Swarms of Magnetic Bacteria Could Be Used to Deliver Drugs to Tumors

Swarms of Magnetic Bacteria Could Be Used to Deliver Drugs to Tumors

Researchers funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have recently shown that magnetic bacteria are a promising vehicle for more efficiently delivering tumor-fighting drugs. They reported their results in the August 2016 issue of Nature Nanotechnology.

One of the biggest challenges in cancer therapy is being able to sufficiently deliver chemotherapy drugs to tumors without exposing healthy tissues to their toxic effects. One way researchers have attempted to overcome this is by developing nanocarriers — extremely small particles packed with drugs. The nanocarriers are designed so they’re only taken up by cancer cells, thereby preventing the drugs from being absorbed by healthy tissues as they travel through the body’s circulation.

Yet while nanocarriers do a good job protecting healthy tissues, the amount of drug successfully delivered to tumors remains low. The main reasons for this shortcoming are that nanocarriers rely on the circulation system to carry them to the tumor, so a large percentage are filtered out of the body before ever reaching their destination. In addition, differences in pressure between the tumor and its surrounding tissue prevent nanocarriers from penetrating deep inside the tumor. As a result, nanocarriers aren’t able to reach the tumor’s hypoxic zones, which are regions of active cell division that are characterized by low oxygen content.

“Only a very small proportion of drugs reach the hypoxic zones, which are believed to be the source of metastasis. Therefore, targeting the low-oxygen regions will most likely decrease the rate of metastasis while maximizing the effect of a therapy,” says Sylvain Martel, Ph.D., Director of the Polytechnique Montréal NanoRobotics Laboratory and lead researcher of the study.

Martel and his research team were attempting to develop robotic nanocarriers that would travel to hypoxic zones when they realized nature may have already created one in the form of a bacteria called magnetococcus marinus or MC-1. MC-1 cells thrive in deep waters where oxygen is sparse. In order to find these areas, the bacteria rely on a two-part navigation system. The first part involves a chain of magnetic nanocrystals within MC-1 that acts like a compass needle and causes the bacteria to swim in a north direction when in the Northern Hemisphere. The second part consists of sensors that allow the bacteria to detect changes in oxygen levels. This unique navigation system helps the bacteria migrate to and maintain their position at areas of low oxygen.

With funding support from NIBIB and others, Martel’s research team conducted a series of experiments to show that the bacteria’s unique navigation system could be exploited to more efficiently deliver drugs to tumors.

In an initial experiment, mice that had been given human colorectal tumors were injected with either live MC-1 cells, dead MC-1 cells, or as a control group, non-magnetic beads (roughly the same size as the bacteria). The injection was made into the tissue directly adjacent to the tumors after which the mice were exposed to a computer-programmed magnetic field, meant to direct the cells or beads into the tumor. Upon examination of the tumors, the researchers found minimal penetration of the dead bacterial cells and the beads into the tumor, whereas the live bacterial cells were found deep within the tumor and especially in regions with low oxygen content.

“When they get inside the tumor, we switch off the magnetic field and the bacteria automatically rely on the oxygen sensors to seek out the hypoxic areas,” says Martel. “We constrain them to the tumor and then let nature do the rest.”

Next, the researchers wanted to see whether attaching vesicles loaded with drugs to the cells would affect their movement into the tumors. They attached approximately 70 drug-containing vesicles to each bacterial cell. The cells were then injected into another set of mice with colorectal tumors and exposed to the magnet. After examining the tumors of those mice, the researchers estimated that on average, 55% of the injected bacterial cells with attached vesicles made it into the tumor. For comparison, some researchers estimate that only approximately 2% of drugs delivered via current nanocarriers make it into tumors.

“This proof-of-concept work shows the potential to tap into the intricate and optimized cell machinery of single celled organisms such as bacteria,” said Richard Conroy, Ph.D., director of the Division of Applied Sciences and Technology at NIBIB. “The ability to actively and precisely target drug delivery to a tumor will help reduce side effects and potentially improve the efficacy of treatments.”

The next step for Martel’s team is to determine the effects of the drug-loaded bacterial cells on reducing tumor size. They would also like to test whether the bacteria can be used to deliver other types of cancer-killing medicines such as molecules that instruct the immune system to attack tumors.

