Weight loss drugs of a new class

High cal foodI once attended a pharmacology conference at McCormick Place in Chicago. It’s a huge conference centre and navigating its many halls is daunting for someone like me who has no sense of direction. Ambling towards the lecture theatre I wandered through the exhibition hall festooned with donut stands, pretzel stalls, breakfast burritos, waffles and pancakes. If my breakfast then left me thirsty, I could wash it all down with a morning caramel macchiato from the ubiquitous Starbucks booth. The irony on this day was the morning lecture was on the development of anti-obesity drugs.

Around 9% of the world’s population is undernourished (660 million people) while about twice that number are classified as obese. In the United States, 42% of the adult population is classified as obese, with around 28% in the UK.  But before I get too holier-than-thou, there’s evidence to suggest humans are evolutionarily hard wired to overeat when there’s an abundance of food and so perhaps obesity is an inevitable consequence of a developed economy? Obesity leads to other conditions such as cancer, diabetes and heart disease, putting pressure on already stretched clinical services, and therefore represents a genuine medical need.

Anti-obesity drugs have a rocky history. Drugs such as fenfluraminephentermine and lorcaserin have all been withdrawn, at least in some countries, because of serious side effects. But there may, just possibly, be two new drugs that offer some hope. They started out as treatments for type-2 diabetes – and are still prescribed as such, but a serendipitous observation in the clinical trials led to a redirection towards appetite suppression. 

The two drugs are semaglutide and tirzepatide. They are both small proteins (more accurately termed polypeptides) with lipid molecules attached to facilitate their crossing of biological membranes. Semaglutide and tirzepatide are made from 31 and 39 amino acids respectively and are classified as recombinant DNA produced polypeptides, meaning they are manufactured through genetically engineered bacteria. These drugs are therefore a long way from traditional chemical synthesis and exemplify how modern biochemical technology has impacted on healthcare. (Incidentally, insulin is manufactured through genetically engineered organisms, a technology first identified in 1978, and so the process has a reasonable track record). 

How do semaglutide and tirzepatide work? The story starts, perhaps unsurprisingly since we’re talking about weight gain, with eating. As food passes from the oesophagus into the gastrointestinal tract, the duodenum releases two hormones. One is called gastric inhibitory polypeptide (GIP) and the other is called glucagon‐like peptide‐1 (GLP‐1). Although each of the two hormones has their own receptors, they nevertheless have similar actions. Combined, they signal the pancreas to release insulin and suppress the production of the glucagon, two hormones involved in regulating blood sugar (for a more detailed account of the pharmacology of GIP and GLP-1 see here).

Semaglutide mimics the action of GLP-1 and tirzepatide mimics both GLP-1 and GIP, explaining why they were originally developed to treat type-2 diabetes. But the release of GIP and GIP-1 has effects other than on glucose metabolism. They slow gastric emptying and signal the brain’s hypothalamus to suppress the feeling of hunger. (The rare genetic disorder Prader-Willi Syndrome, where patients overeat because they constantly feel hungry, may be caused by a dysfunctioning hypothalamus). Semaglutide and tirzepatide therefore, in effect, highjack the body’s hormonal signalling system, resulting in apatite suppression. Clinical trials of the two drugs have achieved weight loss of between 15 and 22%, which is pretty impressive.

These drugs do not however, offer the “eat anything you like without consequences” panacea that some may seek but are reserved for those patients with obesity at the more severe end of the spectrum. They might for example, offer an alternative to bariatric surgeries. The drugs, being peptides can’t survive the digestive processes of the gastrointestinal tract and so have to be administered by weekly injection; as far as we know currently, this would be for a lifetime. Moreover, side effects vary from patient to patient but include vomiting, nausea, diarrhoea and constipation (the effects can be eased to some extent by increasing the dose over time). So at least for now, weight management for the majority of us remains very much in the balance between calorific intake and expenditure.


an image of the author’s ankle taken by gamma-scintigraphy. The darker areas show regions of osteoarthritis.Arthritis is a term used to describe several inflammatory conditions affecting joints. As is so often the case with medical history, the name was derived from observed symptoms but subsequently it was found these were the result of a plethora of different causes. Today, “arthritis” covers around 100 different conditions associated with joint disease. Rheumatoid arthritis, for example, is an autoimmune condition, where the patient’s immune system attacks the tissues of joints. Osteoarthritis, on the other hand, is caused by physical damage to joints, particularly protective cartilage. Osteoarthritis has particular interest for me as I am a sufferer. It started with a motorcycle accident when I was in my early 20s and over the years damage to cartilage in my ankles has worsened to the point it can now be difficult to walk for more than a few meters. The condition leads to chronic pain, sometimes severe enough to be debilitating. There are few drugs available to manage osteoarthritis. Sometimes anti-inflammatories have benefit and opioid-type drugs are used to ameliorate pain. Opioids over the long term however, become less effective and have problems of their own.

