In Vitro Fertilization: The Laboratory Baby Boom

Right before midnight, on July 25, 1978, Lesley and John Brown welcomed the birth of their little girl. Her name was Louise Brown, and she was born in Oldham, England. Three years later, across the world, Judith and Roger Carr welcomed their second child, Elizabeth, in Norfolk, Virginia. Two baby girls born in two different countries. Unlike millions of other babies born during that time span, Louise and Elizabeth each graced the covers of national magazines after their birth. What made these two babies so special? They were the first babies conceived using in vitro fertilization (IVF) in England and the United States.

            Since Louise Brown’s birth, over six million IVF babies have been born throughout the globe. IVF is a method that helps couples with fertility problems to conceive a child. Simply put, instead of fertilization occurring within the body, it occurs in the lab. This might be needed if a woman has damaged fallopian tubes, those tubes that connect the ovaries to the uterus, since this prevents eggs being fertilized and embryos reaching the uterus (where a fetus develops). Other scenarios can direct couples toward IVF such as problems with ovulation (egg production), sperm production, genetic disorders, or other conditions affecting reproduction.

A sequence of general steps is followed during IVF. Since eggs are required to form an embryo, synthetic hormone treatments are given to stimulate the production of multiple eggs at one time (typically, only one egg is released per month). This process is referred to as ovarian stimulation, can take 8-12 days, and increases the chances of fertilization. Yet, there are many possible side effects of the intense hormone treatments, which all doctors should educate their patients on. Ultrasounds and estrogen tests are used to monitor the eggs throughout this process. Once the eggs look ripe for fertilization, a shot is administered to commence the eggs’ release. About 36 hours later, the eggs are sucked up using a thin needle and suction (fortunately the woman is sedated). This process can result in several eggs being collected in about 20 minutes.

Once eggs are retrieved, they are fertilized with the father’s sperm in a lab. As you might expect, sperm is usually collected in a simpler method that does not require hormone treatments. Once the eggs are fertilized, and now referred to as embryos, one embryo (or sometimes multiple – to increase the likelihood of success) are implanted into the uterus to continue developing. In some cases, embryos are given about six days to develop in the lab before they’re tested for genetic diseases and chromosome number. This gives doctors greater confidence that implanted embryos do not carry common diseases or chromosomal abnormalities.

While IVF is usually associated with couples, it’s important to note that eggs or sperm can come from donors. Additionally, embryos can be implanted into a gestational carrier: a woman that carries the baby to term.

The goal of IVF is to conceive a healthy baby. Since its initial success with Louise Brown, millions of babies have been conceived using IVF, and it’s easy to imagine the joy that IVF has provided for families throughout the world. 

List of Sources

1.     The Telegraph. “Louise Brown, the first IVF baby, reveals family was bombarded with hate mail.” Victoria Ward. July 24, 2015. www.telegraph.co.uk/news/health/11760004/Louise-Brown-the-first-IVF-baby-reveals-family-was-bombarded-with-hate-mail.html

2.     WWW.mayoclinic.org (search for “in vitro fertilization” at top of screen. Then, click on top search result “In vitro fertilization (IVF) – Overview – Mayo Clinic.” See information in “Overview” and “Procedure Details” tabs.)

3.     WWW.columbiafertility.com (search for “typical IVF timeline” at top of screen. Then, click top search result “The Typical IVF Timeline: 6 Steps You Need to Know.”)

4.     WWW.urmc.rochester.edu (search for “IVF step by step” at top of screen. Then, click top search result “IVF Step-by-Step.”)

Sperm Storage and Cryptic Female Choice

The above video from Science News shows two male cuttlefish violently competing for a single female to mate with. The second "intruder" male arrives to the scene after the first male mates with the female. The two males engage in a violent, inky fight, and the female eventually flees the scene. One explanation for why the first male remains to fend off the intruder, even after successfully mating with the female, is that female cuttlefish store sperm. A female can store packets of male sperm from multiple matings. This suggests that even after mating with a female, a male might hang around to prevent other males from mating with her, as seen in the video. This increases the chance that the male's sperm is selected for fertilization, instead of another male's genetic material, and helps him secure his paternity.

Cuttlefish represent just one type of animal that is capable of sperm storage. Various species of insects, birds, and reptiles are also capable of this. In fact, females of such species can select which male's sperm they want to fertilize their eggs in a process called "cryptic female choice." This allows females to select sperm that can increase offspring quality and number.

VSGC Conference

Yesterday I attended the annual Virginia Space Grant Consortium (VSGC) Conference. In association with NASA, the VSGC generously awards college students, at both the undergraduate and graduate level, funding to help with their research. As a graduate research fellow, I was invited to present my research and also hear about a lot of interesting research being done by others.