In addition, the team is working to expand the types of tumors the bacteria could be used for. Currently, the bacteria have to be injected very close to the tumor because, if injected into arteries, the excessive blood flow and the distance needed to travel would impact the number of bacteria that reach the tumor. This limits the drug delivery approach to cancers that are easily accessible such as colorectal, prostate, and potentially breast cancer. However, Martel’s team has shown in animals that they can transport the bacteria through arteries and sufficiently close to the tumor by first encapsulating them in magnetic carriers and propelling them by the magnetic field of an MRI scanner. The bacteria can then be released from the carriers, like torpedoes from a submarine, once close to the tumor. This multi-step approach could potentially open the door for using the bacteria to deliver drugs to tumors deeper in the body.

Martel says that preliminary test results of the bacteria in mice and rats and the fact that the bacteria die within 30 minutes of being injected, suggest that they could potentially be safe in humans.

“These bacteria are really the perfect machine. They replicate, they’re cheap, and we can inject hundreds of millions or more at a time,” says Martel.

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You Can’t Blame Your Genes If You Don’t Lose Weight, Study Finds

You Can’t Blame Your Genes If You Don’t Lose Weight, Study Finds

Carriers of the FTO gene are known to be on average 3 kilos (6.6lbs) heavier and 70% more likely to be obese.

However, researchers at Newcastle University, publishing in The BMJ today, report that in a review of eight studies involving over 9,000 people, carrying this gene did not prevent them losing weight.

John Mathers, Professor of Human Nutrition at Newcastle University, who led the study, said: “You can no longer blame your genes. Our study shows that improving your diet and being more physically active will help you lose weight, regardless of your genetic makeup.”

Getting the weight off

Obesity is a major health problem and, in the UK, more than 25% of adults are obese. For some people, carrying the risk variant of the FTO gene can lead to them being heavier and increasing their risk of obesity. The FTO gene has been shown to have the biggest effect in this area.

In a major collaborative systematic review and meta-analysis, the international team used individual data from 9,563 adults who were enrolled in randomised controlled weight loss trials around the world to find out whether carrying the risk version of the FTO gene affects how much weight people lose.

They found that carrying the risk version of the FTO gene had no effect on weight loss as Professor Mathers explains: “We were excited to find that people with the risk version of FTO respond just as well to weight loss interventions as everyone else.

“This is important news for people trying to lose weight as it means that diet, physical activity or drug-based weight loss plans will work just as well in those who carry the risk version of FTO.

“For public health professionals, it means that the adverse effects of the FTO genotype on weight gain are not an impediment to weight loss interventions.”

FTO gene carriers

lady on scales

Importantly, the team found that the response to weight loss interventions for people carrying the risk variant of the FTO gene was similar for men and women, younger and older and people of different ethnicities.  However, most people in the studies were Caucasians with smaller numbers of those from Black/ African American and Hispanic backgrounds. The team say future research should explore effects of FTO on weight loss in other ethnic groups. In addition, the effects of other obesity-related genes on weight loss remain to be investigated.

In a linked editorial in The BMJ, Dr Alison Tedstone, chief nutritionist at Public Health England, says the causes of the obesity epidemic are multiple and complex, but current evidence suggests they have little to do with gene profiles.

She argues that, if we are to turn back the tide of obesity, a focus on personalised interventions based on the genome “may not pay off, at least in the short term.” Instead, she says “a rebalancing of research towards whole systems approaches including environmental drivers may be of greater benefit to the population in the long term.”

Fungus In Humans Identified For First Time As Key Factor In Crohn’s Disease

Fungus In Humans Identified For First Time As Key Factor In Crohn’s Disease

A Case Western Reserve University School of Medicine-led team of international researchers has for the first time identified a fungus as a key factor in the development of Crohn’s disease. The researchers also linked a new bacterium to the previous bacteria associated with Crohn’s. The groundbreaking findings, published on September 20th in mBio, could lead to potential new treatments and ultimately, cures for the debilitating inflammatory bowel disease, which causes severe abdominal pain, diarrhea, weight loss, and fatigue.

