Part IV: The Future of Medical Scanning

The future of medical scanning is prognostic; hyperpolarised MRI scans are very promising since they can identify trace levels of biomarkers indicating future disease. Carbon-13-enriched glucose can act as a tracer to detect abnormal metabolism characteristic of burgeoning Type-2 diabetes. Para-hydrogenated bicarbonate ions can be injected to examine microenvironment pH levels suggestive  chronic inflammation.

Preemptive molecular scanning has the potential to form a prognosis before symptoms even appear – saving patients from years of suffering.

Another new avenue of development in the medical scanning sector that is gaining traction is the utilisation of artificial intelligence (AI) in analysing scans. Currently, a large wealth of information can be yielded from a single patient visit; however, trawling through vast amounts of data makes the diagnostic process time-consuming and labour intensive – increasing the risk of misjudgement and oversight.

Additionally, at the moment, a large proportion of valuable scan data is eventually discarded. This presents a significant waste of Big Data which could be repurposed for training the neural networks of AI systems to recognise subtle patterns in a scan, hence supporting faster and more reliable diagnoses.

Within the last decades, imaging techniques are being rapidly perfected and fine tuned even for extremely niche requirements. The rapid emergence of new technology and the tremendous advancement in medical scanning is epitomised by the very recent development of the highly-sensitive wearable MRI scanner which is adept at imaging the intricate interplay of bones, tendons and ligaments in motion; the image produced by this cutting-edge technology is reminiscent of the very first radiograph featuring the hand of Röntgen’s wife.

The juxtaposition of the two scans (taken just over a century apart) highlights the major strides made in the field of medical scanning.

In these scans, I do not see my death, as Röntgen’s wife did, but rather, the limitless potential for life-saving scanning technology.

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The figures quoted in this essay have been meticulously researched and documented. Below is the bibliography for this section of my essay:

“Super-Cool Imaging Technique Identifies Aggressive Tumors.” National Institute of
Biomedical Imaging and Bioengineering, National Institutes of Health, https://www.nibib.nih.gov/news-events/newsroom/super-cool-imaging-technique identifies-agressive-tumors [Last Accessed: 03 Mar 2019]

Zhang, Bei, Daniel K. Sodickson, and Martijn A. Cloos. “A high-impedance detector-array glove for magnetic resonance imaging of the hand.” Nature Biomedical Engineering 2 (2018): 570-577. Nature. Print. [Last Accessed: 25 Feb 2019]

Image Credit:

Zhang, Bei, Daniel K. Sodickson, and Martijn A. Cloos. MR image from wearable glove
coil design. Nature Biomedical Engineering, Nature, May 2018. Web.
https://www.researchgate.net/figure/Wearable-glove-coil-design-and-images-a-Photos-of-the-glove-coil-with-the-hand-stretched_fig4_324952145

Röntgen, Wilhelm. “Hand mit Ringen (Hand with Rings).” Wikipedia, Wikimedia
Foundation Inc., 22 December 1895

Part III: Nuclear Magnetic Resonance

As opposed to x-ray and ultrasound scanning devices, MRI uses the body’s innate magnetic properties to produce scans. Magnetic resonance imaging takes advantage of the high abundance of hydrogen nuclei (protons) in soft tissues of the body (which contain water and fat) and the fact that, often, diseases are manifested as an increase in water content as a natural consequence of inflammation.

Every hydrogen proton in the body has a spin and, hence, a small magnetic moment (1). An MRI machine applies a very strong magnetic field across the body to align all the hydrogen protons with the field (2). A radiofrequency pulse is then introduced which forces the hydrogen protons to realign against the magnetic field (3). Once the pulse is removed, the hydrogen protons return to their original alignment and release electromagnetic energy as MR signals which can be detected (4).

Tissue can be analysed and differentiated based on how much energy its constituent hydrogen protons release and how long it takes for them to return to their original  alignment (the relaxation time). Since the development of the first MRI scanner, several variants of the underlying principle have emerged to address niche situations.

BOLD fMRI
Blood-oxygen-level dependent functional MRI (BOLD fMRI) works on the principle that an increase in neuronal activity is always accompanied with an increase in oxygenated blood flow in local capillaries as the demand for oxygen increases.

The haemoglobin which delivers oxygen to the activated neurons is paramagnetic when deoxygenated (T-state) but diamagnetic when oxygenated (R-state); this unique magnetic property (caused by its different quaternary structures) results in slightly different electromagnetic emissions from the hydrogen protons within the haemoglobin depending on the level of oxygenation.

The MR signal can be analysed to infer a plethora of information – allowing clinicians to monitor the level of brain activity in a patient suffering from neurodegeneration and enabling researchers to discover the regions of the brain responsible for both instinctive reflexes and complex contemplation.

With its extreme versatility and minimal health risks, MRI arguably forms the heart of modern radiography – however, for certain patients with underlying ailments, the very scanning modality that is renowned for its safety can be deadly.

Safer Contrast Agents
Contrast agents are frequently used in MRI scans to alter the relaxation time of the hydrogen protons through their interaction with strongly paramagnetic gadolinium ions in the dye – this changes the MR signal intensities and increases the contrast of the scan. The gadolinium ions then accumulate in the kidneys for elimination. However, in cases of poor renal function, this can prove to be toxic. Patients with advanced chronic kidney disease, if injected with a typical gadolinium-based contrast agent, are at a significant risk of developing painful, debilitating disorders including contrast-induced nephropathy.

Just last year, a team at Massachusetts General Hospital devised a solution by proposing an alternative, safer manganese-based contrast agent (Mn-PyC3A) which not only produces identical contrast enhancement but is also made of an essential element which poses no risk to human health.

Hyperpolarisation
Within the past decades, although MRI has become indispensable in medical diagnostics, its sensitivity leaves much to be desired. In a typical MRI scan, due to the way that the molecular energies are naturally distributed, the MR signal from only 1 in 200,000 molecules is actually detected. Consequently, vital molecules (including potential cancer biomarkers) remain undetected due to their inherently low concentrations (<1mM) – severely restricting the scope of MRI.

Hyperpolarisation can overcome this sensitivity challenge by skewing the distribution of molecular energies and enabling detection of significantly more molecules. In hyperpolarisation, parahydrogen (polarised H2) or carbon-13 is chemically incorporated into an array of molecules (including glucose, urea, and pyruvate) and injected into the patient as tracers. This can increase the detected MR signal by up to 100,000 fold.

Hyperpolarisation drastically improves the imaging of metabolic activity – which is essential for tumour detection and monitoring. Cancer cells perform rapid glycolysis to obtain energy to fuel growth and division – converting pyruvate into the byproduct lactate in the process. A significant biomarker of aggressive, rapidly-growing tumours is a high lactate concentration. To assess the metabolic activity of a tumour, the patient is injected with carbon-13 enriched pyruvate and the concentration of hyperpolarised lactate produced is measured.

Unlike all other scanning methods, this technique yields information about not only the anatomy of a tumour but also its biochemistry – proving to be invaluable in assessing the efficacy of cancer treatment. Remarkably, within 24 hours of starting a new treatment, hyperpolarised MRI scans can reveal if a tumour is responding.

