How to make a ‘three-parent’ baby | Science News for Students

How to make a ‘three-parent’ baby

Scientists combined an egg, sperm and some donor DNA to create a baby
Feb 21, 2017 — 7:10 am EST
Zhang baby

Fertility doctor John Zhang holds a baby boy (whose face has been blurred for privacy). The boy is the world’s first child created by spindle transfer —  a technique to replace faulty mitochondria. Such children have been dubbed “three-parent” babies.

 New Hope Fertility Center

A baby born in April 2016 may have opened the door to a new world of reproductive medicine. This boy became one of the first intentional “three-parent” babies. The vast majority of this boy’s DNA came from his mother and his father. A small bit of extra DNA came from an unrelated woman. This child got some of his genetic inheritance from each of these adults.

Because of that bonus DNA from the unrelated woman, some people say babies like this boy have three parents.

Scientists didn’t go to all of the effort to mix the DNA from these three people as an experiment. In fact, they did it to overcome a problem in the boy’s mother. That woman had a problem with her mitochondria (MY-toh-KON-dree-uh). These are important little structures — or organelles — present in her cells.

Many cells, including those that make up humans, contain special components that function like little organs. That gives rise to their name, organelles, which actually means little organs. Organelles perform special tasks for their parent cells. And one of the more notable of these organelles is the mitochondrion. Its main job is to help power its cell. To do this, the mitochondria harvest energy contained in the bonds linking atoms in the cell’s fuel (such as glucose). Mitochondria then use that energy to create another molecule, known as ATP (for adenosine triphosphate). That ATP actually serves as the energy source for cells.

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animal cell diagram
Mitochondria, one of several types of organelles found within the cytoplasm of a cell, contain a small amount of DNA. A mutation in that DNA can cause disease.

But some of the mitochondria in the boy’s mother have a mutation. That genetic alteration causes Leigh syndrome, a fatal disorder. Most of her mitochondria work properly. That's why the mom does not have the killer disease. But she can pass on DNA from the faulty mitochondria to her children. And this can put them at risk of Leigh syndrome. Two of her children had already died from the disease. She also had suffered four miscarriages.

It was in hopes of giving this couple a healthy baby that doctors worked to find healthy mitochondria to substitute for her unhealthy ones. Normally, a woman passes on her mitochondria to her offspring through her egg (dad’s sperm don’t contribute any). These organelles also contain a small amount of DNA — just 37 genes. (Most of the roughly 20,000 protein-producing genes needed to make a human are stored in a compartment called the nucleus.) Mutations in some mitochondrial genes most often pose a risk to organs that need lots of energy, such as the brain and muscles. There is no cure or effective treatment for many of these mitochondrial diseases.

The technique used to create the baby boy is new and controversial. His birth, though, caps nearly three decades of work to to produce healthy human eggs by manipulating the organelle. The new baby appears to have been saved from a deadly genetic disease. Still, there are ethical and safety concerns about his three-parent heritage.

And a three-parent baby girl born in January raises even more concerns — in part, just because she is a girl.

Producing healthy babies

Researchers first began swapping mitochondria between egg cells to treat infertility problems almost 20 years ago. Jacques Cohen was one of those researchers.

He’s a scientist who studies human embryos. In the late 1990s, he and colleagues at Saint Barnabas Medical Center in Livingston, N.J., were looking for a way to help women who were unable to have children by in vitro fertilization. Also known as IVF, this process involves taking egg cells from a woman and sperm cells from a man, then incubating them in a dish. Some of those eggs and sperm will combine to form embryos — the first stages of creating a new individual.

human embryo
With in vitro fertilization, or IVF, an embryo that developed in a laboratory dish is transferred into a woman’s womb where it may develop into a baby.

Doctors then transfer some of those embryos into the woman’s womb. With luck, one or more will develop into a baby. But some couples’ embryos never developed normally. No one knows why. Cohen’s group thought a dose of cytoplasm — the jellylike “guts” of a cell — from a donor egg might give the implanted embryos a better shot at success.

