Category: Joseph Smith

by Joseph Smith

In my last blog post I discussed the use of a gene-editing technology, termed CRISPR, and the controversy surrounding its potential for use in human studies. Today I will talk about an experimental gene therapy, distinct from CRISPR, that has been used to restore the immune systems of young children with X-linked severe combined immunodeficiency (SCID-X1).

SCID-X1 is caused by mutations in the gene that encodes interleukin 2 receptor common gamma chain (IL2RG), located on the X chromosome. As a result, these children are unable to produce two essential types of immune cell, T cells and natural-killer (NK) cells. Furthermore, functional T cells are required for the proper development of B cells and so these patients also possess a defective B cell population. For those that suffer from this disease the lack of a functional immune system means that infection with viruses or bacteria, that a healthy individual will often fight off, can actually be fatal. As a result, unless they are cured, these children are destined to a life of isolation.

The current gold standard in therapy entails undergoing a bone-marrow transplant from a matched donor. However, this is not always possible and so scientists around the world have sought an alternative therapy, for almost two decades. One potential treatment involves delivering a functional copy of the IL2RG gene into the children’s cells using a viral transporter, consequently restoring their immune system. Historically, trials utilising this method have had mixed results, leading to only partial restoration of immune function. Moreover, early trials led to some children developing leukaemia through unintentional activation of proto-oncogenes, highlighting the risks associated with the technology.

On the 17th April scientists published the results of a study wherein 8 infants with SCID-X1 were treated using the same approach; however, researchers utilised a different virus. This version is better at delivering IL2RG to slowly-dividing stem cells, which will eventually form the patients’ immune cells. Encouragingly, all of the children who underwent this treatment went on to produce the essential cell types required for a functional immune system, T cells, B cells, and NK cells. Furthermore, up to 2 years after treatment the children are showing no signs of leukaemia. The results of this study mean that these children, that would otherwise be unable to leave the protective confines of specialist hospital facilities, are now living normal and healthy lives.

This study represents a landmark improvement in the treatment of patients with SCID-X1. However, it is too early to tell whether this treatment is a permanent cure for the disease. It is not known how these children’s immune systems will function in the long-term. Is it possible that the effects will wear off? For now, the restoration of immune function alongside improved quality-of-life is an indisputable success for these patients.

by Joseph Smith

Most scientists will have heard of genome editing in some form or another; whether it’s altering the genes of a cell line through radiation or targeting specific regions of the genome by inserting additional base pairs or entire genes. Undoubtedly, a large proportion of the general public will also have an idea as to what genome editing means, even if it is as a result of watching Jurassic Park! Due to recent advances in DNA editing technology, the prospect of using the technique to alter the genome of a human being is now less fantasy than reality. But even if we could edit our own DNA, does that mean we should?

Last year, scientists were forced to answer this question when the first genome edited babies were born, despite the practice being against government regulations. He Jiankui, a geneticist from the Southern University of Science and Technology of China, took to YouTube in November 2018 to announce his controversial studies. Jiankui claims that he successfully edited the DNA of human embryos using a technology called CRISPR-Cas9. These embryos were then implanted by IVF and 9 months later the first genome edited babies were born. But what part of their DNA had been edited and why? Jiankui claims that, using CRISPR-Cas9 technology, he was able to disable a gene called CCR5. This gene encodes the CCR5 receptor which allows the HIV virus to enter cells and by disabling it, theoretically, the virus cannot infect them. On the surface this might sound like a great idea; if we can prevent a disease then surely it must be beneficial?

However, the general response from the scientific community has been one of public outcry. Many view Jiankui’s use of the technology as being both dangerous and irresponsible. Scientists are yet to reach a consensus as to how genome editing technologies such as CRISPR-Cas9 should be used. Despite the potential benefits there are a great number of risks associated with such techniques, both scientifically and morally. Although genome editing may be used to prevent disease, it has the potential to be used for ethically questionable purposes, such as to select for specific traits. Further to this, it cannot be guaranteed that by editing one part of the genome you do not affect another, which could have disastrous consequences. In Jiankui’s case, experts have stated that there was no reason to have edited these babies’ DNA, as although the father was HIV-positive, there is no real risk of transmission. Furthermore, HIV-positive mothers are able to undergo caesarean section to avoid transmission of the virus. The Southern University of Science and Technology of China has stated that they were unaware of Jiankui’s research. The university have launched an independent investigation into his claims.

