Joaquim Cabral-Teixeira (jcabralt@ucsd.edu)

Graduate Program:  Molecular Pathology
Lab PI: Dr. Mark Mercola
Undergraduate Education: Faculty of Sciences University of Lisbon
Med-into-Grad Clinical training area: Cardiovascular Diseases
Clinical mentor: Dr. Sotirios Tsimikas stsimikas@ucsd.edu

Memorable advice: “Once you get to the clinic, ask questions, get involved, look for other departments or services once integrated in your clinical team, find new interests within the hospital you are visiting. Do not limit yourself to a scheduled program if you are given one, those are mere guidelines that will help you find your way. Do not wait for a formal schedule/introduction to start attending meetings.  Start visiting the departments, start talking to people and integrate yourself in the medical community and activities.  Once integrated you should feel free to build up on that backbone and exchange ideas with your clinical mentors. You will find most people are happy to talk to you and show you procedures, case studies, have you visit and examine their patients, and learn their techniques.  Many will also be interested in what you do in the lab.”

Rationale for Med-into-Grad training:
Medical training and identification of medically-relevant research issues:
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
Diagnostic, therapeutic, and research collaborations:
Student-specific experiences:
Long term impact.:
Advice for new trainees--autumn preparatory quarter:
Advice for new trainees--winter clinical training quarter:
Take home perspective on Med-into-Grad at UCSD:

Rationale for Med-into-Grad training: Heart failure is the leading cause of morbidity and mortality in the developed world and results from the inability of endogenous cells to overcome the irreversible loss of cardiomyocytes. Replacement therapies being investigated generally involve transplantation of immature cardiomyocytes that are hoped to integrate into the damaged tissue and the stimulation of cardiomyocyte replication in the damaged myocardium. Immature cardiomyocytes, such as from fetal material or human embryonic stem cells, only divide a few times before exiting cell cycle. Therefore, both of these therapies would be greatly enabled by a deeper understanding of the mechanisms that 1) underlie the cardiodevelopmental program, and 2) block cardiomyocyte replication in the postnatal heart. Differentiation of ESCs towards any particular lineage is inefficient and the controlling mechanisms are poorly understood. Part of the inability to efficiently identify cardiac progenitor cells derives from the lack of understanding about the cell surface molecular signature of such cells. Finally, immature cardiomyocytes have a limited proliferative capacity, which becomes negligible once these cells terminally differentiate into their adult state.
My thesis research is based on the development of 3 main ideas:
1) Identification and characterization of small molecules that have the potential to increase the yield of cardiomyocytes obtained by differentiating murine ESCs under defined growth conditions;
2) Use of phage display nanotechnology to identify biorecognition molecules that identify precursors of specific lineages in ESC cultures;
3) Identification and characterization of small molecule inducers of adult cardiomyocyte proliferation.

Laboratory research can be very self-absorbing. I often lose perspective and it’s very easy to miss the broader picture so focused I am on trying to solve the questions and challenges particular to my research project. Moreover, though attempting to provide clinicians with novel and improved therapeutic tools, I lacked exposure to and understanding of the reality of the disease that motivates my research, the patients whose lives are increasingly impacted by the disease’s progression, and the field’s major and most urgent therapeutic needs. I became interested in the Med-into-Grad program once I realized how beneficial to my future research it would be to gain a close insight into how to diagnose and treat cardiovascular diseases.  Reading about cardiovascular diseases could never provide me with the practical knowledge that arises from being in a clinical setting. Moreover, some if not much of the knowledge we generate at the bench is not directly applicable to improving human health. This program offers the training and knowledge that will hopefully help a new generation of biomedical scientists to bridge the gap between the laboratory and the clinic and I wanted to be on that frontline.
 