“Cytoplasm is the most complicated fluid in the universe,” says Cohen. It contains mitochondria, other organelles, proteins and other molecules that do the work of the cell. The mother's egg normally supplies all the goodies an embryo needs to live for the first few steps of development.  But Cohen thought that some of his patient’s eggs might need extra help.

So he extracted 10 to 15 percent of the cytoplasm from an egg donated by another woman. He injected this along with a single sperm cell into a recipient egg. From 1996 to 2001, he performed the procedure 37 times. And this technique proved quite successful. It produced 17 babies for 13 couples!

Cohen later tested eight of the children born this way. Two carried some mitochondria that had come from the donor. That was in addition to some that came from the child’s actual mother. Some of the other six children may have had donor mitochondria at levels too low for his tests to  see back then, Cohen now says. But the finding made him curious.

So Cohen and his colleagues tracked down 13 of the 17 children. All were now teenagers. In surveys, their parents said that the kids seemed basically healthy. Cohen doesn’t know whether mitochondria or other parts of the cytoplasm played a role in producing the children. His group stopped performing the technique in 2001 (because of regulatory issues).

Fixing mitochondria

Other scientists have also tried to replace faulty mitochondria more intentionally. The first such attempt in 1983. And it involved mice.

Pronuclei are the central, DNA-containing parts of fertilized eggs. One comes from the egg and another comes from dad’s sperm. At this early stage in development, the two have not yet fused into a single nucleus. (Nuclei is the plural form of nucleus.)

In a technique known as pronuclear transfer, researchers fertilized the mother mouse’s egg and a donor egg at the same time. The pronuclei were removed from the donor's fertilized egg and discarded. Those from the mother’s fertilized egg were sucked out and then injected into the empty donor egg.

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Pronuclear transfer

pronuclear transfer
Pronuclear transfer was the first technique that scientists tried in their attempts to keep diseases due to faulty mitochondria from being passed from a mother to her child.
T. Tibbitts; Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception, Human Fertilisation and Embryology Authority, June 2014

Talk of applying this technique in humans promptly raised a few concerns.

Some people claimed that it is not ethical. They argued that it manipulates — maybe even destroys — two embryos.

That’s one issue. Scientists have a more technical one. They note that mitochondria tend to glom onto the nuclei. So unacceptably high numbers of mitochondria from the mother’s egg — including disease-carrying ones — may still find their way into the donor egg, notes Shoukhrat Mitalipov. He is a mitochondrial biologist at Oregon Health & Science University in Portland.

Last June, scientists reported they had refined pronuclear transfer to reduce the number of disease-carrying mitochondria that could enter embryos. Fewer than 2 percent of the mitochondria from the mother’s egg made it into the donor’s egg. But an earlier study suggested that even a half that amount might be dangerous. That’s because mutant mitochondria may copy themselves. Eventually, they might take over the cell and cripple its energy production.

Fertility clinics in the United Kingdom are allowed to use pronuclear transfer to make human babies where there was a high risk of mitochondrial diseases. In fact, none has done so. yet New York fertility doctor John Zhang is involved in the new baby boy’s case. He tried the pronuclear-transfer technique with colleagues at Sun-Yat Sen University of Medical Science in Guangzhou, China. That was more than 10 years ago. Five embryos that were made this way were implanted into a 30-year-old woman. Three grew into fetuses. None, however, survived to birth. Zhang published these results last year in Reproductive Biomedicine Online.

In January 2017, doctors in Ukraine announced that a baby girl was born from this method. Her parents had tried IVF.  But, like Cohen’s patients, the couple’s fertilized eggs never grew into an embryo that could be implanted. Instead of adding cytoplasm from a donor egg as Cohen had, fertility doctor Valery Zukin at the Nadiya Clinic in Kiev instead used pronuclear transfer. And they report success — a baby girl. 

Labs in Ukraine and Germany confirmed that most of the baby’s DNA is from her mother and father. Only her mitochondrial DNA comes from an egg donor. Zukin used the same technique again. Another couple is now expecting a baby boy next month.

