Haemophilia Researchers: Edward Tuddenham, Amit Nathwani
Haemophilia is a disease that impairs blood clotting, a process used to stop bleeding when a blood vessel is cut or damaged. Both the A and B versions of the condition result from inheriting mutations on the X chromosome. Haemophilia B results from a mutation in the gene that makes the FIX protein, which is vital for blood clotting. We are currently carrying out clinical trials to see if gene therapy is an effective way to treat haemophilia B. Gene therapy is a treatment where a new gene is inserted into cells in order to make a therapeutic protein. In this case, to make FIX proteins the person can’t naturally make.
Immunodeficiency Researcher: Siobhan Burns
1
2
3
4
Primary immunodeficiency is a disorder where part of the body’s immune system is missing or does not function normally. Patients who suffer from this are diagnosed and treated at the Royal Free Hospital. We research these conditions in order to treat patients more effectively.
First we examine the levels of different immune cells in patients. We are particularly interested in cells from the innate immune system – the non-specific first line of defence our bodies use to protect us.
We then examine how these immune cells interact – something called functionomics – to reveal more information about how the patient’s immune system is working.
Finally, we look for genetic mutations that could be causing abnormal immune function. All this information feeds back into how we develop treatments for our patients.
Immunotherapy of cancer Researchers: Clare Bennett, Ronjon Chakraverty, Emma Morris
Bone marrow transplants are commonly used for the treatment for leukaemia or lymphoma. This therapy not only provides the patient with a new bone marrow but also a new immune system.
✗
✓ Donor T cells from bone marrow transplant
Dendritic cells in our blood identify cancer cells, then trigger the immune response by alerting the rest of the immune system (T cells).
Immune cells (known as T cells) from the donor can attack cancer cells in the blood. Unfortunately, the cancer-killing T cells may also damage normal parts of the body in a process called graftversus-host disease (GVHD). The aim of our research is to study how the donor immune cells behave in situations where they cause GVHD. In an alternative approach we are trying to make T cells that will only recognise leukaemia cells, and will not recognise healthy cells. We hope that these T cells will not attack healthy tissues.
Graft-versus-tumour: donor T cells successfully kill tumour cells
Graft-versus-host disease: donor T cells attack healthy tissues in skin, liver and gut
Bone marrow is extracted from a part of the hip using a large-gauge syringe.
Immune problems in the skin: scleroderma Researcher: Chris Denton
Some cells in our bodies, called fibroblasts, produce connective tissue that is made up of proteins such as collagen. In scleroderma (also called systemic sclerosis) there is an over-production of these proteins, leading to thickening or scarring of the skin, blood vessels and internal organs.
The damaged vessel walls attract and activate white blood cells, enabling them to move from the blood into the skin. This allows white blood cells to release chemical signals that cause cells known as pericytes to become collagen-producing fibroblasts.
Current research is leading to a better understanding of the origins of fibroblasts and the ways in which they are activated in diseases such as scleroderma. By understanding the basic mechanisms that cause the disease we are able to develop treatments that may help patients. Ongoing work is evaluating which are the most promising and also the safest so that they can be used in clinical trials.
Fibroblasts are essential for normal tissue healing, but in sclerodema they become over-active and produce too much collagen.
Scleroderma Fibrosis Over production of collagen
Chemical immune signals
Scleroderma affecting the thumb with skin ulceration.
X-Ray showing abnormal build-up of calcium on the bones, known as calcinosis.
Damaged blood vessel wall Activated white blood cell
blood vessel supplying skin
Microscopic view of fibroblastic build-up (arrows) in the lung.
Immune response: protection versus regulation Researchers: Lucy Walker, David Sansom
Protection
Conventional T cell Danger: viruses and microbes
Your immune system has developed a remarkable solution for knowing which molecules are dangerous – such as bacteria and viruses – and which are part of your body. Millions of immune cells are produced. Each has its own, randomly generated specificity, meaning it can recognise any tiny bit of protein, from the capsule of a virus to a hair follicle.
GO Unfortunately this system also generates cells specific for proteins that make every part of us. These cells, if left unchecked, have the potential to cause autoimmune diseases.
Dendritic cell T cells become activated and protect us from infections
Bacteria
Viruses
Fungi
Regulatory immune cells called T cells function to prevent autoimmunity. They work by ‘hoovering up’ the ‘GO’ molecules that trigger immune responses. Understanding this process may help us develop new treatments for autoimmune diseases.
Regulation
Regulatory T cell
✗ ✗ Conventional cells are not activated. Regulatory T cells ‘hoover’ the GO signal and prevent autoimmunity
Diabetes
Multiple Sclerosis
Arthritis
GO
Lysosomal storage disease Researchers: Atul Mehta, Derralynn Hughes Lysosomes are cell structures that are known to contain more than fifty different enzymes. These enzymes are capable of breaking down a range of molecules, including waste from the cell and even the cells itself when it dies. Mutations can cause various problems with the enzymes and how they work. This can result in conditions that affect whole organ systems, called lysosomal storage diseases. We work to understand how these mutations affect the lysosome and to provide support and therapies for sufferers. Lysosomes
Normal breakdown of molecule within lysosome Pompe Disease: glycogen accumulates in lysosomes causing damage to muscle and nerve cells. Molecule to be broken down
Molecule breakdown results in small end products that diffuse into the cell
Gaucher’s Disease: causes skeletal disfigurement.
Abnormal breakdown of molecule within lysosome. Due to the enzyme deficiency, the molecule is not broken down and is stored in the lysosome.
Fabry Disease: caused by abnormal storage of fats, known as lipids.
HIV Researchers: Margaret Johnson, Sabine Kinloch
Our group has had an unprecedented view on the state of HIV in the UK over the last 25 years. Through close collaboration with epidemiologists we have accumulated data from every clinic visit, resulting in a unique cohort. We use this information and research into HIV to further the development of antiretroviral drugs that people take to combat the virus. We hope that our work not only improves the outcomes of people on these drugs, but also increases the numbers of people who have access to them. Out of 33 million expected to be infected worldwide, 60% do not have access to these vital drugs. Our current focus is on the eradication and prevention of HIV infections, and the development of a vaccine.
Breaking and entering: virus tactics Researcher: Joe Grove
Viruses are parasites that hijack the machinery in host cells in order to replicate
Viruses interact with cells in a specific way to gain entry Receptors
A virus’s eye view of the cell
Virus entry
Cytoskeleton
In response to infection by a virus, the immune system produces proteins called antibodies. These bind specifically to the virus particles, neutralising their effects by blocking their entry in to cells.
In the case of viruses that cause chronic infections (e.g. HIV and hepatitis C), infections continue despite the production of antibodies. This is because these viruses have strategies to evade antibodies.
Standard microscopy
Super-resolution microscopy
Renal and liver transplant Researchers: Doug Thorburn, Mark Harber
The prevalence and incidence of chronic kidney and liver disease is increasing for various reasons, and thousands of people are waiting for liver and kidney transplants. One of the problems of transplantation is getting the balance between too much and too little rejection by the recipient’s body. This can result in infection or rejection respectively, both of which are life-threatening complications. To identify who is at risk of these complications we are trying to identify predictive markers that will allow us to change the individual patient’s immunosuppression. We hope to find more sophisticated ways of individualising patient’s treatment and increasing patients’ long term prognoses.
Graph showing a patient’s immune response to cytomegalovirus (CMV).
While initially strong, the patient’s immunity to CMV virus drops significantly by the 5th week, permitting a reactivation of the CMV virus and viraemia (where viruses enter the bloodstream).
% T cells
CMV virus level
0.6
6000
0.4
CMV virus level in the blood
Immunity levels to CMV
0.2
CMV infection after transplantation can affect almost every organ. Chest radiographs can be used to diagnose CMV pneumonia.
4000
2000
0.0 0
20
Days post transplant
40
60
80
0 100
Left: Lung damage caused by CMV can lead to hemorrhagic pneumonia; right: Dramatically enlarged nucleus of lung cell characteristic of CMV infection.