The figure above shows a prostate tumour before and only 48 hours after starting treatment. The MRI scans in the first row show a slight decrease in tumour size whilst the graphs in the second row (which refer to the detected concentrations of lactate and pyruvate) show that the lactate concentration has plummeted – highlighting the success of the treatment.

 

This biochemical change is further illustrated in the lactate concentration maps (last row) generated from the hyperpolarised MRI scans.

With MRI hyperpolarisation, clinicians can swiftly identify the ideal treatment for each patient based on the unique metabolism of the tumour – representing a major milestone in advances toward personalised medicine.

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The figures quoted in this essay have been meticulously researched and documented. Below is the bibliography for this section of my essay:

Berger, Abi. “How does it work?: Magnetic resonance imaging.” BMJ 324.7328 (2002): 35. PubMedCentral (PMC). Web. [Last Accessed: 21 Feb 2019]

NIBIB gov. “How Does an MRI Scan Work?” Youtube, 16 Apr 2013, https://www.youtube.com/watch?v=1CGzk-nV06g&feature=youtu.be [Last Accessed: 21 Feb 2019]

Devlin, Hannah. “Introduction to FMRI.” Nuffield Department of Clinical Neurosciences, University of Oxford, [Last Accessed: 22 Feb] https://www.ndcn.ox.ac.uk/divisions/fmrib/what-is-fmri/introduction-to-fmri 

“MRI contrast agent.” Wikipedia, Wikimedia Foundation Inc., [Last Accessed: 22 Feb 2019] https://en.wikipedia.org/wiki/MRI_contrast_agent

“Contrast Dye and the Kidneys.” A To Z Health Guide, National Kidney Foundation, https://www.kidney.org/atoz/content/Contrast-Dye-and-Kidneys [Last Accessed: 22 Feb 2019]

Gale, Eric, and Peter Caravan. “Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System.” ACS Chem. Neurosci. 9.3 (2018): 395-397. ACS Publications. Web. [Last Accessed: 22 Feb 2019]

Freeman, Tami. “Medical innovations: A safer MRI contrast agent.” physicsworld: Focus On Biomedical Physics. June 2018: 6. Print. [Last Accessed: 22 Feb 2019]

“What is hyperpolarisation?” Centre for Hyperpolarisation in Magnetic Resonance (CHyM), University of York, https://www.york.ac.uk/chym/hyperpolarisation/ [Last Accessed: 24 Feb 2019]

Miloushev, Vesselin, Kayvan Keshari, and Andrei Holodny. “Hyperpolarization MRI.” Top Magnetic Resonance Imaging 25.1 (2016): 31-37. PMC. Web. [Last Accessed: 03 Mar 2019]

Iali, Wissam, Peter J. Rayner, and Simon B. Duckett. “Using parahydrogen to hyperpolarize amines, amides, carboxylic acids, alcohols, phosphates, and carbonates.” Science Advances 4.1 (2018). American Association for the Advancement of Science. Web. [Last Accessed: 24 Feb 2019]

Ward, Christopher, et al. “Noninvasive Detection of Target Modulation following
Phosphatidylinositol 3-Kinase Inhibition Using Hyperpolarized 13C Magnetic Resonance Spectroscopy.” Cancer Research 70.4 (2010): 1296-1305. American Association for Cancer Research. Web. [Last Accessed: 04 Mar 2019]

“Super-Cool Imaging Technique Identifies Aggressive Tumors.” National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, https://www.nibib.nih.gov/news-events/newsroom/super-cool-imaging-technique identifies-agressive-tumors [Last Accessed: 03 Mar 2019]

“Cambridge extends world leading role for medical imaging with powerful new brain and body scanners.” Research – News, University of Cambridge, https://www.cam.ac.uk/research/news/cambridge-extends-world-leading-role-for medical-imaging-with-powerful-new-brain-and-body-scanners [Last Accessed: 03 Mar 2019]

Peirce, Andrea. “Hyperpolarized MRI: A New Tool to Assess Treatment Response within Days.” Memorial Sloan Kettering Cancer Centre, Sloan Kettering Institute,
https://www.mskcc.org/blog/hyperpolarized-mri-new-tool-assess-treatment-response within-days [Last Accessed: 03 Mar 2019]

Image Credits:

T-state: Liddington, R. “PDB ID 1HGA.” 1992. Originally published in the Journal of
Molecular Biology 228:551. Reproduced in Lehninger PRINCIPLES of BIOCHEMISTRY
(Seventh Edition). Print.

R-state: Silva, M. “PDB ID 1BBB.” 1992. Originally published in the Journal of
Biological Chemistry 267:17,248. Reproduced in Lehninger PRINCIPLES of BIOCHEMISTRY (Seventh Edition). Print.

Ward, Christopher, et al. “Figure 6. Effect of everolimus treatment on GS-2 tumour
xenografts” Cancer Research, American Association for Cancer Research, Web,
http://cancerres.aacrjournals.org/content/70/4/1296

 

Return to the Stamataki Lab

I’ve kicked off this summer with a trip to Birmingham to meet with Dr Zania Stamataki. During my prior work experience here, I improved my wet lab skills by learning essential techniques such as splitting cell lines, performing serial dilutions, and imaging plates with confocal microscopy.  This year, I chose to hone my computational biology skills to best prepare me for a future in research; Dr Scott Davies introduced me to bioimage informatics through training me to work with the ZEISS Efficient Navigation (ZEN) microscopy software.

The ZEN software can be used to process the plethora of data that a single imaged experiment can yield. I worked with data from an experiment in which Huh-7 hepatocytes (from an immortalised liver carcinoma cell line) are co-cultured with live T-cells and imaged using confocal microscopy.

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I personally found this sophisticated mode of imaging fascinating so I did a little more research into the bioengineering responsible for the high resolution and vibrancy of the  cellular interactions captured by the confocal microscope. Unlike the humble optical microscopes of my school, which only need light and a pair of eyes to visualise cells, confocal microscopes require far more exotic elements: lasers and fluorescent dyes.

 

GFP

One of the most widely used fluorescent biomarkers is green fluorescent protein (GFP) which is used in this experiment to highlight the cell membranes. GFP is a very important tool in research as it enables us to look beyond the cell surface and visualise organelles and protein movements. GFP has a unique sequence of the amino acids serine, tyrosine, and glycine which can be triggered to undergo chemical transformations in the presence of UV light. This special amino acid sequence is buried deep within the molecule’s barrel structure of intertwined protein sheets.

 

When activated, a cyclisation reaction occurs in which glycine forms a chemical bond with serine. This new closed amino acid ring spontaneously dehydrates and oxygen surrounding the GFP molecule forms a new double bond with the tyrosine – creating the fluorescent chromophore. In this way, GFP automatically assembles its own chromophore which can be used by researchers as tracking dyes. For instacnce, through genetic engineering, the GFP protein can be incorporated into the genome of specific cells or be used to label proteins of interest.  It is especially perfect for studying live cells since the alternative small fluorescent molecules (ex. fluorescein isothiocyanate) are highly phototoxic and inflict more damage upon live cells during imaging.

In the microscope images I worked with, GFP had been used to label the hepatocyte cell membranes. The T-cells were stained a vibrant blue whilst a cytoplasmic dye had rendered the hepatocyte cytoplasm red. The smaller dark regions enclosed within  cytoplasm are the hepatocyte nuclei.