Some people are concerned that these babies might have health problems later. Some people also may see this as an ethical problem. Why? The technique was not used to prevent mitochondrial diseases, but instead as a type of fertility treatment.

Marcy Darnovsky is one of the critics. She is executive director of the Center for Genetics and Society in Berkeley, Calif. Doctors such as Zukin are selling unproven and possibly dangerous services to customers, she charges. “This is the ugly face of commercial and status incentives driving unscientific human experimentation,” she said in statement about the baby girl’s birth.

Dividing cells

Doctors used a different technique — spindle transfer — to produce the baby boy born last April. The body’s genes reside in the DNA found in the body’s 46 different chromosomes. When a cell divides to create egg or sperm cells, it splits those 46 chromosomes into two equal sets of 23. To get portioned out properly, those chromosomes attach themselves to protein fibers. Those fibers are known as spindles. The new transplant technique gets its name from those fibers.

The technique starts with two unfertilized egg cells. One comes from the mother and the other from a donor. In both cells, a membrane surrounding the nucleus has broken down. The spindle in each has not, however, completed a separation of the chromosomes.

Researchers remove the spindle and its attached chromosomes from the donor egg and discard them. Then they do the same to the mother’s egg — except that they keep her spindle and chromosomes. These they inject into the donor’s nearly empty egg. Then the researchers add the dad’s sperm cell into this egg to fertilize it.

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Spindle transfer

spindle transfer
The three-parent baby boy born last year was created using a this technique, called spindle transfer.
T. Tibbitts; Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception, Human Fertilisation and Embryology Authority, June 2014

Mitalipov in Portland pioneered spindle transfer. In 2009 he showed that he could produce healthy baby monkeys with it. Those experiments showed that fewer of the mom’s mitochondria made it into the donor egg than with pronuclear transfer. Typically, the carryover amounted to 1 percent or less.

But Mitalipov would like to do even better. “This 1 percent is haunting us,” he says.

Spindle transfer has another possible downside: Chromosomes may fall off the spindle. That could result in an embryo with too few chromosomes — or too many if some are left in the egg from the donor. Both cases usually result in abnormal development. Of the five embryos on which Zhang performed spindle transfer, only one developed normally. That was the baby boy born last April.

Tests reportedly found that he has 1 percent of his mom’s mitochondrial DNA. At 3 months old, he appeared healthy. What his health will look like, long-term, however, is unknown. Besides the risk of even trace levels of mitochondria ballooning, another study suggests that the child’s health, over time, might be affected by mismatches between the parents’ nuclear DNA (which is not from mitochondria) and the donor’s mitochondrial DNA.

A controversial birth

Some researchers take issue with the moniker “three-parent” baby. Cohen, for one, says the term is wrong. Mitochondrial DNA does not contribute to a person’s traits. So, he argues, the person who donates mitochondrial DNA is hardly a "parent."

Andrew R. La Barbera agrees. He is chief scientific officer of the American Society for Reproductive Medicine. “A person’s essence as a human being comes from their nuclear genetic material,” he says, “not their mitochondrial genetic material." So children conceived using mitochondrial transfer have just two parents, he maintains.

But there are bigger controversies here than what makes a parent. Opponents of these techniques worry that none has been fully tested.

Darnovsky says, “We wish the baby and family well, and hope the baby stays healthy.” But until these techniques are shown to be safe, she says, “I have a lot of concerns about this child and about future efforts to use these techniques.”

Zhang also drew fire for going to Mexico to perform the procedure. In America, researchers are banned from doing things that could alter human DNA in a way that can be passed from generation to generation. Spindle and pronuclear transfer both do this. The worry is that genetic changes of future generations won’t stop with preventing diseases. Policy makers wanted to outlaw efforts to make genetically enhanced “designer babies.”

However, a panel of experts said in February 2016 that it is ethical to make three-parent baby boys. But not girls. Why? Fathers almost never pass mitochondria on to their babies. So baby boys born through such techniques should never pass along the donor’s mitochondria.

A baby girl, though? That would be a very different story.

