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Take part in the Big Butterfly Count 18th July - 10th August 2025

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Take part in the Big Butterfly Count 18th July - 10th August 2025

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Be part of this nationwide survey and help take the pulse of nature. Butterfly declines reveal the poor health of the environment. We need your sightings.

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Attend an online lecture on the future of immunity

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Attend an online lecture on the future of immunity

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Our understanding of the human immune system today is vastly different from that of 50 years ago. This knowledge has led to immune-based therapies that would have seemed like science fiction to our grandparents: monoclonal antibodies, T-cell therapies, anti-cancer vaccines, precision immune suppression – the list is endless. In this lecture, we look to the future and ask, “What next for immunity?”

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Protecting endangered species

We're working with some of the most endangered species on the planet to restore the natural world.

We are always there for wildlife. Whether it's through our cutting-edge science, or inspiring the next generation of conservationists at our Zoo's. We've completed the most comprehensive scientific study of average wildlife populations to shape conservation globally, replanted over one million mangrove trees and rescued pangolins from the clutches of the illegal wildlife trade.

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We're working with some of the most endangered species on the planet to restore the natural world.

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Find out how DNA can help us understand evolution

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Find out how DNA can help us understand evolution

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Learn.Genetics [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2018 [cited 2023 Nov 27] Available from https://learn.genetics.utah.edu/

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Learn.Genetics [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2018 [cited 2023 Nov 27] Available from https://learn.genetics.utah.edu/

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Learn.Genetics [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2018 [cited 2023 Nov 27] Available from https://learn.genetics.utah.edu/

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Your guide to the Practical endorsement certificate

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Your guide to the Practical endorsement certificate

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The species we recognise as our own - anatomically modern humans - has existed for only 300,000 years, a blink of an eye in evolutionary terms. And yet during that time our species has been shaped by strong evolutionary forces, often unwittingly as an indirect result of human activities.

In this lecture, we'll find out how disease outbreaks, the rise of civilisation and even the invention of agriculture have left their traces in our DNA.

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A 300,000-Year History of Human Evolution

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The species we recognise as our own - anatomically modern humans - has existed for only 300,000 years, a blink of an eye in evolutionary terms. And yet during that time our species has been shaped by strong evolutionary forces, often unwittingly as an indirect result of human activities.

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Rare white penguin spotted in Antarctica

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A penguin with leucism from the gentoo species has been filmed in the icy climate in early January.

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‘Don’t hold your breath’ is an expression you’ve probably
heard many times, but may not have thought too much about. In this free course, Blood and the respiratory system, you’ll study why…

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This free course, Meiosis and mitosis, looks at how units of inheritance are transmitted from one generation to the next. First you will look at what happens to the chromosomes of animals and ...

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Microbes often get a bad name. Whilst some of them do cause disease, others play vital roles in recycling nutrients in the soil to enable plants to grow, and in breaking down human waste. Without ...

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Professor Sanjay Popat FRCP PhD 23rd January 2024
Understanding our genes is the fundamental basis to understanding cancer and how to treat it. Most of the cells in the human body have a central structure called a nucleus. Within this nucleus, are our chromosomes; we have 46 of these to be precise, that's 22 pairs, numbered 1-22, one of which we inherit from our mother and one of which we inherit from our father. In addition, we have another set called X and Y that determine if we are male or female. The chromosomes are tightly coiled into strands of DNA: the basic building blocks of life. And it's our DNA that is the blueprint for everything that the cell does: it is a sequence of letters (nucleic acids), and that precise sequence of letters determines how that individual cell functions.

So how does this miracle occur? Well, there's a lot of complex biology, but from the sequence of nucleotides of DNA, a modified copy of this sequence called mRNA is created. Here, every 3 letters or bases is important as each three letters encodes an amino acid, a part of a protein called - the machinery of a cell. The RNA is subsequently read, and a string of amino acids is made which then ends up being a protein. So, you can see how the DNA sequence turns into a protein which then does the functions of a cell.

In recent years we have witnessed three major events that have allowed us to harness this biology to transform the way we treat cancer.

The first of these was publication of the first draft of the human genome in 2001. It was amazing that prior to then, our actual understanding of the DNA sequence of all 23 pairs of chromosomes in human beings was relatively limited. The reason that this publication was so fundamentally important was that it allowed us to understand what normal genetic sequence is, and alongside it, all of its normal variations. And by understanding what's normal, only then can we begin to understand what is abnormal and especially when this comes to cancer. At the same time, TIME magazine published an influential article on how it predicted that we would use this understanding of genetic sequence to help predict which drugs we took for what condition: a prophecy which is now in routine clinical care for cancer.

Understanding the human genome allowed us to better understand the cancer genome. We knew that if a sperm cell or an egg had a mutation- a change in the nucleotide sequence or a different spelling letter in the DNA- then this mutation would be present in every single cell of all of us. However, what we have identified is that if the same mutation does not occur within the egg or sperm but occurs later on in development, within a tissue such as the skin or the lung or the colon then that genetic abnormality is only present within that particular group of cells these are called somatic mutations. And this is exactly what we have identified occurs in cancer. Specifically, mutations otherwise known as spelling mistakes within the DNA sequence, occurring within particular cells of a particular organ, not present in any other part of the body.

Now when we look at the sequence of DNA, we actually find multiple different abnormalities that occur in nature. The commonest type that we see are called mutations. This is, as I explained before, when the spelling mistake of the DNA sequence changes, and this results in an abnormal protein. There are different classifications of mutations classified as transitions or transitions, missense mutations, or insertions or deletions.

Indeed, when looking more detail not only do we find abnormalities within the DNA sequence, but sometimes we see major structural abnormalities within the chromosomes themselves, for example where arms of chromosomes are interchanged, a process called a gene rearrangement or more commonly a gene fusion, because genes are broken up and fused next to each other when they normally wouldn't be.

We have also learnt that the DNA sequence does not all turn into a protein. Within the DNA strand the amount of DNA sequence that encodes a protein is called in exon and it is interspaced with large regions of genomic junk, by large, called introns. Not all exons turn into proteins, and multiple different proteins can be made from the same genetic sequence through a process called alternative splicing. And what we have learned in cancer is that sometimes DNA mutations cause of alternative splicing resulting in an abnormal protein.

Lung cancer is a superb example for how abnormal genetics causes cancer and how that can be identified and drugged. Through multiple large scientific studies of looking at the DNA sequence of lung cancers, we have identified that in a particular type of lung cancer called adenocarcinoma we have found many different types of genetic abnormality, usually mutations, and sometimes gene fusions, all of which function through the same way. They all change the DNA sequence to result in an abnormal protein which normally is not functioning within the cell, but then is abnormally forced to switch on and function without any regulation, out of control of the normal cellular processes, effectively switching "on" that cell and preventing it from dying at the end of its natural life. That cell then divides and forms 2 daughter cells each of which harbours the same genetic mutation as the parents, and those 2 daughters cells become for 4, and those become 8 and so on and so forth. Hence, we can see that the fundamental basis of many different types of adenocarcinomas is in fact a genetic alteration such as a mutation within the DNA of 1 particular cell. These are otherwise known as a driver genetic alteration which drives the cell to growing and dividing and replicating, with the same genetic abnormality being found in all of the daughter cells identified within the cancer.

Sometimes we find other abnormalities within the chromosomes when parts of the chromosomes with multiple copies of the same region, a process called amplification. This also causes cancer in some cancer types.

The second major event that occurred, was mapping of the human receptor protein tyrosine kinome. Protein tyrosine kinases were at that time a newly identified major type of protein which is usually found on the cell surface. These function as receptors and sense outside factors and transduce these signals to the inside of the cell to instruct the nucleus what to do. Our understanding of the genetic sequence of what encodes these proteins was also critical as we discovered exactly what these kinases do and how critical they are in regulating the cell and causing it to grow and divide when stimulated.

The third major event that occurred was that our medicinal chemists identified a new class of drug. These were called kinase inhibitors and whilst the first kinase inhibitor was developed for hypertension, these turned out to be particularly important in cancer where these were called tyrosine kinase inhibitors. This is a entirely new class of drug: a pyrido[2,3-d] pyrimidine derivative that was able to highly effectively inhibit a kinase protein.