Medical training and identification of medically-relevant research issues:  During my medical training I was able to observe and in some instances participate in procedures as fascinating as: open chest surgery, catheterization, electrophysiology and pace maker devices, critical care of patients with cardiovascular complications, cardiology outpatient consults, echocardiography, electrocardiography, management and care of cardiac complications secondary to other diseases or cardiac unrelated surgery.
In many patients I observed that the cardiovascular disease originated from prolonged unhealthy lifestyles, with a persistence of lack of exercise, poor weight management and dietary habits, and smoking. The literature and the statistics show us a correlation between all these factors and cardiovascular diseases, but those numbers rapidly turned into individuals once I was face to face with their health problems and their life stories. The injury to the arteries of the heart and limbs was in some cases extensive and irreparable, the consequences only avoidable by prevention. Not only medical but also economical and social changes need to occur with respect to cholesterol management to help prevent cardiovascular diseases. On the other hand, there was a large genetic component that I was unaware played such an important role not just on the onset of the disease but mostly its progression. As an example, when a 30 years old active and otherwise healthy patient suffers from hypercholesterolemia, there are clearly more than poor dietary habits at play. The sooner we are able to predict if and when a patient is at risk for developing an occluding thrombus that may lead to a pulmonary embolism or cardiovascular stroke, the quicker and simpler the intervention and the better the chances of a positive outcome. Furthermore, there clearly is a need for drugs that not only indicate and resolve the thrombus but also that treat chronic cardiovascular disease and other diseases with cardiovascular repercussions such as diabetes. Many different pathologies often have a common underlying pathophysiological mechanism. Perhaps the most efficient way of treating all or most with the least amount of intervention is to focus the research and therapeutic effort on treating the molecular mechanisms from which several complications originate, while treating the symptoms with conventional drugs.   

Long term impact: The research I have been developing using rat cardiac tissue could well be performed on human cardiomyocytes, a type of tissue that is however not readily commercially available for technical and clinical reasons. Participating in the MIG program opens new opportunities of collaboration and I foresee the chance of establishing parallel research studies using cardiac tissue obtained from clinical collaborators. Furthermore, a cross talk between the laboratory and the clinic can clearly optimize resources usage and define how to best approach the problems at hand. After all the clinicians understand the human model of disease in a similar fashion to how a biomedical researcher understands the animal models yet further in a practical and applied context. Moreover, Dr. Tsimikas leads a research laboratory focused on lipoproteins and their role on cardiovascular disease. This allows Dr. Tsimikas to take advantage of his and his laboratory collaborators’ discoveries to best treat his patients. In fact Dr. Tsimikas often discusses with his patients the most recent findings from his laboratory. The laboratory researcher can do the reciprocal.

Training in diagnostics & therapeutics; identification of unmet diagnostic & therapeutic needs: In general terms, therapies for cardiovascular disease focus on the amelioration of complications, or management and maintenance of healthy physiological levels of cholesterol, lipids and triglycerides, hypertension, diabetes mellitus, obesity an physical activity, coronary heart disease and heart failure, pulmonary artery hypertension, arrhythmias and atrial fibrillation, and thrombosis. Atherosclerosis, a progressive disease of the arteries, results from the deposit of fatty substances, cholesterol, calcium, and other products, forming a plaque in the inner lining of the vessel. 75% of deaths from cardiovascular disease result from atherosclerotic complications. Currently there are no medications available for the direct treatment of the chronic inflammation of atherosclerosis. Treatments aim at reducing LDL-cholesterol and therefore the risk of heart disease, or decreasing platelet aggregation in the case of atherothrombosis. Drugs being developed that inhibit production of VCAM-1 and others involved in the inflammatory process, or that inhibit the activity of Lp-PLA2, seem promising. Statins are at present the first line agents used to lower LDL-cholesterol and glycerids. A new drug Rosuvastatin, approved by the FDA in 2003, demonstrated regression of atherosclerosis in clinical trials. Hypertension is defined as blood pressure greater than 140/90mm Hg and is the leading risk factor for coronary heart disease, heart failure, myocardial infarct, stroke and renal insufficiency. Risk levels are two times as high in people with diabetes. Combinations of drugs that target more than one heart disease risk factor are becoming more popular as well. Patients who suffer from both hypercholesterolemia and hypertension have a greater risk of suffering a heart attack or stroke than people with only one condition. Furthermore, patients who have both conditions experience 60% of all cardiovascular events. Similarly, pulmonary hypertension (PH) is a mean pulmonary artery pressure above 25 mmHg. Pulmonary arterial hypertension is a rare form of PH. Once the blood vessel’s wall suffers degradation, the blood flow to the lungs ceases to occur normally, the function of the vessel’s smooth muscle is impaired and blockages can form by platelet aggregation. The condition is often not diagnosed until it is quite advanced and can be mistaken with diseases such as asthma. PAH is currently treated mainly with calcium channel blockers, diuretics and anticoagulants in order to alleviate symptoms despite not treating the disease. There are now a number of new potential drugs that can target the causes of PAH: a type-A selective endothelin receptor antagonists might soon enter the market. Atrial fibrillation (AF) is a disorder in the rhythm of the atria, which reduces the myocardium’s ability to effectively function. AF can result in a rapid, irregular heart rate; when blood is not fully expelled from the atria, it may pool and clot and result in a stroke. Current treatments for AF include drugs, cardioversion, radio ablation, surgery, or pacemakers. Drugs currently being used offer modest efficacy and potentially serious side effects. The most advanced drug in the pipeline is dronedarone, a novel multi-channel blocker that procures the maintenance of sinus rhythm and ventricular rate control in patients with AF. Also, an intravenous formulation of RSD1235 selectively blocks ion channels in the heart shown to be active during AF. Lastly, an atrial repolarization delaying agent is being developed which has a novel mechanism of action with unique partition of effects on the atrium and ventricle of the heart. Lastly, thrombosis is the general term for the formation of a blood clot in the large blood vessels, obstructing blood flow. Anti-coagulant and anti-platelet drugs lead the market as preferred treatment for thrombosis. Of those, the most commonly used agent to treat atherothrombosis is clopidogrel; enoxaparin for venous thrombosis.

Research collaborations: Being in the final months of my thesis research before graduation, this was perhaps no longer the best time of my thesis research to establish new collaborations that could feed into my project. I did however have the opportunity to contact with young clinicians who are just as excited about clinical research as their senior mentors and who seem to produce a considerable amount of publishable data during their continuous medical training. This is very inspiring and encouraging.

Student-specific experiences: My training has first and foremost humanized the disease I am trying to help treat; it has shown how important it is that researchers and clinicians work together so as to more rapidly advance in our discoveries. It has taught me the language of patient care and how people’s lives can be so profoundly affected by their health condition. It has also shown me how deeply the clinicians care for their patients.

Advice for new trainees - autumn preparatory quarter: Do your homework, learn about the disease, the diagnostic methods, the most common approaches, things to look for, techniques and tools used, get familiarized with the pharmacology and most common terms and abbreviations – learn the “language”. There is only so much that can be taught during the preparatory quarter, which is general and cannot be focused on any particular area but aims at giving you an overview of the different diseases and particular areas of research and does it well. Contact the trainees that preceded you and exchange ideas with your fellow trainees, they all were of extreme value to my preparation for the winter clinical training quarter and probably saved me time and effort trying to figure out what could best help me achieve my goals with the MIG program.

Advice for new trainees - winter clinical training quarter: Ask questions, get involved, look for other departments or services once integrated in your clinical team, find new interests within the hospital you are visiting. Do not limit yourself to a scheduled program if you are given one, those are mere guidelines that will help you find your way. Do not wait for a formal schedule/introduction to start attending meetings, start visiting the departments, start talking to people and integrate yourself in the medical community and activities.  Once integrated you should feel free to build up on that backbone and exchange ideas with your clinical mentors. You will find most people are happy to talk to you and show you procedures, case studies, have you visit and examine their patients, learn their techniques, and many will also be interested in what you do in the lab, what your perspective is on certain areas of investigation, a recent finding published on a scientific journal, or on where you think the effort should be focused.

Take home perspective on Med-into-Grad at UCSD: It clearly was a unique opportunity to broaden my knowledge of the disease and model I study in the lab but also to focus and reshape my future research on more practical and perhaps realistic therapeutic approaches to solving the problems and open questions of my specific field in Pathology. I also understand there are opportunities for new therapies in areas that are less competitive therefore safer to invest resources on during these early years of my scientific career. I recommend the MIG program to all PhD students who wish to bridge the gap between the bench and the clinic and meet the most urgent therapeutic needs with their research.