Power Words

(more about Power Words)

adenosine triphosphate (ATP)     This is a molecule that cells make to power almost all of their activities. Cells use oxygen and simple sugars to create this molecule, the main source of their energy. The small structures in cells that carry out this energy-storing process are known as mitochondria. Like a battery, ATP stores a bit of usable energy. Once the cell uses it up, mitochondria must recharge the cell by making more ATP using energy harvested from the cell’s nutrients.

biomedicine     The field of research that explores the biological basis of injuries or disease and their treatments.

cell     The smallest structural and functional unit of an organism. Typically too small to see with the naked eye, it consists of watery fluid surrounded by a membrane or wall. Animals are made of anywhere from thousands to trillions of cells, depending on their size. Some organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

chromosome     A single threadlike piece of coiled DNA found in a cell’s nucleus. A chromosome is generally X-shaped in animals and plants. Some segments of DNA in a chromosome are genes. Other segments of DNA in a chromosome are landing pads for proteins. The function of other segments of DNA in chromosomes is still not fully understood by scientists.

colleague     Someone who works with another; a co-worker or team member.

cytoplasm     The liquid or jellylike material that makes up most of a cell and exists outside of its nucleus. Some important functional components of a cell exist in this cytoplasm, such as mitochondria, which break down nutrients and convert them into a form of useful energy.

development     (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape. (in economics and social sciences) The conversion of land from its natural state into another so that it can be used for housing, agriculture, or resource development.

disorder     (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.

DNA     (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. It is built on a backbone of phosphorus, oxygen, and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

embryo     The early stages of a developing vertebrate, or animal with a backbone, consisting only one or a or a few cells. As an adjective, the term would be embryonic — and could be used to refer to the early stages or life of a system or technology.

ethics     (adj. ethical ) A code of conduct for how people interact with others and their environment. To be ethical, people should treat others fairly, avoid cheating or dishonesty in any form and avoid taking or using more than their fair share of resources (which means, to avoid greed). Ethical behavior also would not put others at risk without alerting people to the dangers beforehand and having them choose to accept the potential risks.

fertility     Ability to reproduce.

fertilize     (in biology) The merging of a male and a female reproductive cell (egg and sperm) to set in create a new, independent organism. (in agriculture and horticulture) To provide basic chemical nutrients for growth.

fiber     Something whose shape resembles a thread or filament of some kind.

gene     (adj. genetic) A segment of DNA that codes, or holds instructions, for producing a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

generation     A group of individuals born about the same time or that are regarded as a single group. Your parents belong to one generation of your family, for example, and your grandparents to another. Similarly, you and everyone within a few years of your age across the planet are referred to as belonging to a particular generation of humans. The term also is sometimes extended to year classes or types of inanimate objects, such as electronics or automobiles.

genetic     Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.

in vitro fertilization    A type of fertility treatment to help a woman become pregnant. Some eggs are removed from a woman’s ovaries and then incubated in vitro — meaning outside the body (usually in a dish) — along with male sperm cells. If those sperm fertilize the eggs, a lab will allow the eggs to mature into embryos. Then a few of those embryos will be implanted into the woman’s uterus. If all goes well, one or more of them will develop into a healthy baby.

Leigh syndrome    Symptoms of this disorder tend to show up in infancy and progressively worsen. A child will lose mental abilities and the ability to control movements. Death tends to occur within a few years, usually when the lungs fail to work. Symptoms may progress more slowly in some people. And a small share of affected people may not show symptoms until they become adults. Symptoms trace to damaged areas (lesions) in the brain. The disease is caused by faulty mitochondria in the affected person’s cells.

membrane     A barrier which blocks the passage (or flow through of) some materials depending on their size or other features. Membranes are an integral part of filtration systems. Many serve that same function as the outer covering of cells or organs of a body.

miscarriage     The death of a fetus in a pregnant animal, especially a human.

mitochondria     (sing. mitochondrion ) A structure in all cells (except bacteria and archaea) found outside of their nuclei. Here the cell breaks down nutrients and converts them into a form of energy known as ATP.

