Category Archives: Human Genetics

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...

An important question in medication asks how individual changes in DNA can predict variation in disease and health. New research from the Clemson Center for Human Genetics identified several metabolites that may function intermediates to translate variation within the genome to variation in advanced traits. Published lately in Genome Research, the findings may, in the future, help doctors better monitor metabolite variation as an indicator of disease.

The central dogma of molecular biology shows how DNA is transcribed into RNA, which is translated into proteins. Many of those proteins operate as enzymes that catalyze chemical reactions between small molecules that perform the applications laid out in our DNA, often known as metabolites. These metabolites, collectively known as the metabolome, carry out important functions, from producing or storing energy to serving as building blocks for our cells.

On this groundbreaking examine led by Mackays former postdoctoral researchers Shanshan Zhou and Fabio Morgante, researchers sought to measure hundreds of metabolites discovered throughout the experimental model system of the common fruit fly, Drosophila melanogaster, to gauge how these metabolites fluctuated alongside variation in genetic information.

As soon as the metabolites had been recognized, the remainder of the examine was carried out computationally, correlating variation in metabolites with DNA variants and variation in a variety of traits measured in 40 totally different fruit fly lines.

However, this comprehensive research fills in gaps of missing information that create extra avenues for research in the future. Because the technology to measure the metabolome improves, databases containing metabolomic information will expand.

The rest is here:
New Research Identified Hundreds of Metabolites and Small Molecules That Are Potential Indicators for The Disease - The News Kahn

A domesticated fox in Russia.Photo: Getty Images

Decades ago, a Soviet geneticist purposely bred foxes to make them extra tame, an experiment that produced a host of unanticipated physical changes in the animals. Its one of the most famous experiments in genetics, but it might not have gone down in the way we were told. A new opinion paper argues these foxes werent wild to begin with and that the domestication syndrome associated with the changes doesnt exista claim thats stirring up controversy among some biologists.

As the story goes, geneticist Dimitry Belyaev, who worked at the Institute of Cytology and Genetics in Novosibirsk, USSR, took 30 male and 100 female wild foxes (Vulpes vulpes), and, over the course of the next few decades, bred only the most human-friendly individuals. The experiment began in 1959, and by the late 1970s10 generations laterBelyaevs foxes were exhibiting the desired behavior, showing affection toward humans in a manner eerily reminiscent of dogs.

At the same time, however, the foxes acquired a host of unanticipated and unintended physical characteristics that distinguished them from the source population, such as floppy ears, turned-up tails, piebald coats, and wider faces, among other traits.

None of these physical characteristics were selected for, but Belyaev believed these traits were tied to the selected behavioral change (i.e. tameness), which somehow influenced the rise of unexpected traits. The Russian Farm-Fox Experiment, as its now called, has since been used by biologists to showcase the sweeping influence of domestication on a species. It also invigorated a term used to describe the phenomenon: domestication syndrome, as these sorts of physical changes have been documented in other domesticated animals, such as dogs, horses, and cows.

But as a new opinion paper published in Trends in Ecology & Evolution points out, a critical part of this story isnt actually true: the original foxes used in the experiment werent actually taken from the wild. Moreover, and perhaps more controversially, the authors, who include Elinor Karlsson, a biologist from the University of Massachusetts Medical School, and Gregor Larson, a paleogeneticist from the University of Oxford, contend that domestication syndrome is a half-baked concept thats probably not even a real condition.

That Belyaevs foxes werent originally wild seems to be the case. The authors provided evidencemuch of it already publicly availableshowing that Belyaev acquired the foxes from Soviet fur farms, which in turn had acquired their foxes from Canadian breeders, specifically fox farms in Prince Edward Island. Canadian entrepreneurs had been domesticating foxes since the late 19th century, selecting for both appearance and behavior, according to the paper. So by the time Belyaev got his hands on them, these foxes were already going through domestication.

And in fact, Belyaev himself admitted as much, describing the founding population as fur-farm foxes, but because he referred to them as wild controls, he unintentionally created a misconception.

The story wed heard was that the Russian scientists had started with a wild population of foxes, selectively bred the least fearful foxes, and as a result of that selection, also gotten foxes with white spots, curly tails, and other changes, Karlsson told Gizmodo. But up in Canada, they had foxes that were not fearful and already had white spotting (we dont know about curly tails)decades before the project started. And then we found the fox project in Russia didnt start with wild foxes, but with fur farm foxes originally from Canada. It totally changes the way I think about cause and effect in the project, she said.

Karlsson said her team concluded that Belyaev was continuing a domestication process that had already started many decades earlier in Canada.

Were not saying they are indistinguishable, said Karlsson of Belyaevs later generations of foxes and the founding group from the Soviet fur farms. But she said her team doesnt think that any of the changes since the Russian project started would suddenly qualify the foxes as now being domesticated.

Its entirely possible, she said, that Belyaev created even more friendly foxes, but even before this experiment began, we know the foxes were already okay being around humansand some of them were pretty happy about it, at least according to the photos and storiesand were breeding in captivity, which are the essential elements that are used to qualify them as being domesticated.

But the larger issue described in the paper is that there isnt really any good definition for domestication, Karlsson said, which made this hard to write about!

Karlsson and her colleagues argue against the existence of a so-called domestication syndrome, which they define as a suite of behavioral and morphological characteristics consistently observed in domesticated populations. The term was coined by botanists in the early 20th century, but Charles Darwin hinted at its existence in his 1868 book, The Variation of Animals and Plants Under Domestication. It was eventually applied to mammals in the 1980s, and its usage has risen dramatically since the 1990s, according to the new research.

Upturning the concept is a big deal, because domestication syndrome has inspired many related ideas, including the neural crest hypothesis and the pedomorphosis hypothesis. The neural crest hypothesis suggests neural crest cellsa specific class of stem cellsare a common factor in influencing the biological cascade that leads to multiple unanticipated physical changes in a species. The pedomorphosis hypothesis, also known as neoteny, suggests some of the changes introduced by domestication have a distinct juvenile quality and that selecting for tameness and other attributes effectively maintains a species, or at least some of its attributes, at an underdeveloped level. (In fact, some scientists argue that humans have tended to select mates with more juvenile features, leading to the hypothesis that humans exhibit certain features consistent with self-domestication.)

The authors looked to various domesticated mammalian species in order to further scrutinize the concept of domestication syndrome. In addition to domesticated foxes, the authors examined the characteristics of other species of domesticated animals, including dogs, cats, goats, pigs, rabbits, rats, and mice. The researchers charted their anomalous traits, such as shorter jaws, curled tails, drooping ears, changes in coat color and patterning, earlier sexual maturation, decreased brain size, and other attributes typically associated with domestication syndrome. Their comparative analysis revealed many gaps and inconsistencies among the species studied.

Their main complaint is that domestication syndrome has no standard definition that is applicable to all domesticated species. These hypotheses assume that the domestication syndrome exists, but with little supporting data, wrote the authors. The defining characteristics vary widely and have not been observed in most domesticated species. Many studies fail to distinguish traits that accompanied domestication from those only in modern breeds, and some traits are reported anecdotally without any accompanying frequencies or measurements.