The topics ranged from Aerospace and Astrophysics to Chemistry and Biology. The students presenting were just as diverse as the research they discussed. The mix of students, professors, NASA engineers, and other industry professionals made for interesting conversations, and I'm sure everyone left the conference with new ideas. Some of the exciting research topics I learned about are described here:

How giant molecular clouds' magnetic fields allow for the formation of stars. 

How mammoth fossils are less degraded in different environments than others (permafrost being the best for maintaining fossil integrity).

How a new radiation-blocking material is being designed for potential use in space.

How some proteins can remain stable in extremely harsh environments (such as potential environments in space). 

How the properties of spider silk are being tested using rare, high-speed cameras.

The Sterilization of Mosquitoes

Many infamous viral disease such as malaria, Zika, dengue, West Nile, and yellow fever are all carried and transmitted to new hosts by mosquitoes. For many years researchers have been looking for ways to prevent the spread of these dangerous viruses, and they often target mosquitoes. One method is to sterilize mosquitoes, thus reducing the amount of carriers. Male mosquitoes can be sterilized by infecting them with a certain bacteria (Wolbachia) that modifies their sperm. When a Wolbachia-infected male mates with an uninfected female mosquito, his sperm kills the eggs after fertilization. When the infected male mates with an infected female, her modified egg is compatible with his modified sperm, and the eggs survive.

While this sterilization method is being used, scientists didn't really understand all the mechanisms underlying how it works. To understand why this bacteria causes sterilization, a group of scientists from Vanderbilt University pinpointed two genes in Wolbachia called cifA and cifB and inserted them into male fruit flies. They found that these males could no longer reproduce with normal female flies, but just like in the mosquitoes, they could still reproduce with infected females. The infected females "rescue" the modified sperm which reminded scientists at the Yale School of Medicine of antidotes and toxins. They used simple yeast cells to test this hypothesis and put the "toxin" gene into the yeast, which resulted in the yeast cells dying. On the other hand, when they put both the "toxin" and "antidote" genes into the yeast, they survived.

These experiments in both fruit flies and yeast mirror what is happening in mosquitoes. Since the discovery of this gene pair, researchers have considered adding extra copies of these genes into bacteria, creating a "super Wolbachia" that more potently sterilizes the mosquitoes. Yet, this could "essentially crash the population" said coauthor of the fruit fly study Seth Bordenstein. While the creation of bacteria with multiple copies of the genes has not yet been attempted, this research unveils the genes responsible for the sterilization of mosquitoes, and helps fight against the spread of viral diseases.

Link to news article: https://www.sciencenews.org/article/bacteria-genes-offer-new-strategy-sterilizing-mosquitoes?mode=topic&context=87

Gene-Editing Policy

A group of experts recently met to discuss the use of gene-editing. This group from The National Academies of Sciences and Medicine issued a recommendation on Feb. 14th stating that altering germline cells (such as eggs, sperm, and embryos) should be allowed if the editing cures genetic diseases, but does not enhance health or abilities. Germline cells are reproductive cells, and any genetic modification in these cells will be passed on to future generations- a very useful tool for curing a disease in not just one person, but their future offspring. Co-chair of the recent panel Alta Charo, says "We are not trying to greenlight heritable germline editing...We're giving it a yellow light." In other words, the panel of experts is trying to find the special circumstances in which the use of germline editing is justified by a very great need for its healing potential. Some examples of these special cases would be curing cystic fibrosis or Huntington's in someone, and thus eliminating the disease from any of their future offspring.

This recent recommendation, for allowing germline editing in certain cases, goes against a global summit's previous recommendation that gene-editing should not be used in the germline. Many scientists fear that allowing any form of germline editing would open the floodgates for other, less necessary, applications (such as designing a baby's eye-color or increasing athletic ability). Marcy Darnovsky, director of the Center for Genetics and Society in Berkeley, says “Once you approve any form of human germline modification you really open the door to all forms...I’m feeling very unsettled and disappointed by what they are recommending.”

Clinical trials that would produce heritable changes in the human genome are currently banned in the U.S. Still, the debate about germline gene-editing rages on, and this recent recommendation may pave the way for a change in policy.

Link to Science News article:
https://www.sciencenews.org/article/human-gene-editing-therapies-are-ok-certain-cases-panel-advises?mode=topic&context=87

Chimera: Hosts to Other Species

In Greek mythology, the Chimera was a fire-breathing hybrid creature with parts from more than one animal (imagine a creature with the body of a goat, dragon wings, and a lion head). In the scientific world, animal hybrids are called "chimeric" and receive their name from this mythical creature, but unlike their namesake, exist in reality. One area of research involving the use of chimeric animals has the ultimate goal of growing human organs in these animals, and then transplanting them into humans.

