Nav: Home

New method allows first look at key stage of human development, embryo implantation

May 04, 2016

Despite significant biomedical advances in recent decades, the very earliest events of human development¬--those that occur during a critical window just after fertilization--have remained an unobservable mystery, until now.

New research from scientists at The Rockefeller University shows, for the first time, molecular and cellular processes in human development that occur up to day 14 after fertilization. Published in Nature on May 4, the breakthrough system is the first in which the process of implantation has successfully been replicated in an experimental setting, outside of the uterus. This novel technique vastly expands the ability to answer basic questions about our own development, as well as to understand early pregnancy loss.

Implantation is a crucial step in human development. Occurring shortly after fertilization, implantation is the process by which the small, hollow ball of cells called a blastocyst attaches to the uterus, allowing an embryo to begin to take shape.

"This portion of human development was a complete black box," says Ali Brivanlou, Robert and Harriet Heilbrunn Professor and head of the Laboratory of Stem Cell Biology and Molecular Embryology. To shed light inside that box, the researchers overcame several key problems: they surrounded the blastocyst with just the right chemical environment, and provided a suitable scaffolding for it to attach to.

Previous research from co-author Magdalena Zernicka-Goetz and colleagues at the University of Cambridge established a similar method using mouse blastocysts, after multiple attempts to define the right combination of factors. This prompted Brivanlou and colleagues, including research associates Alessia Deglincerti and Gist Croft, research specialist Lauren Pietila, and fellow Rockefeller scientist Eric Siggia, Viola Ward Brinning and Elbert Calhoun Brinning Professor and head of the Laboratory of Theoretical Condensed Matter Physics, to adapt the technique and create an attachment culture for human embryos.

"Through this international and multidisciplinary collaboration combining mouse embryology, human embryology, and physics, we were able to create a system that properly recapitulates what happens during human implantation," says Deglincerti. One known difference between mouse and human development is the shape the blastocyst is in as implantation occurs--it is oblong in mice but shaped like a disk in humans. "We actually reproduced the disk," says Deglincerti.

Human variations

Once the system was in place, the researchers determined that the embryos displayed the landmarks characteristic of normal development, including the timing of key events that occur in early embryonic development up to 12 days after fertilization. Viewing this stage of development in such detail for the first time also uncovered some surprises.

For one thing, there were unexpected differences between the team's observations in humans and previous findings from the mouse experiments. "With this work, we can really appreciate the differences between human and mouse, and across all mammals," says Brivanlou. "Because of the variations between species, what we learn in model systems is not necessarily relevant to our own development, and these results provide crucial information we couldn't learn elsewhere."

Also unexpected was a phenomenon they observed known as self-organization. In simple terms, self-organization is when parts of a system become ordered without any outside influence, and it is seen across both living and non-living systems. One example is the formation of a snowflake, where independent water molecules get together in symmetrical shapes and forms with no external force. On a larger scale, self-organization is a factor in the formation of galaxies and cosmos.

"We had seen self-organization using this system in the mouse embryo, and also in human embryonic stem cells, but we did not anticipate we'd see self-organization in the context of a whole human embryo," says Brivanlou. "Amazingly, at least up to the first 12 days, development occurred normally in our system in the complete absence of maternal input."

The scientists originally hypothesized that implantation induced molecular crosstalk necessary for development. They continue to believe this dialogue happens, but their findings indicate that this is not required up to day 12.

Implications for infertility and beyond

In addition to insights into molecular details of this process, the findings from Brivanlou and colleagues have several clinical implications. In the near future, the ability to study implantation in culture is likely to shed light on why some early miscarriages occur and why in vitro fertilization has a high failure rate.

Over the longer term, the work could advance the treatment of a variety of diseases with human embryonic stem cells. "In order for that approach to be effective, we have to understand where these cells are coming from, and what decisions they've made and are about to make at the molecular level," Croft says. "Only with that knowledge, specifically from human cells, can we control their ability to become cell types that are useful for drug screening or transplantation."