Genome editing has been and remains a controversial topic, and it is likely He Jiankui’s studies will have only reinforced the cautioned stance that the scientific community holds.

by Joseph Smith

Cancer is defined as an uncontrolled division of abnormal cells, resulting in a malignant growth or tumour. Recent reports suggest that approximately half of us will be diagnosed with the disease in our lifetime. Moreover, it is predicted that cancer incidence rates will increase by 68% from 2012 to 2030 worldwide. Fortunately, our understanding of how cancer occurs and progresses is also increasing, ] providing opportunities to identify novel druggable, targets. Our improved understanding has also revealed unforeseen challenges that complicate the journey of new drugs from bench to bedside. This is evidenced by the fact that a staggering 95% of leading drug candidates do not make it to the clinic. But why? One of the main reasons is our inability to accurately replicate cancers as they occur in humans. Researchers currently employ a wide array of cancer models in order to understand the biological processes that drive cancer and to test potential therapies. In this article I will discuss some of the most commonly used cancer models and how they might be limiting effective drug discovery.

Cell lines

The first, and probably most well-known, cell line was established in 1951 and derived from a cervical adenocarcinoma tissue biopsy. Henrietta Lacks, the patient from whom the biopsy was taken, succumbed to her cancer only months later however HeLa cells are still used in cancer research to this day. HeLa cells, like other immortalised cell lines, have the ability to grow and divide indefinitely. Furthermore, researchers can easily manipulate cell lines, for example, by increasing or decreasing the amount of a certain protein we may better understand its function within the cell. These traits have resulted in their routine use and they are an essential tool for cancer research, allowing scientists to elucidate the molecular biology of cancer cells. However, cell lines represent a massively simplified version of human cancers, lacking heterogeneity or a tumour microenvironment, including an immune system. These differences mean that a drug that is effective in vitro will not necessarily perform as well when applied in vivo.

Mouse models

In order to better recapitulate human cancers scientists will often utilise mouse tumour models, establishing cell line-derived xenografts within immunocompromised mice. After the cancer cells have been implanted researchers may then treat the mice with a novel anticancer drug, with the view of slowing or ideally preventing cancer growth. Mouse models allow for evaluation of new therapies in vivo within an environment more similar to that seen in humans. For example, the cancer cells have the ability to interact with the microenvironment in which they’re placed. However, in using cell line-derived xenografts these tumours still lack the inter-tumoral heterogeneity seen in the clinic. Notably, this heterogeneity is likely one of the reasons for low response rates seen in many clinical trials, as small populations of drug-resistant cancer cells can ultimately repopulate patients’ cancers.

What are the alternatives?

Both cell lines and mouse models are useful cancer models, but both have major limitations and do not capture the complexity of human cancer. As a result, novel anticancer drugs that prove to be effective in these models often do not have the same effects in humans. So how do we solve this problem? With advances in technology, scientists have developed a multitude of models that aim to overcome the aforementioned issues, such as patient-derived xenografts and explant culture. I will discuss these methods in more detail in the next issue of {react} magazine!

Issue 12 of {react} magazine is currently under development by our dedicated team of student writers, editors and designers. Keep an eye on this blog, our twitter, and facebook for information on the release date!

by Joseph Smith

How does the human brain work?

This question has fascinated and baffled scientists for centuries and, unsurprisingly, has led to a myriad of equally complex questions. In order to elucidate how the human brain works, it is crucial that we first understand the physiological processes that underlie its function, at a cellular level. Despite decades under intense scientific scrutiny little progress has been made in characterising the different subtypes of neuron, the cells responsible for neurological signaling, present in the human brain. However, by using advanced sequencing methodologies, neuroscientists are starting to unravel this diverse and tangled network. A small but significant piece of this puzzle has been solved with the discovery of a new neuron, the rosehip cell.