mitochondrial DNA     DNA passed on to offspring, almost always by their female parent. Housed in mitochondria, this DNA is double-stranded but circular. It’s also very small, only possessing a small share of the genes found in the main package of DNA, the material found in a cell’s nucleus.

molecule     An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).

muscle     A type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in a protein, which is why predatory species seek prey containing lots of this tissue.

mutation     (v. mutate) Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.

nucleus     Plural is nuclei. (in biology) A dense structure present in many cells. Typically a single rounded structure encased within a membrane, the nucleus contains the genetic information.

organ     (in biology) Various parts of an organism that perform one or more particular functions. For instance, an ovary is an organ that makes eggs, the brain is an organ that interprets nerve signals and a plant’s roots are organs that take in nutrients and moisture.

organelle    Specialized structures, such as mitochondria, found within a cell.

pronuclear transfer     A technique being used to assist reproduction for couples where the mother may have faulty (disease-fostering) genes in her cells’ mitochondria. The process fertilizes eggs from two women with sperm. Before the nuclear material in each fertilized egg has a chance to fully integrate as a whole, that material is removed from both eggs. That from the woman seeking to become pregnant is injected into the other (donor’s) egg and allowed to develop into an embryo. Later it will be implanted into the woman and allowed to hopefully develop into a healthy baby.

pronucleus    (plural: pronuclei) Either of a pair of nuclei that came from an egg and sperm and which will ultimately fuse into the nucleus, creating an embryo.

risk     The chance or mathematical likelihood that some bad thing might happen. For instance, exposure to radiation poses a risk of cancer. Or the hazard — or peril — itself. Among cancer risks that the people faced were radiation and drinking water tainted with arsenic.

society     An integrated group of people or animals that generally cooperate and support one another for the greater good of them all.

sperm     The reproductive cell produced by a male animal (or, in plants, produced by male organs). When one joins with an egg, the sperm cell initiates fertilization. This is the first step in creating a new organism.

spindle transfer       A technique being used to assist reproduction for couples where the mother may have faulty (disease-fostering) genes in her cells’ mitochondria. The process works with unfertilized eggs from two women. As the eggs prepare to replicate, creating new cells, nuclear material (known as the spindle and chromosomes) are removed from each egg. Then the material from the egg of the woman seeking to become pregnant is injected into the other (donor’s) largely emptied egg. This egg is now fertilized with sperm and allowed to develop into an embryo. Later it will be implanted into the woman and allowed to hopefully develop into a healthy baby.

syndrome     Two or more symptoms that together characterize a particular disease, disorder or social condition.

trait     A characteristic feature of something. (in genetics) A quality or characteristic that can be inherited.

transplant     (in medicine) The replacement of a tissue or an organ with that from another organism. It is also a term for the material that will be transplanted.

United Kingdom     Often referred to as Britain, its roughly 60 million people live in the four “countries” of England, Scotland, Wales and Northern Ireland. More than 80 percent of the UK’s inhabitants live in England. Many people — including UK residents — argue whether the UK is a country or instead a confederation of four separate countries. The United Nations and most foreign governments treat the UK as a single nation.

womb     Another name for the uterus, the organ in mammals in which a fetus grows and matures in preparation for birth.


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Journal: S.H. Chen et al. A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre. Reproductive BioMedicine Online. Vol. 33, December 2016, p. 737. doi: 10.1016/j.rbmo.2016.10.003.

Meeting: J. Zhang et al. First live birth using human oocytes reconstituted by spindle nuclear transfer for mitochondrial DNA mutation causing Leigh syndrome. American Society for Reproductive Medicine’s Scientific Congress. October 19, 2016.

doi: 10.1016/j.fertnstert.2016.08.004.

Journal: J. Zhang et al. Pregnancy derived from human zygote pronuclear transfer in a patient who had arrested embryos after IVF. Reproductive Biomedicine Online. Vol. 33, October 2016, p. 529. doi: 10.1016/j.rbmo.2016.07.008.

Journal: J.A. Barritt et al. Cytoplasmic transfer in assisted reproduction. Human Reproduction Update. Vol. 7, 2001, p. 428. doi: 10.1093/humupd/7.4.428.