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Over the course of the week, I became proficient in producing orthogonal videos, which showcase the full depth of the hepatocytes, from multiple micrographs in a time lapse. Whilst processing these videos, I witnessed countless interesting phenomena; with Dr Stamataki’s permission, I’d like to share a few of my favourites with you.

Binucleate Hepatocyte Division

When I first starting working with the experiment data, Zania pointed this event out to me and I was both riveted and shaken to my core; this cell defied everything textbooks had me believe about cell biology! In this orthogonal video, a binucleate cell successfully undergoes mitosis to produce not two but three daughter cells.

Binucleate cells can be caused by cytokinesis failure in which the cell membrane fails to form a cleavage furrow so two daughter nuclei are trapped in the same cell. Alternatively, during mitosis, sometimes multiple centrioles form making the cell multipolar- pulling  the chromosomes in several directions and producing several nuclei in a single cell. Judging by how the binucleate cell proceeds to divide into an odd number of daughter cells, its original two nuclei probably arose from the latter mechanism.

Binucleation in vivo is pretty rare and, in a healthy human liver, such cells are incapable of dividing again, instead forced to remain in interphase indefinitely. Binucleate cancer cells, however, have a far different fate; more than 95% can undergo mitosis with a higher rate of chromosomal disjunction error – producing daughter cells with even more mutations. Despite binucleation rarely arising in healthy tissue, this phenomena is less of a rarity in cancer cells due to one of their unique quirks. A prominent biomarker of cancer cells is their multipolar spindles which increase the risk of binucleation and other mitosis abnormalities – leading to an accumulation of mutations in subsequent daughter cells in the cancer tissue.

Lamellipodia Network Formation

Inside the body, liver cells are always in contact with their neighbours with junctions between their lateral faces. In a lab culture, however, liver cells are seen tightly adhered to the plastic that they are grown on, practically clinging to the plate for dear life! The in vitro hepatocytes achieve this through multiple membrane projections known as lamellipodia.

Lamellipodia are made of the cytoskeletal protein actin and, in the video above, can be seen stretching out to not only tether carefully to the confluent monolayer but to also engulf some extracellular material. I’m mesmerised by the rapid yet tentative movement of these hepatocytes’ extensive threadlike network.

Another Kind of ‘Nuclear Fission’

The earlier orthogonal video of two nuclei becoming three was very surprising. In contrast, the phenomena below is absolutely incredible.  Two neighbouring T cells apply a mechanical stress on the hepatocyte’s nuclear envelope great enough to break the nucleus into two ‘daughter’ nuclei without the hepatocyte undergoing mitosis! I find it truly fascinating that the nucleus is not as static an organelle as it is so often portrayed; instead, it is dynamic and capable of distorting and even bifurcating in response to changing cytoplasmic pressures. 

 

 

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As always, I’ve really enjoyed my time at the Centre for Liver Research this year and I’m so grateful to Zania for allowing me to learn so much about the cell biology and immunology of the liver and participate in her current work. Her team is currently in the midst of publishing some amazing cutting-edge research on a cellular mechanism similar to entosis; as soon as it is available to the public, I’ll share it here and, hopefully, write a review article about this interesting hepatocyte process!

WordPress does not support video uploads for this blog so the orthogonal videos in this post were compressed into gifs, hence losing resolution and quality. If you would like to see the original videos, I’ve also uploaded them to my YouTube channel:

• Binucleate Hepatocyte – Abnormal Mitosis
• Extensive Hepatocyte Lamellipodia Network
•  Nuclear Split

Bibliography

Kim, Dong-Hwee et al. “Volume regulation and shape bifurcation in the cell nucleus.” Journal of cell science vol. 128,18 (2015): 3375-85. doi:10.1242/jcs.166330

Shi, Qinghua; Randall W. King (13 October 2005). “Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines” (PDF). Nature. 437 (7061): 1038–42. doi:10.1038/nature03958. PMID 16222248

Yang, F.; Moss, L.G.; Phillips Jr., G.N. “STRUCTURE OF GREEN FLUORESCENT PROTEIN.” Nat Biotechnol vol. 14 1246-1251 (1996). doi: 10.1038/nbt1096-1246. PMID 9631087

 

 

 

Give Me A Break: Bioengineering Solutions to Spinal Fracture

I’m writing this post in a lab at Queen Mary University in the heart of London. Through the EDT Headstart scheme, I have been given the brilliant opportunity to immerse myself in the field of bioengineering (from the physiological level right down to the molecular level) surrounded by leading academics and university lecturers as part of a 4 day residential course.

Absorbing fascinating new information about molecular bioengineering has been a major highlight of the course. On the first day, I attended Dr Karin Hing’s lecture ‘Engineering Biocompatibility for Bone Regeneration’ which inspired my independent group research project on the use of synthetic bone grafts, autografts, and growth factors in spinal fusion.

Biocompatibility lies at the intersection between biology and material science and it refers to the interactions between an artificial material and a living system. With its abilities to bear loads and control homeostasis as well as self-regulate and repair, bone is a particularly interesting natural material – but what is it actually made of? Bone primarily consists of inorganic materials, such as calcium hydroxyapatite, and organic materials, such as the protein collagen, which make up a rigid extracellular matrix. Within this matrix, resides a range of specialised bone cells: osteoblasts, osteoclasts, and osteocytes.

Like ourselves, bone has a life cycle. Our bones are constantly undergoing remodelling, cycling between phases of formation and resorption. In formation, mesenchymal stem cells in the bone marrow differentiate into osteoblasts (bone-forming cells). These osteoblasts create the extracellular matrix (known as the osteoid) and mineralise it with calcium deposits. Next, they find themselves trapped within the bone matrix and they mature into osteocytes which are no longer capable of bone formation, instead serving as a communication port- relaying signals between other bone cells (much like neurons).

Life is centred on balance, a yin and yang of sorts; as new bone is built up, old bone is destroyed through the process of resorption. Osteoclasts are a key player in resorption and prevent new bone formation from getting out of hand. Bone tissue contains rich deposits of minerals such as calcium and, when it is resorbed, the minerals leach out and enter the neighbouring blood stream. Through selective resorption of bone tissue, osteoclasts maintain homeostasis and regulate our calcium levels. Between formation and resorption is the reversal phase in which mononuclear cells inhibit osteoclasts and prepare the bone surface for osteoblasts to build the connective tissue up again.

With its constant repair and remodelling, bone can automatically fix virtually any hairline fracture or microdamage. But when it comes to breaks larger than 2.5 cm (known as critically large defects), the bone can no longer spontaneously heal and will require medical intervention. For instance, in cases of vertebrae fracture, spinal fusion is necessary to heal multiple vertebrae into a single, solid bone – restoring stability to the spine.

