Category Archives: Human Genetics

David Fajgenbaum's life went into overtime the moment a priest read his last rites in November 2010.

At least that's how the Penn Medicine immunologist views his last nine years.

That belief has reshaped the way Fajgenbaum confronts idiopathic multicentric Castleman disease, a rare immune system disorder that has dealt him five life-threatening blows. It's also changed the way he goes about his life.

"When you're in overtime, every second counts. You don't know how much time you have," said Fajgenbaum, a former quarterback at Georgetown University. "It really helps you focus in on what's important and what's not important."

For a while, Fajgenbaum said he "just hoped and prayed" that someone, somewhere, would find a cure and better treatment options for Castleman disease, which kills about 35% of its victims within five years of diagnosis. Then, he realized he might be that person.

That life lesson is among several that Fajgenbaum, 34, recounts in his new memoir, "Chasing My Cure: A Doctor's Race To Turn Hope Into Action." Fajgenbuam wrote the book partly in hopes of boosting awareness of Castleman disease, which has not gained the notoriety of other rare diseases despite its deadly nature.

"We shouldn't either hopeortake action we should hopeandtake action," Fajgenbaum said. "I'm here on the phone because of that turning point."

Idiopathic multicentric Castleman disease the most severe form of the disorder activates the bodys immune system, releasing an abundance of inflammatory proteins that can shut down the liver, kidneys and bone marrow. Relatively little is known about it.

Fajgenbaum, an assistant professor in Penn Medicine's Translational Medicine and Human Genetics division, has spearheaded efforts to identify more effective treatment options for people with Castleman disease. After all, he recognizes his clock may stop ticking at any moment.

Chemotherapy can keep the disease at bay for a while, but it's not a permanent solution, Fajgenbaum said. Patients tend to relapse after treatment, creating a vicious cycle that he knows all too well.

Thus far, the U.S. Food and Drug Administration only has approved one treatment siltuximab for Castleman disease. But it only works in about one-third of patients and Fajgenbaum is not one of them.

Fagjenbaum's research and his personal experience eventually led him to sirolimus, an immunosuppressant typically prescribed for kidney transplant patients. Because the drug inhibits activated T-cells, he suspected it might put his disease in remission.

"I knew if I did not start myself on a drug, there was no way I was going to make it," Fajgenbaum said.

Under the supervision of his doctor, Fajgenbaum began taking sirolimus after his last life-threatening hospitalization six years ago. At the time, Fajgenbaum was simply hoping he'd live long enough to marry his girlfriend, Caitlin something he said he once took for granted.

"The pre-overtime mentality is that we have all the time in the world, that if it's meant to be, it's meant to be," Fajgenbaum said. "But the overtime reality is that none of us have all the time in the world. If it's meaningful and important, then that's exactly what you should do."

Since Fajgenbaum began taking sirolimus, his symptoms have not flared up.

Now, he and Caitlin have a daughter, Amelia. And Fajgenbaum is leading clinical trials examining sirolimus' effectiveness against Castleman disease. Like siltuximab, the drug appears it may help some but not all people battling Castleman disease.

That has Fajgenbaum wondering how many other existing drugs have been overlooked as potential treatments for other diseases. It's another lesson that he expands upon in his book.

"Sometimes, solutions can be hiding in plain site," Fajgenbaum said. "This drug I'm on is in my neighborhood CVS all these years and no one had thought to try it. How many other things are like that ... in science or medicine?"

Since writing the book, Fajgenbaum said he has heard from all kinds of people who have faced challenging health diagnoses, whether it's cancer or some other rare disease.

It's definitely moving the needle, Fajgenbaum said. In September, the month the book was published, more people Googled Castleman disease than ever before. And more people have donated funds to the Castleman Disease Collaborative Network, an organization he co-founded to expedite research efforts.

"It's really been, in many ways, therapeutic to be able to share my story, the ups and the downs," Fajgenbaum said. "Even writing it was therapeutic. To bring back some tough memories, to expose them and to face them."

Sometimes, Fajgenbaum said, it's best to face the tough times with a sense of humor. That's a lesson he gained from his late mother, who died of cancer when he was at Georgetown.

Fajgenbaum recalled flying to Raleigh, North Carolina to see his mother after she had a brain tumor removed. He tentatively walked into her room alongside his family, unsure what to expect. He found his mom sitting, her head shaved and partly covered by a gauze wrap.

She pointed to her head and joked that she looked like the Chiquita banana lady.

"It was exactly what we needed," Fajgenbaum said. "It wasn't what my mom needed. She was going through a really tough time. It wasn't going to make her feel better. But she knew that it was going to make us feel better. By making that joke, it kind of relieved everything. It was like, you're still my mom, you're still you."