The researchers devised a list of three essential criteria consistent with their interpretation of domestication syndrome, namely:

1. Onset: A trait must appear...in conjunction with the onset of selection for tameness.

2. Frequency: A trait must be significantly more common in the selected population.

3. Association: A trait must be associated with tameness in individuals, not just at the population level

When the researchers applied these criteria to domestication syndrome, they were unable to identify a single species for which all three criteria were met. The authors concluded that the Russian Farm-Fox Experiment is overstated as a model for understanding the effects of domestication, while adding that traditional conceptions of domestication need to be re-evaluated and re-defined.

Rather than focus on the domestication syndrome, we should instead consider how domesticated species have changed, and are still changing, in response to human-modified environments, wrote the authors. This effort will provide a robust framework to investigate the cultural and biological processes that underlie one of the most important evolutionary transitions.

In terms of whats happening to the animals, a lot of it might just be something we call genetic drift, which basically comes down to random chance, Karlsson told Gizmodo.

Perhaps unsurprisingly, the new opinion paper is not going over well with some biologists.

David MacHugh, a professor of functional genomics at University College Dublin, wasnt directly involved with the research but said he discussed Belyaevs experiment at length with Larson, a co-author of the paper, prior to publication. As MacHugh told Gizmodo in an email, he was convinced by the teams arguments regarding the Canadian provenance of the source population. As for the authors takedown of domestication syndrome, he was less persuaded.

It is important to note that as data accumulates from genome-scale functional and comparative analyses of domestic animals and their wild [ancestors], we should eventually have sufficient data to fully test the domestication syndrome hypothesis, said MacHugh.

He also said it should be possible to figure out if the biological basis of domestication syndrome is tied to genetic disruptions, or perturbations, that affect the development of various tissues derived from neural crest cells.

In other words, MacHugh believes the jury is still out on the neural crest hypothesis, but future genetics research will be able to finally settle the score. Whats more, he believes ongoing research into ancient DNA will allow paleogeneticists to better chronicle the history of domestication, pointing to a new study he co-authored on this exact subject.

Adam Wilkins, an evolutionary biologist from Humboldt University in Berlin, was less charitable, saying the opinion piece was deeply problematical.

As Wilkins told Gizmodo in an email, hes probably biased, since he was part of the team that put the term domestication syndrome on the map, with respect to mammals (the term had previously been used for plants), in reference to a 2014 paper he co-authored with biologists Richard Wrangham and Tecumseh Fitch.

The root of our disagreement lies, I think, in that we mean something different by syndrome than they do, Wilkins told Gizmodo. They seem to believe that something can only be called a syndrome if the affected individuals all display the exact same set of traits. Whereas we argue that if domestication is accompanied by a range of unselected traits, which might differ somewhat but often overlap, it counts as a syndrome.

Wilkins said he and his colleagues never claimed the existence of an identical set of traits across all domesticated mammals, which he says is implied in the new opinion piece.

Furthermore, under our neural crest cell hypothesiswhich the authors refer to briefly, twice, but do not explain or discusswhat you see is exactly what the hypothesis predicts, said Wilkins.

Specifically, that reductions in neural crest cellsthe result of different mutations in the large set of neural crest cell genesproduce a range of affected traits, he said, pointing to a recent Development and Evolution paper he wrote that provides more color to this claim.

Wilkins also took great exception to the authors assertion that the two fox populationsthe farm-fox population that Belyaev bred from and the foxes he producedwere essentially the same.

No! wrote Wilkins. This shows a lack of understanding of what an evolutionary process is. Belyaev clearly increased the frequencies of those mutant alleles [alternative forms of a gene] and brought them together and with that, he created a new population with distinctive properties. Now, that is evolution, as Belyaev recognized but [the authors] do not, he said.

This point is consistent with a 1999 review of the Belyaev experiment written by biologist Lyudmila Trut from the Institute of Cytology and Genetics of the Siberian Department of the Russian Academy of Sciences. In the paper, Trut describes the remarkable transformations seen in the foxes over a 40-year period, in an experiment that, at the time of her paper, involved some 45,000 foxes and somewhere between 30 and 35 generations.

The founding foxes were already tamer than their wild relatives, wrote Trut. Foxes had been farmed since the beginning of this century, so the earliest steps of domestication, capture, caging and isolation from other wild foxes had already left their marks on our foxes genes and behavior.

Despite this, the breeding program produced an array of concrete results, she wrote. The foxes are unusual animals, docile, eager to please and unmistakably domesticated. When tested in groups in an enclosure, pups compete for attention, snarling fiercely at one another as they seek the favor of their human handler.

Whats more, the unexpected physical changes werent seen until around the eighth to 10th selected generations, as Trut wrote:

The first ones we noted were changes in the foxes coat color, chiefly a loss of pigment in certain areas of the body, leading in some cases to a star-shaped pattern on the face similar to that seen in some breeds of dog. Next came traits such as floppy ears and rolled tails similar to those in some breeds of dog. After 15 to 20 generations we noted the appearance of foxes with shorter tails and legs and with underbites or overbites.

Wilkins raised several other issues with the new paper, including the authors failure to define domestication after claiming that Belyaevs experiment wasnt a true example of domestication. He also wasnt happy that they looked at just seven domesticated species instead of the 26 documented in the scientific literature.

If they had, they would have seen a lot more domestication-associated traits... including many that almost certainly were not deliberately selected by breeders, Wilkins told Gizmodo. They want to attribute all these changes to selection, however; at least, that is what they imply at the end [of the article].

Wilkins believes the array of anomalous traits seen in domesticated mammalswhether these traits are common or not across speciescannot be explained away so easily and that domestication syndrome best describes this biological phenomenon.

Deficiencies in our understanding of Belyaevs experiment notwithstanding, the authors of the opinion piece raise a very good pointdomestication syndrome as its understood today is not a fully formed concept. But that doesnt mean it doesnt exist.

Pleiotropy, in which a single gene influences multiple traits, is very much real, so it makes sense that you could get some unexpected surpriseslike floppy ears when you were only selecting for friendlinessby messing with a multifunctional gene.

Its not immediately obvious that many of the unexpected physical characteristics seen in domesticated animals are truly the result of selection (whether those traits were consciously bred into them or not) or genetic drift. Moving forward, scientists will need to better elucidate the underlying cause of each identified trait.

And if these accidental byproducts or side-effects can be indisputably identified as being the unanticipated consequence of domestication, then we have something that can only be called one thing: a syndrome.

See original here:
Famous Foxes Bred for Tameness Werent Actually Wild in the First Place, Claims Controversial New Paper - Gizmodo

Part one of our three-part PAST LIVES series on Jewish genealogical research. Parts two and three will be available next week.

Jennifer Ortiz has a screenshot saved on her computer. Its an image that captures a moment that changed her life.

Right there on the screen: Stewart Bloom is your father, she said, describing the message she received when she logged in to see the results of her home DNA test.

