provide improvements in medical care.

©CC Rider

14^th Dec 2020

Tocilizumab – a new Covid-19 drug obtained through genetics

Last week, almost buried by the latest positive announcements on Covid-19 vaccines, was the good news of a successful drug trial. Tocilizumab, a drug used for the treatment of severe arthritis, has been shown to more than halve the death rate in hospitalised patients with severe Covid-19 pneumonia.

In severe Covid-19 infections, over-activity of the patient’s immune system presents a danger to their survival, so doctors have been looking for ways to damp down this excessive response. The anti-inflammatory steroid, dexamethasone, was the first drug shown to have positive effects in this way. Now tocilizumab, which has previously been used to reduce immune over-activity in rheumatoid arthritis has been proven to benefit patients with severe Covid-19.

Tocilizumab works in a completely different way from dexamethasone. It specifically targets and blocks a protein on a major activation pathway which normally acts to trigger immune reactions. By blocking this particular protein, immune activation is reduced. So what does this have to do with genetics?

Well firstly, like many proteins in the immune system, the targeted protein could only be identified by first finding its gene. Secondly, once this gene hunting was successful, genetic engineering within research laboratories was needed to study the properties of this protein, and to raise an antibody which would recognise it specifically.

Finally, this antibody was initially generated in a laboratory mouse, so it is a mouse-derived antibody. As a foreign antibody it will not work well once administered into patients. The patient’s immune system will start to neutralise and remove it. To avoid this, more genetic engineering is needed to snip out the small elements of the antibody which actually bind to the target and graft them into a human antibody backbone. Such an antibody is now mostly of human origin and is therefore referred to as a humanized antibody.

Increasingly some our new important and most powerful medicines are humanized antibodies, for use in the treatment of serious diseases including rheumatoid arthritis and cancer.

In the case of tocilizumab, it still needs licence approval for use in severe Covid-19 infection, but since there is much clinical experience of its use in rheumatoid arthritis, this should be a straight-forward process. We can therefore be confident that we now have a new brick in the wall of our defences against the coronavirus.

©CC Rider

23^rd Nov 2020

What is an RNA Vaccine?

Congratulations to Pfizer and BioNTech on the successful interim results of their RNA vaccine against Covid-19. It is an extraordinary achievement to have reached this stage within some 10 months, when normally developing a vaccine this far would take around 10 years. This new candidate vaccine is a novel type of vaccine, being an RNA vaccine. Such vaccines have only been possible in recent years, resulting from advances in genetics. But what is an RNA vaccine, and how do they work?

Most people will be aware that the genes of living organisms, including humans, exist as DNA, or to give it its full chemical name deoxyribonucleic acid. This formal name arises from the fact that its backbone is made up of the sugar, deoxyribose. This is derived from the more usual sugar ribose by removing an oxygen atom from it, hence deoxyribose.

When a gene becomes active, it is copied out as a strand of RNA, in full, ribonucleic acid. RNA is very similar to DNA, but its name is due to a key chemical difference. Its backbone is made from normal ribose, not deoxyribose. This RNA version of the gene then directs the production of multiple copies of the encoded protein.

Many viruses, including Covid-19, do not have DNA. Instead the few genes they possess are in the form of RNA. When such viruses infect a cell, they release their RNA, which then hijacks the cell into making lots of the different viral proteins from which new virus particles can be assembled.

An RNA vaccine mimics this process but in a limited way. An artificial RNA encoding just a single virus protein is produced. Upon injection, this artificial RNA enters some of the recipient’s cells where it makes just the single encoded protein. The process is inherently safe because the other Covid-19 genes are absent, so the other proteins the virus needs cannot be made. Instead the single Covi-19 protein appears on the surface of the recipient’s cells. There it will be detected by the recipient’s immune system as a ‘foreign’ i.e. non-human protein. An immune response will then be triggered. This means that should, at a later time, the recipient encounter Covid-19, they will be protected from it.

One point should be made clear. Just because this is a RNA vaccine, and RNA is closely related to DNA, it cannot alter our own DNA, and so will not change our genetic make-up. In time the vaccine will be eliminated from our cells.

There are a number of hurdles to be overcome before this new vaccine can be licensed, and since this is a new type of vaccine, the authorities regulating the use of medicines will be especially vigilant. Another issue is that since RNA is not very stable, the vaccine will have to be stored and transported at very cold temperatures (-70^o C). This raises complications in delivering it to clinics for use.

Nonetheless this vaccine candidate gives some hope at the end of the long and dark Covid-19 tunnel.

©CC Rider

12^th Nov 2020

Jumping Genes Are More Than Just Junk DNA.

6th Nov 2024

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