Sperm coat protein may be key to male infertility

Sperm coat protein may be key to male infertility

  1:11:00 PM    Science Lover

---

The loss of a protein that coats sperm may explain a significant proportion of infertility in men worldwide, according to a study by an international team of researchers led by UC Davis. The research could open up new ways to screen and treat couples for infertility. A paper describing the work is published July 20 in the journal Science Translational Medicine.

These are normal human sperm. Green dots show the presence of a sugary molecule that allows the sperm to swim through cervical mucus. Credit: Ted Tollner, UC Davis

The protein DEFB126 acts as a "Klingon cloaking device," allowing sperm to swim through mucus and avoid the immune system in order to reach the egg, said Gary Cherr, a professor at the UC Davis Bodega Marine Laboratory and Center for Health and Environment. Cherr is the senior author of the paper.

But the UC Davis researchers found that many men carry a defective gene for DEFB126. A survey of samples from the U.S., United Kingdom and China showed that as many as a quarter of men worldwide carry two copies of the defective gene – which may significantly affect their fertility.

Infertility affects 10 to 15 percent of the U.S. population, said John Gould, associate professor of urology at UC Davis, who was not involved in the research. About half of those cases involve problems with male fertility.One of the mysteries of human fertility is that sperm quality and quantity seem to have little do with whether or not a man is fertile, said Ted Tollner, first author of the paper, who carried out the work as a postdoctoral scholar with Cherr. Tollner is now an adjunct assistant professor in the UC Davis Department of Obstetrics and Gynecology.

"In 70 percent of men, you can't explain their infertility on the basis of sperm count and quality," Cherr said. Studies like this may give us opportunities to explain these cases, Gould said.

If the discovery were successfully developed into a test, it could be used to send couples directly to treatment with intracytoplasmic sperm injection or ICSI, in which eggs are removed from the woman and injected directly with sperm, avoiding an expensive workup to exclude other causes, Gould said.

Tollner and Cherr were looking for ways to make contraceptive vaccines when they started looking at DEFB126. The protein belongs to a class of molecules called defensins, natural germ-killers found on mucosal surfaces. DEFB126 is produced in the epididymis, the structure where sperm are stored after they are produced in the testes, and deposited onto sperm in the epididymis to form a thick coat.



Tollner and Cherr were trying to make antibodies to the human protein, without much success. So they enlisted the help of Professor Charles Bevins, an expert on defensins who had just joined the UC Davis Department of Medical Microbiology and Immunology.

Bevins' lab made a recombinant copy of the human DEFB126 gene, with the aim of generating a purified protein that Tollner and Cherr could use to create antibodies. On their first attempt, they found the gene had a mutation that prevented it from making a protein. But when they used sperm from a different donor, they were able to make the normal protein.

"If we hadn't seen this in the first clone, we would be confused to this day," Bevins said.

Sperm from men with the defective DEFB126 genes look normal under a microscope and swim around like normal sperm. But they are far less able to swim through an artificial gel made to resemble human cervical mucus.When the normal protein is added to the sperm, they recover their normal abilities, the team found.

Working with Edward Hollox at the University of Leicester, England, Xiping Xu at the University of Illinois, Chicago, and Scott Venners at Simon Fraser University, Canada, the researchers were able to look at the frequency of the gene in DNA samples from people in the U.S., United Kingdom, China, Japan and Africa.

They found that worldwide, about half of all men carry one defective copy; a quarter have two defective copies and therefore make sperm that are poor at swimming through mucus.

In collaboration with Xue Liu and other scientists at Anhui Medical University in Anhui, China, the epidemiology team headed by Venners was able to look at the effect of the mutation on a group of couples trying to conceive. They found a statistically significant decrease in the number of pregnancies in couples where the man carried two copies of the defective DEFB126 gene.

Why should a mutation that affects fertility be so astonishingly common? It may be that heterozygotes – men with one normal and one defective gene, but normal fertility – are advantaged in some way, Tollner said.

Tollner noted that compared to sperm from monkeys and other mammals, human sperm are typically poor quality, slow-swimming, and with a high rate of defective cells. It's possible that because humans, unlike most mammals, breed in long-term monogamous relationships, sperm quality just does not matter very much, Cherr said.

However, some researchers believe that, for reasons unknown, human male fertility has been falling worldwide in recent decades. That decline might be unmasking the problems associated with the defective DEFB126 gene.

Cherr said that they hope next to work with a major infertility program in the U.S. to further explore the role of the mutation.
Provided by University of California - Davis

Read More

Scientists grow sperm out of skin tissue

Scientists grow sperm out of skin tissue

  12:48:00 PM    Science Lover

---

Infertile men have been given hope of conceiving children after scientists successfully grew sperm out of skin cells.

The breakthrough came when they took tissue from mice testicles and kept it alive for several weeks.

Breakthrough: Researchers have grown sperm from
tissue that was capable of fertilising an egg, meaning infertile
men could soon be able to fulfil their dreams of fatherhood

Researchers were able to grow sperm cells from this and inject them into female eggs, which produced babies.

The study gives hope to cancer patients who have been made infertile by chemotherapy.

It may allow men to freeze tissue from their testicles for scientists to grow healthy sperm from years later.

Leading fertility expert Dr Allan Pacey said: “It could help discover new drugs or treatments to stimulate infertile men to produce more or better sperm.

“For men who don’t have sperm to bank, to be able to freeze some testicular tissue and years later have sperm grown in the lab could allow them to have children that were genetically theirs.”