Ortiz is one of millions of people who have taken a DNA test like the ones sold by 23andMe or Ancestry.com. Ortiz, who grew up Catholic in Utah, found out from the test that she was 50 percent Ashkenazi Jewish a result that led to the discovery that she was the child of Bloom, a Jewish photographer in San Francisco, and not the man who raised her.

Thats when my world changed, she said.

But what is 50 percent Jewish?

The question itself is a new wrinkle in the age-old debate of just what it means to be Jewish, which has been given a kick in the pants from the commercialization of a field of science that says it can tell you something new: For a price, you can now choose from one of seven commercial genetic tests to find out just how Jewish you are (among other things).

Its a very interesting, different and complicated and morally ambiguous moment, said Steven Weitzman, director of the Katz Center for Advanced Judaic Studies at the University of Pennsylvania and former director of the Taube Center for Jewish Studies at Stanford University.

In the past few years, commercial gene testing has taken off, driven by aggressive advertising that purports to tell the real story behind your ancestry. The magazine MIT Technology Review analyzed available data to estimate that more than 26 million people had taken at-home tests since they first went on the market more than a decade ago.

Its really beginning to seep into peoples consciousness, Weitzman said.

Sunnyvale-based 23andMe and Ancestry.com, headquartered in Utah, will ask you to spit in a tube and then, several weeks later, will give you a pie chart that might say, for example, 20 percent Swedish, 8 percent Greek and 11 percent German. Or, perhaps, 39 percent Ashkenazi Jewish.

But is there such a thing as 39 percent Ashkenazi? Yes, according to professor of epidemiology and biostatistics Neil Risch, director of UCSFs Institute for Human Genetics.

Its very easy to identify someone whos Ashkenazi Jewish, said Risch, who also does research on population genetics for Kaiser Permanente Northern California.

Thats because there are genetic markers distinct to the Eastern European Jewish population, partly due to a population founder effect, a way of saying that they descend from a small number of ancestors. Also, Jews in Europe tended to marry other Jews, making them endogamous.

Jews were not allowed to intermarry, Risch said. He added that on top of that, there were other external factors; for centuries, Christian churches forbade their flock from marrying Jews.

Ashkenazi Jews share a genetic profile so distinct that even commercial tests can spot it, unlike the difference between, say, Italians and Spaniards, who share a more diffuse Southern European profile. Risch said that although commercial genetic tests will show a percentage of your heritage from very specific regions in Europe, these results should be taken with a grain of salt.

Those kinds of subtle differences are challenging and have to be looked at with some skepticism, Risch said.

I call it entertainment genetics, said Marcus Feldman, a Stanford biology professor and co-director of the universitys Center for Computational, Evolutionary and Human Genetics, when you go and find out where your ancestors came from.

But for Ashkenazi Jews, heritage is pretty clear. Pick a street, Feldman said. Then pick any two Ashkenazi Jews at random walking down it.

Theyd be fifth to ninth cousins at the genetic level, Feldman said. Ashkenazi Jews are actually that closely related, all descended from a small group of people.

But what about Sephardic Jews looking to get a quantitative peek at their heritage? Theyre out of luck. 23andMe communications coordinator Aushawna Collins said that the company hasnt collected enough data on those populations yet to be able to pinpoint what makes them unique in terms of genes. Risch said its because genetically they are not distinct enough from other Mediterranean peoples.

But even if science can determine whether people have Ashkenazi genes, can one extrapolate from that how Jewish they are?

What is 39 percent Jewish? Thats nonsense, said Weitzman, a former professor of Jewish culture and religion at Stanford, where in 2012 he started an interdisciplinary course on Jewish genetics with biology professor Noah Rosenberg. You cant be half Jewish. Youre either Jewish or not Jewish.

Rabbi Yehuda Ferris of Berkeley Chabad would agree.

You cant be part kosher, you cant be part pregnant, you cant be part Jewish, he said.

However, even Ferris and his wife, Miriam, have done at-home DNA tests although they did it to find relatives, not to figure out their Jewishness.

It was extremely shocking, Ferris said dryly. Im 100 percent Ashkenazi Jewish and shes 99 percent.

For zero dollars we could have told you the same thing, Miriam Ferris added.

As an Orthodox rabbi, Ferris goes not by percentages but by the matrilineal rule in establishing Jewishness.

If your mother is Jewish, youre Jewish, he said. Thats it.

The concept of matrilineal descent is an old one, but genetics are giving it a new twist, especially in Israel where the Chief Rabbinate has used gene testing to weigh in on the crucial question of who is a Jew. (In Israel, immigrants must prove their Jewish status to marry, be buried in a Jewish cemetery or undergo other Jewish life-cycle rituals.)

Thats an interesting and disturbing new phenomenon, Weitzman said.

The way the rabbinate has used gene testing is by examining mitochondrial DNA, which gives much less information than testing of the more extensive DNA in the cell nucleus, which is what home tests do. But unlike nuclear DNA, mitochondrial DNA is almost always passed from mothers to their children. This dovetails nicely with the notion of matrilineal Jewish descent, and rabbis in Israel have now begun accepting mitochondrial DNA testing for people, primarily immigrants or children of immigrants from the former Soviet Union, who have inadequate documentation of their Jewish status.

The test can identify Jews descended from four founder women ancestors. However, it can be used only to prove a positive, as half of Ashkenazi Jews dont have the characteristic mitochondrial chromosomes at all. Still, for people who have no paper or eyewitness proof of Jewish descent, genetic testing can be the deciding factor.

When you dont have enough information, it might be the linchpin, Ferris commented.

The rabbinates use of mitochondrial DNA testing is controversial, with some critics calling it humiliating. The Yisrael Beiteinu party, which represents Russian-speaking immigrants, is trying to challenge it in Israels Supreme Court.

Outside of Israel, too, not everyone is comfortable with using science to figure out who is a Jew. Its something the world has seen before.

People were also using science to figure out who people were. We called that race science, Weitzman said.

And the people who did it?

I mean Nazis, he clarified.

Genetics have been used against Jews in the most virulent way, said UCSFs Risch. But he thinks that Jews are inclined right now to trust the science because its a field filled with Jewish researchers. We love science because were all the scientists! he said.

In the past two decades, there has been a rash of research on the genetic components of Judaism, a boom coinciding with the Human Genome Project, which ran from 1990 to 2003. Much of it was done by Jewish scientists. The initial research on mitochondrial DNA in Ashkenazi Jews was done in 2006 by Israeli geneticist Doron Behar; he is now CEO of genetic analysis company Igentify.

In 1997, a study of traits in the Y chromosome, passed only from father to son, found that more than 50 percent of men with the last name Cohen (or Kahan or Kahn or other variants) had a certain marker, giving some support to the idea of a hereditary Jewish priesthood.

In 2010, medical geneticist Harry Ostrer did work that found various communities of Jews shared a common Middle East ancestry. And in 2009, Feldman, who is also director of Stanfords Morrison Institute for Population Biology and Resource Studies, studied to what degree Jewish groups in different places were related. (This last topic has been studied further, including by Risch.)