A few years later, Fajgenbaum found himself walking around the hospital with his father on New Year's Eve. This time, Fajgenbaum was the patient. His stomach was filled with 30 pounds of fluid, the result of his ill-functioning kidneys and liver.

As they passed the family waiting area, they stopped to help a man who was laying on the floor, noticeably drunk. The man thanked Fajgenbaum's father, wishing him and his "pregnant wife" the best of luck.

"We just burst into laughter," Fajgenbaum said. "I turned to my dad and said, 'Man, you've got an ugly wife.'

"If I hadn't had my mom's example ... maybe I would have just burst into tears and gone back to my room. Rather, that's hilarious. This drunk guy thinks I'm a pregnant woman because of the size of my belly."

That moment, nearly nine years ago, came just several weeks into Fajgenbaum's "overtime" session. He's overcome a lot since and learned a great deal. But he knows there's more work to be done for him and for others.

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His life in 'overtime,' Penn doctor races to find better treatments for rare Castleman disease - PhillyVoice.com

Pumping iron: A gene called BOLA2 helps proteins capture iron, which is crucial for red blood cells to transport oxygen.

Design Cells / Science Photo Library

IN BRIEF

Extra copies of a gene called BOLA2 predispose people to autism and may protect against iron deficiency, according to a new study1.

Repeats of the gene make people susceptible to deletion or duplication of a region on chromosome 16 that is tied to autism. The benefit of anemia prevention may explain why the repeats evolved despite their potential harm.

The rearrangement is highly compensated by an adaptation, says co-lead researcher Alexandre Reymond, director of the Center for Integrative Genomics at the Universit de Lausanne in Switzerland.

The extra copies are unique to humans, who typically have six. Our closest ancestors Neanderthals, Denisovans and chimpanzees each have only two, suggesting that the repeats confer an important evolutionary advantage. What that advantage is, however, has been a mystery.

One clue lies in the genes function: BOLA2 helps proteins capture iron. Having fewer repeats is associated with anemia, the researchers found.

Its very interesting, says Emily Casanova, research assistant professor of biomedical sciences at the University of South Carolina in Greenville, who was not involved in the study. My only question is why BOLA2 duplications would have been selected for. What might have been some of the driving factors?

BOLA2 repeats flank a stretch of chromosome 16 called 16p11.2, a hotspot for deletions and duplications that can lead to autism. As eggs and sperm form, the BOLA2 repeats cause DNA to break and rejoin in unusual ways in the 16p11.2 region.

Reymond and his colleagues counted BOLA2 repeats in 130 people who have a deletion of 16p11.2 and in the genetic sequences of 635 controls from two data repositories.

They found that 16p11.2 deletion carriers tend to have fewer BOLA2 repeats than controls do: four as opposed to the usual six. The findings suggest that some BOLA2 copies are lost when deletions in 16p11.2 form.

Because BOLA2 helps proteins latch onto iron, the researchers wondered whether too little of it has consequences for red blood cells; iron is crucial for the cells to transport oxygen.

The researchers analyzed blood samples and medical information from 83 deletion carriers. They found that 8 of the 15 people with only three BOLA2 repeats have signs of anemia, compared with 5 of 68 who have four or more repeats.

The researchers found a similar pattern when they examined genetic and medical information for 379,474 people in the UK Biobank. They found anemia in 20 percent of people with a 16p11.2 deletion, compared with 5 percent of controls. (Anemias prevalence in people with a duplication is no different than in controls.)

Mice missing a copy of 16p11.2 also have low iron levels, and their red blood cells show signs of mild anemia, the team found. Two strains of mice that lack one or both of their copies of BOLA2 show similar traits. The findings were published 7 November in the American Journal of Human Genetics.

The results jibe with those from a March study, in which researchers found an increased risk of anemia in people with a 16p11.2 deletion2.

The link of the BOLA2 copy number to anemia is quite strong, says Bernard Crespi, professor of evolutionary biology at Simon Fraser University in Vancouver, Canada, who was not involved in the study. Why humans evolved a higher number of BOLA2 genes, thats the hard question.

The factors that selected for extra BOLA2 copies remain a mystery. Having extra BOLA2 might have been beneficial as early humans shifted away from a diet based on red meat to one that is less rich in iron, Reymond says. Or perhaps the repeats arose because they protect people from infections, he says: Many pathogens depend on iron they scavenge from their hosts, and BOLA2 might interfere with that process.

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Gene repeats tied to autism may prevent anemia - Spectrum

The Centre for Human Genetics, Bengaluru, is hosting the second edition of the Indo-Swiss Meeting Meeting on Evolutionary Biology, held in India this year. The meeting is jointly organised by the Indian Society of Evolutionary Biologists, Centre for Human Genetics, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) and Swissnex India. The gathering brings together faculty and students from India and Switzerland. The three day meeting begins on the 12th of December and continues until the 14th.