The reason osteoarthritis is painful might seem obvious. Bones of the joins rubbing on each other, leading to inflammation and sometimes bleeding within the joint. The complexity of biochemistry however, is not something which should be taken for granted. Recent research suggests an unexpected pathway triggers osteoarthritic pain.

Artemin is a protein released from vascular smooth muscle, which then binds onto another protein called GFRα3. One artesian protein binds centrally to two GFRα3 proteins, which triggers nerves acting as relay stations between neurones (known as preganglionic neurons) near to the inflamed joint. This mechanism is already known as a response to heat and cold. If you want to trigger artemin-GFRα3 simply place your hand in a bowl of ice cold water. What’s new is the association of artemin and GFRα3 with arthritic pain. 

Opioid-type drugs bind to receptors in the spinal cord or brain (the three main receptors being known as mu, delta and kappa) and have a generic effect on the sensation of pain. These drugs also cause sedation and euphoria, patients can become dependent and they can have adverse effects on the gastrointestinal tract. If the artemin-GFRα3 pathway effect is confirmed, then this may offer a new more specific target for pharmacologic intervention of osteoarthritic pain, something likely to be welcomed by the 8.5 million suffers in the UK, including me.

Being realistic however, and knowing how long new medications take from concept to market, then I doubt I will see this potential new class of drugs in my lifetime. But all new treatments start somewhere and so perhaps in the next 20-years, we might see some long awaited advances. Non-arthritic fingers crossed.

Homeopathy Awareness Week

It’s world homeopathy awareness week and so I thought I would oblige and make people aware of one of the most prevalent and pernicious forms of alternative medicine in existence. There are many who steadfastly believe in homeopathy even though the foundations not only have no basis in reality, they are really quite bizarre.

Preparation of a homeopathic remedy involves taking a substance which causes similar symptoms to some disease or ailment, followed by an enormous dilution of the substance to the point where not a single molecule remains. The resulting “therapy” (which is now just water) is then claimed to have therapeutic benefit while being devoid of side-effects.

To give an example, a dripping nose and running eyes are symptomatic of the common cold. According to the homeopathic ethos, onions offer treatment because they cause similar symptoms. The homoepath dilutes an extract of onion to make, for example, a 30C preparation. The 30C notation shows that the extract undergoes a one in a hundred dilution, thirty times over. To put this level of dilution into context, it is equivalent to ten billion times more dilute than a single atom contained within the planet Earth.

So what’s the harm if some gullible people want to spend their money on rather expensive water? If homeopathy only applied to treating running noses, then perhaps that’s not so bad. The trouble is however, some homeopaths claim to treat serious conditions such as haemophilia, AIDS, a replacement for vaccination, diabetes and infectious disease including Covid-19. Some homeopathic organisations are careful about what they recommend and may even say homeopathy should not replace regular medication. I’ll give credit for an attempt at ethical behaviour, but not all homeopaths are so moral. Many homeopaths also claim homeopathy is good science, and by inference all the genuine medical researchers in the world are bad scientists. Believe me, homeopathy is not science by any definition of the word, but this does not stop the proponents of homeopathy from trying to sound scientific. Perhaps at the more bizarre end of homeopathy sit remedies such as Murus Berlinensis – a scientific sounding name for an ultra dilution of pieces of the old Berlin wall – yes the Berlin wall, the one that was demolished in 1989.

The counter argument for homeopathy has focused on the huge dilution factors. Skeptics point out that the idea that ultra-dilution increases potency contradicts the laws of physics, chemistry, biology and just about any other legitimate science. Homeopaths respond by saying that water has a memory of the starting material, although there is no evidence for such an effect. Homeopaths also claim preparation of the dilutions are special through striking the vial in a process they call “succussion”. The physics behind succussion remains unclear.

There are many clinical studies that have looked at homeopathy. The homeopaths will select those that claim to show efficacy, science will look at all the data and conclude there is no effect. Of course, bad science can provide evidence for whatever you choose.

