The Doctoral Thesis - PhD

Today's main topic has been the Doctoral Thesis but also research in general. We have discussed what might be your underlying reasons to embark in doing a PhD as well as which are the important points to consider when making this decision. Whatever the motivation or driving forces you may have, we can only but encourage you to pursue this fascinating and enriching experience. Below you have some videos to illustrate the topic both from a realistic but also humorous point of view.

Last but not least we have been talking about the final exam. As promised in the following link entitled Consejos para el ESTUDIO de la asignatura you can find some useful tips in Spanish on how to study the subject "Introduction to Research".

The final exam will start at 11.30 a.m. on December 19th, 2014 in rooms 3A, 3C and 3E of the Med School.

We wish you all the best and hope that you pass the examinations with flying colours!

Nanotechnology in biomedicine

Many diseases are caused by alterations in biological processes at the molecular or nanometric level. Mutated genes, misfolded proteins, and infections caused by viruses or bacteria can produce cellular malfunction, translating into serious diseases. These molecules and infectious agents have a nanometric size and may be located in biological systems protected by nanosized barriers such as the nuclear pore with a diameter of 9 nm.

Nanotechnology is defined as the design, characterization, production and application of materials, structures, devices and systems in the nanometric range (1-100 nm).

The application of nanotechnology to medicine is changing the way we look at cancer:

Nanomedicine is aimed to use the characteristics and physical properties of nanomaterials for the diagnosis and treatment of diseases at the molecular level.

In the figure below you can see some of the most frequently used materials in nanomedicine:

Taken from Kim et al. N Engl J Med 2010

Of particular interest is the one-atom thick layer of graphite, called graphene. The Nobel Prize in Physics 2010 was awarded jointly to the Russian researchers Andre Geim and Konstantin Novoselov "for groundbreaking experiments regarding the two-dimensional material graphene". Graphene is the basic structural element of carbon nanotubes. Below, you can see a video showing how the medical applications of graphene could be in the future:

MEDICAL APPLICATIONS OF NANOTECHNOLOGY

Nanodiagnosis: the diagnosis of some diseases can be improved by using nanoparticles that interact with the molecules related to the disease present in the blood, body fluids or tissues.

Drug release: nanotechnology may be more effective in drug delivery and reaching the target tissue than conventional systems.

Some aspects of the application of nanotechnology in the diagnosis and treatment of cancer can be seen in the following video:

Nanotechnology has also potential in regenerative medicine, particularly in the diagnosis and management of cardiovascular diseases, in the development of prosthesis and in the creation of artificial retina.

Other fields where nanotechnology could have application are: treatment of infectious diseases, nanosurgery and odontology.

In the following video a technique using nanoparticles aimed to reduce the toxicity of radiotherapy and improve the effectivity of the treatment is explained: 

The use of nanoparticules raises novel and important ethical concerns regarding mainly the potential toxic side effects in the body and the potential ecological impact on the environment.

Familiarize yourself with the following concepts:

• Definition of nanotechnology
• Principal nanomaterials
• Applications in biomedicine
• Advantages and disadvantages of nanotechnology
• Main ethical concerns

Stem cells

Stem cells are undifferentiated cells with the ability to divide through mitosis to produce more stem cells (self-renewal) and that can differentiate into specialized cells. 

The relevance of stem cells in biomedical research was reflected in the decision to award Sir John B. Gurdon (Dippenhall, United Kingdom, 1933) and Professor Shinya Yamanaka (Osaka, Japan, 1962) the Nobel Prize of Medicine in 2012 for their findings in this research topic.

 

 Taken from the Official Website of the Nobel Prize.

Stem cells are widely studied, due to their potential therapeutic use and for their inherent interest. As explained during the lesson, stem cell research is now focused on regenerative medicine as well as on the treatment of a wide variety of diseases, including cancer, Parkinson disease, multiple sclerosis, and spinal cord injuries, among others. However, most of the clinical trials using stem cells as therapy are still in early clinical phases. The following video explains what stem cells are and how scientists are harnessing their medical potential:

 

Classification of stem cells according to developmental potentials

• Totipotent stem cells derive from the fusion of a sperm cell with an egg cell (zygote) or from the first few divisions of the fertilized egg (morula). Totipotent stem cells can give rise to an entire functional organism or to any cell type of the body, including the extraembryonic tissues (i.e. placenta, umbilical cord, amniotic sac).
• Pluripotent stem cells derive from the inner cell mass of the blastocyst. Pluripotent stem cells can differentiate into nearly all cell types of the three embryonic germ layers (endoderm, mesoderm, ectoderm), but not into an entire functional organism.
• Multipotent stem cells can develop into more than one cell type, but only those of a closely related family of cells (i.e. multipotent blood stem cells are capable of differentiating into erythrocytes, lymphocytes or platelets).
• Unipotent stem cells can produce only one cell type, their own, but have the property of self-renewal, which distinguishes them from non-stem cells.