The highlight of the event is the line-up of talks by various researchers from both countries on the topic of evolutionary biology.

We have about a hundred participants registered for the event and we hope to have a great discussion during the three days, said Prof Amitabh Joshi from JNCASR, who is also the coordinator of this event. This meeting, currently in its second edition, hopes to bring increased collaborations between researchers from both the countries, he says.

The presentations during the meeting span a huge spectrum of evolutionary biology, with Principal Investigators and doctoral and postdoctoral students from different institutes, presenting their research to a wider audience.

It feels nice to be here for the second edition of this meeting in India and I am hoping to meet many researchers and network with them, says Dr Rolf Kmmerli, from the University of Zurich. He had attended the first version of the meeting held in Switzerland. This year, the gathering is bigger than last year. he says.

The meeting hosts six talks by Swiss researchers and twelve by senior and early-career Indian evolutionary biologists. There is also a poster presentation and panel discussion organised as a part of the event. Additional details and the information on speakers can be found here.

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The second Indo-Swiss Meeting on Evolutionary Biology begins today - Research Matters

captionA file photo of a DNA double helix in an undated artists illustration released by the National Human Genome Research Institute to ReuterssourceThomson Reuters

Harvard University geneticist George Church recently discussed his plans to create a dating app that matches users based on their DNA, sparking debate whether the concept is helpful or harmful.

Church, who does gene-editing research, appeared on CBS 60 Minutes on Sunday and talked about why he believes his dating app concept, called Digid8, is needed.

According to Church, his app-to-be will prevent users from being matched with other users who share certain genes linked to rare genetic diseases like Tay-Sachs, which destroys a persons brain and spinal cord nerves, or cystic fibrosis, which causes chronic lung infections.

Church said his app concept could prevent people from having children with inherited genetic disorders because itd stop people with the same genetic predispositions from matching in the first place. He said the concept, if used widely, could eliminate many of todays genetic diseases entirely.

But critics of Churchs idea said its reminscent of eugenics, a philosophy that promotes selective breeding to create a physically superior race of humans, and one that was popularized by Nazis during the second World War to create a pure master race.

To use the app, which is currently unavailable and still in its development phase, users will first submit a saliva sample to a lab, similar to existing genetic testing services like 23andMe. Then, the lab would run various genetics tests on the spit specimen to determine what genetic diseases a person may carry.

According to Church, that information would remain confidential to the lab so not even the person who submitted the specimen would know the results. When they use dating apps then, theyd only be matched with people would dont have those same disease genes so the likelihood they pass them onto their future children is slim.

About 5 percent of children are born with a severe genetic disease, and so that means youre compatible with about 95 percent of people, Church said on 60 Minutes. Were just adding this [tool] to all the other dating criteria.

People who have criticized Churchs concept said it could have a snowball effect where people use it beyond its intended purpose of preventing genetic diseases.

Its not the technology itself thats problematic. Its how we use it, Vardit Ravitsky, a bioethicist at the Universit de Montral, told Medium.

People with disabilities, transgender people, people of color could be discriminated against using Digid8, Vice writer Janus Rose recently wrote.

The app could end up being used to weed out people who others deem genetically undesirable or inferior, Rose wrote, and put them at a disadvantage on these dating platforms that are meant to be inclusive of people regardless of ability, gender identity, and other factors.

Churchs genetics lab previously received funding from the late Jeffrey Epstein, a socialite and convicted pedophile who had a known interest in transhumanism, a eugenics-based philosophy that uses technology in an attempt to enhance the human population.

But Church said his app has nothing to do with eugenics because hes not requiring people to partake in it like classic eugenics does through forced sterilization, breeding, and extermination of certain people.

Church also said his lab works with an ethicist with the goal of making genetic testing technologies available to all people.

There are a lot of diseases which are not so serious which may be beneficial to society in providing diversity, for example, brain diversity. We wouldnt want to lose that, Church said on 60 Minutes. But if [a baby] has some very serious genetic disease that causes a lot of pain and suffering, costs millions of dollars to treat and they still die young, thats what were trying to deal with.

Until Digid8 officially launches, though, we wont know how the app will actually be used or abused.

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A Harvard geneticist is creating a dating app that matches users based on DNA, and people are worried its eugenics - Business Insider

Hardly a week goes by without a report announcing the end of work as we know it.

In 2013, Oxford University academics Carl Frey and Michael Osborne were the first to capture this anxiety in a paper titled: The Future of Employment: How susceptible are jobs to computerisation?.

They concluded 47% of US jobs were threatened by automation. Since then, Frey has taken multiple opportunities to repeat his predictions of major labour market disruptions due to automation.

In the face of threats to employment, some progressive thinkers advocate jettisoning our work ethic and building a world without work.

