Sudhansu K. Dey, Ph.D., is the Lova Riekert Chair and Professor of Pediatrics at the University of Cincinnati, and director of the Division of Reproductive Sciences at Cincinnati Children’s Hospital Medical Center. The former director of the Division of Reproductive and Developmental Biology at Vanderbilt University Medical Center (he moved to Cincinnati in July 2008), Dey received the 2008 Carl G. Hartman Award from the Society for the Study of Reproduction for his creative and significant contributions to the field.
After receiving his doctorate in physiology from the University of Calcutta, Dey completed his postdoctoral work in reproductive biology at the University of Kansas. He was a member of the faculty there for nearly 30 years before coming to Vanderbilt in 2002. Recently, he shared his thoughts about the importance of developmental biology in understanding human disease, and challenges to the scientific enterprise in the United States.
What do you consider to be your most important scientific contributions to date?
The most significant contribution from our group is the establishment of a novel concept that during early pregnancy, a short delay in the attachment of the embryo to the wall of the womb adversely affects later developmental processes leading to defective feto-placental growth and poor pregnancy outcome.
The state of uterine receptivity, also termed the window of implantation, lasts for a limited period, and it is only during this time that the womb is conducive to support normal embryonic growth. Therefore, the quality of implantation determines the quality of pregnancy and fetal well-being; failure to achieve on-time implantation is a risk factor for an adverse pregnancy outcome.
The birth of this concept is the result of a series of genetic and molecular studies that used genetically engineered mouse models.
Why is developmental biology critical for understanding human disease?
There is emerging evidence for an association between early development and the onset of diseases such as coronary and heart diseases, obesity and diabetes and osteoporosis in adult life. The quality of pregnancy is a critical factor, since subtle changes during in utero fetal life can have profound consequences later in life.
Early onset of intrauterine growth restriction, recurrent abortion, preeclampsia (a hypertensive disorder of pregnancy) and preterm delivery are important developmental and reproductive health issues, and are associated with uterine and placental deficiencies. A transient postponement of blastocyst attachment in mice produces detrimental ripple effects throughout pregnancy, indicating that one cause of these end results is defective implantation.
Understanding preimplantation embryo development, implantation of embryos in the uterus, postimplantation embryonic growth and how the placenta forms also will advance our knowledge in several basic physiological processes.
These include: paracrine and juxtacrine epithelial–epithelial interactions and epithelial–mesenchymal-extracellular matrix interactions, involving cell migration and invasion, the formation of blood vessels from bone marrow-derived precursor cells (vasculogenesis) and from pre-existing vessels (angiogenesis), and vascular permeability, as well as regulated growth (proliferation, differentiation, polyploidy and apoptosis).
These processes involve numerous signaling pathways that are common to many other systems under either normal or pathological conditions. For example, many of the characteristics and signaling pathways that are operative during early development are also active during tumorigenesis—the difference being that tight regulation occurs during pregnancy, while dysregulation of the same pathways occurs in tumorigenesis.
Another interesting area of research is the similarities in plasticity of both multipotent tumor cells and embryonic stem cells (ES). Both these cell types are profoundly influenced by bi-directional microenvironment for expressing specific phenotypes and are amenable to reprogramming. Therefore, understanding the intricacies of early development might help to better understand the complexities of tumorigenesis, and might one day reveal that “life and death are linked by a common thread.”
What are some of the challenges to making further progress?
The entire research enterprise in the United States is at a crossroad.
On the one hand, enormous technological advances have set the stage for ground-breaking discoveries, but on the other hand, dwindling federal research dollars for basic research make it difficult for scientists to take advantage of this opportunity.
In addition, federal, state and institutional bureaucratic regulatory burdens (for example, compliance with animal protocols and institutional review boards) are creating a tremendous stress on investigators and raising the levels of despair and frustration in them, resulting in reduced scientific innovation and productivity. Investigators are spending more and more time in writing and rewriting grants and addressing and untangling bureaucratic red tape.
Like adding salt to the injury, increases in research costs are passed on to investigators by institutional leadership in the face of shrinking federal research dollars provided through the National Institutes of Health (NIH). Investigators, especially junior and mid-career scientists, are increasingly worried that they will be unable to put bread and butter on the table for their families if they fail to receive grants that provide a major portion of their salaries.
These are not the only challenges the scientists are now facing. Federal restrictions on human stem cell research in the United States are also hindering progress in a field that has enormous clinical applications in regenerative medicine and correcting genetic errors that lead to various diseases.
Scientists here and in Japan have circumvented some of these obstacles by creating induced pluripotent stem (iPS) cells in mice and humans through the ectopic expression of four transcription factor genes (Oct4, Sox-2, Klf4 and Myc) in non-embryonic cells. While this is a huge breakthrough in the field, iPS cells must be compared alongside with human embryonic stem cells to determine their utility as true pluripotent cells.
The unwillingness of the U.S. government to allow the expansion of the repertoire of human stem cell lines is having dire consequences on stem cell research and it is driving prominent scientists to pursue their work outside the country.