Creating organs from nanomaterial and stem cells Researcher: Alexander Seifalian
We build organs using 3D scaffolds – structures made from biomimetic nanomaterial inspired by butterfly wings, and using the patient’s own stem cells.
1
We have built a trachea, a tear duct, breast filler, facial organs, a coronary artery and an artery in the leg. Currently, we are developing a heart, an esophagus, a urethra, stents, skin and bones.
2
Ingredients: growth factors (left), 3D scaffold (middle), patient’s own stem cells (right)
Growth factors and stem cells are sprayed onto a scaffold
3
Scaffold is placed in a bioreactor that mimics human physiological conditions to encourage cells to grow within the scaffold
Scanning electron micrograph of a butterfly wing that inspired the nanomaterial for the 3D scaffold. The scaffold is manufactured using a 3D bioprinter.
4
The fledging nose is placed under the patient’s forearm skin where it acquires blood vessels and skin
+
+
5
The nose is harvested from the arm, covered with skin then stitched into position on the face
Protecting against a common virus Researchers: Paul Griffiths, Matt Reeves
Once infected, the virus stays in your body for the rest of your life. It rarely causes problems but, when it does, it can be very harmful. CMV can affect people with weakened immune systems, such as transplant patients. In these people, it can cause symptoms such as fever, fatigue and abdominal pain, but it can also have more serious outcomes. Through work done in the Institute, we are reducing the harms caused by infections and are working towards creating a vaccine against the virus.
Effect of disease for selected diseases 8 7 6 5
Number of babies affected 4 per year (1000s) 3
Congenital rubella syndrome HIV Spina bifida Down’s syndrome
© Jacob Johan
Cytomegalovirus (CMV) is a common virus. Spread by bodily fluids such as saliva, many people are unaware that they are first infected as a child.
Toxoplasmosis
An estimated 7 babies in every 1000 are born with congenital CMV in the UK. Of these, only about 25% will have problems, but they can be serious, making CMV a common cause of deafness.
Fetal alcohol syndrome Cytomegalovirus
2 1 0
Screening programme
Antenatal advice
Method of identification
Neither
CMV damages healthy cells, resulting in ‘owl’s eye’ nuclei.
Centre for cell, gene & tissue therapies Researcher: Mark Lowdell, Martin Birchall
Cell, gene and tissue therapies are the ultimate personalised medicines. UCL is one of the World leaders in this field. The new centre in the Royal Free Hospital is a state-of-the art rebuild of the first such facility in the UK. Past successes have included the first organ grown for a child from his own bone marrow stem cells. Over the next year we will continue to break new ground, performing the first voice box repair with a stem cell derived patch.
Above: An organ donor windpipe before removal of the donor cells. Left: An engineered biocompatible windpipe in a purpose-built bioreactor for stem cell population and growth prior to surgical implantation in a 19 year old cancer patient.
An organ donor windpipe after removal of all of the donor’s cells. The donor cell removal creates a scaffold to on which to grow the patient’s stem cells.
The decellularised donor scaffold after recellularisation with patient stem cells in the laboratory being implanted into the patient to replace the faulty windpipe.
UCL BioResource • Do you want to be involved in Medical Research studies? • Are you willing to give a small sample of blood? • Are you willing to be part of a pool of volunteers supporting studies in to a range of medical conditions? In the UK around 20 million people are said to be living with a chronic disease such as diabetes or heart disease. The UCL BioResource has been set up to help in the fight against these and other major common and rare diseases. It is establishing a pool of thousands of local volunteers with and without health problems.
Volunteers will be asked to donate a small blood or saliva sample and give consent to be contacted and invited to participate in medical research studies on the basis of data gathered from samples and information they have supplied. Interested? Please contact the recruitment team T. 020 3447 5369 E. uclbioresource@ucl.ac.uk UCL BioResource 1st floor, Maple House (Suite 1B) 149 Tottenham Court Road London W1T 7DN