If machines can do our work, why not reduce the working week drastically? We should be mature enough to decide what truly matters to us, without tying our identity to a job, or measuring happiness in dollars and professional status. Right?

Not quite.

The reality is that work is tied to our constitution as a species. And this fact is too often overlooked in discussions about the future of work.

Recent studies have raised alarms that advances in automation and artificial intelligence (AI) will leave all sectors open to the threat of machines replacing human workers.

The power of AI will supposedly, according to these studies, even make high-skilled specialists redundant threatening medical practitioners, bank associates and legal professionals.

Predictions about the rise of the robots either take a pessimistic stance, focusing on disruptions to economic organisations, or view undoing work as an opportunity to move to a fairer social model.

However, these views disregard the central role work has played in humanitys development.

Philosophers including Karl Marx, Henri Bergson and John Dewey argued that working is a defining trait of humans.

Findings over the past two decades have confirmed that features of modern Homo sapiens are directly tied to their tendency to work.

Three basic ideas of the old philosophers are reaffirmed by contemporary research in archaeology, anthropology and genetics.

First, humans havent evolved to fit into their environments as seamlessly as other animals. Humans have had to compensate for a lack of fit.

They did this by learning about the ecosystems around them, the plants and animals they could eat, and the natural processes they could use, or should avoid. This knowledge was applied to create instruments, tools and weapons.

Very early on, humans mobilised their knowledge and skills to shape their immediate surroundings and become the dominant animal.

Knowledge of nature, technical skills and intervention in the environment are all characteristics of humans capacity to work. These allowed us to adapt to highly diverse geographies and climates.

Each new generation has to learn the skills and knowledge that will enable it to sustain its particular mode of survival.

Australian philosopher Kim Sterelny has shown in detail how evolution selected genetic traits that sustain humans capacity to learn, specifically by enhancing social behaviour and tolerance towards the young.And as humans worked on nature, they also worked in ways that influenced their minds, and their bodies.

It has been demonstrated that cooperation in humans reaches a level unknown in other species. This cooperative capacity has its roots in each individuals dependency on the knowledge, skills and efforts of others.

No human is able to sustain himself on his own, and collaboration exceeds what each person can produce alone. Even the most brilliant astrophysicist calls the plumber to fix a broken toilet.

Humans have to work to survive, and this entails working with, and for, others.

Acknowledging the anthropological depth of work means admitting current scenarios advocating the end of work are not the right answer. They take an unrealistic view of who we are.

We need to recognise work as a human need. As Marx said: Labour has become not only a means of life, but lifes prime want.

The question should not be whether theres room for human work in an automated future. The question should be: how will human work find its place next to machines and robots?

Even if automation becomes widespread, well still apply our minds, bodies and hands to productive tasks. Well still experiment and learn from others.

If machines could truly do all human work, then theyd make humans redundant, as 2001: A Space Odyssey anticipated back in 1968. While this isnt a pleasant scenario, its not a likely one either.

Automation might bring major social and economic disruptions in the short term, but it wont get rid of the need for humans to work.

Human needs are also infinitely complex. Nobody can foretell what new activities, techniques and consequent modes of working will fulfil future needs.

Even if we reject the modern work ethic, well still find ways to learn through action and emulate experts.Human intelligence is geared toward producing useful goods, so well continue to look for purposeful activities, too. And well seek collaboration with others for mutual benefit.

This is the influence of work on us. We are heir to thousands of years of evolution, and it would be pretentious to assume evolution could stop with us.

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Work is part of being human - robots won't stop us doing it - TechCentral

An algorithm akin to the annoyingly helpful one that attempts to auto-complete text messages and emails is now being harnessed for a better cause. A group of Drexel University researchers are using its pattern-recognition ability to identify microbial communities in the body by sifting through volumes of genetic code. Their method could speed the development of medical treatments for microbiota-linked ailments like Crohns disease.

In the last decade, scientists have made tremendous progress in understanding that groups of bacteria and viruses that naturally coexist throughout the human body play an important role in some vital functions like digestion, metabolism and even fighting off diseases. But understanding just how they do it remains a question.

Researchers from Drexel are hoping to help answer that question through a clever combination of high-throughput genetic sequencing and natural language processing computer algorithms. Their research, which was recently published in the journal PLOS ONE, reports a new method of analyzing the codes found in RNA that can delineate human microbial communities and reveal how they operate.

Much of the research on the human microbial environment or microbiome has focused on identifying all of the different microbe species. And the nascent development of treatments for microbiota-linked maladies operates under the idea that imbalances or deviations in the microbiome are the source of health problems, such as indigestion or Crohns disease.

But to properly correct these imbalances its important for scientists to have a broader understanding of microbial communities as they exist both in the afflicted areas and throughout the entire body.