 Taken from Eckfeldt et al. Nature Reviews Molecular Cell Biology 2005;6:726-737

Classification of stem cells according to their origin

• Embryonic stem cells derive from the embryonic stage of morula (totipotent stem cells) or from the inner cell mass blastocyst (pluripotent stem cells). Due to their high developmental potential, embryonic stem cells can give rise to teratomas, that are tumors containing differentiated elements of all three embryonic germ layers. Isolation of human embryonic stem cells results in the destruction of the fertilized embryo, which raises ethical issues.
• Adult or somatic stem cells originate from adult tissues and they have the ability to divide or self-renew indefinitely and generate the cell types from the tissue from which they originate. This type of cells are multipotent stem cells.
• Induced pluripotent stem cells (iPS): Professor Shinya Yamanaka (University of Kyoto, Japan) reprogrammed, for the first time, murine skin fibroblasts into multipotent stem cells that could develop into all cell types of an adult mouse by introducing four factors Oct3/4, Sox2, c-Myc and Klf4. He named the cells induced pluripotent stem cells (iPS) and these results were published in the prestigious Cell journal in 2006. In the present video, you can see the methods used to obtain iPS cells:

 

You will have to know the:

• Classification and characteristics of stem cells according to their developmental potential (totipotent, pluripotent, multipotent and unipotent stem cells).
• Classification and characteristics of stem cells according to their origin (embryonic, adult and inducible pluripotent stem cells).
• Genes implicated in the induction of iPS cells.

Current and future developments in surgery

Surgical techniques and instrumentation have experienced a spectacular development in the last decades. The development of microsurgery, bioengineering, imaging techniques and endoscopy, as well as the development of robotics have allowed progress of surgical procedures unimaginable only a few years ago. Advances in fields such as minimally invasive surgery, tissue engineering, robotic surgery, bariatric/metabolic surgery and transplantation, are clear examples of the rapid development of surgery.

Some of the most interesting and innovative techniques that have been developed over the past few years in different areas of surgery are explained below. Most of them are already in use, but in further development at the same time.

Minimally Invasive Surgery can be defined as the set of diagnostic and therapeutic techniques using natural orifices or minimal approaches to introduce surgical tools and perform surgery inside the human body. Today, more than 65% of surgeries performed in the USA use Minimally Invasive Surgery techniques. Examples include theSILS (Single Incision Laparoscopic Surgery):

or SPL (Single Port Laparoscopy) also known as SPA (Single Port Access Surgery):

Natural Orifice Translumenal Endoscopic Surgery (NOTES) is another minimally invasive surgical technique which consists in entering into the peritoneal cavity through natural orifices (mouth, vagina, anus or urethra) and then through an internal incision in the stomach, vagina, bladder or colon to enter the peritoneum avoiding any external incisions.

Actually there are some innovative transplants that were inconceivable some years ago. For example, the face transplant which is not a skin graft transplant, but where the graft of a whole donor's face is placed onto the patient's disfigured face, attaching nerves, blood vessels and muscles. It allows the patient to have facial expressions whilst skin grafts do not. It is important to note that the patient will not adopt the donor's facial likeness, since the bone structure, and the nerves that move the muscles are different. Examples of recently performed face transplants are shown in the following picture:

  

Recent developments in intrauterine surgery allow surgeons to act on the fetus as if it was a patient, not only administrating medication, but practicing open surgery without interrupting the pregnancy. It can be used as a palliative measure or as a permanent solution. It is normally used to deal with spina bifida and diaphragmatic hernia.

Some of these procedures could not have reached reality without the development of robotic surgery systems. The most extended one is the Da Vinci Surgical System, a sophisticated platform designed to expand the surgeon's capabilities to perform complicated surgical procedures with minimal invasion. It is mainly used for prostatic surgeries, reparation of cardiac valves, and gynecologic procedures:

One of the most recent advances in technology with applications in surgery as well as in telesurgery is Google Glass, a wearable computer with an optical head-mounted display (OHMD):

Google glass was used for the first time in 2013 by the Spanish Dr. Pedro Guillén (Clínica CEMTRO, Madrid) to broadcast a surgery (chondrocyte implantation in the knee) while interacting with other doctors and students in Stanford University (California):

Familiarize yourself with the main innovative surgical techniques explained in class:

• Minimally invasive surgery
• Innovative transplants
• Robotic surgery
• Intrauterine surgery

Cardiovascular research

Why is cardiovascular research so important?

Cardiovascular diseases constitute disorders of the heart and blood vessels, and include coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, congenital heart disease and heart failure. The major causes of cardiovascular diseases are tobacco use, physical inactivity, an unhealthy diet and harmful use of alcohol. 