But Feldman himself has experienced firsthand how his own research has been twisted for what he called racist conclusions when economists drew inferences from his work with fellow Stanford professor Rosenberg to suggest theres a genetic basis for economic success.

We were outraged because those two people were using our data to make these quite racist statements, Feldman said.

Feldman said its common for the public to seize on genome research and try to use it to explain everything from intelligence to criminality; he said scientists have a responsibility to be on alert all the time.

Theres been too much emphasis on the genetic basis of a lot of human behaviors, he said. When genetics is your hammer, everything becomes a nail, he said. So it doesnt matter what human trait youre interested in.

Even if geneticists like Feldman consider home testing kits entertainment, their popularity shows that people are interested in using genetics to figure out who they are, including how Jewish. Weitzman said it might be connected to how hard it is for most Ashkenazi Jews in this country to trace their roots; Jews in Central and Eastern Europe didnt have last names until the 18th or 19th centuries.

A lot of us, we dont know a lot about our ancestors prior to our grandparents, Weitzman said.

So in searching for ancestors, people are turning to the companies that promise results. 23andMes Collins told J. theyd sold 10 million kits in total, and Ancestry.com in May issued an announcement claiming to have tested more than 15 million people.

Cantor Doron Shapira of Peninsula Sinai Congregation in Foster City is one of them. He was always into Sephardic music and food. As a percussionist, he felt drawn to the rhythms.

People have very often asked me, Are you Sephardic? he said. And I always said, Not to my knowledge.

Last year he saw an ad for Ancestry.com, got his DNA testing kit and sent it in with his sample.

It comes back 94 percent no surprise Russian Ashkenazi Jewish European roots, he said.

But the test also revealed 6 percent of his roots were other, including from Southern Europe and the Iberian Peninsula. Maybe Shapira had a Sephardic ancestor after all?

He started to think about which side of the family it could be and considered asking his mom to get tested. It wasnt that the result suggesting a Sephardic ancestor changed his perception of who he was, he said, but it validated something about himself that he and others had always noticed.

I got a little bit excited, he admitted.

And then he got an email update from Ancestry.com.

It says, scratch that, youre now 100 percent Ashkenazi Jewish, he said with a laugh.

But even with the change in result, Shapira says hes not against using home genetic testing to get a peek into his ancestry.

Im inclined to do another one, he said. Just to see if its consistent.

Many others are taking the tests and their results very seriously. People are making life decisions now on the results of this test, Weitzman said. Theyre deciding whether theyre Jewish or not.

Thats what Ortiz has done. If you ask her now if shes Jewish, the 53-year-old has an answer.

Yes, I am, she said. Ill say yes.

She had never been told that the father who raised her was not her biological dad, and when she confronted her parents, they denied it. But she knew it was no mistake when the DNA testing company delivered a startling message with the name of her biological father thats the screenshot shes got saved on her computer.

Ortiz immediately made contact with Stewart Bloom and flew down to San Francisco last year from her home in Portland to visit. There was a lot to process, of course, but for Ortiz its been a wonderful thing and that includes embracing Jewishness, something she said shed always been drawn to.

When I found out Im actually 50 percent, on one level it didnt surprise me, she said.

Now shes converting that number into something deeper: Shes planning a ceremony in Portland with a Jewish Renewal rabbi not a conversion, but something to celebrate her new identity.

It would help me take a step into Judaism, she said. Not just from a biological level but a little more than that.

Thinking about Jewishness in terms of biology is something that bothers Emma Gonzalez-Lesser, a Ph.D. candidate at the University of Connecticut and the author of an article titled Bio-logics of Jewishness. If being Jewish is something in the genes, then that excludes people who have come to Judaism in other ways.

People who convert may not be seen as legitimately Jewish as someone who has 30-something percent ancestry from a genetic test, she said.

And beyond that, she added, there are some ideas underlying the current fascination with genetics that arent being questioned, like the question of whether Jews are a race.

I think part of our societal fascination with genetic testing really rests on this assumption that race is really this biological function, she said.

(Prominent researchers like Feldman, Rosenberg and Risch have been caught up in the sensitive question of whether studying the genomics of populations leads to a biological definition of race; the issue has been written about at length and remains controversial.)

Weitzman said the interest in ancestry reflects a trend around the world of turning to biology, genetics and race as a way to encode identity.

Part of whats going on in the Jewish world right now is a reflection of a broader revival of ethno-nationalism, Weitzman said.

In addition, at a time when American Jews are less likely to go to synagogue or practice rituals in the home, they face more questions about what it means to be Jewish. That may incline them to trust in science to determine their identity, especially when they have only a few dusty boxes of papers, if that, to show their family history. That makes Jewish genes a door into the past.

Theres something hiding inside of you that is preserving your identity intact, Weitzman said. To me, thats part of the appeal.

See the article here:
Who is a Jew? DNA home testing adds new wrinkle to age-old debate - The Jewish News of Northern California

Fine point: Many children with mutations in a gene called PHF21A have tapered fingers.

People who have mutations in a gene called PHF21A tend to have a constellation of traits and conditions, including autism, according to a new study1.

PHF21A encodes a protein that is part of a massive complex that binds to DNA. The genes exact function is unknown, but studies suggest it prevents neuron-specific genes from being expressed in other types of cells.

It is one of several genes implicated in a rare condition called Potocki-Shaffer syndrome2. A 2012 study linked mutations in the gene to two characteristics of the syndrome: intellectual disability and unusual facial features, such as a narrow nose and downturned mouth3.

But PHF21A is also emerging as a strong autism gene. Since 2014, mutations in the gene have turned up in at least three people with autism or traits of the condition4,5,6,7.

The new study details the clinical characteristics of seven children with PHF21A mutations. All of the children have intellectual disability, and three have autism.

This gene might be quite heavily involved in autism and intellectual disability, says lead investigator Hyung-Goo Kim, associate professor of health and life sciences at Hamad Bin Khalifa University in Doha, Qatar.

The findings also add seizures, low muscle tone and unusual-looking hands and feet to the list of traits tied to mutations in the gene. They have done a nice job of showing the spectrum of features seen in these children, says Sarah Elsea, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, who was not involved in the study.

Kim and his colleagues found seven children in the United States and France who carry mutations thought to impair the genes function. In at least six of the children, the mutations arose spontaneously, meaning that the parents do not carry the mutations; only one of the seventh childs parents was available for testing.

All seven have intellectual disability, developmental delay, language delay and motor problems, according to their medical records. Four have seizures, and three of the six children tested for autism have the condition.

All of the children have other notable physical features too, such as a broad nasal bridge, tapered fingers or shortened toes, and four are obese. The findings appeared in October in Molecular Autism.

The researchers analyzed the genes expression levels in a variety of human tissue samples. They found that the gene is most highly expressed in the brain and in muscles.

This finding jibes with the idea that mutations in the gene contribute to problems with brain development and motion.

