Gene editing creates mice with no mom | Science News for Students

Gene editing creates mice with no mom

The first rodents with two biological dads only survived a few days
Nov 9, 2018 — 6:45 am EST
A photo of a tiny newborn baby mouse on a pile of woodshavings. A green-gloved human hand is pointing at the baby mouse.

This mouse pup has two biological fathers and no mother. It was made in a lab using stem cells made from two male mice. Such pups, including this one, lived a few days at most.

LEYUN WANG

For the first time, mice have been born with no moms. Researchers created them from genetic material retrieved from two dads. Alas, the pups did not live long.

Similar mice created with no dads, fared better. Those that were born tended to survive into adulthood. Some even gave birth to their own pups.

Scientists had to edit the animals’ genes for either type of moms-only or dads-only pups to be born. That’s why this unusual reproduction took place in a lab.

Researchers started by turning skin cells from male mice into stem cells. Such cells can later become any type of cell. Biologists turned the stem cells into a type similar to those that become eggs or sperm. Then they injected these pre-egg cells with sperm from another male. These grew into embryos. Finally, the scientists implanted the embryos into female mice. Although those females gave birth to the mouse pups, they were not genetically related.

The researchers described their novel findings October 11 in Cell Stem Cell.

Pups without pops

The researchers wanted to learn why mammals need two parents of opposite sexes to reproduce.

Sperm from one parent usually are needed to fertilize an egg from the other parent. But certain non-mammals can sometimes reproduce with only one parent. These include turkeys, snakes and sharks, notes study coauthor Qi Zhou. Zhou works at the Chinese Academy of Sciences in Beijing. Females of those species can sometimes make young from an unfertilized egg. This process is called parthenogenesis (PAR-then-oh-JEN-eh-sis). 

Researchers had made zebrafish before that had only the DNA of one father. But until now, no one had gotten mammals to reproduce without moms.

A small brown mouse is held by two green-gloved outstretched hands. The mouse's pups are also being held.
This adult female mouse has two biological mothers. She survived to have pups of her own.
LEYUN WANG

For their new study, scientists started by making mouse pups with two mothers. These pups were smaller than usual and born with some abnormalities.

The problem: Some genes that the pups inherited from their mothers were “marked.” The marks are molecules called methyl groups. They are attached to DNA near a gene. This type of epigenetic marking — also known as imprinting — can make genes more or less active.

To avoid this, the researchers used a type of molecular “scissors.” It snipped out three imprinted DNA regions near important genes. These scissors are known as CRISPR/Cas9. The scientists edited the DNA of female pre-sperm stem cells in this way. Then they injected the edited cells into eggs from other female mice to make embryos.

The researchers implanted 210 of these embryos in female mice. About 14 percent of them survived to birth. These pups grew normally and became adults. These dad-free females later gave birth to their own pups. This result matched what the researchers had seen before.

Mice minus moms

Making embryos from the stem cells of two male mice wasn’t nearly as successful.

Male-only reproduction is called androgenesis (An-droh-JEN-eh-sis).

To make embryos from the stem cells of two dads, the researchers had to snip out twice as many imprinted pieces of DNA — six, not three.

Then they implanted 1,023 of these embryos into female mice. Out of all these embryos, only 1.2 percent survived to birth. Those pups were twice the normal size and soon died. Cutting out a seventh imprinted DNA region produced pups of normal size. But only two of these lived more than 48 hours. Neither lived to become an adult.

(The researchers point out that even in their study, they couldn’t get away with having no females at all. After all, females had to carry the embryos with two dads in their wombs. For that reason, it would be extremely hard for males to have babies on their own in the wild.)

This work is an important first step in understanding the role of imprinted regions in fetal development, says B. Duygu Özpolat. She’s a developmental biologist at the Marine Biological Laboratory in Woods Hole, Mass. She was not involved in the new work.

Imprinting errors are important to understand. They underlie some human birth defects and genetic conditions. So knowing how the process works might help scientists one day correct those defects, Özpolat says.

For instance, the Chinese team notes that one of the imprinted regions snipped out of the two-mom mice is similar to a region in people. When a human gets an extra copy of that piece of DNA, they develop what’s known as Silver-Russell syndrome. Fetuses and babies with the extra imprinted bit don’t grow normally. In the future, snipping out the extra imprinted DNA might lead to healthy babies, these researchers say. 

Making mammals from parents of the same sex might also offer some help to certain endangered species, Özpolat says. Some species are represented only by animals of one sex. For instance, the last male northern white rhinoceros died earlier this year, leaving just two females. Gene editing might help researchers bring white rhinos back by making all-female populations from stem cells grown in labs.

Although possible, Özpolat says, “It might be too expensive, and might not work for every species. But it’s something.”

Some human same-sex couples hope to have a biological baby together. But, Özpolat says, “that’s the far future.” Right now, it remains just a dream.