There is a move by the Center for Scientific Review at the NIH to reorganize the peer review process to reduce the length of grant applications, to ensure high-quality review by experienced reviewers and a quick turn-around time of reviews for new investigators, and to provide an open deadline for submitting grants by reviewers. All of the changes that are being implemented or planned to be implemented have good intentions.
While some of the changes will be welcomed by the investigators, if the funding situation does not significantly improve, we scientists can be listed as an endangered species. This is a very difficult time for the entire research enterprise in the United States, and we — meaning the government, general public, scientists and their institutional leadership — must work together to address these issues.
What is the responsibility of the scientist to speak up, to challenge government policies and society itself?
The scientific community should forcefully articulate the problems to the leadership at the institutional, state and federal levels without any reservation. The scientific societies should follow the same suit which they do by lobbying to Washington. These are good practices, but often do not meet with success.
What we need is a “million scientists march” to Washington involving scientists, educators, graduate students, postdoctoral fellows, research personnel, people from biotech and pharmaceutical companies, and citizens who care for scientific discoveries that improve health and mankind. This approach may educate the society at large, draw the attention of decision-making bodies and raise the stature of scientific research and the benefits society reaps from it.
The NIH Roadmap and its emphasis on big science and translational research are good concepts, but these concepts should only be pursued if Washington appropriates separate funding to NIH for these purposes, not at the cost of investigator initiated basic science research projects. Otherwise, we may lose a generation of young and mid-career investigators.
As Judith Bond, Ph.D., former president of the American Society for Biochemistry and Molecular Biology, wrote in 2006: “Funding strategies must provide opportunities for exploring new ideas, taking advantage of an unexpected finding or serendipitous discovery. There is no single path to discovery, problem-solving and knowledge creation.”
Is the preeminence of U.S. science being threatened by the “globalization” of biomedical research?
Surely, the current bureaucratic regulatory burdens and dwindling funding environment in the United States have created a great deal of anxiety in the scientific community. Our preeminence in scientific leadership is being threatened by increasing research investments in Europe, Japan, China, India, Singapore and South Korea. This rise in research growth in other countries will boost the U.S. scientific enterprise only if we embrace and partner with them from our strengths, not from our weaknesses.
If we increase our investments in science and take our research to a new level, then scientific interactions and exchanges will bring benefits globally to humankind. In failing to do so, we will face a reverse brain drain, meaning that U.S. scientists will relocate their research programs in those countries.
This has already started. Several U.S. scientists have relocated their programs in other countries, and many foreign-born scientists who settled in the United States for the quest of science are now returning to their home countries to further their scientific pursuits. The scientific environment here is becoming less attractive to them. The situation is likely to get worse, since fewer U.S. students are interested in pursuing a science career. There should be an all-out effort at the national and local levels to combat this deteriorating situation.
What must we do to protect and nurture quality science in this country?
If we want to maintain our leadership position in science and technology, there has to be a radical change in our culture at all levels. There has to be an infusion of resources for pursuing careers in science and to convince our young generation that pursuit of science is noble and serves humankind.
We need to see substantial increases in federal funding to stop further erosion within the scientific community. There are now remarkable opportunities to establish scientific exchange programs with other countries which are substantially investing on science and technology.
Does the United States have a responsibility to aid the scientific enterprise in developing countries?
Absolutely. One major objective of scientific discoveries is to fulfill human needs and curiosity. Everyone in the world should have that privilege and opportunity, especially in these days of globalization. The only way this objective can be fully realized is if the developing countries also engage in scientific pursuits, but they will, of course, require help from other advanced countries.
Where will we be in 10 or 20 years in our ability to understand human health, and intervene to treat or prevent disease?
My guess is that molecular and personalized medicine will take center stage. There will be significant advances in our understanding of the genetic and epigenetic causes of human diseases, such as cancer, Alzheimer’s, Parkinson’s, diabetes, obesity and infectious diseases like HIV. The success of these research initiatives will, however, depend upon the national investment in basic sciences.
What advice do you have for the young person who is considering a career in science?
Have dreams and passion for knowing the unknown. It should be made clear that doing research is not a glamorous profession or hobby, it is a passion.
Upon taking office as president of the American Society for Cell Biology in 1997, Mina Bissell, Ph.D., said, “If biomedical research is truly what you want to do, then you must be willing to pay the price … It takes time, patience, stubbornness, years and years of seven-day weeks and 18-hour days, years of poverty-level wages, predictions of doom and failure, rejections of papers and grants, depression and self-doubt … But one persists. One continues because this is what one must do. This is what you want to do.”
The passion for research needs to be seeded when students enter high school and college. It should be made clear that the pursuit of scientific research is only for those who are truly dedicated to this endeavor. The students should be reminded that the pursuit of science is a wonderful world if you love it.
Of course, there must be in place the resources and infrastructure to nurture the dreams, imagination and passion in young men and women who are considering careers in science.