What do we use to bridge the gap between vertebrae? That’s where bone grafts come in. Traditionally, a bone graft involves removing a small portion of bone from the hip (where it will naturally heal back) and transplanting it between the vertebrae to promote bone growth at the fusion site. If the graft comes from the patient’s own body (which is currently the gold standard in spinal fusion) then it is referred to as an autograft. Allografts come from a cadaver or live donor and are used when the fracture is too large to bridge with the patient’s own bone.

harvesting an autograft from the iliac crest (hip)

The reason autografts are considered the gold standard is because they can integrate into the patient’s fracture more rapidly and completely and there is no risk of immune rejection or bio-incompatibility. However, autografts require the patient to undergo two surgeries – giving rise to an array of new complications including donor site morbidity and secondary infections. Additionally, multiple incision sites may be necessary to extract an ideal autograft which increases the risk of nerve injury and bone damage at the donor site. But allografts are not without their flaws either; they come with a risk of immune rejection and disease transmission and there are long waiting times to even obtain an allograft due to a shortage of eligible donors.

Recently, synthetic alternatives to bone grafts (such as calcium sulfate and collagen) have emerged. Initially, these synthetic bone grafts were bio-compatible but still did not promote bone healing. Let’s take a closer look into what is necessary for a graft to support successful bone formation. Firstly, we have osteoconduction which is the graft’s ability to support the attachment, migration, and growth of osteoblasts within the structure. Then, there is osteoinduction which refers to the graft’s ability to stimulate stem cell differentiation into bone cells (osteogenesis).

Ever tried gardening? The properties of an ideal bone graft are similar to those needed to grow a plant. Osteoconductivity (the scaffold properties of the graft) can be seen as the pot and soil, osteogenesis by the actual seeds, and osteoinductivity is best represented by the fertilisers and water that stimulate plant growth.

At the very least, a synthetic graft must be osteoconductive for a successful fusion. On the third day of the course, I had the chance to enhance my wet lab skills via testing protein adsorption in a range of synthetic grafts. The experiment involved incubating five types of graft material (both organic and inorganic) in an albumin solution and using a colorimeter and calibration curves to assess the efficiency of protein adsorption in each of the graft types.

The first synthetic grafts were bio-compatible but also bio-inert meaning that they had were osteoconductive but not osteoinductive. To overcome this issue, subsequent designs of synthetic grafts tend to be infused in growth factors. Growth factors stimulate differentiation of stem cells and growth of living tissue – accelerating bone formation.

The most widely studied growth factor is bone morphogenetic protein 2 (BMP) which acts as a chemotactic agent by recruiting stem cells to the fusion site and prooting their differentiation. BMP even stimulates the growth of blood vessels (angiogenesis) through the damaged bone which helps support new bone formation.

the structure of BMP-2

BMP is considered safe for use in spinal fusion and eliminates the need to take a large portion of the patient’s own bone cells in a graft. The only downside is that it is currently very expensive – increasing spinal fusion surgery costs by up to $15,000.

BMP works alongside, and can be incorporated into, both types of graft. Synthetic grafts can be made of bioabsorbable polymers (such as lab-grown collagen or calcium sulfate structures) which carry doses of growth factors. As the material dissolves in the body, the BMPs are gradually released, helping sustain bone growth. In autografts, the patient’s own cells can even be genetically engineered to express specific growth factors in greater quantities.

It has become increasingly clear that bone grafts cannot be developed solely from an engineering perspective. As Dr Alvaro Mata explained in his lecture on bioinspired materials, nature is a particularly important source of inspiration for designing any bioengineered system, particularly synthetic bone grafts. Structure at even the smallest levels, such as the arrangement of structural protein nanofibres, affects cell signalling and growth to a large degree.

Biomimetic design is developed through an appreciation of nature’s own design. Through dissecting a bovine metacarpal joint, I gained a far better understanding of the interplay between bone and cartilage that makes smooth movement effortless.

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As the end of my week at Queen Mary’s bioengineering department crept closer, my team began to prepare a presentation showcasing our independent research in the fascinating field of spinal fusion. This presentation was the perfect culmination of the amazing molecular bioengineering techniques I had studied and carried out in the lab. To my absolute delight, we were awarded the 1st place prize for our level of detailed research and our debate style of presentation – a rewarding end to an incredible week!

Part II: Ultrasound Technology

In sharp contrast to the potentially mutagenic radiation emitted by x-ray based scanning devices, ultrasound has a long-standing reputation of being extremely safe – to the extent that it has even been trusted with imaging the delicate structures of the developing foetus. The surprising truth about this medical scanning modality so commonly associated with growth and new life, is that it was developed in response to a tragic mass death.

In the aftermath of the sinking of the Titanic, physicist Paul Langevin invented the world’s first transducer, the hydrophone – a scanning device which could detect hidden threats in the depths of the sea. Inspired by Langevin’s innovation, in 1942, neurologist Karl Dussik designed an ultrasound transducer capable of detecting hidden threats of tumours lurking in the depths of the brain. From that moment onwards, the field of medical ultrasound scanning blossomed.

The 1970s saw major advances in ultrasound technology which made it possible to view the organic structures of the human body as they truly are – dynamic, changing forms that can only be fully understood through their movement.

Doppler Ultrasound
The Doppler ultrasound was one of the first medical scanning devices designed to monitor the flow and velocity of blood. The transducer emits a series of pulses at the blood vessel; whilst the echoes received from stationary tissue are identical from pulse to pulse, the time taken for the echoes to return from the blood vary slightly with each ultrasound pulse. The resulting Doppler frequency is observed and can be used to calculate the blood velocity with the following equation

Blood velocity abnormalities can indicate the presence of blockages, including blood clots and vascular tumours, radically improving diagnosis of a range of conditions from deep vein thrombosis to atherosclerosis.

Ultrasound Needle
Most recent developments in ultrasound technology have been focused on designing portable devices perfectly suited to niche, yet critical, situations. An all-optical ultrasound transducer, which can be fitted into the tip of a needle, has recently proven successful in a preclinical swine study by researchers at University College London and Queen Mary University of London.

Currently, during keyhole procedures, surgeons are forced to rely on external ultrasound probes and pre-operative scans to visualise soft tissues and structures. This minimally invasive ultrasound device images tissue in real time to assist in surgery.

The compactness of the ultrasound transducer is crucial for its use in keyhole surgery. Instead of a bulky electronic transducer, the ultrasound needle uses an all-optical transducer which exploits the photoacoustic effect (in which ultrasound waves are formed when light is absorbed). The tip of the needle consists of two 300μm optical fibres. The transducer optical fibre is coated in a multiwalled carbon nanotube polydimethylsiloxane composite capable of absorbing laser light and generating ultrasound pulses. These pulses are reflected off the tissue and detected by the receiver optical fibre which converts the ultrasound echoes back into light.

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The figures quoted in this essay have been meticulously researched and documented. Below is the bibliography for this section of my essay:

Constantin, Chilowsky, and Paul Langevin. Production of submarine signals and the location of submarine objects. US 1471547 A, United States Patent and Trademark Office, 19 May 1917. [Last Accessed: 05 Feb 2019]

Deane, Collin. “Doppler Ultrasound: principles and practice.” Doppler in Obstetrics, ISUOG Educational Committee, [Last Accessed: 16 Feb 2019] https://sonoworld.com/client/fetus/html/doppler/capitulos-html/chapter_01.htm

Freeman, Tami. “Medical innovations: All-in-one imaging.” physicsworld: Focus On
Biomedical Physics. June 2018: 6. Print. [Last Accessed: 18 Feb 2019]

Finlay, Malcom et al. “Through-needle all-optical ultrasound imaging in vivo: a preclinical swine study.” Light: Science & Applications (2017) Nature. Web. [Last Accessed: 19 Feb 2019]

Image Credits:

Deane, Colin. Diagram of Doppler ultrasound. Doppler in Obstetrics, ISUOG
Educational Committee, 2002. Web.
https://sonoworld.com/client/fetus/html/doppler/capitulos-html/chapter_01.htm#fig02

Finlay, Malcom et al. Schematic and inset photo of sharp inner needle. Light: Science
& Applications, Nature, 01 December 2017. Web. nature.com/articles/lsa2017103.pdf

Scanning Devices for Medical Applications – Part I

This is the essay commended by judges from Newnham College, Cambridge. I am delighted to share with you this work that took me almost a month to write and far longer to research. I loved the experience of writing this essay and immersing myself in this fascinating topic.

However, it is important to note that, since this was a 2500 word academic essay, it does make for heavier reading than my previous articles written specifically for this blog.

So brew some tea, find a comfortable reading nook, and settle in for this comprehensive exploration of the field of medical scanning from its origins over a century ago to its potential for the coming decades.

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PART I : ORIGINS AND X-RAYS

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The disciplines of engineering and medicine have long been intertwined, with physics concepts supporting the development of diagnostic tools and clinical demands fuelling exciting innovations in engineering.

Scanning devices for medical applications, all of which consist of an emitter and sensor, lie at the very heart of the intersection of these disciplines. Since its inception, over a century ago, this technology has been constantly evolving with new developments.

Origins
In a darkened laboratory in Würzburg, Germany (1895), an eerie glow emanating from a screen behind his cathode ray tube propelled Wilhelm Röntgen to discover invisible rays. These rays were capable of not only penetrating the heavy black paper insulating the Crookes tube but even Röntgen’s own skin. Astonished by his discovery of “a new kind of ray”, Röntgen began to experiment with the penetrating abilities of the x-ray to produce one of the first radiographs: his wife’s hand adorned with her engagement ring.

Shocked by the sight of the internal structures of her own hand, she reportedly gasped, “I have seen my death”. Despite such a macabre initial critique, x-rays captivated the world’s attention and optimism for their applications; Röntgen’s moment of serendipity gave rise to the ceaselessly evolving field of medical imaging.

X-Ray Modality Technology
X-rays are passed through the patient and are absorbed, to varying degrees, by different tissues in their body. In indirect flat-panel detection, unabsorbed x-ray photons are transmitted through the body and strike caesium iodide crystals in the first layer of the detector. The crystals scintillate when excited by radiation – emitting flashes of visible light proportional to the energy of the x-ray photons. Amorphous silicon photodiodes in the detector’s second layer transform light into electrical charges to produce digital images.

X-Rays and Cancer 
X-rays play an essential role in mammography; pre-cancerous breast tissue contains clusters of microcalcifications (minor calcium hydroxyapatite deposits) which act as major indicators of accelerated cell division. Microcalcifications can go undetected in biopsies. However, in x-ray scans, these deposits are clearly revealed as bright white specks due to their very high x-ray absorption – enabling early detection.

CT Scan
The humble x-ray also forms the basis of the revolutionary multisection CT scanner (a scanning device introduced in 1992 that aims a narrow beam of x-rays at the patient in a complete spectrum of angles); this device outputs multitudes of cross-sectional ‘slices’ (tomographic images) which can be digitally ‘stacked’ to produce three-dimensional models. The technique improves both diagnostic accuracy and spatial resolution in the Z axis due to the creation of thinner tomographic slices. This also reduces the risk of partial volume artefact formation (imaging errors which occur when tissues with varying thickness and radiation absorption are in close proximity).

EOS Scan
The latest x-ray modality technology addresses a major drawback of CT scanning: its significant radiation exposure. The EOS scanner, developed in 2007, is a vertical scanner consisting of two pairs of perpendicular radiation sources and detectors. This allows for precise 3D reconstruction as well as imaging of the skeletal system in its natural weight-bearing posture. This innovation helps clinicians identify and diagnose subtler issues which are only apparent in the patient’s skeletal system in the context of its typical load-bearing alignment (as opposed to its relaxed alignment when the patient is lying down in a CT scanner).

The implementation of revolutionary particle physics technology allows high-resolution (254 μm) radiographs to be taken with significantly less radiation exposure than CT scanners. The EOS scanner uses a proportional multiwire chamber (first developed by the Nobel Prize winner Georges Charpak) which enables extremely sensitive detection of even single x-ray photons – allowing a significant reduction in x-ray exposure without compromising the resolution.

This unique aspect makes it particularly suited for monitoring scoliosis in adolescents. Since scoliosis is eight times more prevalent and more severe in females than in males, adolescent girls are typically exposed to excessive radiation from the multiple CT scans (up to 5 per year) necessary to assess the progression of this condition. High level of radiation exposure, especially during a critical phase of rapid growth, increases the risk of developing cancer; growing breast tissue is highly sensitive to the carcinogenic effects of ionising radiation which cause a 69% increase in breast cancer incidence.

The EOS scanner, with its significantly lower radiation exposure, is proving to be vital in limiting the risk of cancers whilst safely monitoring scoliosis.

 

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The figures quoted in this essay have been meticulously researched and documented. Below is the bibliography for this section of my essay:

“History of Radiography.” NDT Resource Centre, National Science Foundation,
https://www.ndeed.org/EducationResources/CommunityCollege/Radiography/Introduction/history.htm [Last Accessed: 28 Jan 2019]

“X-Ray.” Wikipedia, Wikimedia Foundation Inc., https://en.wikipedia.org/wiki/X-ray [LastAccessed: 28 Jan 2019]

Cruz, Robert. “Digital radiography, image archiving and image display: Practical tips.” Canadian Veterinary Journal, 49.11 (2008): 1122-1123. PMC. Web. [Last Accessed: 04 Mar 2019]

Wang, Zhentian, et al. “Non-invasive classification of microcalcifications with phase-contrast X-ray mammography.” Nature Communications 5 (2014). Nature. Web. [Last Accessed: 01 Mar 2019]

Rydberg, Jonas et al. “Multisection CT: Scanning Techniques and Clinical Applications.” RadioGraphics 20.6 (2000): 1787-1806. RSNA. Web. [Last Accessed: 30 Jan 2019]

Bell, Daniel, and Vikas Garg et al. “Partial volume averaging (CT artifact)” Radiopedia, Radiopedia, https://radiopaedia.org/articles/partial-volume-averaging-ct artifact-1?lang=gb [Last Accessed: 30 Jan 2019]

Illés, Tamás, and Szabolcs Somoskeöy. “The EOS (TM) imaging system and its uses
in daily orthopaedic practice.” International Orthopaedics 36.7 (2012): 1325-1331.
ResearchGate. Web. [Last Accessed: 31 Jan 2019]

“Information and Support.” NSF, National Scoliosis Foundation,
https://www.scoliosis.org/info.php [Last Accessed: 02 Feb 2019]

Morin-Doody, Michele et al. “Breast cancer mortality after diagnostic radiography: findings from the U.S. Scoliosis Cohort Study.” Spine 25.16 (2000): 2052-2063. NCBI. Web. [Last Accessed: 02 Feb 2019]

Image Credits:

Röntgen, Wilhelm. “Hand mit Ringen (Hand with Rings).” Wikipedia, Wikimedia
Foundation Inc., 22 December 1895.