Zhou adds that it could be too dangerous to try this technique in people. There’s no guarantee that the imprinted regions involved in mouse reproduction are the same ones involved in people. In fact, he adds, using this technique with people “is not one of our goals.” 

Power Words

(for more about Power Words, click here)

biology     The study of living things. The scientists who study them are known as biologists.

Cas9     An enzyme that geneticists are now using to help edit genes. It can cut through DNA, allowing it to fix broken genes, splice in new ones or disable certain genes. Cas9 is shepherded to the place it is supposed to make cuts by CRISPRs, a type of genetic guides. The Cas9 enzyme came from bacteria. When viruses invade a bacterium, this enzyme can chop up the germs DNA, making it harmless.

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

coauthor     One of a group (two or more people) who together had prepared a written work, such as a book, report or research paper. Not all coauthors may have contributed equally.

CRISPR     An abbreviation — pronounced crisper — for the term “clustered regularly interspaced short palindromic repeats.” These are pieces of RNA, an information-carrying molecule. They are copied from the genetic material of viruses that infect bacteria. When a bacterium encounters a virus that it was previously exposed to, it produces an RNA copy of the CRISPR that contains that virus’ genetic information. The RNA then guides an enzyme, called Cas9, to cut up the virus and make it harmless. Scientists are now building their own versions of CRISPR RNAs. These lab-made RNAs guide the enzyme to cut specific genes in other organisms. Scientists use them, like a genetic scissors, to edit — or alter — specific genes so that they can then study how the gene works, repair damage to broken genes, insert new genes or disable harmful ones.

develop     To emerge or come into being, either naturally or through human intervention, such as by manufacturing. (in biology) To grow as an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape. (as with towns) The conversion of wildland to host communities of people. This development can include the building of roads, homes, stores, schools and more. Usually, trees and grasslands are cut down and replaced with structures or landscaped yards and parks.

development     (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape.

developmental     (in biology) An adjective that refers to the changes an organism undergoes from conception through adulthood. Those changes often involve chemistry, size and sometimes even shape.

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.

egg     The unfertilized reproductive cell made by females.

embryo     The early stages of a developing organism, or animal with a backbone, consisting only one 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.

endangered     An adjective used to describe species at risk of going extinct.

epigenetic change     Molecular switches that can turn a gene on or off. Methyl groups — chemical clusters each made of one carbon and three hydrogen atoms — latch onto DNA near a gene. It’s these methyl groups that can alter the programmed activity of a gene. Individuals can acquire an epigenetic change at any time during their lives.

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.

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

gene editing     The deliberate introduction of changes to genes by researchers.

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.

imprinting      (in genetics) The development of methyl groups or other markers that can control the activity of the genes to which they are associated.

mammal     A warm-blooded animal distinguished by the possession of hair or fur, the secretion of milk by females for feeding their young, and (typically) the bearing of live young.

marine     Having to do with the ocean world or environment.

methyl group     (in chemistry) Three hydrogen atoms bonded, chemically, to a carbon atom. This amazingly common quartet of atoms is then attached — through the carbon — to some other molecule. (in genetics) When attached to a gene, the methyl group can act like a new switch to turn the gene’s activity on or off, up or down.

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).

novel     Something that is clever or unusual and new, as in never seen before.

parthenogenesis     An unusual form of reproduction where animals sometimes produce healthy offspring from an unfertilized egg.

population     (in biology) A group of individuals from the same species that lives in the same area.

pup     A term given to the young of many animals, from dogs and mice to seals.

sex     An animal’s biological status, typically male or female. There are a number of indicators of biological sex, including sex chromosomes, gonads, internal reproductive organs, and external genitals. It can also be a term for some system of mating between male and female animals such that each parent organism contributes genes to the potential offspring, usually through the fertilization of an egg cell by a sperm cell.

shark     A type of predatory fish that has survived in one form or another for hundreds of millions of years. Cartilage, not bone, gives its body structure.

sharks     A family of primitive fishes that rely on skeletons formed of cartilage, not bone. Like skates and rays, they belong to a group known as elasmobranchs. Then tend to grow and mature slowly and have few young. Some lay eggs, others give birth to live young.

species     A group of similar organisms capable of producing offspring that can survive and reproduce.

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.

stem cell     A “blank slate” cell that can give rise to other types of cells in the body. Stem cells play an important role in tissue regeneration and repair.

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

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

zebrafish     A small tropical freshwater fish belonging to the minnow family. Zebrafish are used frequently in scientific research because they grow quickly and their genetic makeup is well understood.

Citation

Journal: Z.-K. Li et al. Generation of uniparental mice from hypomethylated haploid ESCs with imprinting region deletionsCell Stem Cell. Published online October 11, 2018. doi: 10.1016/j.stem.2018.09.004.