Researchers should next test whether the mutations impair the proteins function, says Gholson Lyon, a principal investigator at the Institute for Basic Research in Developmental Disabilities in New York City, who was not involved in the study.

Kim and his colleagues plan to study blood cells from the children to try to better understand how the mutations contribute to autism.

View original post here:
Mutations in emerging autism gene tied to distinct traits - Spectrum

Remember these two names, Lulu and Nana. They are twin girls born in China in October 2018, and we already know they are going to be famous.

They are the worlds first genetically-edited humans, and their progress through life will be monitored intensively by medical researchers over the coming years.

Dont doubt their future celebrity. Remember the headlines when Dolly the sheep arrived in 1996, the worlds first mammal cloned directly from an adult cell. Or how about Louise Brown, who made headlines in 1978 as the first baby to be conceived using invitro fertilisation (IVF) techniques.

Although the methods used to bring about these three births are light years apart, all three involve the delivery of an offspring using unorthodox methods.

All three were also controversial in their day. There was no end of condemnation and criticism about playing god and defying the laws of nature for the first two, but now IVF is commonplace for lots of medical reasons and is accepted as a standard medical practice. And news of another species successfully cloned in the lab would not make headlines today.

However, the genetic modification of the twins is a different matter, a genetic change introduced before birth to deliver a permanent alteration of their original genome that will be passed down from generation to generation.

Prof He Jiankui of the Southern University of Science and Technology carried out the genetic change needed to permanently modify the twins genome. He introduced a mutation that gave Lulu and Nana resistance to the Human Immunodeficiency Virus, the virus that causes Aids, and revealed his successful genetic modification one year ago this month.

The backlash was immediate and severe. There was international condemnation that China allowed experimentation on humans. Last January his university sacked him.

The scientific community also criticised the work as having crossed an important red line for genetics research, the reality that we still know too little about how even the smallest genetic change might have unexpected impacts downstream in other parts of the genome.

It was bad enough that a modification had taken place, but the modification was in the germline, the cells that bring about the next generation and the next and the next.

Perhaps the lure of notoriety proved too strong or the desire to be the first, but He Jiankui crossed that line, helped along the way through use of a gene-editing method known as CRISPR-Cas9.

This method emerged over several years, and has become the gene-cutting tool of choice because it allows very tight control over how a gene can be modified, added to or deleted.

When it came into widespread use the scientific community recognised immediately that controls on its application were necessary to prevent its use in human gene modification. This should have prevented He Jiankui from attempting such a daring and defiant experiment but it didnt, and Lulu and Nana were the result.

They were born healthy but now scientists will want to know whether there are unexpected or unwanted effects or other issues that arise. Already researchers have raised doubts about the gene modification that confers resistance to HIV, which means some level of susceptibility to the virus may remain.

The modified gene, known as CCR5, also has other roles in the body, and its modified actions may affect the lifespan of the twins. One large study involving 410,000 subjects showed that people with a similar mutated version of CCR5 were 20 per cent more likely to die before reaching the age of 78.

Despite these misgivings there is no doubt that CRISPR-Cas9 will in the future be used to modify the human genome in the battle against difficult diseases such as cancer and in genetic disorders caused by specific gene mutations. The tool is far too important to avoid its eventual use, or the use of some other similar but as yet unidentified gene-cutting method.

Similarly there is little doubt that online charlatans will offer promised but undeliverable cures using CRISPR-Cas9, as was the case with earlier technologies such as stem cells.

Lulu and Nana, meanwhile, will get on with living their lives, doing what babies do. Their names are pseudonyms in an attempt to conceal them from public view, but it is likely that we may learn their real names in the future.

Lulu and Nanas story came to mind in light of research published last week (November 21st) in the journal Cell about how attempting to create designer babies using other advanced technology could still remain a costly waste of time.

It involves choosing an embryo based on its potential to be tall or smarter than average, but accomplishing this via something like CRISPR-Cas9 is too far beyond our current abilities. Instead the international team of scientists set up a model to simulate one method called pre-implantation genetic testing.

This involves screening the genome for genes that have an association to a given trait, in this studys case intelligence and height, and giving them a score. The team found, however, that at best the top-scoring embryo might be expected to be 2.5cm taller than average and at best 2.5 IQ points above average.

Lurking behind all of this remains the most challenging of issues, the ethics surrounding the use of this technology.

As usual the ethics questions that should have been asked first are the ones obscured by the advance of these promising discoveries.

The rest is here:
Lulu and Nana are the result of a defiant experiment in human gene modification - The Irish Times

The ability to fight disease is a driving force in human survival. Inflammation has emerged as a key weapon in this process. As pathogens change and evolve, the immune system adapts to keep up.

However, to what extent might such evolutionary adaptations also give rise to autoimmune conditions such as lupus and Crohn's disease?

This was a central question in a recent Trends in Immunology review by two scientists from Radboud University, in Nijmegen, Netherlands.

To address the issue, first author Jorge Domnguez-Andrs, a postdoctoral researcher in molecular life science, and senior author Prof. Mihai G. Netea, chair of experimental internal medicine, examined studies in the fields of virology, genetics, microbiology, and immunology.

They focused on people of African or Eurasian descent and how their ancestral origins may have influenced their risk of autoimmune diseases.

Of particular interest was how common pathogens in different communities related to changes in people's DNA, particularly when this involved inflammation.

The team found that the genetic changes made it harder for pathogen infections to take hold.

Over time, however, it seems that inflammation-related diseases, such as inflammatory bowel disease, Crohn's disease, and lupus, have emerged alongside improvements in immune defenses.

The findings also suggest that the human immune system continues to evolve and adapt to changes in environment and lifestyle.

"There seems to be a balance," says Domnguez-Andrs.

"Humans evolve to build defenses against diseases," he continues, "but we are not able to stop disease from happening, so the benefit we obtain on one hand also makes us more sensitive to new diseases on the other hand."

He observes that autoimmune diseases in today's humans tend to emerge later in life. These would not have caused health problems for our ancestors because their lives were much shorter.

"Now that we live so much longer," he explains, "we can see the consequences of infections that happened to our ancestors."

One of the examples that Domnguez-Andrs and Netea cover in detail in their review is malaria.

"Among various infectious diseases," they write, "malaria has exerted the highest evolutionary pressure on the communities across the African continent."

Malaria is a mosquito-borne disease that makes people very ill with flu-like symptoms, such as chills and a high fever.

While there has been much progress in the fight to control and eliminate the potentially fatal disease, it continues to threaten nearly half of the world's population, according to the World Health Organization (WHO).

The cause of malaria is parasites belonging to the species Plasmodium. These parasites spread to humans through the bites of infected female Anopheles mosquitoes.

Domnguez-Andrs and Netea note that Plasmodium has been infecting people in Africa for millions of years. During that period, the immune systems of those human populations have evolved stronger resistance to infection by increasing inflammation.

However, the downside of increasing inflammation to withstand infectious disease is that it favors health problems that tend to occur later in life.

Modern humans of African descent are more prone to developing such conditions, which include atherosclerosis and other cardiovascular diseases.