Perhaps most importantly, this new method opens the door to a wide variety of studies, never before possible, on the molecular events that occur during the very earliest stages of human development.

"We're going to take a step back to the first day and systematically move forward," says Brivanlou. "We'd like to get the complete molecular signature, and then move on to how these cells communicate with one another to figure out what cell type they are supposed to become. There is a lot more to be studied during this stage and we look forward to shedding more light on this vital step in human development."

Embryonic ethics

In accordance with internationally recognized bioethical guidelines, the group's experiments were concluded on day 14 post-fertilization, well before even the earliest signs of nervous system development are observed.

An accompanying Nature commentary, however, suggests that the current 14-day limitation should be reappraised. Rockefeller's Amy Wilkerson, corresponding author Insoo Hyun of Case Western Reserve University School of Medicine, and Josephine Johnston of the Hastings Center argue that it is crucial to understand how the guideline applies to different types of embryo research in different jurisdictions and to re-evaluate its pros and cons.

"Now that it has become possible to culture human embryos to the 14-day limit and perhaps beyond, the time is right for the scientific community to educate the public about the potential benefits and to work with regulators on ethical consensus to guide this important research," says Wilkerson, associate vice president of research support at Rockefeller.

While Brivanlou plans to focus on understanding initial implantation in more detail in the near term, the commentary authors suggest that revisiting the 14-day rule in a way that can both support research and accommodate diverse moral concerns could allow scientists to model additional aspects of early human development, and potentially shed light on the disorders that result in early pregnancy losses and birth defects.
About The Rockefeller University

The Rockefeller University is the world's leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 79 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world's most revolutionary and transformative contributions to biology and medicine. During Rockefeller's 115-year history, 24 of our scientists have won Nobel Prizes, 21 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States.

Rockefeller University

Related Fertilization Articles:

Male infertility research reveals how a new life begins
Research into a genetic mutation causing some men to be infertile shows that an important protein in the sperm that is a key component of the egg fertilization process, known as phospholipase C zeta (PLC-zeta), is ineffective in these individuals.
Research aims to improve In vitro fertilization success rates
An Simon Fraser University engineering scientist is working with the Pacific Centre for Reproductive Medicine (PCRM) to develop machine vision software that could help improve fertility treatments.
What happens in the cell nucleus after fertilization
A team of scientists at the Helmholtz Zentrum M√ľnchen shows changes in the immediate environment of DNA after the ovum and sperm fuse to form the zygote.
Uterine microbiota play a key role in implantation and pregnancy success in in vitro fertilization
Endometrial microbiota (bacteria in the uterine cavity) play an important role in determining whether women are able to get pregnant via in vitro fertilization (IVF), according to a new study published in the American Journal of Obstetrics and Gynecology.
Future increase in plant photosynthesis revealed by seasonal carbon dioxide cycle
Doubling of the carbon dioxide concentration will cause global plant photosynthesis to increase by about one-third, according to a paper published in the journal Nature.
Female fish can favor sperm from preferred males despite external fertilization
Biologists studying a small, colorful fish in the Mediterranean Sea have discovered a new way in which a female can choose the best father for her offspring.
New findings and research methods leading to elucidation of fertilization mechanism
A Japanese research group has determined the crystal structure of the JUNO protein, an egg surface protein essential for fertilization.
Iron fertilization won't work in much of Pacific, says study
Over the past half-million years, the equatorial Pacific Ocean has seen five spikes in the amount of iron-laden dust blown in from the continents.
BPA determined to have adverse effects on couples seeking in vitro fertilization
Exposure to Bisphenol-A (BPA) may lead to reduced quality of embryos during reproduction.
Carbon dioxide fertilization greening Earth, study finds
From a quarter to half of Earth's vegetated lands has shown significant greening over the last 35 years largely due to rising levels of atmospheric carbon dioxide, according to a new study published in the journal Nature Climate Change on April 25.

Related Fertilization Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".