So, putting this all together, we discovered that genetic alterations occurring within the DNA of the cell resulted in abnormal receptor protein kinases sitting usually at the surface of the cell which regulated the growth of the cell, and these genetic alterations resulted in kinases being activated all the time when they would normally be under very tight control. These activated kinases resulted in a signal for growth and cell division to be propagated to the cell to force it to grow when it otherwise would not have. This whole process could be effectively terminated with simple straightforward tablets called tyrosine kinase inhibitors which effectively switch off the activity of the abnormally activated kinase.

The final event that has transformed our understanding of genomics in the cancer field is the development of genetic technologies and their costs. Here, mapped against Moore's law where the cost of computing has decreased over the years, the costs of genomics have markedly reduced over time, allowing complex technologies to be routinely implemented into clinical care.

Indeed, when trying to understand the genetic sequence, the gene in the cancer of a human being can be analysed through many ways. We could for example do a very basic test when we perform something called PCR to look for mutations or deletions within a gene, or we could consider more complex technology call whole exome sequencing when we are trying to sequence all of the coding regions of the DNA: sequencing hundreds or thousands of genes, or we could go even further to look at the whole genome itself. Each of these different processes have different benefits and different limitations and can be used in different scenarios. We may find that we actually want to know more about the RNA than to DNA as this may help us to better identify gene rearrangements and this can be pursued through RNA sequencing through a variety of technologies.

I want now to spend some time talking about non-small cell lung cancer and specifically adenocarcinoma as a paradigm for precision oncology. We all know that Sir Richard Doll presented his seminal paper back in 1954 where he took a cohort of doctors born between 1900-30 and followed them up and demonstrated that the cigarette smokers were dying on average 10 years earlier than never smokers and postulated a direct relationship between tobacco and death from cancer, specifically lung cancer.

And indeed, when we think about lung cancer, we typically think of the character on the left of the screen who always has a cigarette in his mouth. However up to 20% of all lung cancers occur in people that have never smoked. Indeed, famous faces have developed this condition including the late Roy Castle, and the late James Brokenshire. Indeed, many advocates would say that anyone can get lung cancer, not just smokers: If you have lungs, you can get lung cancer it just does not take tobacco to cause this diagnosis.

Now when we look at lung cancer in never smokers it remains a major cause of death, given that 20% of a big problem itself is still a big problem, accounting for more deaths than cervix cancer, pancreas cancer and indeed prostate cancer.

Now one of the fundamental problems we have with lung cancer is that it is a malignancy of an internal organ. And hence picking it up at an early stage is problematic because we do not know that there is a cancer growing inside as the lungs can take on quite a bit of growth before any abnormalities become clinically evident. As a consequence, lung cancer has usually spread to other parts of the body at the time of diagnosis, and indeed this means that most patients have stage IV cancer at the time of diagnosis, which in itself is incurable.

Now one of the great examples of the implementation of genomics into routine care has been the gefitinib story.

Here, in 2002 AstraZeneca were testing a new kinase inhibitor and remember this is a targeted therapy tablet, called AZD1839. This drug switched off the kinase of the EGFR protein, known to be important in lung cancer signalling. And in a seminal publication of a phase 1 trial published by Professor Ranson from Manchester he demonstrated quite remarkable benefit in a handful of patients with widespread metastatic lung cancer with just this simple tablet. However, many patients derived no benefit whatsoever, and it remained quite unclear why some patients benefited with remarkable rapid tumour shrinkage and others did not. This early benefit of AZD1839 which was subsequently called gefitinib, was so marked in some patients that it resulted in approval by the FDA. Indeed, in the US and in parts of Europe this tablet was in widespread use, but it remained entirely unclear exactly who would benefit. It certainly seemed to provide a benefit particularly in groups of people who were never smokers or indeed had Southeast Asian ethnicity.

Subsequently AstraZeneca performed a clinical trial where they randomly allocated several hundred patients to receive either gefitinib or not. Unforutnatly and shockingly to many, the trial demonstrated that on average it did not prolong survival. And on this basis, the FDA withdrew gefitinib from the market. It continued to be used in other parts of the world where clinicians still reported a small proportion mainly of never smoker's and patients with from East Asia were most likely to benefit.

This all changed in 2004 where 2 groups from the US reported seminal findings that told us the biological basis of benefit from gefitinib. Here, they reported that when they took the lung tissue of patients with lung adenocarcinoma and sequenced the EGFR gene in patients that were being treated with gefitinib. Lo and behold they identified that patients that harboured a genetic mutation in the EGFR gene that switched on the EGFR kinase protein, all these patients responded to gefitinib, whereas those that by and large did not harbour a mutation in the EGFR did not respond, opening up the first concept of precision oncology: giving an EGFR kinase inhibitor only to patients with activating mutations in the EGFR gene as these patients benefitted and others without the mutation, did not. On the basis of this and other clinical trial data, the FDA and other regulatory authorities gave approval for gefitinib for EGFR mutant NSCLC: the first genotype-specific approval for a common cancer.

We know a lot about these mutations about these mutations now. We know that they are not heritable by enlarge, that they occur de novo within the lungs, as a founder driver mutation, the first mutation that occurs in an airways cell to cause cancer, and that they are predominantly seen in never smokers, are sometimes seen in former and at a low level in current smokers. Data also demonstrates that there is an increased incidence of these mutations in patients in Asia. Therefore, we cannot tell just by simply looking at the patient if the tumour harbours an EGFR mutation, we actually have to take the tissue, sequence the DNA of the EGFR gene and see whether the mutation is present.

This is one of the first cases of EGFR mutation we identified in our clinic in routine clinical care, a young patient who was a never smoker who was hospitalised with a large tumour in her left chest causing significant breathlessness and oxygen dependency. Her tumour was biopsied, and shown to have an EGFR mutation, and we were able to access the EGFR kinase inhibitor gefitinib and she started it immediately. Within 3 days her cough had disappeared. Within 1 week she was able to walk up the stairs. When I later saw her after 2 weeks, she had come off oxygen completely. When we scanned her after 8 weeks her tumour had mostly melted away. This is a remarkable benefit, and the benefit that we would have never seen with chemotherapy.

Hence moving forward from 2004 where we were classifying lung cancer according to what it looked like under the microscope with a traditional view of tumours being mostly adenocarcinoma or squamous cell carcinoma, moving forward now we now give non-small cell lung cancer a molecular diagnosis, wanting to know what the genetic abnormality status is at multiple different genes in routine clinical care. Indeed, in order to optimally treat patients these days, we cannot do so and cannot select the right drug for them unless we know the genetic sequence of the tumour to allow us to better understand whether there is an opportunity to use a highly effective kinase inhibitor.

Indeed, as the science developed, we identified further genetic alterations in lung cancer, the next one being identified was a gene rearrangement in the ALK gene otherwise known as an ALK fusion. At that time Pfizer was developing a drug called PF-02341066, which later became known as crizotinib, a highly potent ALK kinase inhibitor. These scans were one of the first patients we identified to have an ALK fusion with widespread bilateral disseminated lung cancer, you can see on the slide here, who was treated with crizotinib, and again had a very similar dramatic response as a previous patient with marked resolution of symptoms and cancer within days of starting treatment.

Bring us forward to 2024, we can now take a group of patients with non-small cell lung cancer at time of diagnosis, take their tissue, and analyse it, with gene sequencing to identify which of a group of genetic alterations is present, which then determines whether we treat the patient upfront with immunotherapy with or without chemotherapy, or whether we find a activating genetic alteration which allows us to use a highly effective kinase inhibitor resulting in dramatic improvements.