Hendriks, Eva, et al. “Regression of Breast Artery Calcification.” Cardiovascular
Imaging, Journal of the American College of Cardiology, August 2015.
http://imaging.onlinejacc.org/content/8/8/984/F1

EOS Imaging, Paris, France. A reconstructed 3D model of the full vertebrae of a
scoliosis patient based on an EOS TM 2D examination. Reproduced by Illés, Tamás in
International Orthopaedics 36.7 (2012): 1325-1331. Web. https://www.researchgate.net/figure/Full-body-surface-reconstructed-3D-model-based-on-an-EOS-TM-2D-examination_fig3_221867288

 

A Toast to the Maillard Reaction

Earlier this year, I wrote an article on the Maillard Reaction and the science that underpins toast and ageing for the Oxford Scientist Schools Writing Competition in response to the prompt “How does science impact your everyday life?”.

This morning, I was delighted to find that my article was selected as a runner-up and published on the Oxford Scientist website! You can read it here or below…

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We all have our little morning rituals. I, for one, greet the day by performing a series of complex chemical reactions – and so do you. I am, of course, referring to  the Maillard Reaction which takes place in practically every kitchen and café throughout the country. We have this beautiful cascade of reactions to thank for the rich, invigorating aroma of freshly roasted coffee and the golden glow of toast.

The Maillard reaction refers to a chain of reactions between amino acids and reducing sugars and it is named after the prominent French chemist Louis-Camille Maillard who first investigated these reactions in 1912.  Subsequent chemists, such as John E Hodge in 1973, further researched the culinary significance of these reactions and their impact on  flavour, aroma, and appearance.

When a slice of bread first enters the confines of a toaster, the temperature of the heating coils quickly rise to an optimum 154° C  at which point the system is provided with enough thermal energy to begin the Maillard reaction. The reactive carbonyl group on a reducing sugar reacts with the amino group of an amino acid within the bread to produce a nitrogen-substituted glycosylamine molecule.  The glycosylamine molecule then isomerises to produce a ketosamine which undergoes further reactions depending on the environment.

The slightly acidic conditions of white bread (which typically has a pH of 5.0 – 6.2) allows for the formation of melanoidins. Melanoidins are long, polymeric pigments (much like the melanin in our skin). In more alkaline conditions, the melanoidins are produced faster and in a greater quantity – resulting in a deeper shade of brown.

Recipes for Bavarian-style pretzels manipulate the Maillard reaction to create the glossy brown glaze of the baked goods; the dough is first dipped in weak lye solution to increase the alkalinity of the coating before baking.

During the Maillard reaction, hundreds of other organic compounds may be formed depending on a variety of factors such as the types of amino acid present, and the temperature and pH of the environment. When coffee is roasted, heterocyclic aromatic compounds are formed- including furans (which give coffee its caramel-like bittersweet scent) and pyrazines (which add earthy notes to coffee’s flavour profile). Due to its sheer complexity, the Maillard reaction can result in an impressive range of potential flavours – to the delight of chefs and chemists alike.

Whilst you were musing over the complex science responsible for enhancing the flavours of your breakfast, if you had completely forgotten about the bread in the toaster, you would become acquainted with the darker side of the Maillard reaction. As the temperature rises and the bread is subjected to high levels of thermal energy for a longer period of time, a potentially carcinogenic product, acrylamide, is formed. Such  compounds are a natural consequence of cooking, however as the bread suffers for even longer within the toaster, reactions such as pyrolysis become more prevalent and the concentration of acrylamide in the toast increases- leaving behind an acrid taste in your mouth.

Surprisingly, the Maillard reaction impacts our lives even after we have left the kitchen; at a much slower rate, it is constantly occurring within our bodies – forming a range of potentially deadly, undesirable products: advanced glycation end products (AGEs).  Over the course of a lifetime, the accumulation of AGEs on DNA can lead to neurodegeneration and degenerative eye diseases (including cataract formation). Researchers are currently looking into preventing ocular degeneration and reducing the effects of ageing through inhibition of the Maillard  reaction.

The Jekyll and Hyde nature of the Maillard reaction has  a profound impact on our everyday lives. It gives us the gift of golden toast, the manna of students everywhere; however, in our golden years, the very same reaction accelerates our inevitable decline. Currently, the formation of insidious products during the Maillard reaction is unavoidable. Instead of fearing ageing and burnt toast, we should strive for a deeper knowledge of the intricacies of the Maillard reaction which will allow us to work with its innate chemistry- making our everyday lives healthier and more delicious.

Ri Summer School: Forensics

Every summer I look forward to attending some of the several Summer School workshops organised by the Royal Institution; this year I particularly loved the LYSC Forensics workshop (01.08.18) which focused on the DNA fingerprinting process to identify and compare DNA samples.

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Understanding the basics of DNA can help us get a better understanding of forensics and how techniques can be used to identify criminals from only a few drops of blood at a crime scene.

DNA (deoxyribonucleic acid) is a long molecule which consists of billions of smaller units known as nucleotides. Just as there are differences in our appearances, there are also differences in our DNA which are known as genomic variations. The genomic variations between people tend to be very minor and the more closely related two people are, the smaller the variation between their genomes. Two random, non-related people would have 99.9% of their DNA in common and yet there are still more than three million differences between your genome and anyone else’s.

These variations arise due to mutations – changes that occasionally occur in a DNA sequence during replication. When a mutation occurs in a in a sperm cell or an egg cell, it will be passed along to the offspring. Your genome contains around 100 mutations which make it unique.

Most genome variations are relatively minor; to help put this into perspective, I like to visualise the human genome as a book. If you’ve ever been to the Wellcome Collection, you might have discovered the Library of the Human Genome – an expansive bookcase containing a human genome typed out in a series of 109 books.  With that in mind, the books of your genome and mine would essentially tell the same story but yours might have a typo on page 17 of book 56 whilst mine might be missing a few letters on the penultimate page of book 34.

(Credit: Wikipedia)

The differences seem so small that it is remarkable that they can be detected through the use of forensic techniques.

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The workshop explained and guided us through the restriction fragment length polymorphism (RFLP) technique of DNA fingerprinting; this process was the first DNA profiling technique which was inexpensive enough to see widespread application.

In the workshop, we were presented with (isolated) DNA found at a hypothetical crime scene and samples of DNA from five ‘suspects’. By adding a restriction endonuclease (a type of digestive enzyme produced by bacteria), we chemically ‘cut’ the DNA into fragments. My work experience at the Centre for Liver Research proved extremely helpful during the workshop as I was already comfortable with using a micropipette to transfer and mix substances.

The next step in the process involved separating the fragments through the process of gel electrophoresis. Gel electrophoresis takes advantage of the fact that DNA is negatively charged and that, due to genomic variation, the isolated fragments of DNA will be of different sizes.

First, we prepared the gel by pouring agarose into a casting tray and pressing a well comb into the molten agarose. When the agarose set, the comb was removed to create a series of wells in the gel.