The study, carried out by Takehiko Ogawa at Yokohama University in Japan, created healthy baby mice, which later had babies themselves.

Separate research by Chinese scientists have created gay mice in a lab by reducing their serotonin. When they injected the brain chemical back into their brains, the males began chasing females again within 35 minutes.

Read More

Nobel Prize in Physiology or Medicine 2010 Was Awarded to Robert G. Edwards for IVF Fertilization

Nobel Prize in Physiology or Medicine 2010 Was Awarded to Robert G. Edwards for IVF Fertilization

  12:10:00 AM    Science Lover

---

Robert Edwards has been awarded the 2010 Nobel Prize for the development of human in vitro fertilization (IVF) therapy. His achievements have made it possible to treat infertility, a medical condition afflicting a large proportion of humanity including more than 10% of all couples worldwide.

In vitro fertilization. (Credit: iStockphoto)

As early as the 1950s, Edwards had the vision that IVF could be useful as a treatment for infertility. He worked systematically to realize his goal, discovered important principles for human fertilization, and succeeded in accomplishing fertilization of human egg cells in test tubes (or more precisely, cell culture dishes). His efforts were finally crowned by success on 25 July, 1978, when the world's first "test tube baby" was born. During the following years, Edwards and his co-workers refined IVF technology and shared it with colleagues around the world.

Approximately four million individuals have so far been born following IVF. Many of them are now adult and some have already become parents. A new field of medicine has emerged, with Robert Edwards leading the process all the way from the fundamental discoveries to the current, successful IVF therapy. His contributions represent a milestone in the development of modern medicine.

Infertility -- a medical and psychological problem

More than 10% of all couples worldwide are infertile. For many of them, this is a great disappointment and for some causes lifelong psychological trauma. Medicine has had limited opportunities to help these individuals in the past. Today, the situation is entirely different. In vitro fertilization (IVF) is an established therapy when sperm and egg cannot meet inside the body.

Basic research bears fruit

The British scientist Robert Edwards began his fundamental research on the biology of fertilization in the 1950s. He soon realized that fertilization outside the body could represent a possible treatment of infertility. Other scientists had shown that egg cells from rabbits could be fertilized in test tubes when sperm was added, giving rise to offspring. Edwards decided to investigate if similar methods could be used to fertilize human egg cells.

It turned out that human eggs have an entirely different life cycle than those of rabbits. In a series of experimental studies conducted together with several different co-workers, Edwards made a number of fundamental discoveries. He clarified how human eggs mature, how different hormones regulate their maturation, and at which time point the eggs are susceptible to the fertilizing sperm. He also determined the conditions under which sperm is activated and has the capacity to fertilize the egg. In 1969, his efforts met with success when, for the first time, a human egg was fertilized in a test tube.

In spite of this success, a major problem remained. The fertilized egg did not develop beyond a single cell division. Edwards suspected that eggs that had matured in the ovaries before they were removed for IVF would function better, and looked for possible ways to obtain such eggs in a safe way.

From experiment to clinical medicine

Edwards contacted the gynecologist Patrick Steptoe. He became the clinician who, together with Edwards, developed IVF from experiment to practical medicine. Steptoe was one of the pioneers in laparoscopy, a technique that was new and controversial at the time. It allows inspection of the ovaries through an optical instrument. Steptoe used the laparoscope to remove eggs from the ovaries and Edwards put the eggs in cell culture and added sperm. The fertilized egg cells now divided several times and formed early embryos, 8 cells in size.

These early studies were promising but the Medical Research Council decided not to fund a continuation of the project. However, a private donation allowed the work to continue. The research also became the topic of a lively ethical debate that was initiated by Edwards himself. Several religious leaders, ethicists, and scientists demanded that the project be stopped, while others gave it their support.

The birth of Louise Brown -- an historic event

Edwards and Steptoe could continue their research thanks to the new donation. By analyzing the patients' hormone levels, they could determine the best time point for fertilization and maximize the chances for success. In 1978, Lesley and John Brown came to the clinic after nine years of failed attempts to have a child. IVF treatment was carried out, and when the fertilized egg had developed into an embryo with 8 cells, it was returned to Mrs. Brown. A healthy baby, Louise Brown, was born through Caesarian section after a full-term pregnancy, on 25 July, 1978. IVF had moved from vision to reality and a new era in medicine had begun.

IVF is refined and spreads around the world

Edwards and Steptoe established the Bourn Hall Clinic in Cambridge, the world's first centre for IVF therapy. Steptoe was its medical director until his death in 1988, and Edwards was its head of research until his retirement. Gynecologists and cell biologists from all around the world trained at Bourn Hall, where the methods of IVF were continuously refined. By 1986, 1,000 children had already been born following IVF at Bourn Hall, representing approximately half of all children born after IVF in the world at that time.

Today, IVF is an established therapy throughout the world. It has undergone several important improvements. For example, single sperm can be microinjected directly into the egg cell in the culture dish. This method has improved the treatment of male infertility by IVF. Furthermore, mature eggs suitable for IVF can be identified by ultrasound and removed with a fine syringe rather than through the laparoscope.

IVF is a safe and effective therapy. 20-30% of fertilized eggs lead to the birth of a child. Complications include premature births but are very rare, particularly when one egg only is inserted into the mother. Long-term follow-up studies have shown that IVF children are as healthy as other children.

Approximately four million individuals have been born thanks to IVF. Louise Brown and several other IVF children have given birth to children themselves; this is probably the best evidence for the safety and success of IVF therapy. Today, Robert Edwards' vision is a reality and brings joy to infertile people all over the world.

Read More