For my part, I don’t find the clinical studies that helpful as the fundamental premise of homeopathy is so implausible. And for my money, although the theory of increased dilution leading to increased potency is absurd, this does not deliver the homeopathic coupe de grass. There is another aspect of homeopathy that is often overlooked, the one that claims a substance that causes similar symptoms to some ailment will also be an effective cure. This is what’s known in homeopathic circles as the law of similars.

Let’s imagine that a scientist with the combined mental acuity of Newton, Einstein and Feynman won the Nobel Prize by showing that water had a ‘memory’. Homeopathy proven, right? Well no, because it still doesn’t explain how (to use the above example) onion is an effective treatment for the common cold. Back before it was known germs caused disease, back when leeches were state-of-the-art medicine, back when people died of what we might consider minor ailments today, a teleological philosophy prevailed. Plants effective against heart disease, for example, had heart-shaped leaves. Walnuts were good for the brain because they looked like little brains. If you are not familiar with the mushroom Phallus impudicus, then Google an image and take a guess what medical condition it might be used for.

These were the origins of the law of similars based upon medieval superstitions. Samuel Hahnemann continued with those traditions and applied the law of similars when he invented homeopathy in 1796. That the shape of a plant directs a physician towards its therapeutic use is not part of modern science. Those who argue against homeopathy seem to focus on the ridiculousness of the dilution but not so much on the ridiculousness of the law of similars. I am not sure why because either one of these hypotheses invalidates homeopathy as a science but the two together are a synergistic double whammy.

Homeopaths often provide lists of credentials (sometimes rather dubious) and lists of celebrities and other famous people, including the British Royal Family, who believe in homeopathy. Some pepper their narratives with the language of science; some become indignant and fire off salvos of ad hominems at their critics; some even just make stuff up to win the argument. Not all homeopaths do this and some may genuinely believe in what they do, but none of these things makes it real, none of these things makes it science.

Is Chocolate Toxic?

IMG_3811It’s rare that governments of the world act in unison and so today goes down in regulatory history as the day the US FDA, the European EMA, the UK MHRA and the Australian TGA have simultaneously issued restrictions on the use of theobromine.

I suspect most people are not aware of theobromine or this new legislation and so a little background. Theobromine is an alkaloid stimulant and a vasodilator (meaning it causes an increase in blood flow). It has been on the list of prohibitive substances for race horses since the 1970s and its adverse effects in dogs are also well established. It is only now, however, that authorities have extended restrictions to humans. Why has it taken so long? Part of the problem is that theobromine is present in chocolate – the world’s favourite confectionary. Regulatory agencies therefore agreed an outright ban of chocolate was impracticable but have instead issued regulations limiting its sale. Different countries are taking different approaches, but here in the UK, from the end of this month, chocolate will only be available through a doctor’s prescription. A government spokesperson said that, “we have delayed bringing in this legislation because we do not want to spoil Easter – it’s what the people would have wanted.”

Pharmacologists have pointed out that humans metabolise caffeine to theobromine and other alkaloids and so they are concerned restrictions on chocolate may be extended to tea and coffee. But there’s no sign of this yet – we will have to wait and see.

Controversial Alzheimer’s drug

AlzheimersLast year a new drug to treat Alzheimer’s arrived on the scene called aducanumab, trade name Aduhelm, made by Biogen in Cambridge Massachusetts. It’s claimed this drug is different to its predecessors because it targets the causative biology of the disease – but it’s not without some controversy. To explain, let’s first look at what we know about the causes of Alzheimer’s, then pick up the story of aducanumab from there.

Although we know quite a lot about the pathology of Alzheimer’s, we still do not know the underlying cause. The three most widely accepted hypotheses concern (1) the formation of plaques between brain neurons, (2) the presence of tangles within the neurones and (3) the loss of a neurotransmitter chemical called acetylcholine. Let’s look at plaques first. Membranes throughout the body, and within the synapses of neurons in particular, contain a protein called amyloid precursor protein, or APP. It has several functions, but within the brain it’s implicated in neurone repair. Like all proteins, APP is subject to turn-over, meaning existing protein is broken down and removed, while new protein is synthesised to replace it. Three enzymes called α- β- and ɣ-secretase digest APP into small fragments which are then eliminated. But if β-secretase predominates, APP is only partly shredded and the remaining fragments clump together into plaques that sit between nerve cells, inhibiting neuronal communication.

While amyloid plaques form outside cells, tangles form inside cells. They originate from structures called microtubules which, amongst several functions, act as highways for nutrients. A protein called tau maintains the structure of microtubules, but tau can become misshaped. This leads to damage to the microtubules and the formation of tangled tau protein. These tangles then block the neuron’s transport system, inhibiting communication between neurones.