Another example of how ancestral changes in DNA leave imprints in the immune systems of modern humans is the interbreeding of early Eurasians with Neanderthals.

Modern humans whose genomes harbor remnants of Neanderthal DNA have immune systems that are better able to withstand staph infections and HIV-1. However, they are also more prone to asthma, hay fever, and other allergies.

Improvements in technology are making it more possible to find the downsides that can accompany disease-fighting adaptations.

Next generation sequencing, for example, is allowing scientists to delve more deeply into what happens at the DNA level between pathogens and the organisms that they infect.

Not only is new technology getting better at revealing genetic changes that occurred in our ancestors, but it is also showing that the human immune system continues to evolve and adapt.

In Africa, there are still tribes that hunt for food as their ancestors did. Thanks to new tools, scientists can see how the gut bacteria of these tribes are more diverse than those of, for example, contemporary African American people, who buy food in stores.

Other changes that have had an effect on DNA are the improvements in hygiene that have occurred in recent centuries. These have reduced exposure to pathogens and the diversity of gut bacteria.

"This reduced microbiota diversity in Western societies," the authors observe, "has been associated with a higher incidence of the so-called 'diseases of civilization,' such as cardiovascular diseases, diabetes, obesity, and autoimmune disorders, which are very unusual in hunter-gatherer societies, compared with communities living a Western-type lifestyle."

Domnguez-Andrs and Netea are extending their research to populations whose ancestry is other than African or Eurasian.

"Today, we are suffering or benefiting from defenses built into our DNA by our ancestors' immune systems fighting off infections or growing accustomed to new lifestyles."

Jorge Domnguez-Andrs, Ph.D.

View original post here:
Humans and autoimmune diseases continue to evolve together - Medical News Today

Country doctor James DeLine talks about his work with the Amish

In 33 years at the La Farge clinic, Dr. James DeLine has gained the trust of many Amish. He understands their beliefs and their financial limitations, and he leaves the medical decisions to the families.

Mark Hoffman, Milwaukee Journal Sentinel

MILWAUKEE, Wis.It is 5 degrees below zeroand a light powdering ofsnow swirls across the roads of Vernon County.Afew horses and buggies clop through the chillmorningair, but Perry Hochstetler leaves his buggy at the family farmand has a driver take him to his doctors appointment.

TheHochstetlersare Amish. With no health insuranceanda modest income, they cannot afford most doctors.

They can afford James DeLine, once the lone doctor in the western Wisconsin village of LaFarge. Population 750.

When he became the village doctor in 1983, DeLine had no experience treating the Amish and no idea the crucial role they would play in his work. Today, about 20% of the doctors patients are Amish or Old Order Mennonite, part of a Christian population called Plain People. They are known for their separation from the modern world and adherence to a simple lifestyle and unadorned dress.

Something of a throwback himself,DeLine, 65, is a short,bespectacledman with a walrus mustache, a doctor who carries a brown medical bag to house calls. For years, he carried his equipment in a fishing tackle box.

He knows the families on every local farm and their medical histories. He knows whos beenborn,andcalls on the mothers and infants to make sure they are healthy. He knows whos dying, and looks in on them in their final days, sitting by their bedside, talking in a gentle voice, making sure they have what they need for pain.

Amish farms are clustered together along Highway D between Cashton and La Farge.Mark Hoffman / Milwaukee Journal Sentinel

As a young doctor,DeLine never imagined he would find himselfsomedaywith one foot planted solidly in medicines past, the other in its future.

The doctor who makes housecallsalso collaborates with English and American geneticists studying some of the rarest diseases on Earth. Some occur at much higher levels among the Amish, Mennonites and other closed communities that dont allow marriage to outsiders. This prohibition increases the likelihood that when a rare, disease-causing mutation appears in the community, it will take root and pass from generation to generation.

It has taken DeLine and his staff years to gain the trust of Plain People, some of whom are wary of medicine and technology.Often,theyfear that going to a hospital or clinic will mean surrendering the decision-making to doctors who neither respect their beliefsnor understand their financial limitations.

DeLine, not a religious man himself, accommodates the beliefs of patients and parents; he has always viewed them as the ultimate decision-makers.

At first glance, Hochstetler seems an unlikely candidate for a rare disease or a health problem of any kind. Work at the local sawmill and his family farm has given the 26-year-old father of two a lean muscular frame. Beneath the skin lies another story.

He has the vasculature of an 80-year-old smoker,DeLinesays.

He inherited the genetic mutation that causes an illness most people have never heard of: sitosterolemia. Only 100 cases have been described in the medical literature, but DeLine has 13 patients with the condition, including four of Hochstetlers 10 siblings and their father.

The disease prevents the body from getting rid of lipids from vegetable oils and nuts, causing them to build up and clog the arteries.

Since diagnosing the disease,DeLinehas treated Hochstetler with a cholesterol-lowering drug called Zetia.

Without diagnosis and treatment,Hochstetlercould by now havesuffereda heart attack, a trauma that Zetia should delay, thoughfor how long isuncertain. There is no cure for sitosterolemia.

Im not afraid, he says. If I die young, I guess Im going to die young. I cant do much about it. I cant say I ever get low and have the blues about it.

Saving grace: The story of an Amish community and the fight for their children's lives

A blizzard almost kept the doctor and village from their appointment.

It was February 1983. DeLine drovehis familyover hilly country roads, staring out the windshield into flurries and fearingtheir carmight not makeit to LaFarge.

DeLinehad just completed his residency at the Wausau Hospital Center. Now, a10-membercommitteeof localswas recruiting him to fill LaFargesvacancy for a doctor. Thevillage had beenwithout one for a couple ofyears.

The doctor liked the friendly villagers, a welcome change from the suit-and-tie types hed interviewed with in other places.

He was 28 years oldwith a bad car, a growing family and $30,000 in unpaid student loans. The average salary for a family doctor in America was then around $80,000, enough to settle down and beginpaying offhis debt.

But the people of LaFargewantedDeLine needed him. Their offer: $20,000.

That would have to coverDeLinesannual salary, the salary of an assistant to answer the phones and handle billing, plus all the clinic equipment andexpenses. .

DeLine took the offer.

The photo of country doctor Ernest Guy Ceriani, made famous in a groundbreaking Life Magazine photo essay by W. Eugene Smith, hangs on James DeLine's refrigerator door at his home in La Farge.Mark Hoffman / Milwaukee Journal Sentinel

DeLinegrew up in New Lenox, Illinois, a farming community outside Joliet.

The village of 1,750 was mostly cornfields. DeLine remembers it asthe kind of place where children grew up building forts during the day and watching bonfires at night. DeLine had twin sisters five years younger than him. Their father owned a restaurant.

From an early age, though, itjust seemed like Id be going to medical school. It was meant to be.

DeLineremembers nights when he could hear his mother struggling to breathe. He could hear his father, too, trying to persuade her to go to the hospital.

She had rheumatic heart disease and took blood thinners starting in her 30s. She sometimes joked about needing a valve job.

DeLinewas 17 when his mother went in for the procedure.

