Just as fashion changes from year to year and culture to culture, “sexy” genes, or genes specific to sex, also change rapidly. But there is one sex-specific gene so vital, its function has remained unaltered throughout evolution and is found in almost all animals, according to new research from Northwestern Medicine.
The gene, called Boule, is responsible for sperm production. Northwestern scientists also discovered in their research that Boule appears to be the only gene known to be exclusively required for sperm production from an insect to a mammal.
“This is the first clear evidence that suggests our ability to produce sperm is very ancient, probably originating at the dawn of animal evolution 600 million years ago,” said Eugene Xu, PhD, assistant professor of obstetrics and gynecology at Feinberg. “This finding suggests that all animal sperm production likely comes from a common prototype.”
Xu is senior author of a paper on the study that was published on July 15 in PLoS Genetics.
The discovery of Boule’s key role in perpetuating animal species offers a better understanding of male infertility, a potential target for a male contraceptive drug and a new direction for future development of pesticides or medicine against infectious parasites or carriers of germs.
“Our findings also show that humans, despite how complex we are, across the evolutionary lines all the way to flies, which are very simple, still have one fundamental element that’s shared,” Xu said.
“It’s really surprising because sperm production gets pounded by natural selection,” he said. “It tends to change due to strong selective pressures for sperm-specific genes to evolve. There is extra pressure to be a super male to improve reproductive success. This is the one sex-specific element that didn’t change across species. This must be so important that it can’t change.”
Boule is likely the oldest human sperm-specific gene ever discovered, Xu said. He originally discovered the human gene in 2001.
Prior to the new findings, it was not known whether sperm produced by various animal species came from the same prototype. For the study, Xu searched for and discovered the presence of the Boule gene in sperm across different evolutionary lines: human, mammal, fish, insect, worm and marine invertebrate.
You can teach an old drug new chemotherapy tricks. Northwestern Medicine researchers took a drug therapy proven for blood cancers but ineffective against solid tumors, packaged it with nanotechnology and got it to combat an aggressive type of breast cancer prevalent in young women, particularly young African American women.
That drug is arsenic trioxide, long part of the arsenal of ancient Chinese medicine and recently adopted by Western oncologists for a type of leukemia. The cancer is triple negative breast cancer, which often doesn’t respond well to traditional chemotherapy and can’t be treated by potentially life-saving targeted therapies. Women with triple negative breast cancer have a high risk of the cancer metastasizing and poor survival rates.
Prior to the new research, arsenic hadn’t been effective in solid tumors. After the drug was injected into the bloodstream, it was excreted too rapidly to work. The concentration of arsenic couldn’t be increased, because it was then too toxic.
A new arsenic nanoparticle — designed to slip undetected through the bloodstream until it arrives at the tumor and delivers its poisonous cargo — solved all that. The nanoparticle, called a nanobin, was injected into mice with triple negative breast tumors. Nanobins loaded with arsenic reduced tumor growth in mice, while the non-encapsulated arsenic had no effect on tumor growth. The arsenic nanobins blocked tumor growth by causing the cancer cells to die by a process known as apoptosis.
“The anti-tumor effects of the arsenic nanobins against clinically aggressive triple negative breast tumors in mice are extremely encouraging,” said Vince Cryns, associate professor of medicine-endocrinology at Northwestern University Feinberg School of Medicine, an endocrinologist at Northwestern Memorial Hospital, and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “There’s an urgent need to develop new therapies for poor prognosis triple negative breast cancer.”
Cryns and Tom O’Halloran, director of the Chemistry of Life Processes Institute at Northwestern, are senior authors of a paper on the research, which was published July 15 in Clinical Cancer Research. Richard Ahn, a student in the medical scientists training program at Northwestern, is lead author.
“Everyone said you can’t use arsenic for solid tumors,” said O’Halloran, also associate director of basic sciences at the Lurie Cancer Center. “That’s because they didn’t deliver it the right way. This new technology delivered the drug directly to the tumor, maintained its stability and shielded normal cells from the toxicity. That’s huge.”