 

According to the World Health Organization, cardiovascular diseases are the number one cause of death globally. An estimated 17.3 million people died of cardiovascular diseases in 2008. Recent advances in the diagnosis and treatment of atherosclerosis and heart failure, two cardiovascular diseases with high prevalence, are explained below.

Atherosclerosis

Atherosclerosis is a disease in which a plaque composed by fatty substances, cholesterol, calcium and fibrin (a clotting material in the blood) builds up in the inner lining of an artery. The plaque may partially or totally block the blood's flow through an artery. Atherosclerosis can lead to serious problems, including heart attack, stroke or even death.

Taken from the National Heart, Lung and Blood Institute web page 

INNOVATION IN THE DIAGNOSIS: there are novel imaging techniques that are used to evaluate the narrowing and the presence of atheromatous plaques in the coronary arteries. In the following pictures, you can observe hybrid images combining PET and MRI that have been developed to improve the specifity and sensitivity of the diagnosis:

 

Taken from Trujiman et al. Stroke 2013; 44:3568-70.

INNOVATION IN THE TREATMENT: Coronary angioplasty, also called percutaneous coronary intervention, is a procedure to relieve blocking or narrowing of the coronary arteries. Angioplasty involves temporarily inserting a tiny balloon to widen the clogged artery and it is often combined with the permanent placement of a wire called stent to help prop the artery and decrease the chance of it narrowing again. In the next video, you can see how the stents are used to treat several coronary heart diseases:

Heart failure

Heart failure, also known as congestive heart failure, occurs when the heart cannot pump enough blood to supply the body's needs for blood and oxygen. Common causes of heart failure include myocardial infarction, atherosclerosis, hypertension or valvular heart diseases, among others. The underlying mechanisms of heart failure can be observed in the following video:

Treatment depends on the severity and cause of heart failure. In a chronic patient with stable condition treatment consists of lifestyle changes (smoking cessation, light exercise and dietary changes) and medications. Depending on the etiology, severe heart failure can be treated with implanted devices (i.e. pacemaker or ventricular assist devices). In patients at the end-stage of heart failure, after using all the alternative therapies, heart transplant is required. During the heart transplant, the patient's own heart is either removed (orthotopic procedure) or, less commonly, left in place to support donor heart (heterotopic procedure). The first human transplant was performed by Christiaan Barnard in 1967 in South Africa. Sadly, the patient, Mr. Louis Washkansky (in the picture with Professor Barnard), died of pneumonia 18 days later after the heart transplant due to a weakened immune system.

INNOVATION IN THE TREATMENT: an artificial heart is a device that replaces the heart to bridge the time to heart transplantation. In 1969, Denton A. Cooley and Domingo Liotta replaced, for the first time, the heart of dying man with an artificial heart; the patient lived for 65 hours. Currently, most commonly used artificial hearts are Cardio-West and AbioCor. The main difference between them is that Cardio-West is connected to an external power source, while AbioCor is completely inserted in the chest and its battery is charged through the skin with a special battery charger.

Taken from the National Heart, Lung and Blood Institute web page.

Stroke

 

A stroke occurs when the blood supply to part of your brain is interrupted or severely reduced, depriving brain tissue of oxygen and food. Stroke is the second leading cause of death and the first cause for adult impairment. A ischemic stroke (left picture) occurs as a result of an obstruction within a blood vessel supplying blood to the brain, while an hemorrhagic stroke (right picture) occurs when a weakened blood vessel ruptures. About 87% of all strokes are ischemic strokes.  

New developments in cardiovascular research focus on novel tools for the prevention, diagnosis and treatment of cardiovascular diseases.

1. Identify the healthy habits that prevent cardiovascular disorders as well as risk factors.
2. Know the characteristics of the novel vascular imaging techniques and the use of coronary stents used for the diagnosis and treatment, respectively, of atherosclerosis.
3. Familiarize yourself with the different types of artificial hearts.
4. Be aware of the possibilities and limitations of the different procedures (orthotopic or heterotopic) and types (allograft or xenograft) of heart transplant.

Stephanie Fae Beauclair, better known as Baby Fae, was born in 1984 with hypoplastic left heart syndrome. Her mother, Teresa Beauclair, contacted with Dr. Leonard Bailey, a handful physician and researcher interested in saving infants born with fatal heart defects. Baby Fae became the first patient of a xenotransplant procedure receiving the heart of a baboon. A xenotransplantation is the transplantation of living cells, tissues or organs from one species to another. The procedure was successful, but Baby Fae died 21 days later of heart failure due to the rejection of the xenotransplant. The story of Baby Fae was documented in the film "Stephanie's Heart: The Story of Baby Fae"; you can see the trailer below:

One year later, Dr. Bailey performed the first infant allograft heart transplantation on Baby Moses, whose actual name is Eddie. An allotransplantation is the transplantation of living cells, tissues or organs from a genetically non-identical donor of the same species. Now 29-year-old Eddie holds the distinction of being the oldest living infant heart transplant recipient.