The third hypothesis on the cause of Alzheimer’s involves a neurotransmitter chemical called acetylcholine. It’s one of the most important neurotransmitters released in the spaces between one nerve cell and another (called a synapse). Once released, it’s rapidly broken down by an enzyme called acetylcholine esterase. As an aside, nerve agents such as Sarin and VX, inhibit the action of acetylcholine esterase, meaning the acetylcholine transmitter remains in the synapse, constantly firing the nerve cell. With Alzheimers, levels of acetylcholine are lower than normal so the cells do not trigger properly. Current Alzheimer’s drugs such as Rivastigmine, like nerve agents, inhibit acetylcholine esterase (although in not such a drastic way) thus increasing the levels of acetylcholine.

Getting back to the subject of this blog post, aducanumab is an antibody which targets amyloid plaques in the brain (the “mab” part of the name tells you it’s an antibody). The theory is that as aducanumab removes amyloid plaques, so neurones start to communicate again, thus reducing the symptoms of Alzheimer’s. Biogen point out that aducanumab is the first new treatment since 2003, but its action assumes the plaque hypothesis has validity, and that’s not universally accepted. Some scientists believe amyloid plaques are in fact a symptom of the disease, rather than its cause. Sceptics of the plaque hypothesis cite the fact that drugs which target plaques have a poor track record in alleviating symptoms of Alzheimer’s. Others explain the poor track record by pointing out damage to the brain is irreversible and so timing of administration of anti-plaque type drugs is critical. The root cause of Alzheimer’s might, of course, be more complex than any of the single hypotheses. Indeed, a recent study found evidence that cells of the immune system called macrophages clean up amyloid plaques and tau tangles during sleep.

The US Food and Drug Administration (FDA) approved aducanumab contrary to the advice of its scientific advisory board, and since its approval, three members of the board have resigned. (The European Medicines Agency has not approved aducanumab). The drug is available in the United States and the FDA will monitor its efficacy. I guess in time we’ll know which side of the plaque hypothesis is right – if indeed either side is right.

The world’s most expensive drug is not a drug


Reports have appeared in the media recently headlining “the world’s most expensive drug”

The subject of these headlines is Libmeldy, but the media seems obsessed with its cost, rather than what Libmeldy actually is. And, by the way, Libmeldy is no more a drug than my bird-watching binoculars are the James Web Space Telescope, but we’ll come to that in a moment.

Libmeldy is the brand name for Atidarsagene autotemcel, made by Orchard Therapeutics, a company based in London, UK and Boston, US, and developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Libmeldy is used in treating a neurodegenerative disorder known as metachromatic leukodystrophy or MLD for short. The “metachromatic” part of the name, incidentally, is because under the microscope diseased cells have a different colour to their surroundings.

MLD is an autosomal recessive disorder, meaning that it’s caused by two malfunctioning genes. Humans have 46 chromosomes arranged in 23 pairs (chromosomes 1-22 plus the X/Y, chromosome, XX for female and XY for male). We inherit one chromosome in the pair from our father and the other from our mother. If we inherit a faulty gene from either parent, then there’s a reasonable chance we’ll have a functioning gene from the other parent. Those suffering autosomal recessive disorders however, have inherited faulty genes from both parents. MLD is extremely rare – in fact, so rare that it’s hard to pin down how often it presents. Best estimates put it at one in 40,000, totalling about 160,000 individuals worldwide (equivalent to about 5 children born with MLD per year in the UK). Despite its rarity, it’s nevertheless devastating for sufferers and their families. Symptoms start as a child, with difficulty walking, muscle wastage, loss of vision, dementia, and death usually occurring within 10 years of onset.

The cause is with a faulty ARSA gene on chromosome 22. Genes make proteins and proteins are the toolbox of life; everything from muscles to enzymes, from antibodies to receptors on the surface of cells. The ARSA gene makes an enzyme called arylsufatase-A which breaks down fatty chemicals in the body called sulfatides. Sulfatides are important in maintaining nerve function, particularly the myelin sheath which coats nerve cells and acts something akin to the insulation on domestic wiring. (Multiple sclerosis is perhaps the best known disease caused by the breakdown of the myelin sheath). Like most chemicals in the body, healthy levels of sulfatides are maintained by a balance between their manufacture and their breakdown. Without the arylsufatase-A enzyme however, sulfatides build up, leading to nerve damage.