The fragments are separated by passing an electric current through the gel. This causes the negatively-charged DNA to move from the wells to the positively-charged electrode through the agarose. Shorter fragments can move easily through the pores in the agarose and so will move faster and migrate farther than longer fragments in a given time. This separates the fragments of DNA into bands. The unique pattern of bands of the suspects’ DNA can then be compared to that of the DNA found at the crime scene.

(A blue loading dye was added to the DNA samples before pipetting them into the gel. The dye is co-migratory and so will separate and migrate at the same rate as the DNA fragments. )

After the gel was run, we used a transilluminator to better see the bands of DNA fragments.

From this, we could conclude that the DNA found at the crime scene belonged to Suspect 3 – the experiment was a success!

 

Work Experience: Centre for Liver Research, University of Birmingham

Over the course of the two weeks of my work experience, I had the opportunity to try out new laboratory techniques and to explore various aspects of the research being done at the University of Birmingham, Centre for Liver Research. In this account I will focus solely on the major highlights (despite each day having been amazing and enriching in its own right).

On the first day, I was greeted warmly by Dr Zania Stamataki and given a tour of the Medical School building and the IBR building. We discussed about the research being done by her team concerning hepatocytes and their interaction with the immune system (mainly CD4+ T-cells). Having completed a FutureLearn course on the liver (Liver Disease: Looking after Your Liver – University of Birmingham) provided me with a decent background to understanding the fascinating concepts Zania introduced me to. I learnt the basics of cell-in-cell structures and the vital efferocytosis that hepatocytes perform and what these processes mean for inflammation and the development of cancer and metastasis.

In the afternoon, Janine Fear lead an induction in which I was exposed to the many fascinating laboratories and ‘behind-the-scene’ areas such as the waste disposal and incineration systems, the autoclave room, and the liquid nitrogen cooling systems. One of the many surprising things I was shown was the autoclave tape – I couldn’t help but marvel at the simple yet ingenious concept of tape that changes colour when exposed to the high temperatures of the sterilisation process. Janine Fear also informed me of the lab safety procedures and that the labs I would be working in are classed as Category 2 and that the majority of the labs are fitted with Class II biosafety cabinets. As part of the induction, Janine also taught me basic skills (such as how to use a micropipette and a pipette gun) which I later utilised when performing experiments.

After the induction, I was introduced to Adam McGuinness (a PhD student) who showed me several culture flasks (containing hepatocytes and T-cells) under a light microscope. He also explained that the nutrient medium provided to the cells contains an indicator which changes to yellow as the solution becomes acidic (because CO2 is produced as the cells metabolise) – indicating that the medium should be changed. I recalled that a similar process was used by the BactAlert machines in the serology lab in Mumbai (where I shadowed Dr Salunke last year); the machine detected low pH of blood cultures (which indicates sepsis: bacteria in the blood produce CO2 – making the blood acidic). The hepatocytes cultured in this lab were from a cancer cell line (Huh7) – I learnt that cell lines are ideal for research as they can survive and replicate better than primary cells in vitro.

On day two, Zania and I discussed the role of a researcher and the many facets of the job (including the process of writing and revising publications and some aspects of what makes for a high-impact publication worthy of a renowned journal such as Cell or Nature). Our discussion then drifted back to Zania’s current research and she explained to me that the host cells of cell-in-cell structures can fail to divide as the cell inside them becomes a physical obstruction to cytokinesis. Fascinated by this concept, I spent the rest of the morning reading publications* on cell-in-cell structures which Zania recommended to me (including one written by her former PhD student, Alex Wilkinson).

In the afternoon, I observed Adam performing an experiment to image a host cell hepatocyte failing to divide due to a T-cell inside it. He explained the various fluorescent cell tracker dyes and cytoplasm stains which would be used to image the experiment. We then visited Dr Omar Qureshi who introduced us to the impressive Celldiscoverer 7 (ZEISS) capable of fluorescence microscopy and performing time-lapse imaging.

The next day,  imaging experts from ZEISS explained the process of analysing the images produced by the Celldiscoverer 7; the analysis software can be configured to automatically count the number of cell-in-cell structures and identify any host cells which failed to divide.

Afterwards, I followed Adam to a meeting with the rest of the students who are taking the same PhD course (Sci-Phy). One of the major advantages of shadowing both a student and a PhD supervisor was that I gained exposure to the many aspects of completing a PhD course (such as writing a thesis and preparing for a viva) from different perspectives. During this meeting, Adam presented his plans for a mini-project which involved using machine learning to identify and quantify cell-in-cell structures.

In the afternoon, I attended an interesting lecture (presented by Alejandra Tomas from Imperial College) with Zania regarding current research into improving pancreatic beta cell function.

On the fourth day, I had the very exciting chance to do some ‘hands-on’ work; under the direction of Zania, I ‘split’ a cell culture of hepatocytes. Since the hepatocytes are from a cancer cell line, they can be repeatedly ‘split’ to allow them to proliferate and be used for various experiments. It was delightful to have this opportunity which enabled me to sharpen my skills in handling pipettes and working with the hepatocytes. I also learnt how to care for the surfaces and machines in the lab; I cleaned all the worktops in the labs with 70% IMS (Industrial Methylated Spirit) and Trigene before commencing my work, which ensures that the surfaces are sterile.

The afternoon provided another opportunity to immerse myself further in the topic of cell-in-cell structures and I read two absorbing publications: ‘Cell-in-cell phenomena, cannibalism, and autophagy’ and ‘Entosis enables a population response to starvation’. I found the latter article intriguing as it introduced the idea of host cells obtaining nutrients and biomass through phagocytosis of neighbouring cells as part of a coordinated response to long-term glucose starvation.

On day five, I observed Adam perform another experiment which explored the relationship between the number of necrotic T-cells provided to hepatocytes and the number of phagocytosis events (in which cell-in-cell structures are formed). The experiment used serial dilutions of necrotic T-cells; hepatocytes can engulf dead T-cells easily (even in low quantities).  Following this, we imaged the experiment using the smaller, yet equally impressive, CX5 fluorescence microscope.

In the afternoon, we analysed the images from this experiment to yield averages for the number of cell-in-cell structures observed with the different concentrations of T-cells. I performed some manual counts with the help of an image editing software (Image J) whilst Adam began to use Matlab (a programming language) to automate this process.

On the first day of my second week with the University of Birmingham, I attended a conference with Zania (who chaired the third session) on stromal microenvironments in health and disease. A variety of speakers from the University of Birmingham (and a plenary speaker from Barts Cancer Institute) presented their research on a vast range of topics connected to stromal cells (cells that make up the supporting tissue of organs) from potential cures for rheumatoid arthritis (presented by Andrew Filer) to identifying indicators of myeloma and hallmarks of cancer (presented by Dan Tenant). These presentations helped to further enhance my understanding of the incredible research undertaken at the University of Birmingham.

Two days later, I had the pleasure of meeting visiting Professor Lucie Peduto from the Pasteur Institute. Her research lab has a strong focus on stroma which relates to the liver stromal microenvironment researched here. In the afternoon, I attended her seminar on the relationship between stromal cells, fibrosis, and cancer; having attended the conference on stromal microenvironments earlier that week allowed me to gain a better understanding of her research.