“We already know that bacteria, in addition to genetic and dietary factors, play a major role in causing Crohn’s disease,” said the study’s senior and corresponding author, Mahmoud A Ghannoum, PhD, professor and director of the Center for Medical Mycology at Case Western Reserve and University Hospitals Cleveland Medical Center “Essentially, patients with Crohn’s have abnormal immune responses to these bacteria, which inhabit the intestines of all people. While most researchers focus their investigations on these bacteria, few have examined the role of fungi, which are also present in everyone’s intestines. Our study adds significant new information to understanding why some people develop Crohn’s disease. Equally important, it can result in a new generation of treatments, including medications and probiotics, which hold the potential for making qualitative and quantitative differences in the lives of people suffering from Crohn’s.”

Both bacteria and fungi are microorganisms — infinitesimal forms of life that can only be seen with a microscope. Fungi are eukaryotes: organism whose cells contain a nucleus; they are closer to humans than bacteria, which are prokaryotes: single-celled forms of life with no nucleus. Collectively, the fungal community that inhabits the human body is known as the mycobiome, while the bacteria are called the bacteriome. (Fungi and bacteria are present throughout the body; previously Ghannoum had found that people harbor between nine and 23 fungal species in their mouths.)

The researchers assessed the mycobiome and bacteriome of patients with Crohn’s disease and their Crohn’s-free first degree relatives in nine families in northern France and Belgium, and in Crohn’s-free individuals from four families living in the same geographic area. Specifically, they analyzed fecal samples of 20 Crohn’s and 28 Crohn’s-free patients from nine families and of 21 Crohn’s-free patients of four families. The researchers found strong fungal-bacterial interactions in those with Crohn’s disease: two bacteria (Escherichia coli and Serratia marcescens) and one fungus (Candida tropicalis) moved in lock step. The presence of all three in the sick family members was significantly higher compared to their healthy relatives, suggesting that the bacteria and fungus interact in the intestines. Additionally, test-tube research by the Ghannoum-led team found that the three work together (with the E. coli cells fusing to the fungal cells and S. marcescens forming a bridge connecting the microbes) to produce a biofilm — a thin, slimy layer of microorganisms found in the body that adheres to, among other sites, a portion of the intestines — which can prompt inflammation that results in the symptoms of Crohn’s disease.

This is first time any fungus has been linked to Crohn’s in humans; previously it was only found in mice with the disease. The study is also the first to include S. marcescens in the Crohn’s-linked bacteriome. Additionally, the researchers found that the presence of beneficial bacteria was significantly lower in the Crohn’s patients, corroborating previous research findings.

“Among hundreds of bacterial and fungal species inhabiting the intestines, it is telling that the three we identified were so highly correlated in Crohn’s patients,” said Ghannoum. “Furthermore, we found strong similarities in what may be called the ‘gut profiles’ of the Crohn’s-affected families, which were strikingly different from the Crohn’s-free families. We have to be careful, though, and not solely attribute Crohn’s disease to the bacterial and fungal makeups of our intestines. For example, we know that family members also share diet and environment to significant degrees. Further research is needed to be even more specific in identifying precipitators and contributors of Crohn’s.”

Can Nicotine Protect the Aging Brain?

Can Nicotine Protect the Aging Brain?

Everyone knows that tobacco products are bad for your health, and even the new e-cigarettes may have harmful toxins. However, according to research at Texas A&M, it turns out the nicotine itself—when given independently from tobacco—could help protect the brain as it ages, and even ward off Parkinson’s or Alzheimer’s disease.

Ursula Winzer-Serhan, PhD, an associate professor at the Texas A&M College of Medicine, and her collaborators found that nicotine’s ability to be neuroprotective may be partly due to its well-known ability to suppress the appetite. Their research is published in the Open Access Journal of Toxicology.

Using animal models, Winzer-Serhan and her collaborators added nicotine to the animal’s drinking water. There were three different groups that received nicotine at three different concentrations (low, medium and high) corresponding to occasional, low and medium smokers, respectively, in addition to a control group that did not receive any nicotine.

The two groups that received nicotine at low and medium doses didn’t show any levels of the drug in their blood and they experienced no changes in food intake, body weight or number of receptors in the brain where nicotine acts. In contrast, the group getting the highest concentration of nicotine ate less, gained less weight and had more receptors, indicating that at higher doses, the drug gets into the brain where it can impact behavior. However, even at high doses, it didn’t seem to have worrying behavioral side effects like making the individuals more anxious, which the researchers were concerned could happen.

“Some people say that nicotine decreases anxiety, which is why people smoke, but others say it increases anxiety,” Winzer-Serhan said. “The last thing you would want in a drug that is given chronically would be a negative change in behavior. Luckily, we didn’t find any evidence of anxiety: Only two measures showed any effect even with high levels of nicotine, and if anything, nicotine made animal models less anxious.”

The next step is to test nicotine’s potential anti-aging effects using aged animal models. Although early results indicate that nicotine can keep older individuals from gaining weight like the control group does, Winzer-Serhan hasn’t yet determined whether this lower body mass index translates into less degeneration of the brain. It is also unclear if nicotine’s effects are related only to its ability to suppress appetite, or if there are more mechanisms at work.

Because there are still so many unknowns, Winzer-Serhan urges caution. “I want to make it very clear that we’re not encouraging people to smoke,” she said. “Even if these weren’t very preliminary results, smoking results in so many health problems that any possible benefit of the nicotine would be more than cancelled out. However, smoking is only one possible route of administration of the drug, and our work shows that we shouldn’t write-off nicotine completely.”

Still, Winzer-Serhan cautions people not to purchase nicotine-containing products just yet. “Although the results are intriguing, we would need large-scale clinical trials before suggesting anyone change their behavior,” she said. “At the end of the day, we haven’t proven that this addictive drug is safe—and it certainly isn’t during childhood or adolescence—or that the benefits outweigh the potential risks.”

Quadruple Helix Form Of DNA May Aid In The Development Of Targeted Cancer Therapies

Quadruple Helix Form Of DNA May Aid In The Development Of Targeted Cancer Therapies

Scientists have identified where a four-stranded version of DNA exists within the genome of human cells, and suggest that it may hold a key to developing new, targeted therapies for cancer.

In work funded by Cancer Research UK and EMBO, the researchers, from the University of Cambridge, found that these quadruple helix structures occur in the regions of DNA that control genes, particularly cancer genes, suggesting that they may play a role in switching genes on or off. The results, reported in the journal Nature Genetics, could also have implications for cancer diagnostics and the development of new targeted treatments.

Most of us are familiar with the double helix structure of DNA, but there is also a version of the molecule which has a quadruple helix structure. These structures are often referred to as G-quadruplexes, as they form in the regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’. These structures were first found to exist in human cells by the same team behind the current research, but at the time it was not exactly clear where these structures were found in the genome, and what their role was, although it was suspected that they had a link with certain cancer genes.

“There have been a number of different connections made between these structures and cancer, but these have been largely hypothetical,” said Professor Shankar Balasubramanian, from Cambridge’s Department of Chemistry and Cancer Research UK Cambridge Institute, and the paper’s senior author. “But what we’ve found is that even in non-cancer cells, these structures seem to come and go in a way that’s linked to genes being switched on or off.”

Starting with a pre-cancerous human cell line, the researchers used small molecules to change the state of the cells in order to observe where the G-quadruplexes might appear. They detected approximately 10,000 G-quadruplexes, primarily in regions of DNA associated with switching genes on or off, and particularly in genes associated with cancer.

“What we observed is that the presence of G-quadruplexes goes hand in hand with the output of the associated gene,” said Balasubramanian. This suggests that G-quadruplexes may play a similar role to epigenetic marks: small chemical modifications which affect how the DNA sequence is interpreted and control how certain genes are switched on or off.

The results also suggest that G-quadruplexes hold potential as a molecular target for early cancer diagnosis and treatment, in particular for so-called small molecule treatments which target cancer cells, instead of traditional treatments which hit all cells.

“We’ve been looking for an explanation for why it is that certain cancer cells are more sensitive to small molecules that target G-quadruplexes than non-cancer cells,” said Balasubramanian. “One simple reason could be that there are more of these G-quadruplex structures in pre-cancerous or cancer cells, so there are more targets for small molecules, and so the cancer cells tend to be more sensitive to this sort of intervention than non-cancer cells.

“It all points in a certain direction, and suggests that there’s a rationale for the selective targeting of cancer cells.”

“We found that G-quadruplexes appear in regions of the genome where proteins such as transcription factors control cell fate and function,” said Dr Robert Hänsel-Hertsch, the paper’s lead author. “The finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works.”

Dr Emma Smith, Cancer Research UK’s science information manager, said: “Figuring out the fundamental processes that cancer cells use to switch genes on and off could help scientists develop new treatments that work against many types of the disease. And exploiting weaknesses in cancer cells could mean this approach would cause less damage to healthy cells, reducing potential side effects. It’s still early days, but promising leads like this are where the treatments of the future will come from.”

Lab Discovers Titanium-Gold Alloy that is Four Times Harder than Most Steels

Lab Discovers Titanium-Gold Alloy that is Four Times Harder than Most Steels

Titanium is the leading material for artificial knee and hip joints because it’s strong, wear-resistant and nontoxic, but an unexpected discovery by Rice University physicists shows that the gold standard for artificial joints can be improved with the addition of some actual gold.

Crystal structure of beta titanium-3 gold

“It is about 3-4 times harder than most steels,” said Emilia Morosan, the lead scientist on a new study in Science Advances that describes the properties of a 3-to-1 mixture of titanium and gold with a specific atomic structure that imparts hardness. “It’s four times harder than pure titanium, which is what’s currently being used in most dental implants and replacement joints.”

Morosan, a physicist who specializes in the design and synthesis of compounds with exotic electronic and magnetic properties, said the new study is “a first for me in a number of ways. This compound is not difficult to make, and it’s not a new material.”

In fact, the atomic structure of the material — its atoms are tightly packed in a “cubic” crystalline structure that’s often associated with hardness — was previously known. It’s not even clear that Morosan and former graduate student Eteri Svanidze, the study’s lead co-author, were the first to make a pure sample of the ultrahard “beta” form of the compound. But due to a couple of lucky breaks, they and their co-authors are the first to document the material’s remarkable properties.

Emilia Morosan and Eteri Svanidze

“This began from my core research,” said Morosan, professor of physics and astronomy, of chemistry and of materials science and nanoengineering at Rice. “We published a study not long ago on titanium-gold, a 1-to-1 ratio compound that was a magnetic material made from nonmagnetic elements. One of the things that we do when we make a new compound is try to grind it into powder for X-ray purposes. This helps with identifying the composition, the purity, the crystal structure and other structural properties.

“When we tried to grind up titanium-gold, we couldn’t,” she recalled. “I even bought a diamond (coated) mortar and pestle, and we still couldn’t grind it up.”

Morosan and Svanidze decided to do follow-up tests to determine exactly how hard the compound was, and while they were at it, they also decided to measure the hardness of the other compositions of titanium and gold that they had used as comparisons in the original study.

Eteri Svanidze and Emilia Morosan

One of the extra compounds was a mixture of three parts titanium and one part gold that had been prepared at high temperature.

What the team didn’t know at the time was that making titanium-3-gold at relatively high temperature produces an almost pure crystalline form of the beta version of the alloy — the crystal structure that’s four times harder than titanium. At lower temperatures, the atoms tend to arrange in another cubic structure — the alpha form of titanium-3-gold. The alpha structure is about as hard as regular titanium. It appears that labs that had previously measured the hardness of titanium-3-gold had measured samples that largely consisted of the alpha arrangement of atoms.

The team measured the hardness of the beta form of the crystal in conjunction with colleagues at Texas A&M University’s Turbomachinery Laboratory and at the National High Magnetic Field Laboratory at Florida State University, Morosan and Svanidze also performed other comparisons with titanium. For biomedical implants, for example, two key measures are biocompatibility and wear resistance. Because titanium and gold by themselves are among the most biocompatible metals and are often used in medical implants, the team believed titanium-3-gold would be comparable. In fact, tests by colleagues at the University of Texas MD Anderson Cancer Center in Houston determined that the new alloy was even more biocompatible than pure titanium. The story proved much the same for wear resistance: Titanium-3-gold also outperformed pure titanium.

Morosan said she has no plans to become a materials scientist or dramatically alter her lab’s focus, but she said her group is planning to conduct follow-up tests to further investigate the crystal structure of beta titanium-3-gold and to see if chemical dopants might improve its hardness even further.