But does this really matter? Does this really transform the outcomes of our patients? Back in 2014 our US colleagues reported on a study they had been performing for several years, the Lung Cancer Mutation Consortium LCMC study. Here, a group of centres in the US took their patients with newly diagnosed stage IV non-small cell lung cancer, analysed the tumours at a number of different genes, and if their tumour had a genetic alteration they were allocated to a tablet kinase inhibitor and they looked at the outcome in those that receive the tablet, those that had a genetic alteration but did not receive kinase inhibitor, and those that were allocated standard treatment at that time called chemotherapy. What they demonstrated was a clear benefit for identifying a driver mutational genetic alteration and giving that patient targeted therapy, increasing the median survival by 1 1/2 years.

Now in 2024, in routine clinical practice, patients with non-small cell lung cancer particularly adenocarcinomas should have their tumour sequenced at at least 8 different genes, to look for particular genetic alterations. If these are identified, the tumour should be matched to an appropriate kinase inhibitor, many of which are now approved for use, having proven their safety and efficacy often over chemotherapy in randomised clinical trials.

Indeed, when we look at what is available here in the NHS, we can clearly see that the vast majority of approved kinase inhibitor is against genetic altered targets in lung cancer are funded within the NHS.

However, we have a problem. Because these treatments are not curing our patients. Ultimately after a period of time be it 1 year, 2 years, 3 years and sometimes even longer, the cancer recurs. And what we have identified is that applying the selection pressure of drug therapy changes cancer, which evolves to become resistant to the drugs that it is being exposed to.

And since then, we have learnt quite a lot about resistance mechanisms to drugs, mostly through the great help and support our patients who have aided us through research efforts. Drugs may stop being effective through pharmacokinetic effects. Patients may refuse to take the drugs usually because of difficult side-effects. There may be drug-drug interactions resulting in a reduced bioavailability of the drug, or the drug may simply not penetrate well enough to certain parts of the body, typically the brain, resulting in growth of the tumour in such sanctuary sites.

Studies of biopsies of patients with tumour growth despite initial benefit and subsequent growth, have demonstrated a number of new different genetic changes that have occurred within the tumour to cause the drug resistance. The commonest thing that we see is that the genetic alteration initially seen is still there, but a second genetic alteration has occurred, to prevent the drug from binding to the kinase inhibitor. But we also see other new genetic alterations occurring called bypass tracks where cells learn to bypass the signalling cascade which is being inhibited and switch on either pathway and sometimes cells themselves transform to more aggressive subtypes looking completely different under the microscope.

We can see that genetic alterations occur in patients with cancer, particularly lung cancer, and that identifying these are particularly important. So how do we deliver tumour genetic testing at scale in routine clinical care in the clinic with high quality and confidence?

Well, biomarker testing and reporting is a complex process. Somebody once told me that it's not that difficult, it's not rocket science, and I would retort that actually it is really quite a complex process. We have to remember that a patient has been newly diagnosed with cancer in the lungs, and is often really quite unwell, with respiratory symptoms and usually rather significant medical complications. We have to obtain the pathological sample; it has to be analysed in the genetic lab the genetic lab has to report on the findings that they identify and that report has to reach the treating oncologist.

However, there are many steps in this process where problems can occur. Who orders the molecular tests? Is it the respiratory physician or the pathologist as the oncologist has never met the patient at that point. How long does it take for the sample to get from where the biopsy is sitting, which is usually in a different place to where the molecular laboratory is, and where is the actual sample sitting, because the pathology laboratory may be a remote location from where the samples actually got taken from the CT scanning suite or the bronchoscopy suite. About the lab, they generally do a great job in analysing the specimen. But has the best test been performed for the question that is being asked, often this is bit of a gray zone in the laboratory just performs a standard test for all lung cancers. And finally, who receives the report? The person that receives the report is the actioning oncologist who is often not the person that orders the test in the first place. The person ordering the test is usually the pathologist and then when the oncologist receives the report, it is usually in often complicated genomic language. So how does the oncologist interpret the report when they have not been trained to do so as the whole area of genomics has been implemented and been mushrooming within recent years.

We also have to recognise that there are many different tests that can be performed on cancer specimens. Indeed, all molecular tests have their limitations, and one would argue that the gold standard test is actually whether the patient benefits from the drug when you actually give it. We use single-gene tests which are fast but waste DNA and can give false negatives as they are not that sensitive and are usually looking to see if a predefined set of mutations is present or not. We have now generally moved over to panel-based sequencing of DNA and RNA which allows us to examine many 10s to 100s of genes at the same time which is a highly efficient way of analysing tumours. But this technology can be slow, and interpreting the results can be really quite problematic. We can use simple straightforward pathology techniques called immunohistochemistry which are fast and efficient, but false negatives and false positives can be quite common depending on the test, and the sample may need molecular verification, anyway. And for certain questions we can use a technology called FISH which for gene rearrangements had been the gold standard but again can be slow and is prone to false negatives and positives and does not give us genomic breakpoint data that may be important.

The other thing that we have identified is that it's not only what is in the foreground that we are looking for IE the driver genetic alteration, but that the background genomic architecture matters. Hence whilst we are looking for certain genetic alterations such as mutations or fusions, we have to be aware of what is lurking in the background, specifically which other genetic alterations are there, that may impact on how the drug works, and how the patient fares.

So far, I have spent a lot of time talking about genetic alterations occurring within the tissue of the cancer itself but what about heritable mutations, mutations that patients are born with, throughout all of their cells in their body. Can these mutations cause cancer, and then their presence to help us with drug decision making?

The answer to both of these questions is yes, it is important, and it does help us. A classic example is that of BRCA 1 and 2 mutation detection which cause sensitivity to PARP inhibitors. Heritable BRCA1 and BRCA2 mutations are very rare in general, and predispose to the development of breast, gynae, and prostate cancers. Seminal work performed in our institution, identified that tumours with these mutations in them resulted in sensitivity to a type of drug called PARP inhibitor, as the cells were no longer able to repair their own DNA. This led to the first phase 1 trials of PARP inhibitors in patients with heritable with BRCA mutations and cancer led by my colleagues at our institution and subsequently globally, identifying that the PARP inhibitor olaparib resulted in quite dramatic benefit in patients born with these mutations that had subsequently developed cancer attributable to these mutations. Indeed, olaparib is now routinely used in breast, ovarian, prostate and pancreatic cancers, in patients with these BRCA genetic alterations, a true example of translation of science into routine effective care, from an academic laboratory to globally changing the face of cancer.

Well, what about lung cancer? Do we see similar issue in lung cancer? Here the story is more complex. BRCA mutations tend not to cause lung cancer. And by and large, the mutations that we find in lung cancer occur within the lung cancer itself, and patients generally are not born with a heritable susceptibility to lung cancer. At least that is what we thought. In our institution we have recently reported on the data where we have mainstreamed testing patients for mutations that they were born with alongside mutations within their cancer in specific groups. Indeed, when we took patients with EGFR mutant lung cancer and looked at their own genes that they were born with we identified that just under 1 in 10 of these patients actually had a heritable susceptibility to cancer. This clearly has huge implications for those patients' families.

And now we are testing patients' tumours in extensive detail, one question asked is "can we identify these germline or heritable mutations through simply testing the cancer itself?" Well, the answer is yes, these can be identified, although not directly and we see signals of this but cancer gene test reports do not often make it obvious that the genetic abnormality identified may be in the tumour as well as being in each of the cells of the individual, and hence potentially a heritable mutation.

But much of what I have been talking about has been on the basis of taking a tissue sample of the cancer and genetically analysing that tissue. A process by which we have to put either a needle into the chest to get a sample of the tumour, or a camera in the airways otherwise known as a bronchoscope to obtain a sample of the tissue directly. Procedures that none of us I think would want to volunteer to have if we did not need to.

Over recent years we have learnt much from analyzing the blood. We have actually identified that from a simple blood draw we can look at the plasma, which is the part of blood without any cells, and at a very, very, very, low level, we can sometimes find fragments of DNA which have originated from tumour cells in the patient. Indeed, we now have technologies available, which can simply, from a blood draw, analyse these small fragments of DNA, to tell us about the tumour genetics, called circulating tumour DNA or ctDNA.

