Mara Lorenzi

Mara Lorenzi attended a Classic Lyceum in Italy, and her favorite subjects were philosophy and ancient Greek. She surprised both herself and her teachers when she chose to study Medicine at the University. Retrospectively, she thinks that the choice was actually consistent with her passion for philosophy, because research became her main endeavor. The road to research was not easy for a medical student in Italy a few decades ago; there was very little structure for research, let alone for research apprenticeship. She explored England as a destination (and was privileged to work briefly there with giants of clinical research in diabetes – Drs. David Pike, PJ Watkins, and Robert Tattersall), but could not turn down the offer of a fellowship in San Francisco. She trained at the Metabolic Unit of the University of California San Francisco in clinical research related to diabetes and metabolism, and also did an Internship and Residency to be able to practice medicine in the US.

But just as she thought that she had all her weapons in place – training in clinical research, qualifications to practice medicine in the US, a new faculty position as Assistant Professor of Medicine at the University of California San Diego (UCSD) – to  begin working independently on the scientific questions she had accumulated since medical school, Dr. Lorenzi had to acknowledge that her questions had evolved in a direction that required another set of tools, those of basic research. Taking time out for further training was not an option, because by now Dr. Lorenzi had also the responsibility of directing the Diabetes Clinic at UCSD Medical Center. Eventually, with the help of wonderful colleagues and a young technician, the life of a new laboratory began. In 1987 Dr. Lorenzi moved her laboratory to the Schepens Eye Research Institute, where she is currently Senior Scientist and George & Frances Levin Scholar in Diabetic Retinopathy. She is Professor of Ophthalmology at Harvard Medical School, and Clinical Associate in Medicine at the Massachusetts General Hospital.

What were these pressing questions? Diabetes has been the center of Dr. Lorenzi scientific interest since medical school, and she was after the mechanisms for the “complications” of diabetes. A pervasive disease in wealthy as well as poor societies, then and increasingly now, diabetes would be little more than a nuisance if it did not cause chronic complications. These are: retinopathy (disease of the retina that may lead to blindness), nephropathy (disease of the kidney that may lead to kidney failure and the need for dialysis or transplantation), neuropathy (nerve abnormalities that may cause pain or the incapability to perceive pain, and thus lead to injuries), and large-vessel disease (an acceleration of atherosclerosis in the coronary and other arteries that makes heart attacks more common and more severe in diabetic individuals). At the core of all these complications of diabetes there is one single feature: damage to the blood vessels.

The most immediate question that Dr. Lorenzi wanted to address was whether the high blood glucose of diabetes was itself the culprit of the vessel damage. Her laboratory introduced a simple approach to the question: isolate the cells that line the blood vessels, expose them to high glucose in culture for days and weeks, and examine their behavior. The laboratory eventually demonstrated that high glucose is toxic to the cells of the vessels. The researchers saw a subtle type of toxicity, very compatible with the fact that the complications of diabetes have a long latency; their early signs begin to appear only after 10-15 years of diabetes. This toxicity was manifested by a small increase in the death rate of the cells and by a reduced capability to replicate; this is a combination of events that interferes with keeping the lining of the vessels intact and smooth so that blood can flow. (As an aside, this toxicity became of great interest to researchers investigating a seemingly very different consequence of diabetes – the high incidence of congenital malformations among children of diabetic mothers. It is conceivable that during the extremely rapid growth of the embryonic period, acceleration of cell death and decreased capability to replicate interfere with orderly progression of development.) As for the cells of the blood vessels, the high glucose was able to change the production of specialized proteins by the cells; they were now producing more of the glue-like material that keeps cells anchored to the wall of the vessels and more molecules that accelerate the formation of blood clots. This indicated that high glucose interferes with how the cells of blood vessels are programmed, and alters their function.

The obvious second question was whether the retinal vessels of diabetic patients exhibited the same abnormalities as those caused by the high glucose in cultured cells. In other words, was diabetic retinopathy really a consequence of that subtle toxicity of high glucose? Dr. Lorenzi’s lab examined a large number of eyes donated for research through eye banks, and found a remarkable correspondence between the effects of high glucose in the cultured cells and the effects of diabetes on the eyes’ retinal blood vessels. Most impressive in the vessels of diabetic patients were two features: an obvious acceleration of cell death of the type called apoptosis (representing “suicidal” death), and the presence of small clots called microthrombi (which can be viewed as the consequence of the compromised survival and altered function of the cells that line the vessels). It is easy to envision that these types of abnormalities will cause the vessels to become obstructed and useless. Hence, abnormalities attributable to the effects of high glucose can explain the most dreaded feature of early diabetic retinopathy – the closure of small blood vessels – which translates, for the retina, into lack of oxygen and nutrients. 

A retina starving for oxygen and nutrients will attempt to grow new blood vessels. When this happens, diabetic retinopathy will have become proliferative retinopathy, a sight-threatening stage. It is sight-threatening because the newly formed vessels are fragile and break easily, letting blood into the normally transparent vitreous jelly. These vessels also have an abnormal location, and they may exert traction and detach the retina. Ophthalmologists consider proliferative retinopathy an emergency to be treated promptly. The treatment is quite invasive – laser burning of most of the retina except its central portion to eliminate the stimulus and the ground for proliferation of new vessels. In spite of its harshness, laser photocoagulation is a most effective intervention to save sight.

But wouldn’t it be better to protect the vessels of the retina from diabetes and never let proliferative retinopathy develop? Dr. Lorenzi is adamant that prevention is the choice that will pay the big dividends. Her current question is how to deal with the toxicity of high glucose, to prevent its damaging consequences on the retinal vessels. The first maneuver is to recommend that diabetic patients keep their blood glucose as close as possible to the normal values, and to help them to do that. But this is easier said than done, because the treatments of diabetes available today are imperfect and seldom can achieve levels of blood glucose that are completely normal. Hence there is a need to identify treatments that pre-empt the effect of the residual high glucose. Such treatments should be able to interfere with the mechanisms used by high glucose to induce vessels damage, and should be sufficiently safe to be given to patients from the very onset of diabetes and over many decades, to prevent damage to the retinal vessels and perhaps to vessels throughout the body.

Dr. Lorenzi has identified two drugs that are very successful in preventing retinopathy in diabetic rats. One is an aldose-reductase inhibitor, which inhibits a pathway of transformation of glucose that occurs only when glucose is elevated and which generates toxic imbalances in cells. The other is aspirin at a low-intermediate dose. Additional drugs successful in animal models have been identified by other investigators. The most immediate challenge is now to ascertain if one or more such drugs could be helpful in human diabetic retinopathy. Clinical trials to study prevention are inevitably very long and expensive, and it is thus conceivable that only the most promising drugs will be brought to trials. Dr. Lorenzi is attempting to develop new tools to screen for such promising drugs in humans, and thus generate confidence to begin definitive clinical trials.