Not that long ago, medical science thought it impossible to treat genetic disorders such as MLD, but medical science never stands still. Libmeldy in that respect is very likely a game changer, but as I said above, it’s not a drug, it’s far more than that, it’s a gene therapy treatment. It’s made from stem cells derived from the patient’s own bone marrow (known technically as haematopoietic stem cells, which are destined to become white blood cells). Medical scientists then insert a working copy of the ARSA gene into these cells, which are re-injected into the patient. A few days before treatment another medicine, busulfan, is given to clear out existing bone marrow cells so they can be replaced with the modified cells in Libmeldy.

Stem cells are a kind of proto-cell and have no specific role other than to differentiate into more specialised cells. We might liken them to substitute players in a game of rugby. Sitting on the benches, they play no part in the game until called upon to substitute for an injured player. But once on the field, the fresh player becomes part of the team just as much as his injured predecessor. You can’t however, just inject a gene into the body and expect it to work – you also need what’s known a vector. The vector in the case of Libmeldy is a modified Lentivirus. This family of viruses is well known for inserting DNA into host cells, and they are responsible for diseases such as HIV. Before conspiracy theorists start Tweeting that the pharmaceutical industry is giving children aids, the viral vector is deactivated and used only for insertion of the ARSA gene.

Libmeldy therefore takes the patient’s own stem cells, adds a working gene and uses an inactivated virus to insert that gene into the body’s cells. This is medical science at the cutting edge, putting the cost of the treatment into context – you are buying a therapy based on years of scientific research. A fact that much of the general media seemed to have missed as they got lost in the fog of the price.

With MLD being so rare, it’s difficult to conduct the usual clinical trials with many thousands of patients. So far they have tested it on around 30 individuals over about 10 years and have shown it restores in the order of 70% of motor neurone function. Libmeldy is approved in the European Union and the UK (which are sadly separated these days) and is an investigational therapy in the United States. But it’s under scrutiny so a more complete assessment won’t come, perhaps for several years. At the very least however, it offers hope and it may even offer a solution.

Covid-19 and the brain

Covid MRI brainA common symptom of Covid-19 is anosmia (loss of the ability to smell) which suggested to some that the virus could get into the brain. More recent evidence seems to bear this out, although there is still a lot of speculation.

I once attended a lecture by Martin Rees, the UK’s Astronomer Royal, who astonished the audience by saying astronomy was a simple subject. He qualified his statement by explaining astronomy is simple compared to biological science particularly, biochemistry. We may be able to figure out the beginnings of the Universe, we may be able to count the stars it contains and we may be able to figure out its end. But we are unlikely to figure out but a fraction of the billions, or trillions of different molecules and their interactions going on in the human body. And within all that complexity, the brain stands supreme. The chemical and cellular interactions within that squidgy ball are… well, mind blowing.

All that complexity makes the brain vulnerable, and it doesn’t take much to upset its function. It’s not surprising therefore that the brain has evolved some special methods of protecting itself, and above all, that task falls upon the blood-brain-barrier. The blood-brain-barrier exists is a construction of cells and proteins along the walls of a network of blood vessels surrounding the brain. There are a variety of specialised cells in the blood-brain-barrier, including, amongst others, endothelial cells and astrocytes. Endothelial cells, or to be more precise in the blood-brain-barrier’s case, cerebral vascular endothelial cells, are associated with what we know as tight junctions, which are unusual in the biological sciences because their name actually describes them in plain language. Astrocytes help maintain tight junctions by secreting substances which regulate their properties – opening them up to some substances, like nutrients, while keeping others, like toxins, out. This combination of cell types and tight junctions is something akin to an Anglo-Saxon shield wall, able to let friends pass while also repelling the enemy. On the whole, the shield wall of the blood-brain-barrier prevents undesirables from getting through, but like the Anglo-Saxons found out at the battle of Hastings, things can go very wrong.

There are questions about whether its SARS-CoV-2 (the causative virus for Covid-19) that gets into the brain or whether it’s the virus’s spike protein (known as S1 protein). Some viruses can get into the brain – perhaps Rabies lyssavirus (rabies) being the most notorious. Of course SARS-CoV-2 is nowhere near as deadly as rabies but sometimes, besides anosmia, Covid-19 has been known to cause memory loss, loss of cognition and even strokes. SARS-CoV-2 is an enigmatic virus and there’s still much we don’t know, including how it, or the spike protein, defeats the blood-brain-barrier. From animal models, it appears to attack astrocytes directly, triggering an immune response, leading to an increase in circulating pro-inflammatory cytokines, known as cytokine storm syndrome. It’s this cytokine storm that then potentially leads to brain damage. The immune system, in this case, goes off the tracks (something anti-vaxxers seem to miss when they claim “they have an immune system”. That’s like vowing never to use a bus because I have a car, and assuming the car will never breakdown). MRI scans have shown damage to grey matter, but the images show little consistency from patient to patient, something as yet not understood. Once again, SARS-CoV-2 proves enigmatic.