So, one of the questions I often get asked is if you find a genetic alteration from the tissue does it actually relate to that same genetic alteration you can find swimming in the blood and at a very, very, low level. And the answer is that most of the time it does: there is concordance between the mutations of genetic alterations in tissue and the blood. But often we find patients who have a genetic alteration in the tissue, but we cannot detect it in the blood and that can be for a variety of reasons such as the tumour is not shedding adequate amounts to leach out into the blood. The alternative is that we can find genetic alterations in the blood, but not identified them in the tissue. This sometimes occurs when the tissue sampled does not reflect the whole of the genetics of the tumour because of where the needle went in may have a slightly different genetic profile to another area, or perhaps the blood genetic abnormality is not coming from the tumour but leaching out from the white cells of the blood, a process called clonal haematopoiesis.

Indeed, understanding and analysing ctDNA is complex, because when we look at the genetic material from plasma, we have to understand whether the genetic alteration we are looking at is derived from the tumour, which is what we would like to see, from the white cells leaching out into the blood, a process called clonal haematopoiesis, or indeed whether the mutation directly represents a mutation present in every cell of the body, particularly the white cells called a heritable or germline mutation. Therefore, analysing blood genomics through circulating tumour DNA is a complex task.

Nevertheless, ctDNA testing may revolutionize clinical care. Here is a typical clinical pathway for what happens to patients revered from their GP to hospital when lung cancer is suspected. They attend the hospital respiratory clinic and have usually had a CT scan just before the clinic. The respiratory physician looks at the CT scan and suspects lung cancer. Patients then undergo additional investigations such as PET scans or brain scans if necessary and some sort of biopsy to get a piece of tissue to make the diagnosis, either an image guided biopsy or a bronchoscopy, usually. Thereafter the pathologist will review the tissue biopsy and confirm the diagnosis of NSCLC and the case will be discussed in the multidisciplinary team meeting. Molecular evaluation of the sample will be requested, and the patient will then begin drug treatment according to the molecular diagnosis. However, the time frame from tissue sampling until staring drug therapy can be 3-4 weeks if not longer: a very unsatisfactory state of affairs. Could this whole wait time be truncated by the use of ctDNA? What would happen if we tested patients for ctDNA with a simple blood draw alongside their tissue biopsy undergoing their usual analysis?

We evaluated this process at our Institution in just under 250 patients and published our results. What we found was that there was extremely good concordance for important genetic alterations (tier 1 genotypes) between tissue and ctDNA genotyping. However, ctDNA analysis identified 25% more genetic alterations that tissue missed and similarly tissue 25% more genetic alterations that ctDNA missed: thus, using both in parallel is complimentary and increased the number of patients with important genetic alterations by nearly half (46%).

But the implications of bringing in this assay were even more important. ctDNA results were available in a median of 8 days from time of sampling versus 22 days for tissue biopsies and as a consequence, results were available to clinicians much more rapidly. Indeed, time to gentotyping results improved by 63% when using ctDNA over tissue testing. This has major implications. Because genetic information is so important for drug decision making, the time to starting treatment improved from a median of 35 days to 16 days: an improvement of 54%.

But these data have other implications, what happens if the scan suggests lung cancer in a very frail patient, but the biopsy is complex or risky or if a patient has undergone a biopsy, but the tissue material is insufficient for molecular testing? Again, ctDNA can be very useful in planning if a biopsy is really worth the while in patients with major risk factors and prevent re-biopsy in patients with insufficient tissue for molecular testing.

But what happens if the timing of the blood draw is not later in the pathway, once the tissue biopsy has confirmed lung cancer, but much earlier in the pathway, right at the beginning, at the time the patient goes to the hospital and has a CT scan where lung cancer is suspected. Well, we performed a pilot study of this process when COVID hit, as all lung biopsies were initially paused and massively delayed. Here, we tested 49 patients, and in one fifth (22%) we were able to start a targeted therapy either with or without the tissue or molecular results.

Indeed, here is a case of a lady with a mass in the chest in whom a tissue biopsy was delayed due to COVID. Here, ctDNA confirmed a druggable MET14 alteration and she was able to commence tepotinib, a MET inhibitor, at the same time as the biopsy was being planned with good and durable shrinkage and of the tumour thereafter.

We have now liaised with NHS England and with our guidance they are implementing ctDNA testing into the respiratory clinic at the time of first appointment, in a pilot study to evaluate what the clinical benefits are and its cost effectiveness. Phase 1 of 700 patients in England has completed and we are nearly completing phase 2 implementation of a further 1800 patients. I do hope that this programme will result in ctDNA implemented routinely in the clinic and if so, England will be the World's first country to implement this ctDNA at scale. If successful, I am sure this concept will be taken forward in other tumour types.

So, what does the future hold? You won't be surprised to hear that there is a huge amount of activity in genomic technologies and their clinical implementation ongoing.

When it comes to tissue analysis, our understanding of the complexities of the human and cancer genome are very much in their infancy. The more we analyze of the genome the more we find. Implementing exome and whole genome sequencing in the clinic is now possible, although there are still huge limitations on the bioinformatics aspects. For example, we know that cancer genetic alterations can be clustered into at least 21 different unique signatures, which can help us identify how that cancer arose; for example a tumour may have a genomic signature typical of tobacco exposure or of UV light exposure. But how this information will be useful in the clinic remains unknown.

Similarly, there is an ongoing explosion in research for implementation of ctDNA. For example, if a patient has undergone curative surgery, its fairly straightforward to do a ctDNA test to see if there is any residual tumor-derived DNA identified, as this may predict those that need additional consolidation treatment sich as chemotherapy or not: IE the technical utility has been proven. However, whether we should or not remains unproven: what are the pros and cons of this technology (such as false positives and false negatives) and what is the cost effectiveness? Similarly, we can test a group of healthy individuals with ctDNA to see if this is present implying that they may have cancer on board. Again, the technical utility has bene proven, but whether we should or not, ie the clinical utility, remains unproven, and the subject of ongoing research with initial data suggesting that ctDNA is effective in identifying some cancers in otherwise healthy individuals but less sensitive when limited to early stage curable cancers, and whether this improves mortality or not, remains unknown.

And with that, I'd like to thank you for your attention.

© Professor Sanjay Popat, 2024

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How Cancer Genomics is Transforming Cancer Care

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Using lung cancer as a case study, this lecture will explore the transformative impact of genomics on personalised cancer treatment. What are the challenges of implementing tumour sequencing in routine care, its effect on drug development, and how can we maximise clinical benefit?

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An interesting lecture in December about chemicals that affect our health. Why not listen online.

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Have a Question? No Registration Required https://app.sli.do/event/wnsgwEyyo9Y7GdbRVEHm1M

The forever chemicals, or PFAS (Per- and polyfluorinated alkyl substances) represent a large family of highly persistent synthetic chemicals widely used in everything from carpets to non-stick cookware, to firefighting foams and furniture textiles.

They are highly persistent in nature and have been found in the blood and breast milk of people and wildlife globally.

They are linked to cancer, liver damage, decreased fertility, and increased risk of asthma and thyroid disease. How can we reduce our exposure to them?

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Have a Question? No Registration Required https://app.sli.do/event/wnsgwEyyo9Y7GdbRVEHm1M The forever chemicals, or PFAS (Per- and polyfluorinated alkyl substances) represent a large family of highly persistent synthetic chemicals widely used in everything from carpets to non-stick cookware, to firefighting foams and furniture textiles.

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Why not download a podcast on an every day Medical issue.

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Series that demystifies health issues, bringing clarity to conflicting advice.

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Their mum, Angie Benhaffaf, told me: "From the very first scan at 12 weeks they were given no hope of survival but to see them, over 60 surgeries later, is amazing. They have not let this define them.

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Conjoined twins: Defying the odds to survive

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They were not expected to survive but Ruby and Rosie, now 11, are celebrating with five other sets.

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Watch this series of videos on the topic of Respiration

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A2 Biology - Respiration: Mitochondria structure and functions (OCR A Chapter 18.2)

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Watch this series of videos on the Nervous system

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A2 Biology - Neurones (OCR A Chapter 13.2)

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Watch the series of videos on Biological molecules

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Find the summary notes on this site for the autumn Test

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Fatema A.

University of Westminster - MSc Biomedical Sciences

Experienced science and maths tutor for students of Key Stages 4 and 5 of all abilities. Let me help you enjoy learning!

This topic is included in AS Paper 1 and Paper 2, and A Level Paper 1, Paper 2 and Paper 3 for OCR Biology A.

Notes

Summary Notes

Flashcards

Mind Maps

Questions by Topic

2016-2021 papers

More Questions by Topic

2.1 Cell Structure

2.2 Biological Molecules

2.3 Nucleotides and Nucleic Acids

2.4 Enzymes

2.5 Biological Membranes

2.6 Cell Division, Cell Diversity and Cellular Organisation

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OCR (A) Biology A-level Module 2: Foundations in Biology Revision - PMT

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Summary notes and past exam questions by topic for OCR Biology (A) AS and A-Level Module 2 - Foundations in Biology

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Professor Robin May 16 October 2023
Evolution has been described as "Biology's Biggest Idea", a concept so fundamental that, as Theodosius Dobzhansky said, " Nothing in biology makes sense except in the context of evolution ". But where did this idea come from and how has it been shaped over time? And does it even matter anymore?

Throughout this series, we will explore some of the surprising, unexpected and sometimes alarming ways in which evolution impacts our daily lives. But in this first lecture, we are going to lift the lid on some landmark concepts in the history of evolutionary thinking. Along the way, we will meet some of the people who developed those ideas and discover that inspirational ideas often emerge from some rather less-than-inspirational individuals.
Evolution by Natural Selection
Unsurprisingly, our first stop on this short history of big thinkers is the grandfather of evolutionary theory and one of the most famous biologists of all time, Charles Darwin. The story of Darwin's fortuitous role as 'naturalist and captain's companion' on HMS Beagle, and his revelation that natural selection was the force that generated the startling diversity of finches on the Galapagos Islands, is something that is now taught to schoolchildren around the world. But Darwin's ideas were also influenced by much less exotic observations, particularly regarding the impact of domestication on animals such as pigeons. Although 'evolution by natural selection' was far from universally accepted by Victorian England, it perhaps met with less resistance than might otherwise have been anticipated from a population whose minds had already been opened to the flood of new discoveries emerging from the Industrial Revolution.

Darwin was well aware that evolutionary forces must have shaped humans in the same way as they shaped all other living organisms, but - perhaps to avoid upsetting his deeply religious wife Emma - he shied away from discussing this in ' On the Origin of Species...'. The only mention humans get is the famous and rather cryptic sentence, " Light will be thrown on the origin of man ...". The same, however, was not true of Darwin's half-cousin, Francis Galton - our next port of call on this short history.
From Pigeons to People
Galton was a true polymath, with interests ranging from statistics to meteorology. An astute observer of the world around him, he was puzzled by the observation that the offspring of pedigree dogs of different breeds typically do not resemble either parent. Instead, they often appear more similar to what he described as 'ancestral' dogs; the classical mongrel or mix-breed. Galton wondered whether something similar may occur in humans and conducted a now-famous study in which he measured parents and their (adult) offspring. This revealed exactly the same pattern - the children of very tall or very short parents are rarely as tall or short. Instead, they tend to be much closer to the average height of the population as a whole. Thus Galton can lay claim to being one of the first people to apply evolutionary analysis to his own species.

If Galton had stopped there, then history might have recorded him as a hero of evolutionary theory. Unfortunately, however, he didn't. A toxic combination of enthusiasm for this new science and a completely unsubstantiated belief that many of society's ills must be heritable led Galton to propose a scheme to 'improve' the human race through selective breeding. Needless to say, Galton's definition of 'improvement' meant striving towards a white, British, aristocratic elite - coincidentally, the group to which Galton himself belonged. He named this approach 'eugenics' and vigorously extolled the virtues of forced adoption and state-regulated reproduction. In doing so, Galton sowed the seeds of 'scientific racism' and led, albeit indirectly, to some of the most appalling crimes of the 20th century.
Peas and Peacocks
Despite this dark legacy, Galton's approach to using mathematical tools to study heredity changed evolutionary thinking and influenced some of the key thinkers of the next century. Foremost amongst these was Ronald (RA) Fisher, a talented statistician who realised the power of the huge sets of data being accumulated at the time by experimental crop breeding programmes. Fisher developed a number of powerful statistical tools, in particular the 'Analysis of Variance' method which remains a lynchpin of quantitative biology today. He applied this, in particular, to the problem of sex in biology, addressing key questions such as "Why is the sex ratio in most species one-to-one?". And he mathematically demonstrated how sexual selection can lead to ever more extreme features, such as the peacock's tail - a phenomenon now known as the 'Fisher Runaway'.

But, like Galton, Fisher was a complex character. Although it remains unclear whether he believed in scientific racism per se, he nonetheless espoused the repugnant (and scientifically flawed) idea that different human races differ " in their innate capacity for intellectual and emotional development", later writing that marriage between people of different races " can do nothing but harm ". There is a fitting irony that it is the statistical tools developed by Fisher himself which have proved beyond doubt that such ideas are fundamentally incorrect.
Social Insects and Selfish Genes
The 20th century saw a sequence of talented thinkers apply mathematics to biology and make major inroads into evolutionary theory in the process. Sewall Wright, JBS Haldane, Ernst Mayr, Hermann Muller and numerous others created a scientific framework in which theoretical models repeatedly explained evolutionary enigmas. Perhaps nowhere is this more apparent than in the work of our final character in this tour of evolutionary 'big thinkers' - William (Bill) Hamilton.

Hamilton was a mathematician who became interested in a paradox that had also puzzled Fisher, Haldane and many others - if evolution is driven by competition for limited resources and selection of the fittest individuals, then why do some species, such as bees or ants, exhibit apparently altruistic behaviours? What he eventually realised was that such 'self-sacrificing' behaviours can still be favoured by natural selection if they lead to an overall fitness gain for a related individual. This concept, now known as Hamilton's Rule, means that a behaviour will be selected if the cost (C) of an action to an individual is outweighed by the benefit (B) to a related individual, multiplied by their coefficient of relation (r):

Put simply, it is, therefore, worth an individual risking their own life to save two siblings (because each sibling shares, on average, 50% of the individual's genes) or four half-siblings (because each shares 25% of their genes) and so forth - a concept now known as 'kin selection'.

Although Hamilton's work was published in 1964, it remained relatively obscure for over a decade. But in 1976 the concept of kin selection entered the public consciousness with a bang, following the publication of Richard Dawkin's " The Selfish Gene ". Four editions and more than a million copies later, this book set out the argument that natural selection acts at the level of genes, rather than individuals. In doing so, it provided a framework for popular concepts such as 'selfish DNA' (genes which replicate within the genome even when this is disadvantageous to the organism itself) and 'memes' (ideas which - like genes - are selected to replicate and spread within a population).

Perhaps even more importantly, The Selfish Gene once again made evolution a topic for dinner table discussion, as it had been in Darwin's time, and led to a broad understanding that evolution was not just about dead dinosaurs and tropical finches, but rather was a force that continues to shape everyday life today - a subject we will return to in the next lecture.

© Professor Robin May 2023

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A Small History of Big Evolutionary Ideas

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Have a Question? No Registration Required https://app.sli.do/event/aFTxYHr8MPHuzQZs1njTNR **Date change: this lecture was moved from 4th October to 16th October due to rail strike action** The theory of evolution is often described as the biggest idea in the history of humanity. But evolutionary theory itself has evolved over time, often via landmark contributions from some very unusual characters.

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Join the GenePools team to investigate the hidden and invisible life within ponds in urban areas, and their benefit for the environment.

GenePools is a partnership between Natural England, Cefas, the Joint Nature Conservation Committee and the Natural History Museum. We invite you to work with us on the second round of the project!

At a glance

Investigate hidden pond life.

Type of activity: Outdoor sampling of your pond and an online survey.