He saw her once after surgerybut I didnt like how she looked.About the third day, his mother suffered cardiac arrest. She was resuscitated but had sustained a severe brain injury. Days later, the family shut off life support. She was 42.

One week after her death, JamesDeLineset out to become a doctor,leavinghome for the University of Illinois in Urbana-Champaign.

Physician James DeLine eases into his work day starting at 5 a.m. at his home in La Farge.Mark Hoffman / Milwaukee Journal Sentinel

University life was hard.DeLineremained so miredin grief that when he ate, he suffered terrible abdominal pain and had to lie on his stomach for relief.

Still, he took on a demanding schedule.Driven students tended to enter the more advanced honors program in either chemistry orbiology. DeLine, a physiology major, enrolled in both.

He paid for college through restaurant jobs and financial aid.

He went on to medical school, first in Champaign, then at the University of Illinois campus in Chicago. He lived in the citys Little Italysection on the nearwestside. There he met his future wife, Ann Doherty, who worked in a print shop.

DeLinegraduated from medical school on June 7, 1980. The next day, he and Ann married.

A week later, he started his residency in Wausau.

He would work a 24-hour shift, take 24 hours off, then head back for another 24 hours at the hospital. By the time Id stagger home for some rest, he says, I was sleep-deprived, hungry, with a headache.

The schedule bothered his wife. She missed him.In his next job, she would see even less of him.

Physician James DeLine checks on Dean Pease at Vernon Memorial Healthcare in Viroqua. Pease was admitted to the hospital for breathing difficulties.Mark Hoffman / Milwaukee Journal Sentinel

In LaFarge,DeLineworked harder than he had in his residency.

He was on call 24 hours a day, seven days a week. To make ends meet, both for his family and the clinic,DeLineworked five shifts a month in the emergency room at Vernon Memorial Hospital in Viroqua.

Some days he would work 9 a.m. to 5 p.m. at the clinic, then drive to the hospital and work 6 p.m. to 8 a.m. in the emergency room. He would return to the familys home just in time to shower and get to the clinic by 9.

There were times when he was tired, but it didnt slow him down, Marcia Bader, his now-retired office managersays. It was that deep-seated caring that kept him going.

After a morning of driving around visiting patients, physician James DeLine, right, updates the staff at his clinic.Mark Hoffman / Milwaukee Journal Sentinel

It was his wife,AnnDeLine, too.

The woman who had dreamed of being a mother did everything for the couples four children, all born within a five-year span. She washed cloth diapers and hung them out to dry. Shecooked, cleaned, took the children for walks, helped with school and play, and accepted with grace all the times when her husband was called away from holidays and birthday parties.

"The calendar of holidays does not apply," she says. "He helps people when they need him like the volunteer fireman races off when the alarm sounds; like the farmer plants and harvests when the ground and weather are ready."

"Life is lived by needs, not calendars and time slots."

This drawing is a gift from an Amish patient. James DeLine keeps it on his desk at home.Mark Hoffman / Milwaukee Journal Sentinel

Villagers embraced their doctor. Patients said they were accustomed to physicians who talked at them most of the time;DeLinelistened.

The clinic struggled financially in the early years. Not everybody paid their bills, Bader recalls. But the doctor wasnt going to send them to collection firms, and he wasnt going to stop caring for them.

The doctor and his wife became fixtures ofcommunitylife. They went to their childrens cross country meets and other school events. They attended the annual Kickapoo Valley Reserve Winter Festival.

But it was his presence in the homes of area residents that endeared him to them.

My father was diagnosed with colon cancer in 1994. The thing that always struck me was that Dr.DeLinestopped in to see my mom and dad one night after a basketball game, recalls Bonnie Howell-Sherman, editor and publisher of the weekly Epitaph-News in nearby Viola.

That was just unheard of. My mom is going through dementia now and out of all of the people shes met since shes been here, hes the one she remembers.

The villagers didnt just likeDeLine. They depended on him.

They worried about him, too.

Theres been two things about Dr.DeLinethat the whole community has been concerned about, Steinmetz said. One was, how do we keep him? The other was that hestayhealthy.

From time to time, rumors spread that the doctor was sick, even dying.

In 2007,DeLinehad noticed a problem. He would urinate, only to discover a short time later that he needed to go again.

It was prostate cancer.

Courtesy of the Viola Epitaph-News

Feeling, as he put it, reflective, maybe anxious too,DeLineapproached the Epitaph-News editor. He asked to write a series of columns for the newspaper describing his illness and treatment. He would counter the rumors with transparency. He called the column, From the Other Side.

I decided early on that I was comfortable sharing my experience with our community, he wrote in the first column. After all many of you have shared your concerns, fears and symptoms with me for nearly 25 years. Each of us knows that our turn must come for illness and eventually death.

He discussed his fears about surgery to remove his prostate Would I be able to jog again?He evensharedthe frustration of phoning to make a doctors appointment and going through endless computer prompts before reaching a live human voice.

His columns took readers through his surgery, recovery andreturn home.

The way the whole village shared the doctors illness and treatment, thats part of small-town life, explains Howell-Sherman, the newspaper editor.

Its been 12 years sinceDeLinessurgery. The cancer hasnot returned.

An Amish teen pulls farm machinery down a road in La Farge.Mark Hoffman / Milwaukee Journal Sentinel

Of all the relationships the doctor built in LaFarge, the most challenging involved his Amish patients.

DeLine found his medical work was affected by a deeply held principle among the Amish, expressed in the German wordgelassenheit, which means yielding oneself to a higher authority. Among the Amish, the word encompasses a calmness and patience, as well as a belief that individualism must take a back seatto the good of the community and the will of God.

A sign warns motorists they may encounter horse-drawn vehicles on Highway D between Cashton and La Farge.Mark Hoffman / Milwaukee Journal Sentinel

While some Amish visit hospitals and accept modern medical techniques, others prefer natural methods and traditional treatments: herbs, vitamins, supplements and home remedies. In the LaFargearea, it is not unusual for an Amish family to turn to these methods beforedecidingto see DeLine.

Such was the case with Abie and Edna Yoder when their 8-year-old daughter, Barbara, first grew sick in spring 2015.

The girl had little appetite and suffered from a terrible stomachache and bloody diarrhea. Barbara weighed 38 pounds 19 pounds below average for an 8-year-old.

The Yoders took her to a so-called non-traditional doctor used by some of the Amish; these tend to be herbalists, specialists in natural medicine and others, all of whom lack medical degrees.He viewed her blood under a microscope and told the family she might have colon cancer.

The parents worried terribly about their daughters survival, but worried too about putting her in the hands of a traditional doctor. The scenario that haunted them had happened to a 3-year-old Amish boy with leukemia. The boy was given chemotherapy, they say, despite the excruciating pain andultimate failureof the treatment.

He begged to be released to go to Jesus, Edna Yoder recalls.

The Yoders approached a midwife, whosent her husband to speak with DeLine. The husband explained to the doctor the circumstances and the familys hesitation. Then the Yoders brought their daughter.