The penultimate two days of my work experience were by far my favourite; I had the exciting opportunity to perform an entire experiment single-handedly. My detailed observation of the experiments performed by Adam proved very useful as I performed the same experiment he did on day five (which explored the relationship between the number of necrotic T-cells provided to hepatocytes and the number of phagocytosis events).  It felt like a culmination of all my training and learning from the past two weeks and I utilised all the skills I had learnt by shadowing and observing Adam performing experiments. In the morning of my ninth day at the University of Birmingham, I observed the cells I had split and cultured the previous Thursday and was pleasantly surprised to find that they were thriving and ready to use for the experiment. Completing this experiment helped me to develop my organisational skills as I carefully followed the protocol Adam had created and balanced different tasks simultaneously.

Overall, my work experience at the University of Birmingham has been a fantastic experience and I am extremely grateful to Dr Zania Stamataki and Adam McGuinness for teaching and supporting me throughout my time here.

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* I have provided the list of publications I had the pleasure of reading in case you would also like to immerse yourself into this fascinating field:

• Cell-in-cell phenomena, cannibalism, and autophagy: is there a relationship?
• The cell biology of cell-in-cell structures
• Entosis enables a population response to starvation
• Mechanisms of ploidy increase in human cancers: a new role for cell cannibalism
• To stay young, kill zombie cells

Body Slices and Beautiful Books: Visiting the Wellcome Collection

Recently, during the October half-term break, I visited one of the arguably coolest museums in London- the Wellcome Collection. In contrast to many museums I’ve visited in the past, the Wellcome Collection had a unique atmosphere with the exhibits being both mildly unnerving and intensely intriguing. One of the best aspects of the museum was that it encouraged viewers to do more than simply ‘view’- its many drawers and panels allowed visitors to delve deeper into the fascinating collections.

The Wellcome Collection was founded by Sir Henry Wellcome, an extraordinary man who was a “pharmacist, entrepreneur, philanthropist, and collector”. Wellcome had a strong personal interest in medical objects and artworks and, over time, his collections were developed to form this fascinating museum exploring health, life and our place in the world.

The museum has two permanent exhibitions: Medicine Man and Medicine Now. Medicine Man showcases many extraordinary objects from Henry Wellcome’s collection which are grouped by broad cross-cultural themes. Medicine Now focuses on a few key themes of modern medicine and consists of medical objects and artistic responses to medical issues collected since Henry Wellcome’s death in 1936.

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Upon entering the Medicine Man exhibition, I was greeted with an extensive array of glassware; the truly impressive scale of Wellcome’s collection is made tangible with this dramatic display.

The case only displays a fraction of a collection of over 5000 pieces of medical and scientific glassware.

 

An archaic retort flask

Another part of the exhibiton which piqued my curiosity from this exhibition was the collection of glass eyes.

Glass eyes made by W. Halford of London (1870 – 1920)

One of the earliest ocular prostheses dates back to 2900–2800 BCE and has “a hemispherical form and a diameter of just over 1 inch. It consists of very light material, probably bitumen paste. The surface of the artificial eye is covered with a thin layer of gold, engraved with a central circle (representing the iris) and gold lines patterned like sun rays” (Credit: Wikipedia).

Despite sometimes still being referred to as glass eyes, modern ocular prostheses are typically made of  medical grade plastic acrylic in order to avoid issues such as shattering of the prosthetic in the eye. Realism of artificial eyes have been continually developing since the first ocular prosthesis; the main limitation being realistic pupil movement.

Ocularists and eye surgeons have always worked together to make artificial eyes look more realistic. For decades, all efforts and investments to improve the appearance of artificial eyes have been dampened by the immobility of the pupil. The most recent solution to this issue is to use an LCD display to vary the pupil size depending on the light intensity of the environment.

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The next exhibition that I explored was Medicine Now. As I had mentioned earlier, this exhibit revolves around a few aspects of modern medicine:  the body, genomes, and obesity. I was particularly drawn to the body section of the exhibit which focused on the multitudinous methods used to reveal the internal structures of the body that would have been simply unfathomable during Henry Wellcome’s lifetime.

The highlight of this section is the plastinated full body slice of a woman created by replacing all the lipids and water in the donor’s body with epoxy and silicone.

This mildly discomfiting specimen is on loan from the Institute of Plastination, Heidelberg, Germany

Plastination is a relatively new process developed in 1977 by Gunther von Hagens when, during his time as an anatomical assistant at the University of Heidelberg, he saw specimens preserved in plastic blocks for the first time.

He “wonder[ed] why the plastic has been poured around the specimen in a block rather than stabilizing the specimen from within” -BodyWorld

Standard plastination involves four steps: fixation, dehydration, forced impregnation in a vacuum, and hardening.

1. Fixation via formaldehyde is beneficial to prevent the decomposition of the specimen and to ensure the specimen stays rigid, allowing it to be moved to display specific organs.
2. The specimen is then dissected and the slice is submerged in acetone which, under freezing conditions, draws out all the water from the cells and replaces it.
3. During the forced impregnation stage, the slice is submerged in a liquid polymer and a vacuum is created- this forces the acetone to boil off, drawing out of the cells and replacing it with the polymer.
4. Finally, the plastinated slice must be cured with heat or UV light to harden it.

This method allows the internal structures of the body to be viewed in 3D and in an amazing level of detail.

Despite plastination being a modern technique, the desire to observe the inner structures of the human body has been present throughout history. In 1887, paint was injected into the arteries of a woman who was sentenced to hanging so that, when she died, her body could be frozen and cut into slices for anatomical studies. This ghastly, albeit innovative, manner of viewing the internal workings of the body resulted in the following woodcut.

From An Atlas of Topographical Anatomies after Plane Sections of Frozen Bodies (1877) by Wilhelm Braune

The Medicine Now exhibit is not the only place within the Wellcome Collection where I encountered these plastinated body slices…

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To conclude my visit to the Wellcome Collection, I visited the marvellous Reading Room that managed to relax visitors and incite curiosity at the same time.

The Reading Room, like the exhibits, contains unique sections (each with their own collections of objects, fiction, non-fiction, and interactive activities).

Dotted around the room were oddities such as another body slice that greeted me as I entered the Reading Room.

A lateral body slice created by Gunther von Hagens

 

Visitors were encouraged to relax in one of the surprisingly vast array of insanely comfortable chairs and peruse through the books and articles that filled the rooms. I chose to fully recline over the several cushions that flanked the staircase and read Susannah Cahalan’s Brain on Fire (a deeply moving and fascinating account of a rare disease).

I’ve recently finished the book and would highly recommend it!

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As one of the highlights of visiting this museum has been the exploration in anatomy, I couldn’t resist buying a copy of the Bourgery’s Atlas of Human Anatomy and Surgery  which features the most beautiful and exquisitely detailed drawings of the human body (right down to the cellular level).

An example of one of the hundreds of full-colour plates in this beautiful book

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Overall, my visit to Wellcome Collection has been absolutely amazing and inspiring and has compelled me to delve deeper into the world of anatomy.

If you have the chance to visit, I would strongly urge you to do so!