RNA in Sperm Could Be Biomarkers of Male Fertility

Stephen A. Krawetz, Ph.D. Associate Director C.S. Mott Center for Human Growth and Development, Charlotte B. Failing Professor of Fetal Therapy and Diagnosis, Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201MedicalResearch.com Interview with:
Stephen A. Krawetz, Ph.D.
Associate Director C.S. Mott Center for Human Growth and Development,
Charlotte B. Failing Professor of Fetal Therapy and Diagnosis,
Department of Obstetrics and Gynecology,
Center for Molecular Medicine and Genetics,
Wayne State University School of Medicine,
Detroit, MI, 48201

Medical Research: What is the background for this study? What are the main findings?

Dr. Krawetz: The current study developed over approximately the past 20 years of work in my laboratory.  In the mid 1990s, along with David Miller, we independently discovered that sperm contain RNA.  This was followed by our joint publication in The Lancet that began to describe the RNAs in normal fertile males along with our paper in Nature that showed that RNA was delivered to the oocyte at fertilization.  Following these studies we assessed the ability of RNAs to be used as markers of morphologically abnormal sperm (teratozoospermia).  My laboratory then had the opportunity to explore the complexity of the population of sperm RNAs using Next Generation Sequencing.   We recently began the translation of this work from the bench to bedside which takes us to the current paper in Science Translational Medicine that was a multi-institutional collaborative effort.  Members of the team include Dr. Meritxell Jodar, Edward Sendler, Robert Goodrich, from my laboratory, along with Dr. Clifford L. Librach, Dr. Sergey I. Moskovtsev, and Sonja Swanson – CReATe Fertility Center, University of Toronto; Dr. Russ Hauser -Harvard University and Dr. Michael P. Diamond, Georgia Regents University. Here we tackled the issue of idiopathic infertility, that is, unknown infertility, since the couple appears normal in all respects.  We specifically framed our study as the contribution of the male and female as a couple towards the birth of a healthy child focusing on male idiopathic infertility within the setting of a Reproductive Clinic.  Representative publications from my laboratory that outline this part of my research program appear below.

1)            Jodar, M., Sendler, E., Moskovtsev, S. Librach, C., Goodrich, R., Swanson, S., Hauser, R., Diamond, M. and Krawetz, S.A. (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Science Translational Medicine, 7(295):295re6.

2)            Sendler, E., Johnson, G.D., Mao, S., Goodrich, R.J., Diamond, M.P., Hauser, R., and Krawetz, S.A. (2013) Stability, Delivery and Functions of Human Sperm RNAs at Fertilization.  Nucleic Acids Research 41:4104-4117. PMID: 23471003

3)            Platts, A.E., Dix, D. J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J. C., Rawe, V.Y., Quintana, S., Diamond, M.P., Strader, L.F. and Krawetz, S.A. (2007)  Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs.  Human Molecular Genetics. 16:763-773.  PMID: 17327269

4)            Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. and Krawetz, S.A. (2004) Delivering spermatozoan RNA to the oocyte.  Nature 429:154.  PMID: 15141202

5)            Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA profiles of normal fertile men. The Lancet. 360:773-777.  PMID: 12241836

Medical Research: What are the main findings?

Dr. Krawetz: With the use of RNA-Seq (RNA sequencing) we defined a series of 648 RNA elements in a series of males from couples presenting with idiopathic infertility (both the male and female appear normal but sought reproductive care) – yet within the first spermatogenic cycle successfully conceived, resulting in the birth of a healthy child.  These RNAs correspond to exon-sized regions of the genome that we have termed elements.  Using this set of elements we were then able to identify two groups.  The first in which all the elements were present and the second in which at least one element was absent. When all the elements were present the birth of a healthy child could most often be achieved with minimal intervention.   When at least one element was absent the use of ART (Assisted Reproductive Technology) was required to achieve the birth of a healthy child.  This suggested that the elements we defined could serve as biomarkers for male fecundity.

How this may help couples trying to conceive and have a baby:

Dr. Krawetz: It is our goal to use this technology to reduce both the time to live birth of a healthy child and cost when couples seek infertility treatment so as to reduce the stress on the couple.  It is our hope that by identifying the extent of Dad’s contribution, the responsibility for setting the course for the birth of a healthy child can now be more equally shared.  Upon validation this discovery may help to identify those couples who may benefit from ART and those couples who may be successful with minimal intervention.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Krawetz: At present the test is experimental since sperm RNA analysis is technically challenging.  It is being automated so that in the next short while it may become part of a routine examination as we move towards Personalized and Precision Medicine.  The next step before we can make this test generally available is to secure the necessary funding so that we may expand this study to a prospective blinded trial.

Citation:

Jodar, E. Sendler, S. I. Moskovtsev, C. L. Librach, R. Goodrich, S. Swanson, R. Hauser, M. P. Diamond, S. A. Krawetz. Absence of sperm RNA elements correlates with idiopathic male infertility. Science Translational Medicine, 2015; 7 (295): 295re6 DOI: 10.1126/scitranslmed.aab1287

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Stephen A. Krawetz, Ph.D. (2015). RNA in Sperm Could Be Biomarkers of Male Fertility

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