Who can take part? Anyone who has permission and access to an enclosed pond in one of six cities:
Plymouth, Bristol, London, Cambridge, Newcastle and Manchester.

When? Sign up from 1 May. Return samples in the pre-paid packaging by 30 June 2023.

Where? Any enclosed pond that you have permission to sample. This might be your own pond, someone else's private pond or a community pond for which you have the right to sample.

How long will it take? Sampling will take about 15-20 minutes. Online forms, up to 20 minutes to fill in.

We are calling members of the community in Plymouth, Bristol, London Cambridge, Newcastle and Manchester to sample the water in their ponds and share the secrets that hide under their surface.

Together we will investigate the fascinating life that dwells in ponds in urban areas, using novel DNA sequencing methods. We will then dive deep into the data to explore how we can enhance biodiversity in ponds, for the benefit of both people and wildlife.

How to take part

Our method lets you extract the material we want to analyse in a few simple steps.

1) To take part, please complete the sign-up form.

2) We will then send you all the kit you need to take part.

3) Follow the instructions to take your sample and return it to be analysed in the envelope we provide.

4) Finally, complete a short online survey to provide us with some background information on your pond to help us interpret the results. Please note: Only those samples for which we receive completed surveys will be analysed.

Using your data

The personal data we collect from you will be held by Natural England and only used to contact you about this project. You can download our Privacy Notice (PDF 150KB)

David Bass

Cefas, lead researcher in the GenePools team

Building on our first round of investigations

This is the second round of the project - last year we worked with 200 volunteers across Bristol, London and Newcastle. The first round was a huge success and 164 ponds were surveyed in total. We found over 2,250 species, spanning everything from microbes less than one micron in size, to beetles, parasitic wasps, chickens, foxes and dogs.

Thank you to everyone who was involved. We wouldn't be able to do this science without you, our community scientists. We are still analysing the data for publication, and hope you can take part in the survey this year. We also welcome new volunteers from our new cities.

Project resources

Watch the video below for an overview of environmental DNA (eDNA) or read our article.

Watch the Museum's Identification and Advisory Officer, Florin Feneru, sample a pond using the GenePools kit.

Project team and contacts

If you have any queries, please contact the Community Science team at communityscience@nhm.ac.uk with 'GenePools' in your subject line.

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Join the GenePools team to investigate the hidden and invisible life within ponds in urban areas, and their benefit for the environment. GenePools is a partnership between Natural England, Cefas, the Joint Nature Conservation Committee and the Natural History Museum. We invite you to work with us on the second round of the project!

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This session we will be joined by Lucas Pantaleao.

Lucas is a Developmental Biologist currently working at the MRC-IMS. He became interested in biomedical sciences at a very young age, which led him to complete a BSc in Nutritional Sciences and then MSc and PhD degrees in Brazil. In the last years, the aim of his research has been to identify how developmental challenges, such as maternal obesity, exert generational effects upon the phenotype. He assess the physiological consequences of exposure to harmful conditions, and he is particularly fascinated about the prospect of understanding the role of various biomolecules involved the in programming of health and disease.

He will be joining us to discuss his current work and career pathway.
About My STEMM Future Speaker Series
My STEMM Future is a joint initiative from Wellcome Connecting Science and the Youth STEMM Award. The project seeks to support students from backgrounds historically excluded from STEM in completing a Youth STEMM Bronze or Silver Award and develop a portfolio of achievements to support Sixth Form, University or workplace applications.

The Speaker Series aims to highlight diversity in science roles and scientists, and is open to anyone to join.

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my stemm future speaker series: lucas pantaleao

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my stemm future speaker series: lucas pantaleao tickets

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My STEMM Future Speaker Series: Lucas Pantaleao

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This session we will be joined by Lucas Pantaleao. Lucas is a Developmental Biologist currently working at the MRC-IMS. He became interested in biomedical sciences at a very young age, which led him to complete a BSc in Nutritional Sciences and then MSc and PhD degrees in Brazil.

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Experience overview

Welcome to the fascinating world of genomics! Springpod has partnered with Wellcome Genome Campus to help you experience careers in genomics, science and data, and the range of opportunities on offer. From lab and data-based roles to communications and management positions, you'll get an inside scoop into life at a pioneering, industry-leading research campus.

What's included?

In this virtual work experience programme, you'll receive a top-level overview of the world of genomics - from gene editing to ethics and synthetic biology. You'll even complete a series of quizzes and fun activities to help build your understanding of the industry, and have the ability to ask the industry professionals any burning questions in live webinars.

Available dates

To ensure that you get the very best experience, the number of places on each programme is limited. Apply soon to avoid missing your place. Good luck!

Programme dates: 31st July - 11th August

Application deadline: 21st July

What students say

"I really appreciate this opportunity to develop my knowledge and have some inside Information from professionals in this field. It let my be more confident that engineering will be the right choice for me and gave me useful information such as the use of the graduate scheme and how it will help me decide upon a specific area to work in and how my skill set is best used. I am forever grateful for this experience and am extremely thankful. "

Roisin

"Thank you very much for providing such a well-rounded informational virtual work experience for free. It has been very helpful to me so that I can make more informed decisions about my future and has opened my eyes to opportunities I didn't know I wanted to get involved in until now, like a graduate scheme. This work experience has been great and I really appreciate all the hard work and dedication that took to make it."

Leire

"Thank you so much for creating this experience for me. As a year 12 student who didn't even think that the engineering path was even possible for me, taking part and learning more about it has given me lots of motivation and courage to challenge myself and work hard. I have always had a passion for this area in work life, and thanks to you i now have a good idea of where to start. Thank you!"

Scarlett

Ready to find out if this is right for you?

Apply Now

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Genomics, Science and Data Careers with Wellcome Genome Campus

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Welcome to the fascinating world of genomics! Springpod has partnered with Wellcome Genome Campus to help you experience careers in genomics, science and data, and the range of opportunities on offer. From lab and data-based roles to communications and management positions, you'll get an inside scoop into life at a pioneering, industry-leading research campus.

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The law has changed to allow gene-edited food to be developed and sold in England.

The government hopes the technology will boost jobs and improve food production, but safety and environmental worries mean it is not allowed in other parts of the UK.

What is gene-edited food?

For many years, farmers produced new varieties through traditional cross-breeding techniques.

They might, for instance, combine a big but not very tasty cabbage with a small but delicious one to create the perfect vegetable.

But this process can take years, because getting the hundreds of thousands of genes in cabbages to mix in just the right way to produce large but tasty offspring is a matter of trial and error.

Genetic methods remove the random element.

They let scientists identify which genes determine size and flavour, and insert them in the right places to develop the new variety much more quickly.

Which genetic techniques are used?

Genetic modification (GM), which has been common in most parts of the world for more than 20 years, though not in the European Union (EU).

GM involves adding genes to a plant's DNA from a different species of plant - or even an animal. It creates new varieties which could not have been produced through cross-breeding.

Cisgenesis, which is like GM, but involves adding genes from the same or very closely-related species, which the new rules will allow if the resulting crop is something that could have been produced through traditional cross breeding.

Gene-editing (GE), which is a much newer technique that lets scientists target specific genes. The new law lets plant breeders switch them on or off by removing a small section of DNA - again, provided the resulting crop could have been naturally produced.

But you will not see GE produce in shops straight away.

The technology is still relatively new, and it may take several years before new varieties are on sale. But they are on the way.

The legislation also opens the door to the sale of meat, eggs and dairy from gene-edited animals.

But MPs would have to approve this separately, because the government is still considering the potential impact on animal welfare. There is no clear timetable for when this might happen.

The new rules do not require GE foods to be labelled as such, because Westminster considers them no different to conventional produce.

So far, Scotland, Wales and Northern Ireland have not changed their laws on GE crops.

In Japan, you can already buy tomatoes rich in a chemical called GABA, which has a calming effect, and modified sea bream where more of the flesh is suitable for sushi.

A US firm is developing seedless blackberries and stoneless cherries.

In the UK, researchers have developed tomatoes that contain vitamin D. Scientists in Hertfordshire have also been experimenting with gene-edited wheat.