While this research is still very young, several studies of chimeric mice, rats, and pigs, suggest that using one organism to grow an organ of another species, is a viable method for curing disease. One particular study published in Nature, showed that mouse pancreases could be grown in rats. The healthy insulin-producing cells from the mouse pancreases were extracted from the chimeric rats, and transplanted into diabetic mice, which cured the mice of diabetes. The transplanted cells allowed the mice to maintain normal blood sugar for more than a year, giving scientists much hope for the future of this research.

In another study, pig embryos were injected with human stem cells, with the hope of using pigs to grow human organs for disease treatment. Unfortunately, the researchers found that the human cells likely interfered with normal pig development, since only a small percentage of the pig embryos were capable of continuing development for about 28 days. Currently, scientists are working to improve the growth of human cells in pig embryos, and there is hope that one day humans can benefit from this medical technology using chimeric pigs.

Link to news article:
https://www.sciencenews.org/article/mouse-cells-grown-rats-cure-diabetes-mice?mode=topic&context=87

Chimeric mouse embryo containing rat cells (shown in red)

Synthetic DNA Bases

Life's natural genetic code is made up of 4 DNA bases represented by the letters A, T, G, and C. These 4 bases pair to form base-pairs (A-T and G-C). These base pairs have been rearranged to create all types of organisms (penguins, bears, whales, humans, plants, bacteria etc.). In other words, life as we know it is made from these 4 DNA bases.

Scientists from The Scripps Research Institute in California have created 2 new DNA bases they call X and Y. These new bases form a base-pair and have been incorporated in an entirely new organism. The new type of bacteria they created still contains the usual A, T, G, and C bases, but also has the new bases (X and Y) in its genome. This new bacterium has been called the first "semisynthetic organism."

While this new bacterium has no practical applications at this point, the lead researchers on this project suggest that these new bases can allow single-celled organisms to take on new properties, potentially helping scientists create new drugs. We can be comforted by the fact that this technology is only intended for use in single-celled organisms, and we won't be seeing these new X and Y bases showing up in more complex organisms.

Link to article about this research:
https://www.sciencedaily.com/releases/2017/01/170123214717.htm

Sight Restored Using Stem Cells

Stem cells have an amazing potential to heal, but a challenge is ensuring the transplanted cells survive long enough to work. Long-term studies of stem cell therapies have been performed in a variety of model organisms. Notably, researchers from the Buck Institute have provided one of the first demonstrations of long-term stem cell therapy efficacy. They transplanted photoreceptors (cells for receiving light signals), derived from human stem cells, into blind mice and observed long-term vision restoration. They found that even 9 months after injection, the mice were able to perceive light signals (something they were completely incapable of prior to the treatment).

This awesome example not only shows the great potential of stem cell therapies for healing, but can help scientists further develop stem cell therapies that circumvent immune rejection. Dr. Lamba, senior author on the paper, says "That finding gives us a lot of hope for patients, that we can create some sort of advantage for these stem cell therapies so it won't be just a transient response when these cells are put in, but sustained vision for a long time."

Link to article:

https://www.sciencedaily.com/releases/2017/01/170112141243.htm

Genome Editing Trials

For the first time, the exciting gene-editing tool CRISPR-Cas9 has been used in a human. This technology, which I wrote about several weeks ago (refer to post from Nov. 5 for more detail), allows scientists to alter DNA bases to introduce a change to any gene. The concept of altering human DNA is controversial, but the potential health applications are practically limitless. For example, if a disease is caused by a specific, known mutation, scientists could potentially alter that mutation, thus treating the disease. This technology is a hot topic among biologists, and is also currently one of the most-studied tools.

Cancer is one of the main diseases that scientists hope can be treated using CRISPR-Cas9. Because of this, the first use of CRISPR-Cas9 has been in a human patient with aggressive lung cancer. Scientists of the West China Hospital in Chengdu have altered a gene that normally prevents a cell from launching an immune response, so that the immune system is more likely to target and destroy cancerous cells. The researchers hope that after injection into the patient's blood stream, the modified cells will then start attacking the cancerous cells. 

While this Chinese trial, the first of its kind, began in October of 2016, the United States also plans to start a human trial of CRISPR-Cas9 early this year. The U.S. trial is also testing the safety and efficacy of using CRISPR technology to combat several forms of cancer. Since both China and the U.S. are launching CRISPR-Cas9 trials, some healthy competition is predicted to fuel the potentially life-saving research. Carl June, a scientific adviser to the U.S. trial, says "I think this is going to trigger 'Sputnik 2.0,' a biomedical duel on progress between China and the United States, which is important since competition usually improves the end product."