The nanoparticle technology has great potential for other existing cancer drugs that have been shelved because they are too toxic or excreted too rapidly, Cryns noted. “We can potentially make those drugs more effective against solid tumors by increasing their delivery to the tumor and by shielding normal cells from their toxicity,” he said. “This nanotechnology platform has the potential to expand our arsenal of chemotherapy drugs to treat cancer.”
A phase II clinical trial of the first new type of drug for musculoskeletal pain since aspirin shows that it significantly reduces knee pain in osteoarthritis, the most common osteoarthritis pain, according to new research from Northwestern Medicine.
However, phase III trials of that drug, tanezumab, have been placed on clinical hold after 16 out of several thousand participants in the new trial developed progressively worsening arthritis and bone changes that required total joint replacements.
“The bottom line is this is a very effective drug for relieving pain; unfortunately, it appears some people go on to have their osteoarthritis progress more quickly,” said Thomas Schnitzer, MD, PhD, a rheumatologist and professor in the department of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine. “The long-term safety of tanezumab needs to be better understood.”
Schnitzer is a principal investigator and lead author of a paper on the research, which was published September 30 in the New England Journal of Medicine. He also was an investigator on the phase III trial. The other lead author and principal investigator is Nancy Lane, MD, a professor of internal medicine at UC Davis School of Medicine.
Tanezumab is the first new drug for general muscle or joint pain in over 100 years, Schnitzer said, noting nonsteroidals and COX inhibitors are a “fancy form of aspirin.”
“The effects of tanezumab were remarkable,” Lane said. “People on the drug went from having very limited activity to practically being on the dance floor. No medication available today has such dramatic results.”
The drug works by neutralizing or blocking Nerve Growth Factor (NGF), a molecule needed for normal development of the nervous system, but which also gets released when there is inflammation in the body. NGF stimulates nerve cells and triggers pain.
Schnitzer and Lane said the apparent worsening of certain patients’ condition could be because tanezumab helped patients increase their activity and, as a result, put more stress on their diseased joints.
“The FDA may decide it’s too dangerous overall or, rather, that there may be a specific patient population in which it should not be used or who need to be warned about possible serious side effects,” Schnitzer said.
Nearly 27 million adults in the United States have osteoarthritis, according to the U.S. Department of Commerce, and about 40 percent suffer from knee osteoarthritis. The number of people with osteoarthritis is expected to rise as baby boomers reach retirement age and as the number of obese Americans increases. Half of all adults will develop symptoms in the knee at some point in their lives.
The millions of middle-aged and older adults who suffer from insomnia have a new drug-free prescription for a more restful night’s sleep. Regular aerobic exercise improves the quality of sleep, mood and vitality, according to a small but significant new study from Northwestern Medicine.
About 50 percent of people in these age groups complain of chronic insomnia symptoms. The aerobic exercise trial resulted in the most dramatic improvement in patients’ reported quality of sleep, including sleep duration, compared to any other non-pharmacological intervention.
“This is relevant to a huge portion of the population,” said Phyllis Zee, MD, PhD director of the Sleep Disorders Center at Northwestern and senior author of a paper published in the October issue of Sleep Medicine. The lead author is Kathryn Reid, PhD, research assistant professor at Northwestern University Feinberg School of Medicine.
“Insomnia increases with age,” Zee said. “Around middle age, sleep begins to change dramatically. It is essential that we identify behavioral ways to improve sleep. Now we have promising results showing aerobic exercise is a simple strategy to help people sleep better and feel more vigorous.”
The drug-free strategy also is desirable, because it eliminates the potential of a sleeping medication interacting with other drugs a person may be taking, Reid said.
“By improving a person’s sleep, you can improve their physical and mental health,” Zee said. “Sleep is a barometer of health, like someone’s temperature. It should be the fifth vital sign. If a person says he or she isn’t sleeping well, we know they are more likely to be in poor health with problems managing their hypertension or diabetes.”
The study included 23 sedentary adults, primarily women, 55 and older who had difficulty falling asleep and/or staying asleep and impaired daytime functioning. Women have the highest prevalence of insomnia.
Exercise improved the participants’ self-reported sleep quality, elevating them from a diagnosis of poor sleeper to good sleeper. They also reported fewer depressive symptoms, more vitality and less daytime sleepiness.