We are really just beginning to scrape the surface of understanding the health effects of microbiota, said Gail Rosen, PhD, an associate professor in Drexels College of Engineering, who was an author of the paper. In many ways scientists have jumped into this work without having a full picture of what these microbial communities look like, how prevalent they are and how their internal configuration affects their immediate environment within the human body.

Rosen heads Drexels Center for Biological Discovery from Big Data, a group of researchers that has been applying algorithms and machine learning to help decipher massive amounts of genetic sequencing information that has become available in the last handful of years. Their work and similar efforts around the world have moved microbiology and genetics research from the wet lab to the data center creating a computational approach to studying organism interactions and evolution, called metagenomics.

In this type of research, a scan of a genetic material sample DNA or RNA can be interpreted to reveal the organisms that are likely present. The method presented by Rosens group takes that one step farther by analyzing the genetic code to spot recurring patterns, an indication that certain groups of organisms microbes in this case are found together so frequently that its not a coincidence.

We call this method themetagenomics, because we are looking for recurring themes in microbiomes that are indicators of co-occurring groups of microbes, Rosen said. There are thousands of species of microbes living in the body, so if you think about all the permutations of groupings that could exist you can imagine what a daunting task it is to determine which of them are living in community with each other. Our method puts a pattern-spotting algorithm to work on the task, which saves a tremendous amount of time and eliminates some guesswork.

Current methods for studying microbiota, gut bacteria for example, take a sample from an area of the body and then look at the genetic material thats present. This process inherently lacks important context, according to the authors.

Its impossible to really understand what microbe communities are doing if we dont first understand the extent of the community and how frequently and where else they might be occurring in the body, said Steve Woloszynek, PhD, and MD trainee in Drexels College of Medicine and co-author of the paper. In other words, its hard to develop treatments to promote natural microbial coexistence if their natural state is not yet known.

Obtaining a full map of microbial communities, using themetagenomics, allows researchers to observe how they change over time both in healthy people and those suffering from diseases. And observing the difference between the two provides clues to the function of the community, as well as illuminating the configuration of microbe species that enables it.

Most metagenomics methods just tell you which microbes are abundant therefore likely important but they dont really tell you much about how each species is supporting other community members, Rosen said. With our method you get a picture of the configuration of the community for example, it may have E. coli and B. fragilis as the most abundant microbes and in pretty equal numbers which may indicate that theyre cross-feeding. Another community may have B. fragilis as the most abundant microbe, with many other microbes in equal, but lower, numbers which could indicate that they are feeding off whatever B. fragilis is making, without any cooperation.

One of the ultimate goals of analyzing human microbiota is to use the presence of certain microbe communities as indicators to identify diseases like Crohns or even specific types of cancer. To test their new method, the Drexel researchers put it up against similar topic modeling procedures that diagnose Crohns and mouth cancer by measuring the relative abundance of certain genetic sequences.

The themetagenomics method proved to be just as accurate predicting the diseases, but it does it much faster than the other topic modeling methods minutes versus days and it also teases out how each microbe species in the indicator community may contribute to the severity of the disease. With this level of granularity, researchers will be able to home in on particular genetic groupings when developing targeted treatments.

The group has made its themetagenomics analysis tools publicly available in hopes of speeding progress toward cures and treatments for these maladies.

Its very early right now, but the more that we understand about how the microbiome functions even just knowing that groups may be acting together then we can look into the metabolic pathways of these groups and intervene or control them, thus paving the way for drug development and therapy research, Rosen said.

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Teams of Microbes Are at Work in Our Bodies. Researchers Have Figured Out What Theyre up... - ScienceBlog.com

BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. (Nasdaq:SGEN) today announced positive pivotal data from the HER2CLIMB trial evaluating tucatinib in patients with HER2-positive metastatic breast cancer (MBC) were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine (NEJM). The HER2CLIMB trial compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three lines in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. HER2CLIMB is the first randomized pivotal trial completed to enroll patients with metastatic HER2-positive breast cancer who have untreated or previously treated and progressing brain metastases. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

Following progression on trastuzumab, pertuzumab and T-DM1 in the metastatic HER2-positive breast cancer setting, there is no single standard of care regimen and clinical trial participation is often strongly encouraged. There is a significant unmet medical need for these patients, particularly those who develop brain metastases, said Rashmi Murthy, MD, MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine improved overall survival, reducing the risk of death by 34 percent compared to trastuzumab and capecitabine alone. The results from HER2CLIMB demonstrate tucatinib has the potential to become a new treatment option for patients who have been previously treated with multiple anti-HER2 agents, including patients with and without brain metastases.

