In a new laboratory at Dana Doak Children's Hospital in Ichilov, Dr. Naomi Podah-Shaked is developing stem cell-based models, organoids, and tubuloids to understand congenital kidney diseases and test targeted therapies in children and premature infants.
About a year and a half ago, Dr. Naomi Podah-Shaked, a pediatric nephrologist and groundbreaking researcher, returned to Israel from a period of training at Cincinnati Children's Hospital, Ohio. She joined Dana Doak Children's Hospital at the Sourasky Medical Center, Tel Aviv (Ichilov), with the aim of realizing a vision: establishing an independent research laboratory, which will focus on studying congenital kidney diseases using stem cell-based models and organoids of human origin.
When a person is born, the process of forming nephrons – the basic functional units of the kidney – is essentially complete. “The number of nephrons, determined by the 34th-36th week of pregnancy, should be sufficient for a person throughout their life,” explains Dr. Poda-Shaked. Any disruption to kidney development during fetal life may cause congenital malformations of the kidneys and urinary system. While in adults, the main cause of kidney failure is common diseases such as diabetes, in infants and children, congenital malformations of the kidneys and urinary system and various genetic diseases are the main cause of end-stage renal failure. “The two currently accepted treatment strategies for end-stage renal failure – dialysis or kidney transplantation – are general treatment approaches that do not target the cause of the disease and are not personalized, and each of them involves significant risks and severe side effects,” she adds. Therefore, a better understanding of the processes that cause disruption to the normal development of the kidneys may lead to the development of safer and more targeted treatments.
Another population that is particularly vulnerable is premature infants. “Since premature infants are born before they have completed the process of forming nephrons, they begin life with a lower renal reserve, and are therefore more vulnerable to kidney disease later in life,” explains Dr. Poda-Shaked. One of her and her team’s ambitions in the research laboratory is to find new therapeutic or nutritional interventions, already during fetal life, to improve the maturation of the developing kidneys and thus make them resistant to the injuries to which premature infants are exposed after birth. Somewhat similar to the way in which administering the surfactant hormone allows for faster maturation of the lungs.
The question is: How can personalized treatments for congenital kidney diseases be developed?
The goal: personalized treatment thanks to organoid-based models
Nearly ninety percent of new drugs in development that successfully pass the preclinical testing stage (i.e., in laboratory animals) fail to make it to human trials. This is largely due to the differences between lab mice and the human body. “Therefore, I see tremendous potential in human-based research models, such as stem cells and organoids,” notes Dr. Poda-Shaked. Organoids, which are miniature versions of human organs produced in a lab dish from stem cells, are at the forefront of stem cell research and have already led to a number of scientific breakthroughs in a variety of medical fields.
Understanding the basics of AR-RTD disease
For example, Dr. Poda-Shaked recently succeeded in cracking a mystery that had occupied doctors and researchers for years: understanding the basis of a genetic kidney disease, known as Renal Tubular Dysgenesis (AR-RTD). This is a rare and fatal genetic syndrome that affects the formation of one of the parts of the nephron during embryonic life, which usually causes death in the first weeks and months of life. Dr. Poda-Shaked developed an innovative model of the disease, based on 3D organoids. Using it, she was able to prove that the genetic mutations that cause the disease lead to a delay in the secretion of an important growth factor (VEGFA) that is essential for the recruitment and growth of blood vessels to support the developing fetal kidney. In other words, the researchers found that in this disease the kidney does not receive enough “nutrition,” and is damaged precisely at a critical stage of fetal development. The study findings were recently published in the prestigious scientific journal Nature Communications.. “We are now trying to translate the research findings into developing creative and targeted treatments for AR-RTD, which affects infants in Israel – both from the Bedouin diaspora and in other populations. Furthermore, we are applying insights gained from the research to achieve similar achievements for other genetic disorders that cause kidney failure in infants and children,” explains Dr. Poda-Shaked.
The uniqueness of the laboratory lies in the close connection between basic research and clinical work. “We collect urine samples from our patients in the clinic, and from them we grow 3D models called tubuloids in the laboratory, which simulate parts of the nephron structure. The great advantage is that these models contain the unique genetic makeup of each patient, so we can learn exactly what went wrong in the development process of the kidney in their specific case. This allows us not only to better understand the mechanism that causes the disease, but also to test different drugs on the model in the laboratory and develop personalized treatments. In effect, we bring the patient ‘to the laboratory’ to bring back improved therapeutic solutions.”
"We collect urine samples from our patients in the clinic, and from them we grow 3D models called tubuloids in the laboratory, which simulate parts of the nephron structure. The great advantage is that these models contain the unique genetic makeup of each patient, so we can learn exactly what went wrong in the development process of the kidney in their specific case."
The importance of physician-researchers
Dr. Poda-Shaked belongs to a special and limited group of physician-researchers. “I knew from my medical studies that as a physician I would not want to be satisfied with providing existing treatments, or staying within the boundaries of medical knowledge available in books,” she says. Now, dividing her time between her research laboratory and her clinical work in the Pediatric Nephrology Unit, Dr. Poda-Shaked is fulfilling her dream from her school days. “The advantage of physician-researchers lies in the fact that they are directly exposed to the problems and gaps that patients face, and can take that same problem to the laboratory, look for a solution, and return with it to the patient’s bedside.”
On the other hand, physician-researchers face many challenges. They must navigate the burden of clinical tasks alongside managing the research laboratory. Furthermore, they must compete for opportunities to receive research grants with researchers who are engaged in basic research full-time. For this reason, the National Science Foundation created the prestigious 'Mabria' grant in the startup track for physician-researchers - and Dr. Poda-Shaked is among five winners selected in the first cycle. “Such opportunities to support the type of research we conduct are relatively rare, and I am grateful for the backing of the 'Mabria' grant,” notes Dr. Poda-Shaked.
A female team and the combination of home and career
“My lab is currently staffed entirely by women – a completely coincidental but inspiring result,” says Dr. Poda-Shaked. “I see my research as a mission. The goal is not only to understand new mechanisms but to be able to translate the discoveries into treatments that will truly help our patients.”
More of the topic in Hayadan:
