Re-Engineering
the Nuclear Family


April 2014

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Just in time for Mother’s Day, there’s a new assisted reproduction technique in the wings that could help thousands of would-be mothers protect their babies from the risk of inherited disease. It also changes the math of the traditional nuclear family unit by bringing a third parent into the genetic equation. 

The method, developed by researchers at Oregon Health & Science University (OHSU, Portland, Ore.), is hailed as a promising breakthrough in the prevention of a number of life-threatening conditions passed from mother to child through mutations in cell mitochondria. Thousands of babies born each year inherit this exclusively maternal legacy. Abnormalities in mitochondria are linked to pediatric mortality and at least 150 diseases including autism, cardiovascular disease, developmental disorders, diabetes, muscular dystrophy, and Parkinson’s disease. There are no cures for the individual diseases, but scientists believe the new method could eliminate their common cause.

Lead scientist Shoukhrat Mitalipov, Ph.D., says he uses a sophisticated method of cellular surgery called spindle transfer to produce a healthy egg cell (oocyte) that contains the mother’s cell nucleus and mutation-free mitochondria from a donor egg. It’s essentially a matter of extracting the nuclei from both eggs and introducing the mother’s nucleus into the enucleated cell body of the donor egg. Once the reconstructed oocyte has fused, it can be fertilized and implanted in the mother as in a traditional assisted reproductive process.

Although the reconstructed egg contains genetic material from a third parent, Mitalipov says the method does not alter the traits a child inherits from its biological parents. More than 99% of our genetic code is found in the cell nucleus, so the mother’s code remains intact. Mitochondria have 37 genes of their own, but are involved only in the core duties of cell division and metabolism – not in determining features like eye color. As evidence he points to his successful use of the technique in two global firsts – the conception of two healthy monkeys in 2009 and in the creation of normal human egg cells in 2012.  

Spindle transfer creates a third option for couples struggling with mitochondrial risk factors. Many couples happily choose adoption. Others are willing to accept the consequences of having an at-risk biological child. There is no one-size-fits-all solution, but the Mitalipov method adds the choice of conceiving a baby that is free of inherited disease risk but still carries more than 99% of the parents’ genetic information.

The process of spindle transfer, with a mother's nucleus being introduced into a donor's mitochondria. Image: OHSU

Under the Microscope

The spindle transfer process is microsurgery on the smallest conceivable scale with the least possible margin for error. It requires customized apparatus including a high-contrast microscopy and visualization system, laser-assisted cell-handling tools, and a significant level of manual speed and precision.

The Mitalipov approach is less invasive than the traditional method of chromosome transfer, where researchers jab a micropipette tip into the cell and snatch the genetic material. The standard protocol involves pretreatment of the egg with a fluorescent dye that reveals the locations of chromosomes when exposed to UV light. He speculates that either or both of those factors could limit the success rate when working with primate oocytes.

His alternative set-up is built around a specialized imaging system (Oosight, PerkinElmer, Danvers, MA) that zeroes in on genetic material without exogenous tags or dyes. The system enables high-contrast quantitative imaging, providing live and still images of structures of interest within the egg and measurements that reveal important changes during the process. 

Mother and donor cells in the process of fusing together into a regenerated egg. Image: OHSU

 

 

 

Another critical device is a laser-assisted drill (HamiltonThorne, Beverley MA) that bores a precise opening in the protective membrane of the cell wall. Together the instruments help scientists stabilize the structure while a worker inserts a pipette through the bore drilled hole to locate and aspirate the cell nucleus. According to team member Masahito Tachibana, Ph.D., the laser drilling method allows the user to exert less physical force on the pipette while penetrating the cell wall, and that makes it easier to focus on the location of the genetic material, and to work faster.

In the News

Now that Mitalipov has shown the method can work with human eggs, the next step is to secure approval to run complete clinical studies in human volunteers. There are many questions remaining before the therapy could be considered for routine use, and clinical trials are the only way to answer them. U.S. and British regulators are publicly reviewing the question, and the U.S. FDA’s recent public hearings drew testimony from bioethicists decrying the risks of three-parent babies. Some expressed concerns about the potential for new mutations to enter the human gene pool. Others warned of a potential step toward a future of designer babies and unstoppable clone armies. Still others claimed the technique is unnecessary because affected women have the option of adoption.

“We believe a public discussion is a healthy part of this process,” Mitalipov says. He asserts that his only interest is in creating a therapy that breaks the cycle of inherited diseases, and that mitochondrial DNA does not lend itself to the dark side of genetic engineering. “Our continuing work and discoveries can be revolutionary in how we cure and treat many diseases and illnesses,” he says. “We are ready to move forward to clinical trials with this procedure. We are ready to offer new hope to the thousands of families whose lives have been shaken by the tragic effects of these mutations.”

Michael MacRae is an independent writer.

We are ready to offer new hope to the thousands of families whose lives have been shaken by the tragic effects of these mutations.

Shoukhrat Mitalipov,
Lead Scientist, OHSU

 
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