To watch a video and gain more information about this Chinese trial, follow this link:

http://www.usnews.com/news/national-news/articles/2016-11-17/gene-editing-tool-crispr-cas9-used-in-a-human-for-the-first-time

Synthetic Stem Cells

Stem cell therapies have the potential to treat many different diseases and help many people. One way these therapies work is by helping damaged tissue repair itself. Still, there are risks associated with these therapies including immune system rejection, and potentially cancerous growths. Additionally, natural stem cells are fragile, and must be treated with extreme care, which slows therapies and adds another element of risk. To circumvent some of these limitations, scientists are developing procedures that use synthetic stem cells, instead of natural cells.

Scientists from North Carolina State University, the University of North Carolina at Chapel Hill, and First Affiliated Hospital of Zhengzhou University, created synthetic cardiac stem cells, and implanted them into mouse hearts that had been damaged by heart attack. Usually, the damage that heart attacks inflict upon heart muscles are never repaired by the body. Yet, when the researchers injected the synthetic stem cells, they found that the previously damaged heart muscles were effectively repaired, and this repair was comparable to when natural cardiac stem cells are implanted.

These findings are very promising for the future of stem cell research and therapies. Compared to natural stem cells, the synthetic stem cells are more stable and can be modified for use in different parts of the body. Unlike natural cells, the synthetic versions are incapable of replicating, which reduces the risk of tumor formation. And since the synthetic stem cells are designed to bypass the patient's immune system, they are far less likely to be rejected by the body's immune system. Ultimately, using synthetic stem cells instead of natural stem cells may be more affordable and accessible, and could eliminate some of the dangerous side effects associated with stem cell therapies.

To read more about the research done here, check out the following links:

http://wallstreetpit.com/112614-worlds-first-synthetic-stem-cells-implanted/

https://news.ncsu.edu/2016/12/synthetic-stem-cells/

The Skin Gun

A whole field of research revolves around harnessing the power of stem cells to treat many different injuries and ailments. Recently, CNN released an article about a skin gun that sprays a patient's healthy skin stem cells onto severe burns. The goal is to completely heal the severe burns, much faster than typical healing, using the patient's own stem cells.

Developed by a New York biotech firm called RenovaCare, this "CellMist System" requires just about a square inch of unwounded skin. To summarize the process, the patients' healthy skin is removed, the stem cells are isolated from the other skin tissue, suspended in a water-based solution, and sprayed onto the wound where the new skin hopefully begins to grow. The stem cells are not modified in any way, simply isolated and sprayed onto burn wounds.

This skin gun seems to hold much potential for healing burn wounds. While still an experimental treatment, the President and CEO of RenovaCare, Thomas Bold, says "We've seen already a couple dozen patients, and we're very happy about the results." See some results of this treatment for yourself, by watching the video at the link below.

Link to watch the video and learn more:
http://www.cnn.com/2016/12/07/health/skingun-burn-care-technologies/

Myostatin Mutations

Many people strive to be stronger. There are even those who spend hours working out daily and eat high-protein diets to sustain their muscle growth. When we see someone that is completely ripped, we may think something along the lines of "Do they even have time for anything else?" While muscle growth does typically require much effort, if genes involved in muscle growth are mutated in a specific way, then muscles can be altered without a shred of intentional effort.

       Such is the case in Belgian Blue cattle (image below). These cattle have been selectively bred for many years since muscle mass in cattle often means more meat and money for breeders. For a long time, the more muscular bulls and cows were chosen for breeding, and this resulted in more muscular offspring. What breeders didn't necessarily understand, was that they were selecting mutations in the myostatin gene. This gene codes for the protein myostatin which inhibits muscle development. The mutated, shorter form of myostatin doesn't function properly, which results in more rapid muscle growth. This creates "double-muscled" offspring that, instead of having the normal amount of muscle fibers at birth, actually have twice as many muscle fibers. The myostatin mutation is considered a permanent muscle mutation within this cattle breed.

But myostatin has the same muscle-inhibiting function in other mammals. Mutations of myostatin have even been found in humans. Several cases of children born with these mutations have been documented, but have only recently been understood (image of boy with a myostatin mutation below). Additionally, myostatin mutations have been induced in mice to create "mighty mice" by Se-Jin Lee and colleagues at Johns Hopkins. Below, there is an image of a normal, wild-type mouse that lacks any myostatin mutation and a mouse with mutated myostatin. You can clearly see that the mutated mouse has much more muscle mass than the normal mouse. The discovery of myostatin mutations and their effect on increased muscle mass has practical applications. These mutations are currently being studied to potentially help people with muscular dystrophies (conditions with weakening muscles).

Link to primary article about Myostatin mutation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24998/