Radiant Zinc Fireworks Reveal Quality of Human Egg

Radiant Zinc Fireworks Reveal Quality of Human Egg

CHICAGO — A stunning explosion of zinc fireworks occurs when a human egg is activated by a sperm enzyme, and the size of these “sparks” is a direct measure of the quality of the egg and its ability to develop into an embryo, according to new research from Northwestern Medicine.

The discovery has potential to help doctors choose the best eggs to transfer during in vitro fertilization (IVF), the scientists said.

This is the first time the zinc sparks have been documented in a human egg.

“This means if you can look at the zinc spark at the time of fertilization, you will know immediately which eggs are the good ones to transfer in in vitro fertilization (IVF),” said Teresa Woodruff, one of the study’s two senior authors and an expert in ovarian biology at Northwestern. “It’s a way of sorting egg quality in a way we’ve never been able to assess before.”

Woodruff is the Thomas J. Watkins Memorial Professor in Obstetrics and Gynecology at Northwestern University Feinberg School of Medicine and director of Northwestern’s Center for Reproductive Science.

Scientists activated the egg by injecting a sperm enzyme into the egg that triggers calcium to increase within the egg and zinc to be released from the egg. (The eggs in the study were not fertilized with actual sperm because that is not permitted in human research under federal law.)

“It was remarkable,” Woodruff said. “We discovered the zinc spark just five years ago in the mouse, and to see the zinc radiate out in a burst from each human egg was breathtaking.

“All of biology starts at the time of fertilization, yet we know next to nothing about the events that occur in the human. This discovery required a unique partnership between biologists and chemists and non-federal dollars to support the research,” she said.

The study was published April 26 in Scientific Reports.

As the zinc is released from the egg, it binds to small molecule probes, which emit light in fluorescence microscopy experiments. Thus the rapid zinc release can be followed as a flash of light that appears as a spark.

“These fluorescence microscopy studies establish that the zinc spark occurs in human egg biology, and that can be observed outside of the cell,” said Tom O’Halloran, a co-senior author.  O’Halloran is the Charles E. and Emma H. Morrison Professor in Chemistry in the Weinberg College of Arts and Sciences and director of Northwestern’s Chemistry of Life Processes Institute.

Eggs compartmentalize and distribute zinc to control the development of a healthy embryo. Over the last six years this team has shown that zinc controls the decision to grow and change into a completely new genetic organism.

“This is an important discovery because it may give us a non-invasive and easily visible way to assess the health of an egg and eventually an embryo before implantation,” said co-author Dr. Eve Feinberg, who took care of the patients who provided eggs for the basic science study and collaborated with the research team.

Feinberg will become an assistant professor of obstetrics and gynecology at Feinberg and will be ambulatory medical director of Northwestern Medicine’s Fertility and Reproductive Medicine division beginning July 1. Feinberg currently is a physician at Fertility Centers of Illinois (FCI).

“There are no tools currently available that tell us if it’s a good quality egg,” Feinberg said. “Often we don’t know whether the egg or embryo is truly viable until we see if a pregnancy ensues. That’s the reason this is so transformative. If we have the ability up front to see what is a good egg and what’s not, it will help us know which embryo to transfer, avoid a lot of heartache and achieve pregnancy much more quickly.”

First author Francesca Duncan made the human zinc spark discovery. “We now know that the release of zinc at the time of fertilization is a conserved phenomenon, which will help us address one of the largest unanswered questions in reproductive medicine — what makes a good egg?” Duncan said.

Duncan was an assistant research professor in obstetrics and gynecology at Feinberg when she made the discovery and will become the executive director of Northwestern’s Center for Reproductive Science on August 1. She is currently an assistant professor at the University of Kansas Medical Center. Emily Que and Nan Zhang are co-first authors.

In a companion paper published in Scientific Reports on March 18, a zinc spark is shown at the precise time a sperm enters a mouse egg. This discovery was made by Zhang, a postdoctoral fellow at Northwestern. Zhang said little is known about the events that occur at the time of fertilization, because it is difficult to capture the precise time of sperm entry.

The paper is titled “The Zinc Spark is an Inorganic Signature of Human Egg Activation.”

The research was supported by the Thomas J. Watkins Endowment and a research grant from Ferring Pharmaceuticals and the W.M. Keck Foundation. All human egg activation studies were done exclusively with samples from FCI and funds from Ferring Pharmaceuticals.