However, the food industry mainly wants to use GE technology to speed up the development of new varieties of current crops.

Firms also want to be able to tailor crops more precisely: producing starchier potatoes for crisp-makers, or protein-rich veg to use as a meat substitute.

Companies are also keen to introduce traits that improve yields, and to create varieties that are more resilient to climate change.

Are gene-edited foods safe?

Scientists insist that each of the three genetic techniques produces food that is safe to eat, and point out that all food is rigorously tested.

They argue that GM crops have been consumed by billions of consumers in North and South America and Asia for more than 25 years with no ill-effects.

However, concerns over health risks and the environmental impact have meant that neither GM nor GE crops can be commercially produced or sold in the EU, although there are some signs that this may change.

What are the safety concerns?

Many campaigners who are opposed to gene-edited foods make no distinction between these and those produced by the earlier GM technology.

They are worried that GE foods will not require additional testing, and fear the creation of new allergens or toxins.

They are also concerned about the impact GE crops could have on the environment.

However, scientists say that there is no evidence that GM crops have harmed human health or damaged ecosystems, and they expect the same to be true for GE crops.

The Westminster government believes that because gene-edited produce is indistinguishable from natural varieties, they will face less opposition than their GM equivalents.

Recent unpublished polling by YouGov for the Department for Food and Rural Affairs (Defra) backs this view, but a large minority remains opposed:

54% said GE crops were "acceptable"

28% said they were "unacceptable"

The polling also found that 78% were in favour of some environmentally-beneficial applications of GE, such as the reduced use of pesticides and herbicides.

But there was less support for the use of gene-editing in animals, over fears the technology might cause suffering.

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What is gene-edited food and is it safe to eat?

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The law has changed to allow gene-edited food to be developed and sold in England. The government hopes the technology will boost jobs and improve food production, but safety and environmental worries mean it is not allowed in other parts of the UK. What is gene-edited food?

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A toddler with a rare inherited condition has become the first child to be treated by the NHS with a new life-saving gene therapy.

Teddi Shaw was diagnosed in time because her older sister Nala showed symptoms - but it was too late to treat Nala, who is now terminally ill.

Both girls have MLD, which severely damages the brain and nervous system.

The one-off treatment, called Libmeldy, costs £2.875m and is the most expensive medicine ever approved for the NHS.

The BBC was given exclusive access to follow Teddi's treatment over several months and spoke to other families affected by MLD.

Imagine having two daughters with a devastating genetic condition - but only one can be saved.

Three-year-old Nala - and Teddi, who is 19 months old - both have MLD, metachromatic leukodystrophy.

Children with this fatal genetic disease are born apparently healthy, but MLD gradually attacks the brain and body.

Before Nala became ill, she was a completely normal toddler.

"She was always singing, dancing and spinning around everywhere, always laughing - just a cheeky little girl," says her dad, Jake.

But just over a year ago, Nala's walking gradually became uneven and she started falling over more often. She was also showing signs of a tremor.

Her parents Ally, 32, and Jake, 29, became increasingly concerned. Ally was convinced Nala had a brain tumour.

Initially, doctors reassured them nothing was wrong. But then, in April last year, Jake and Ally took Nala to A&E where she had an MRI scan. Forty-five minutes later they had a likely diagnosis.

"When the doctor said 'It's not a brain tumour,' I was doing cartwheels almost, so excited," Ally says.

But her relief evaporated when the doctor mentioned metachromatic leukodystrophy - which they had never heard of before. When she left the room, Jake Googled the term. "I could tell by his face it wasn't good news," says Ally.

MLD is caused by a faulty gene which means children affected cannot produce an important enzyme called ARSA - a protein that helps the body's metabolism work.

As a result, fatty chemicals called sulfatides build up. These gradually destroy the protective layer around cells in the brain and nervous system, leading to a devastating deterioration. Children lose the ability to walk, talk or eat - and eventually to see or hear.

Because both Ally and Jake are carriers of the faulty gene, they were told Nala's younger sister Teddi had a one-in-four chance of also having MLD.

"I thought to myself, it can't happen again, we can't be that unlucky," says Jake. "When we found out, it was just heart-breaking."

A cutting-edge treatment turning a terminal diagnosis into hope for a healthy life.

But for 10-month-old Teddi, there was hope. The disease had not yet affected her and so she became the first patient treated on the NHS with Libmeldy, which must be given before the disease has caused irreparable damage.

Nala's MLD was identified too late for her to be treated. She is already unable to walk or talk, and has to be tube-fed.

"When they told us there was treatment available for Teddi it was kind of a bitter pill to swallow because Nala can't be helped," says Ally.

She says they are sad and "extremely grateful" at the same time.

"I've always said Nala saved Teddi's life. And that's how I wanted to think about it," says Jake.

How does Libmeldy work?

Libmeldy involves altering a patient's own cells to correct the faulty gene. In June 2022, Teddi was hooked up to a machine at Royal Manchester Children's Hospital where blood was removed and filtered, so a single bag of stem cells could be collected. The process looks similar to dialysis.

The cells were then sent to Milan, where scientists used a harmless virus to insert a working version of Teddi's faulty gene - the one which should produce her missing enzyme - back into the stem cells. The gene-corrected stem cells were then sent to Manchester to be infused back into Teddi.

Teddi and her mum Ally moved into hospital in Manchester for the duration of the treatment. Ally, formerly a senior staff member in a children's home, has put work on hold. Meanwhile dad Jake, a carpenter, stayed home in Northumberland to look after Nala.

Before she could be given the replacement cells, Teddi had to have chemotherapy to kill off the remaining faulty stem cells in her bone marrow.

In August, we were back in Manchester to watch Teddi receive Libmeldy.

In her hospital room, Teddi, then 14 months old, had chosen that day to attempt her first tentative steps. Mum Ally said her younger daughter was taking it all in her stride.

"She's doing absolutely fine, considering what she's been through," Ally told us. "She's still just her mischievous normal little self."

The infusion of Libmeldy took less than an hour. Over the following days the gene-altered cells migrated to Teddi's bone marrow and began producing the enzyme she had been missing since birth.

What is remarkable is that this is a one-off treatment, with the hope that it provides a permanent fix for MLD.

Libmeldy was developed by a British company, Orchard Therapeutics. Its CEO and co-founder, Bobby Gaspar, spent many years as a consultant at Great Ormond Street Hospital, while carrying out research into potential therapies.

"Bringing a new medicine to the world that can potentially cure these devastating diseases is incredibly rewarding," he says, adding that it was "a very long journey to develop a medicine like this".

Libmeldy took nearly 20 years to develop, with the first human trials taking place in 2010. It got EU approval in December 2020 and is now available through the NHS.

Doctors who specialise in treating MLD say Libmeldy is a game-changer.

"This truly is a breakthrough," says Prof Simon Jones, one of the consultants involved in Teddi's treatment.

"We have had almost nothing to offer families with this condition for decades. Instead of many years of terrible neurodegenerative disease, we have the potential for a full life, lived healthily."

Now that there is a treatment, it has become even more important to pick up the disease in time.

Teddi's parents, along with other MLD families and the doctors who treat them, are campaigning to have it screened for at birth. In the UK, babies are given a heel-prick blood test which screens for nine genetic conditions, such as cystic fibrosis - but it does not currently include MLD.

"We are letting our children down by not screening for these devastating conditions because they are so preventable if you can identify them at birth," says Dr Gaspar.

It is too early to tell, but the signs are good. Several children from the UK were involved in clinical trials of Libmeldy in Milan, before it became a licensed treatment.

Joe Elson, who is 12, had his gene therapy in Italy in 2014. Nine years on, he is completely healthy and doing well at school. Watching Joe fly his kite on a beach in Kent, it is hard to imagine that he was born with a devastating disease. It appears that Libmeldy has provided a permanent fix for his MLD.

"It's given him his life back. He makes the most of every moment," says his mum, Nicola.

Joe's MLD was only picked up when his older sister Connie was diagnosed. She died last summer. Nicola told us 13-year-old Connie had lost the ability to walk, talk, eat and hold her head up. She had also lost her vision and hearing, and the ability to smile.