Continued innovation to bring new therapies for the treatment of metastatic HER2-positive breast cancer is urgently needed, and we are encouraged by the impressive clinical activity demonstrated with the addition of tucatinib to trastuzumab and capecitabine in the HER2CLIMB trial, said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. Tucatinib demonstrated a statistically significant and clinically meaningful benefit in overall survival, progression-free survival and objective response rate compared to the control arm. We plan to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency by the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients.

Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival (OS) as well as progression-free survival (PFS) in patients with brain metastases at baseline.

Pivotal HER2CLIMB Trial Results

Efficacy:

Safety:

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate. Safety data were evaluated throughout the study.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. The trial is being conducted in North America and is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at http://www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, which is evaluating tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST criteria. Progression-free survival, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at http://www.clinicaltrials.gov.

About Seattle Genetics

Seattle Genetics, Inc. is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in peoples lives. ADCETRIS (brentuximab vedotin) utilizes the companys industry-leading antibody-drug conjugate (ADC) technology and is currently approved for the treatment of multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company has a late-stage pipeline including enfortumab vedotin for metastatic urothelial cancer, currently being reviewed for approval by the FDA, and tisotumab vedotin in clinical trials for metastatic cervical cancer, which utilize our proprietary ADC technology. In addition, tucatinib, a small molecule tyrosine kinase inhibitor, is in late-stage development for HER2-positive metastatic breast cancer and in clinical development for metastatic colorectal cancer. We are also leveraging our expertise in empowered antibodies to build a portfolio of proprietary immuno-oncology agents in clinical trials targeting hematologic malignancies and solid tumors. The company is headquartered in Bothell, Washington, and has a European office in Switzerland. For more information on our robust pipeline, visit http://www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

Forward Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of tucatinib, including its possible efficacy, safety and therapeutic uses; anticipated development activities including ongoing and future clinical trials; and intended regulatory actions, including the plan to submit an NDA to the FDA and a MAA to the EMA by the first quarter of 2020. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the difficulty and uncertainty of pharmaceutical product development, the risk of adverse events or safety signals, the possibility of disappointing results in ongoing or future clinical trials despite earlier promising clinical results, the possibility of delays in the submission of an NDA to the FDA and a MAA to the EMA, the possibility that data from the HER2CLIMB trial may not be sufficient to support approval of tucatinib and the possibility of adverse regulatory action. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption Risk Factors included in the companys Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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Seattle Genetics Announces Positive Tucatinib HER2CLIMB Trial Results in Locally Advanced or Metastatic HER2-Positive Breast Cancer Presented at 2019...

One of the more recent trends among parents-to-be is the so-called gender reveal, a party complete with pink or blue cake to answer the burning question, "Is it a boy or girl?" After all, it's presumed that there's a 50-50 chance you'd have one or the other. In a new article published inCurrent Biology, Michigan Medicine researchers studying the sex chromosomes have discovered genes that, at least in mice, skew that assumed ratio to favor one sex and that could have major implications for male infertility.

"There are a handful of genes known to underlie male infertility but there's still a lot unknown," says Alyssa Kruger, a Ph.D. student within the Department of Human Genetics. Kruger, who works in the lab of principal investigator Jacob Mueller, Ph.D., and their colleagues have been studying the X and Y chromosomes -- which are delivered by sperm to an egg to determine an offspring's sex--across species and across millions of years of evolution.

Sex chromosomes are unique, Kruger explains, because while they were once an identical pair of chromosomes, they independently evolved distinct sets of genes. Upon examining mice sex chromosomes, they found two recently evolved X-linked gene families that are found only in mice. Interestingly, these genes are also present multiple copies. To figure out what the genes are responsible for, Kruger's team removed them from the genomes of some mice using CRISPR and other technologies.

Removing all copies of one X-linked gene family produced mice whose offspring were biased towards being male by a ratio of 60-40. This discrepancy wasn't a result of more Y-bearing sperm--the number of X and Y sperm remained the same in the mice. "This suggests to us that this gene is impacting the relative fitness of X versus Y sperm, but we don't know how. Maybe the Y-bearing sperm are swimming faster or in a straighter line, we don't yet know," says Kruger.

Next, the team decided to increase the copy number of both X-linked gene families to get a better sense of why there are multiple copies. They duplicated these regions of the genome and surprisingly, this also skewed the sex ratio 60-40, only this time in favor of female offspring.

Kruger says that these X-linked gene families appear to be a "dial" for the fitness of X-bearing sperm. Interestingly, a related gene family on the Y-chromosome is also present in multiple copies and may serve an analogous role in Y-bearing sperm. The same sex-skewing has been observed in other experiments using fruit flies and, she says, something similar could be present in humans, though harder to observe. "We think of the back and forth copying of these genes as kind of an evolutionary arms race between the X and Y chromosomes that has played out over 20 million years to maintain the 50-50 male to female sex ratio."

Beyond their sex-ratio effects, an important feature of the two genes is that their complete removal leads to male mouse infertility.

