Eeva™ The Science Behind Eeva
The science behind Eeva came from groundbreaking research conducted at Stanford University and published in the highly regarded scientific journal Nature Biotechnology (October 2010). The renowned team of researchers systematically measured 3 distinct time periods in early human development and were able to predict on day 2 which embryos would continue development through day 5 (blastocyst) with a high degree of accuracy.
Auxogyn has developed the Eeva system for time-lapse imaging along with uniquely intelligent Eeva software that automatically analyzes embryo development against these scientifically and clinically validated cell-division time periods. Eeva’s software not only provides novel quantitative information, but it ensures consistent measurements to assess embryo development versus the manual methods used today in IVF clinical practice.
Auxogyn recently completed a multi-center, 160-patient clinical trial to validate the safety and efficacy of Eeva. The results showed that Eeva is safe and can predict an embryo’s ability to develop into a blastocyst. These results and other supporting data from the study have been used for regulatory filings in Europe and the United States.
Understanding Embryo Development
The Stanford University research team of biologists, engineers and clinical embryologists took a multidisciplinary approach to address a very specific goal: finding non-invasive markers that would enable IVF clinicians to identify viable embryos early. The team combined time-lapse microscope imaging and molecular biology techniques to study an expansive number of (spare) human embryos cultured from the Day 1 pronucleus stage to the Day 5 blastocyst stage. The blastocyst stage is a key indicator of a viable embryo2.
Examining a wide range of potential non-invasive markers - and using gene expression data to assess embryo viability - it became clear that those with the greatest predictive power were the measures of time it took each embryo to achieve specific cell development milestones during the first 2 days after fertilization in vitro.
Normal embryos followed precise patterns of cell division timing in: (1) the duration of first cytokinesis (i.e. the time from when the 1st cell division starts, to when it completes), (2) the time interval between cytokinesis 1 and cytokinesis 2 (i.e. the time from the 2-cell to 3-cell stage), and (3) the time interval between cytokinesis 2 and cytokinesis 3 (i.e. the time from the 3-cell to 4-cell stage). Overall, the remarkable discovery signified that these precise cell division timing parameters could non-invasively predict by Day 2 which embryos would become viable blastocysts.
Embryonic Gene Expression
An essential and unique component of the research was the correlation of imaged embryos with their patterns of gene expression. Genes are collections of DNA that carry instructions for making proteins and other functional molecules of a cell. The transition of a fertilized egg to an embryo is controlled by specific Maternal gene expression patterns from the mother, and specific Embryonic gene expression patterns from the embryo. Gene patterns thus indicate the “molecular health” of the embryo, including how well an embryo is producing the gene products it needs to properly develop and thrive.
Importantly, the gene expression patterns of embryos that followed precise cell division timing parameters were discovered to be distinctly different from the gene expression patterns of embryos that followed abnormal cell division times. Further, gene expression for normal embryos was consistent with the expected levels and timing of Maternal and Embryonic gene expression of in vitro fertilized embryos.
These results, together with additional findings described in the Stanford research (Wong et al1), provided the first link between embryo developmental outcome, cell division events, and the molecular health of the embryos. In addition, since precise cell division timing parameters can predict the health of the embryo as early as Day 2, embryos can be cultured for fewer days in the laboratory and transferred back to the patient prior to Embryonic Genome Activation (when embryo genes turn ‘on’).
Cell Tracking and Prediction Software
Finally, the research developed uniquely intelligent software to automatically analyze embryo development against the scientifically validated cell division time periods. The software not only provided novel quantitative information, but ensured consistent and reliable measurements to assess embryo development versus the manual methods used today in IVF clinical practice.
Bringing Eeva’s Science to the Clinic
Auxogyn and its academic founders discovered fundamental in vitro properties of the human embryo that are important for its further development. Eeva™ harnesses these new biological insights and combines them with advanced software technology to provide clinicians with quantitative information to make informed decisions regarding embryo transfer and treatment path.
Auxogyn was launched in May 2010 with the sole purpose of advancing the field of reproductive health through its uniquely-combined knowledge of early human developmental biology, advanced computer vision technology and best clinical practices in order to make this ground breaking science and technology available to IVF clinicians and patients around the world. With an exclusive license to the patented predictive technology from Stanford, Auxogyn has developed the Eeva™ Test and supporting laboratory system. To ensure the highest quality of product, Auxogyn is committed to rigorous clinical and regulatory validation. In a multi-center, prospective clinical trial of 160 patients with approximately 1,800 embryos,3 Eeva was found to:
- Predict blastocyst formation at cleavage stage with 85% specificity
- Of all the arrested embryos, Eeva predicted 85%, whereas standard morphology predicted 57%
- This means that Eeva reduced the false-positive rate from 43% to 15%
- Increase consistency of embryo assessment across embryologists
Additional scientific and clinical research studies are underway to further the advancement of non-invasive markers which will provide IVF clinicians and their patients with quantifiable information about the health of their embryos. The continuing goal of Auxogyn’s research is to improve fundamental understanding of early in vitro human development and provide sound scientific and clinical evidence to positively impact clinical care in reproductive health.
1. Wong et al, “Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.” Nature Biotechnology, Vol 28, Issue 10, October 2010.
2. Diamond et al, “The clinical need for a method of identification of embryos destined to become a blastocyst in assisted reproductive technology cycles” Journal of Assisted Reproduction & Genetics, 2012 Mar 18 [Epub].
3. Data on file at Auxogyn, Inc.
The role of time-lapse microscopy in stem cell research and therapy
Kevin E. Loewke and Renee A. Reijo Pera, Stem Cells & Regenerative Medicine: From Molecule Embryology to Tissue Engineering, Humana Press, 2010.
Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage
Connie C. Wong, Kevin E. Loewke, Nancy L. Bossert, Barry Behr, Christopher J De Jonge, Thomas M. Baer and Renee A. Reijo Pera, Nature Biotechnology, 2010 Oct; 28(10):1115-21.
The clinical need for a method of identification of embryos destined to become a blastocyst in assisted reproductive technology cycles
Michael P. Diamond, Susan Willman, Philip Chenette and Marcelle I. Cedars, Journal of Assisted Reproduction & Genetics, 2012 Mar 18. [Epub ahead of print]
Human pre-implantation embryo development
Kathy K. Niakan, Jinnuo Han, Roger A. Pedersen, Carlos Simon and Renee A. Riejo Pera, Development, 2012 Mar; 139(5):829-41.
A New Way to Predict IVF Success: Film the Embryo
Alice Park, TIME Magazine, 2010 Oct 4.
Timing is everything in the human embryo
A.A. Kiessling, Nature Biotechnology, 2010 Oct 13.