"It's the most horrific, wicked condition that steals these children away," she says.

It's expected that only about seven or eight children a year in the UK will be eligible for Libmeldy. That is because MLD is rare and usually not diagnosed early enough.

The health assessment body NICE says Libmeldy is one of the most clinically effective medicines it has ever appraised. And, although it has a list price of £2.875m, NHS England has negotiated a confidential discount.

One reason why the price tag is so high is to cover the costs of developing and producing the drug. The price paid by the NHS for this one-off treatment has to be set against the cost of treating children with MLD as they gradually become completely dependent, tube-fed and lose all their senses. And then, there is the suffering endured by patients and their families.

The NHS chief executive Amanda Pritchard describes Libmeldy as a revolutionary treatment offering "a huge moment of hope" for parents and children affected by MLD.

"It means that children like Teddi can do the things that all children should be able to, like going to school and playing with friends," she says.

Back home in Northumberland, Teddi is going from strength to strength.

But seeing her together with her older sister Nala brings home the harsh reality facing Jake and Ally. It is "an absolute blessing", says Jake, that Teddi has received Libmeldy, but "absolutely heartbreaking" to watch Nala's rapid decline.

"Her body is basically kind of gradually shutting down and she will lose most of her senses. So it will come to a point where there's nothing left for her to lose," Jake says.

"You feel like you're grieving from the very start because your child is disappearing almost in front of your eyes," says Ally.

The Shaws know that if Nala had been diagnosed earlier she might have been treated, rather than facing a terminal illness.

Jake, who plays guitar, has recorded a song for his daughter entitled " Lay You Down Easy", which he hopes will raise awareness of the disease, with any money raised going to the MLD Support Association.

Although MLD is not currently screened for at birth in the UK, small pilot studies to screen newborns have begun in five countries - including Germany, where testing has identified the first patient with the condition.

Later this year, Genomics England will start a pilot project offering whole genome sequencing to 100,000 newborns. This will screen for about 200 treatable conditions, and may include MLD.

Could other rare diseases be treated this way?

The simple answer is yes. Royal Manchester Children's Hospital is trialling two other gene therapies for rare disorders, Sanfilippo and Hunter syndromes.

The director of the Paediatric Bone Marrow Transplant Programme, Prof Rob Wynn, says many of his young transplant patients have genetic diseases, and he thinks the approach of correcting the conditions using gene-modified stem cells will be "transformative".

Nala's parents say it would be a fitting testament to her if newborn screening for MLD became the norm.

"I would like to think that if another child was born with MLD, it could be picked up quick enough for them to be saved," says Ally.

Additional reporting by Nicki Stiastny

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UK's most expensive drug Libmeldy saved Teddi Shaw, but is too late for her sister

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A toddler becomes the first to be treated by the NHS with a new gene therapy costing £2.875m.

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DNA graffiti: mutation patterns in cancer | The Royal Society

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Revision for OCR Biology (A) AS and A Level Papers, including summary notes, worksheets and past exam questions for each topic.

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OCR A-Level Biology past papers are previous exam papers that have been used in OCR A-Level Biology exams. They provide students with an opportunity to practice and prepare for their upcoming exams by familiarizing themselves with the format, content, and style of questions asked in the OCR A-Level Biology exams.

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OCR A-Level Biology past papers are important because they allow students to understand the structure and content of the OCR A-Level Biology exams. They also help students to practice answering questions in the same format as the real exam, which helps to improve their exam technique and confidence.

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A gene variant which is known to increase the risk of breast and ovarian cancer has been identified in people with Orkney heritage.

A new study suggests one in 100 people with grandparents from Orkney has a specific mutation of the BRCA1 gene.

It found that most of them could trace their family ancestry back to the island of Westray.

It is believed to be the first time a geographic ancestral link of this kind has been made within the UK.

The researchers also discovered the specific Orkney gene variant in smaller numbers in genetic testing across the UK and even in the US.

Previous research has found that women from certain ethnic backgrounds, such as Ashkenazi Jews, also have a high rate of a specific BRCA gene variant.

Across the UK about 1 in 1,000 people have a BRCA1 mutation, which can leave women at a higher risk of ovarian and breast cancer.

The BRCA genes are present in every person, both men and women, but when a fault occurs in one of them it can result in DNA damage and lead to cells becoming cancerous.

People with a genetic variant have a 50% chance of passing it on to their children.

Awareness of the faulty gene was raised a decade ago when Hollywood actress Angelina Jolie underwent a double mastectomy after discovering she had a BRCA1 variant.

The operation was said to reduce her chances of getting breast cancer from 87% to 5%.

However the NHS advises that risk-reducing surgery is not the only option.

It also advises awareness of changes to breasts, annual breast screenings and MRI scans can help detect breast cancer, while lifestyle changes like healthy eating and exercise can "sometimes reduce risk".

There is currently no reliable screening test for ovarian cancer, it adds.

Analysis by Laura Goodwin, BBC Scotland Science and Innovation Correspondent

Identifying this variant - BRCA1 V1736A - is the result of 25 years of clinical research by Prof Zosia Miedzybrodzka, the director of the NHS Grampian Clinical Genetics service.

Back then the breast cancer screening centre started to detect an increase in the number of families they were seeing and wanted to know why.

As genetic testing grew, the team saw the same gene variant appearing time after time and became suspicious of its significance.

Speaking to patients about their ancestry helped make the link to Westray, an outer Orkney island with a population of just 600.

BRCA1 V1736A is likely to have arisen in a founder individual from Westray at least 250 years ago.

So far 37 women of Orcadian heritage with the variant have been identified.

Some won't ever go on to develop cancer but others have chosen to have risk-reducing surgery.

There are 20 people found to have the gene variant who don't yet know they carry it.

They were among more than 2,000 volunteers who gave genetic data to the Orcades (Orkney Complex Disease Study) study.

The design of the study at the time meant information would not be disclosed.

The team behind it have now asked the Research Ethics Committee for permission to contact the women identified to tell them they have the BRCA1 gene variant.

Prof Jim Wilson of the University of Edinburgh, who ran the study, said: "In a person here on this island hundreds of years ago this variation happened in a BRCA 1 gene and now we are finding many descendants both in Westray and further afield in Scotland and beyond.

"I think this is the most significant thing that I have ever really discovered. Its going to have immediate benefit to society at large."

'It is important that we know'

Former nurse Linda Hagan was born on Westray and has lived there most of her life.

Her parents and grandparents and most of her ancestors were also from the island.

Linda, 69, told the BBC that her younger sister died of breast cancer four years ago.

She should get the results of her genetic screening shortly.

Linda has three daughters and said it would be tough to think she might have passed the gene variant to them.

"But it is important that we know and hopefully something can be done about it," she said.

Grandparents from Westray

The latest research from the Universities of Aberdeen and Edinburgh was published in the European Journal of Human Genetics.

The study looked back at the 80 grandparents of the BRCA1 variant carriers identified in the Orcades genetic study and found 60% were from Westray.

Further ancestral links to the island went back to the early 18th century.

The Orkney population is just 22,000 but there are people with a shared ancestry around the world and the researchers said they should be offered a targeted test for the variant.

Currently in Scotland the test is available to those who know of a direct family connection to the gene or have a history of ovarian or breast cancer in their family.

Planning is under way for a small pilot trial that will offer testing to anyone living in Westray with a Westray-born grandparent, regardless of a family history.

If the pilot is successful, the long-term aim is to offer the test to everyone in Scotland with a Westray-born grandparent who wants it.

NHS Grampian genetics clinic is running a helpline for queries about the gene variant linked to breast and ovarian cancer for those who have grandparents from Orkney. The number to call is 01224 553940. Email inquiries can be directed to gram.orkBRCAgene@nhs.scot

GPs will not be able to assist with gene testing and any questions about this research and next steps should be directed to the helpline.

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Breast cancer gene linked to Orkney islands

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A gene variant known to increase the risk of breast cancer has been found in people with Orkney heritage.