Specifically, removing all copies of both X-linked gene families prevented male mice from producing sperm; they were unable to transform round cells to the elongated cells with a head and tail we recognize as sperm. Says Kruger, "There are a lot of cellular processes that have to happen that aren't. We hope this model will give us a better understanding of the developmental process of sperm production."

Reference: A neofunctionalized X-linked ampliconic gene family is essential for male fertility and equal sex ratio in mice. Current Biology. 2019. DOI: 10.1016/j.cub.2019.08.057.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Genes Linked to Sex Ratio Associated With Infertility - Technology Networks

In research that helps scientists better understand and explore treatments for diseases like Alzheimer's, scientists have developed a line of mice in which the mouse version of the Alzheimer's-associated MAPT gene has been fully replaced by the human version of the gene.

In this new animal model, known as a full gene-replacement model, the MAPT gene will function the same way it does in humans, allowing researchers to more accurately develop and evaluate genetic therapies. The research was presented at the American Society of Human Genetics 2019 Annual Meeting in Houston, Texas.

Researchers have long studied human genes in mice and other animal models, usually by finding and manipulating the animal's version of the human gene being studied, explained Michael Koob, PhD, Associate Professor at the University of Minnesota, who presented the work.

"However, mice have different genes than people, and even if the gene's function is the same, its sequence is different," Dr. Koob said. For this reason, animal model work typically involves a great deal of trial and error, and it requires researchers to make assumptions about why and how a genetic change leads to the observed changes. In addition, drawing conclusions about the role of the human version of the gene in humans - and building on this knowledge by developing therapies - is difficult and prone to error, and the findings do not always translate.

In developing their approach to full gene-replacement models, Dr. Koob and colleagues decided to focus on MAPT, a gene that is known to play an important role in Alzheimer's disease but whose involvement is not well understood. They overcame several technical challenges to do so, such as identifying the boundaries of the gene's protein-coding segments and regulatory regions, inserting the human version into the mouse genome with precision, and working with the gene's relatively large size.

By replacing the mouse's version of MAPT with the human version, Dr. Koob said, "we will be able to better explain how MAPT would function in humans, learn how it contributes to the symptoms and progression of Alzheimer's disease, and do some early testing of the potential efficacy of genetic therapies."

Longer term, the researchers plan to use the same approach to develop full gene-replacement models for other genes involved in Alzheimer's, eventually building up to a mouse model that expresses several genes involved in the disease.

"A mouse model that expresses multiple genes will help us understand the interactions among genes that may contribute to disease," Dr. Koob said.

They have also developed similar models for genes involved in other diseases, such as the neurological disorder spinocerebellar ataxia type 1 and the eye disease Fuchs endothelial corneal dystrophy.

Reference:M Koob et al. (2019 Oct 16). Abstract: Moving human genetics into the mouse: Full human gene-replacement models. Presented at the American Society of Human Genetics 2019 Annual Meeting. Houston, Texas.

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A Mouse Model of the Human Gene Involved in Alzheimers Disease Is Created - Technology Networks

Prime Minister Benjamin Netanyahus Twitter account blew up in July in the wake of an extraordinary tweet: A new study of DNA recovered from an ancient Philistine site in the Israeli city of Ashkelon confirms what we know from the Bible that the origin of the Philistines is in southern Europe. ... The Palestinians connection to the Land of Israel is nothing compared to the 4,000 year connection that the Jewish people have with the land.

Netanyahu, like the hundreds of people who replied to the tweet, interpreted the study as overwhelming proof of Jewish ownership of the Land of Israel and proof that the Philistines who share an etymological history with the Palestinians were new immigrants, having arrived here just 3,000 years ago. Officials from the Palestinian Authority were quick to say that Palestinians are the descendants not of the Philistines but rather of the Canaanite Jebusites, who were ostensibly the original inhabitants of the land.

Netanyahus tweet came a few days after the publication in the magazine Science advances of a study by researchers from Germanys Max Planck Institute for the Science of Human History and the Leon Levy Expedition. The researchers sampled DNA from 10 skeletons found in Ashkelon and concluded that their gene pool came from southern Europe. The finding supports the accepted theory that the Philistines migrated from the area of Greece and settled along what is today Israels southern Mediterranean coast.

The studys authors, however, were infuriated by the prime ministers tweets. They considered responding but decided it might give the tweets more exposure. Netanyahus political spin on the research upset many scholars, who saw it as an example of the danger inherent in bringing genetics into the study of human history. Critics fear that used incautiously, genetic research not only has the potential to distort history but also can become a tool for racist propaganda in the hands of extremist politicians and groups.