Serious neurological problems with Covid-19 are thankfully rare, but we shouldn’t be complacent about a virus where we still have so much to learn. Medical science is well aware of lasting effects, known as long Covid, in some patients, although the cause remains elusive. It’s possible the effects in the brain are the cause, but other effects may also be implicated – currently we just don’t know. The picture is also ever changing as new variants emerge. Some think we have finished with Covid, but it’s unlikely SARS-CoV-2 has finished with us yet – it may still hold a few surprises.

Spinal muscular atrophy and Zolgensma

Screenshot 2021-06-10 at 10.28.50Reports have appeared in the UK media of the NHS administering the most expensive drug in the world to a 5-month-old boy. Onasemnogene abeparvovec (sold as Zolgensma), costing around two and a half million US-dollars (£1.79 million),* is a gene therapy agent to treat spinal muscular atrophy. The headlines quoted the price but gave scant details on what Zolgensma is and how it works. And when you look a little deeper, it turns out there are some parallels with Covid-19 vaccines.

Spinal muscular atrophy is a serious genetic disorder that affects around 1 in 10,000 people worldwide. Being relatively rare, it’s classified in the pharmaceutical jargon as an orphan disease and until recently received comparatively minor attention. Zolgensma was originally developed by a biotechnology company called AveXis, funded largely from charities and the National Institute of Health in the USA and before this, basic research was carried out by the French Muscular Dystrophy Association. In 2018, Novartis bought AveXis for $8.7 billion, and now manufactures and markets Zolgensma.

Different species possess different numbers of chromosomes. The male Australian ant (Myrmecia pilosul) has just one chromosome, the Adder’s tongue fern (Ophioglossum reticulatum) has 1260 and humans have 46. Our 46 chromosomes are arranged as 23 pairs, one in the pair inherited from the father and the other from the mother. (Pears incidentally, have 34 chromosomes arranged in 17 pairs). Within the chromosomes is DNA, and DNA is arranged into genes. The genes comprise a sequence of DNA bases that code for proteins, and proteins make up the stuff of life for every living organism from bacteria to you and me. The human DNA code is around 3-billion bases long and given this complexity, now and again something goes wrong with one of the genes. This is not usually a problem because if there’s one faulty gene then there’s a duplicate in the other paired chromosome that can still do the job. Occasionally however, the genes on both chromosomes go wrong, in what’s called “autosomal recessive inheritance” and then there can be a problem.

On human chromosome number-5 there are a series of genes collectively known as survival motor neuron genes (SMN). There are two types – SMN1 and SMN2 which make SMN protein, one protein in a group called the SMN complex, which is important in maintaining motor neuron cells. These are the nerve cells which transmit signals from the brain and spinal cord to control muscle contractions. The role of the SMN complex is… well,… complex. It’s involved in processing messenger RNA (mRNA), which is the intermediary molecule between the DNA code and its associated protein. mRNA starts out as a “rough draft” known as pre-mRNA and has to go through a number of processing steps before it’s transformed into the working copy. With a faulty SMN complex that final working copy never emerges and so motor neuron-associated proteins are not made. Over time motor neurons therefore degenerate which leads to progressive muscle wasting and within a year or two, it’s usually fatal.

The body has a back-up to the SMN1 gene – SMN2, but SMN2 typically only makes 10% of the SMN1 protein. Some people with spinal muscular atrophy might have multiple copies of the SMN2 gene, in which case the disease is not as severe. On the whole however, most patients have one inoperative SMN1 gene and two SMN2 genes which only make a fraction of the SMN protein required.

Not that long ago there was not only no treatment for spinal muscular atrophy, but most physicians would say there could never be an effective treatment because the root cause goes back to genetics. They were wrong. Zolgensma is not a drug in the normal sense. It comprises two parts, a length of laboratory-made DNA to replace the faulty SMN1 gene and the husk of a virus called vector adeno-associated virus 9 (AAV9). The viral vector is manufactured in isolated Human Embryonic Kidney cells (HEK293) originally grown by Dutch biologist Alex Van der Eb in the early 1970s. The viral genetic material is removed and the SMN1 replacement gene is placed into the empty shell which acts as a vector, delivering DNA to motor neurones. (Without the vector the body would rapidly break the DNA down). This is similar to the Covid-19 vaccine from the Jenner Institute at Oxford, where they developed technology using adenoviruses and modified Vaccinia Ankara (MVA) virus as vectors for genetic material to code for spike proteins on SARS-Cov-2. As the body translates the code into spike protein, so it primes the immune system against future SARS-Cov-2 infection. If you’ve had the Astra-Zeneca vaccine (developed at the Jenner) then you would have received this type of vector vaccine.

The SMN1 gene delivered by Zolgensma is not incorporated into human DNA, but sits within the cell’s nucleus where the normal molecular machinery translates it to SMN protein. The intention is to administer Zolgensma just once to replace the faulty gene but as experience grows over time, the necessity for further administrations cannot be ruled out.

Currently Zolgensma is approved for children under 2-years of age but timing appears important and it should be given as soon after diagnosis as possible. It is administered by intravenous infusion but research continues to develop delivery systems directly into the cerebrospinal fluid, which could make Zolgensma available to a wider patient base.

Zolgensma is not the first gene therapy agent to be approved, there are around a dozen others in use. To give just one as an example, about one in a million people have a deficiency in their lipoprotein lipase gene leading to elevated levels of triglycerides and ultimately liver and pancreatic disease. A gene therapy agent called alipogene tiparvovec uses the adeno-associated virus serotype 1 as a vector to deliver a copy of the human lipoprotein lipase gene to muscles, thereby bypassing the faulty one.

All gene therapy agents are expensive but they are also state-of-the-art pharmacotherapy based on science which goes back to at least 1953, when the structure of DNA was first elucidated. Science is like that. It’s a series of dots that join together from many sources over many years and at the start it’s impossible to predict what the dot-to-dot picture will look like. Let’s hope we are entering a new age of genetic therapy giving hope where before there was none. And then from there, who knows?

* a confidential deal was struck between the NHS and Novartis Gene Therapies which reportedly reduced the price tag. 

A Crisis of Infection

AntibioticsIt’s amazing what humankind can achieve with the right amount of political will and resources. After the attack on Pearl Harbor in December 1941, Roosevelt oversaw the rebuilding of the Pacific fleet in only 6-months. Driven by rivalry with the Soviet Union, Kennedy announced in May 1961, “…we choose to go to the moon …” and just 8-years later Neil Armstrong left his indelible footprint in the lunar dust. December 2019 saw the genesis of Covid-19 and within a year the UK approved the first vaccine. Other vaccines quickly followed, an astonishing achievement facilitated by an estimated global expenditure of 8.5 billion US dollars. Yet behind this story lies a long history of under-investment in vaccine development, regardless of the inevitability of recurring pandemics. And there’s another inevitable pathogenic crisis heading our way under the political radar. We are running out of effective antibiotics.

Despite claims that Covid-19 vaccines materialised through “greed and capitalism” in reality, global public investment fuelled that one year achievement. A pandemic it seems, catalyses political will like little else. Meanwhile, funding applications took up much of the development time towards vaccines such as a BCG* replacement and the recently approved malaria vaccine. Some might say, Covid-19 aside, vaccine development is more to do with accounting than science.

In 1941, a 43-year-old policeman named Albert Alexander scratched his face on a rose bush whilst gardening. The scratch became septic and he became the first person to be treated with one of the earliest antibiotics – penicillin. Unfortunately, supplies at that time were too scarce to save his life. The story marks the start of an antibiotic revolution, but also illustrates how easily death came from even the most minor of wounds. Thirty years after Albert Alexander’s death, we entered what became known as the golden era of antibiotics. It is however, frighteningly poignant to remember that the last truly novel antibiotics, the quinolones, arrived in the 1970s and discovery since this time has been dire.

The trouble with new antibiotics is not science but, once again, political will and resources. Big pharmaceutical companies have all but abandoned development of antibiotics because the “greed and capitalism” model doesn’t work in this instance – anymore than it did for vaccines. This is not some Marxist view of the world – far from it, but a recognition that free markets are not a one-size-fits-all panacea. Over the years many small biotechs have entered the antibiotic market only to go bust. The dilemma is despite an estimated 700,000 deaths worldwide from antibiotic-resistant strains, high development costs make the price per dose prohibitively expensive. The situation is perhaps exemplified by the case of Melinta Therapeutics, which had four antibiotics on the market, one of them for the treatment of much feared hospital acquired resistant infection. Melinta Therapeutics nevertheless declare bankruptcy in late 2019.