The rosehip cell

Recently, an international team of researchers combined physiological and transcriptomic analyses with the view of characterising the different cells present in the human brain. Firstly, tissue was collected from two donated human brains that had been cryogenically preserved. Individual nuclei were then extracted from neurons within the tissue and their transcriptomes analysed by RNA sequencing. By analysing the transcriptome of a cell you can find out which genes that cell expresses, as although every cell contains the same DNA they do not necessarily utilise all of the genes that their DNA encodes. In total researchers sequenced the transcriptomes of 769 nuclei before grouping them into different subtypes based on the genes that they expressed. Of the 16 subtypes identified, 11 were inhibitory, 1 was excitatory, and 4 were non-neuronal cells.

Concomitantly, researchers analysed the morphology and physiology of live cells using tissue from brain surgery and identified a neuron unlike any that had been previously described. Morphologically, these cells were larger than others and had rosehip-shaped bodies, hence the name. Notably, when researchers compared the expression profile of these cells to the previously identified transcriptomic subtypes, they found a match. Rosehip cells were found to express a number of genes associated with axon growth and synapse function. Moreover, rosehip cells were found to be physiologically distinct, and appear to function as inhibitory neurons that control transmission of information between different areas of the brain. Amazingly, when researchers compared the transcriptomic profile of rosehip cells to that of neurons found in mice they were unable to find any cells resembling the newly identified subtype. These data suggest that the rosehip cell is unique to humans.

What are the implications?

This study highlights the power of combining morphophysiological and transcriptomic analyses and identifies a new neuron with distinct properties. Furthermore, the rosehip cell is likely unique to humans; this is particularly important as, due to a lack of available human samples, the majority of studies into neuron function use mice as a model system. Fortunately, transcriptomics can be applied to tissue that has been cryogenically preserved. By continuing to characterise neurons in this way researchers may eventually be able to compare all of the different neuronal subtypes in the human brain and in doing so better understand network function pathology.

In answer to the question “how does the human brain work?” the most accurate answer is probably, “we’re working on it!”.

Want to learn more? This post was based on the Nature Neuroscience paper by Boldog and colleagues found here.

The North East Postgraduate Conference (NEPG) 2018
by Joseph Smith

The NEPG provides a friendly and supportive environment for postgraduate students to present their research, through both poster and oral presentations, and to engage with research going on throughout Newcastle University and the North East. While focusing on the latest medical, health, and bioscience research carried out by top postgraduate students, the NEPG also offers insightful talks by renowned speakers, and participation in interactive workshops.

Moreover, for the first time in the NEPG’s history, the conference will follow a theme, with the initial one being engagement! Scientific engagement is becoming increasingly important for researchers at all levels and being able to disseminate your findings in formats other than peer-reviewed publication is a highly valued skill. This year, the NEPG will offer both keynote speakers and workshops particularly relevant to this area. We hope they will provide a brilliant experience for those taking part!

Firstly, we are very happy to announce our first keynote speaker, Dr Giles Yeo, Principal Research Associate and Scientific Director of the Genomics/Transcriptomics Core at the Department of Clinical Biochemistry, University of Cambridge. Giles is also a member of the Public Engagement Advisory Group at the University of Cambridge and a presenter for BBC Horizon. In line with our engagement theme, Giles will be giving a talk entitled, “Communication of Research to non-experts in the ‘post-truth’ era”, and we can’t wait! Secondly, this year’s theme will provide delegates with the chance to present, or learn to present, their research outputs in a non-academic way, making it understandable to non-scientists. For example, attendees can experience alternative presentation formats like PechaKucha or 3 minute thesis.

So why is scientific engagement important?

To engage with any audience you must be able to communicate effectively. By learning how to explain your research to the general public, you can strengthen these communication skills. Inherently, if you are able to translate scientific research into dialogue that is engaging and understandable to a lay audience, then you will be able to communicate your findings to your peers, or scientists that work in a different field. Not only this, but through effective communication you can raise the profile of your research, whether it is through presenting at conferences, writing papers, or forming collaborations, all ventures with the potential to open doors to your future scientific career.

But scientific engagement doesn’t stop at public understanding! By engaging with the general public you can enthuse others to get involved, whether that’s taking part in a more interactive dialogue between scientists and the public, or inspiring the next generation of researchers!

For more information about NEPG 2018, please visit: https://ne-pg.co.uk/ 
Abstract submission open until 5pm, 6^th July 2018.
Please submit abstracts at: https://ne-pg.co.uk/abstract-submission/