The ability to extract and sequence DNA from samples that are thousands and even hundreds of thousands of years old has led to significant breakthroughs in the study of evolution. By sequencing Neanderthal genomes, scientists have learned about the health, physical appearance and settlement patterns of Neanderthals. Even more important, DNA research led to the discovery of formerly unknown hominids. The most famous being the Denisovans, which was discovered only thanks to a single finger bone found in a cave in Siberia, from which its owners genome was sequenced. The researchers were also able to determine that most modern human beings carry genes from Neanderthals, Denisovans and additional, as-yet unidentified hominids.

Broad brush

These successes led researches to apply genetic tools to later periods, and according to some critics that is where the danger lies. A study published last week in Science Magazine of 4,000-year-old graves in southern Germany determined, using DNA and as well as the objects with which their occupants were buried that the wealthiest men were locals. Poor men, servants and most of the women came from elsewhere, and most of the high-status women were apparently sent to other communities. One can only manage the political conclusions that could be drawn from the study.

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The problem isnt with the research itself, says Raphael Greenberg, a professor of archaeology at Tel Aviv University. Say I want to know about the connection between the Levant and the Greek region. I have various ways to examine it: pottery, inscriptions, symbols, language, and now something new has been added to my arsenal. Thats great, no one will deny that its useful. The problem is that DNA research has an element of magic to it. Only a few laboratories carry out these tests, at very high cost, and no one can argue with them, Greenberg says. He adds that their operators dont make do with presenting their findings; they go on to interpret the results. He believes that DNA researchers should leave conjectures about population migrations to the relevant experts.

The disagreement surrounding Who We Are and How We Got Here: Ancient DNA and the New Science of the Human Past, by Harvard geneticist David Reich, illustrates Greenbergs argument. Reich is considered the most important researcher in the area of ancient DNA, but his critics attack him for reducing complex historical process into simplified sound bites. He has lost some of the soul of what archaeology and sociology are, wrote Anna Linderholm of Texas A&M University in a review published in Current Anthropology. With his investigations he is painting with large brushstrokes a picture of our past, and in doing so, he might be missing some of the finer points. Who we are is much more than the genetics.

Critics argue that genetics alone cannot tell the complex story of the exchange of genetic material between two population groups, which involves not only migrations but also trade, war and the taking of male and female prisoners.

Gene sequencing, says Prof. Assaf Yasur-Landau of the University of Haifa, is a completely new tool whose potential we dont yet understand.... The danger is in making the connection between genetics and cultural. Its absolutely forbidden and borders on racism.

My granny was a Philistine

The dispute over the archaeological use of DNA is part of a broader discussion. Last year Reich published an opinion piece in The New York Times in which he argued that scientists should stop denying the existence of genetic differences between human population groups, rather than viewing race as entirely a social construct with no biological basis.

It is important to face whatever science will reveal without prejudging the outcome and with the confidence that we can be mature enough to handle any findings. Arguing that no substantial differences among human populations are possible will only invite the racist misuse of genetics that we wish to avoid, Reich wrote.

In an open letter produced by a group of 67 scientists and researchers and published on BuzzFeed, they attacked Reichs approach and warned against returning to a racial-genetic understanding of humanity.

Human beings are 99.5% genetically identical.... [Y]ou could genotype all Red Sox fans and all Yankees fans and find that one group has a statistically significant higher frequency of a number of particular genetic variants than the other group.... This does not mean that Red Sox fans and Yankees fans are genetically distinct races, they wrote.

Michal Feldman, an Israeli geneticist who works at the Max Planck Institute, was the lead author on the article on the skeletons from Ashkelon. Were trying to be cautious in our research and also in our press releases, and to explain exactly what we found, she says. We said we saw a genetic component that came from southern Europe, but that it disappeared after 200 years despite the fact that culturally they were still Philistines. Feldman agrees that the genetics must be separated from culture. Theres no such thing as a pure population or separate groups. Only a tiny part of the genome, 0.01 percent, attests to the origin, and most of the genes within that part are of no importance.

Nimrod Marom, an archaeo-zoologist at the University of Haifa, says the danger is of reducing the discussion to the question, Where did your mother come from?. He says that DNA research is more interested in the origin of the Philistines grandmother than in the way he lived here. In the end it doesnt say much about me and doesnt say much about anyone, he says. We get annoyed today when thats done to us, when we are categorized according to where we came from, so theres no reason not to be annoyed when its done to people from other periods.

Greenberg also believes that the danger of reductionism in genetic studies is much greater than getting an inaccurate picture of the past. We object to these classifications in our daily lives, we dont want to be defined by something that we dont see and have no control over. We want to say who we are by what we think and what we identify with. This method expropriates our identify from us. It says your identity isnt your religion and it isnt the food that you like, its what we tell you it is. Theres not really any such thing as the original inhabitants of this land.

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DNA research holds the keys to human history but it's being weaponized by politicians - Haaretz