Unlike Covid-19, the number and impact of resistant strains of bacteria build up over time. They arise by stealth until we realise we’re in a crisis that politicians can no longer avoid. Once we’ve reached crisis, reactive solutions are sought as people die, but with a little foresight and vision, science has the know-how to find solutions before we reach a critical point. If Covid-19 has taught us anything, it’s what we can bring about when we put our minds to it. And I end as I started – it’s amazing what humankind can achieve with the right amount of political will and resources.

* BCG stands for Bacillus Calmette-Guérin, a vaccine used to treat tuberculosis, made from attenuated Mycobacterium bovid.

Magic mushrooms and depression

Screenshot 2021-04-16 at 11.28.56Depending upon where you get your news, you may have seen reports that the active ingredient of magic mushrooms, psilocybin, is being studied as a possible treatment for depression.

Being of a certain age, I remember the 1960s and 70s when magic mushrooms were all the rage. The law at the time was ambiguous in that picking the mushrooms wasn’t illegal but extracting psilocybin was. There were reports of people exploiting the loophole by crawling on all fours to graze directly on the mushrooms. A somewhat risky business, as those people were perhaps not the best at distinguishing psilocybin species from those far more toxic. But back to the topic of this blog post – what’s the link between psilocybin and antidepressants?

Sometimes dismissed with a “pull yourself together,” in reality depression is as real a condition as any biochemical disorder from diabetes to Gaucher disease. By far the most commonly prescribed antidepressants today are the Selective Serotonin Receptor Uptake Inhibitors or SSRIs. An early SSRI was fluoxetine, better known as Prozac, which is still widely used*. Although an effective drug, it’s not without some controversy as its development was based on what’s known as the serotonin hypothesis of depression. Serotonin is a hormone which interacts with receptors in the brain. There are 15 known receptors, with 5-HT1A and 5-HT1B being the most extensively studied (5-HT stands for 5-hydroxytryptamine – the chemical name for serotonin). Serotonin receptors are proteins which when bound to serotonin, mediate the release of a range of neurotransmitters such as dopamine (amongst others). Serotonin is transported across the brain and its concentration partly depends on re-uptake by nerve cells. Inhibiting re-uptake by a SSRI results in higher concentrations of serotonin outside the cells and hence, so the theory goes, there’s more available to bind onto the 5-HT receptors.

The serotonin hypothesis of depression is controversial because the biochemistry of serotonin interactions is complex and not fully understood. There may also be genetic aspects, particularly in sub-types of proteins involved in serotonin transport (known in genetic-pharmacology jargon as polymorphisms). Moreover, evidence of an association between higher levels of serotonin in the brain and depression is not compelling. Even though the pharmacological mechanism isn’t well understood, SSRIs are effective in clinical trials and so they clearly have some influence on all this intricate biochemistry.

Interestedly, psilocybin also acts on 5-HT receptors, 5-HT2A in particular. To be more precise, psilocybin contains a phosphate group on its molecular structure, making it pharmacologically inactive. The phosphate group is removed either by stomach acid or in the bloodstream to form psilocin which is the active substance. It crosses into the brain and reacts with a variety of receptors, including the 5-HTs. It leads to complex reactions in cellular signalling, resulting in cascade effects which ultimately cause alterations to sensory perception. Apart from 5-HT receptors, how psilocybin might affect depression is not understood but, like SSRIs, there appears, perhaps, to be an effect in clinical trials. Now is the time to be very cautious because the clinical trials have so far been very preliminary. The first trial appears to be in 2016, conducted at the Centre for Psychedelic Research at Imperial College, London, with a more recent study this year. The number of participants was small, 59 in the 2016 study and 80 in this years. Other institutions have likewise been studying the effects of psilocybin on depression and Imperial have also been looking at its use to treat Anorexia nervosa. In addition, some imaging studies have been performed using functional-MRI (fMRI) but so far, no extensive trials have taken place.

If psilocybin and its related compounds are eventually developed to treat depression, then I suspect the chemical structure will be modified in an attempt to optimise it’s effectiveness and reduce side effects. I also suspect that the choice of dosages will be challenging. Nevertheless, an interesting area of pharmacology might be on the rise – we will wait and see.

* – Stanley Feldman’s From Poison Arrows to Prozac (how deadly toxins changed our lives forever) tells the fascinating story.