"Dr.DeLinemade it really clear that he would respect our wishes,Edna Yoder recalls.

Their daughter was admitted to American Family Childrens Hospital in Madison.DeLineconsulted with a pediatric cardiologist hed worked with at UW, Amy Peterson.

Dr.DeLinehad noticed that she had interesting looking bumps on her arms and on her legs, Peterson recalls. They were deposits of cholesterol. Dr.DeLineand I started thinking along very similar lines very quickly.

Genetic testing confirmed their hunch. The girl had extremely rare sitosterolemia, the same illness that would later be diagnosed in Perry Hochstetler.

Treatment lowered the girls sitosterol levels and helped her gain weight.

DeLineand Peterson have since foundamong the local Amisha dozen othercases the second largest cluster of the disease in the world.

An Amish farmer makes his way to work on a fence along Highway D between Cashton and La Farge.Mark Hoffman / Milwaukee Journal Sentinel

Almost 200 diseases are found in much higher proportions among Plain People. Scientists have developed a special Amish genetics test that screens the blood for more than 120 of them.

DeLine has seen patients with more than 30of the diseases on the testand has at least two patients with diseases neverdescribed in medicine.

Across the globe, there have beenonly20 to 30 cases of a disease called BRAT1; DeLine has seen six. Babies with the illness are born rigid and are prone to frequent seizures.

When the baby is born you cant straighten the baby, DeLine says. The eyes are jerking, face twitching. Some moms say they have felt things that suggest the babies have been seizing in the womb.

Read the rest here:
In a Wisconsin village, the doctor makes house calls and sees the rarest diseases on Earth - USA TODAY

Amey Vance, Live Well Published 9:54 a.m. MT Nov. 29, 2019

(Photo: Getty Images)

Terence Rhodes is an immuno-oncologist at Intermountain Precision Genomics.(Photo: Intermountain Healthcare)

Knowing your family health history is empowering.

While we cannot change our genetic makeup, knowing your family health history can help you reduce your risk of developing disease. Many common disorders such as heart disease, high blood pressure, stroke, diabetes, and certain cancers tend to run in families. If you know what health problems you might be likely to get, you can tailor preventative care and be sure to receive specific screenings to help you live a longer, healthier life.

Knowing what might be in your DNA is helpful. Some good things to know for your family health history are why and how your parents, grandparents, and possibly siblings passed away. Find out if any of them passed away of a serious illness, died before the age of 60, had cancer, or if any of them had a fatal condition.

A great time to gather this information is at family reunions or get-togethers. Current DNA research has developed so many new ways to fight disease, especially cancer, said Terence Rhodes, MD, PhD and immuno-oncologist at Intermountain Precision Genomics. Knowing if you have a strong family history of particular diseases like cancer, you can take the necessary steps to be screened early. The best chance of cure is always early detection.

New research in DNA has brought new treatments for many genetic illnesses, including certain cancers. Intermountain Precision Genomics is an innovative program that analyzes individual differences in genetics, environments, and lifestyles in order to help medical professionals specifically identify and target the exact illness of each patient.

Intermountain Precision Genomics is on the forefront of using immuno-oncology to treat cancer. Researchers have learned to manipulate the immune system to do what it should do kill cancer cells. Immunotherapy is transforming the way many cancers are treated.

Immunotherapy is like a re-balancing act to help the immune system find and kill cancer cells like it is supposed to, said Rhodes. Immunotherapy is changing the way we treat certain cancers. These therapies started to make a difference in melanoma, lung cancer, bladder and kidney cancer, and is now being used in many more cancer types.

Immunotherapies are typically delivered as an infusion therapy intravenously once every two to four weeks. There are fewer side effects than traditional chemotherapy because the medication is not killing the cancer. It is helping the immune system destroy the cancer cells. DNA research and sequencing has opened the door for immunotherapy to treat cancer. Knowing exactly what is in your DNA is extremely helpful.

Some cancers are hereditary, Rhodes said. A specific example is Lynch syndrome. This genetic cancer syndrome is associated with a higher risk for developing certain cancers. Patients with this syndrome, respond very successfully to immunotherapy treatment.

By analyzing an individuals DNA, Intermountain scientists can look for known disease-causing gene mutations that often indicate a higher risk for certain diseases. As more and more DNA samples are analyzed, medical professionals will better understand the human genome and enhance their ability to prevent diseases such as breast cancer, colon cancer, and heart disease.

Intermountain recently announced a large-scale effort focused on discovering new connections between genetics and human disease.

The HerediGene: Population Study is a collaboration between Intermountain Healthcare and deCODE, a genetics company in Iceland, Rhodes said. Together teams from both organizations intend to analyze DNA from 500,000 participants in Utah and Idaho over the next 5 years. This comprehensive study will enable us to detect disease, or the predisposition for disease, faster and earlier than ever before. Because the best chance of cure is always early detection.

It should be noted that very few people in this study will get a report on their genetic risks. Intermountain expects to find a DNA change known to be associated with hereditary disease in about 3% of the people who participate in the HerediGene: Population Study.

Study team members will offer additional testing to these few participants to confirm the research results. The results of the confirmation testing may have implications for a participants healthcare management.

Participants may choose to share this information with their healthcare provider and family members.

This unique Intermountain study may lead the way in prevention, lowering healthcare costs, and helping people, for generations, live the healthiest lives possible.

For more information on the HerediGene: Population Study, go online to intermountainhealthcare.org/heredigene or call 833-698-1727.

This LiVe Well column represents collaboration between healthcare professionals from the medical staffs of our not-for-profit Intermountain Healthcare hospitals and The Spectrum & Daily News.

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Participating in this family history survey could help genomics effort - The Spectrum

As the quest to understand the complexities of Alzheimers continues, researchers have now identified genetic mutations related to autism that may play a role in the neurodegenerative disease as well.

The study, out of Tel Aviv University, pinpointed thousands of genetic mutations in aging human brains that overlapped with mutations involved in autism and intellectual disability. They also found that many of these mutations occurred in the cell skeleton/transport system, a network of proteins that help organize cells.

We were surprised to find a significant overlap in Alzheimers genes undergoing mutations with genes that impact autism, intellectual disability and mechanisms associated with the cell skeleton/transport system health, Illana Gozes, lead author of the study, said in a news release. Importantly, the cell skeleton/transport system includes the protein Tau, one of the major proteins affected in Alzheimers disease, which form the toxic neurofibrillary tangles

Two decades ago, Gozes and the team at the laboratory discovered a protein known as ADNP. ADNP is mainly known for its connection to ADNP syndrome, a neurodevelopmental disorder that includes intellectual disability and autism spectrum disorder. But the team of researchers identified that ADNP also experiences mutations in the brains of people with Alzheimers.

Gozes built on that in the latest study, which aimed to create a paradigm shift in how people understand Alzheimers. That viewpoint focuses on how genetic alterations that are not inherited, known as mosaic somatic mutations, lead to brain pathology and disease.

The researchers hope the research will help lead to new therapeutic channels down the road.

We found in cell cultures that the ADNP-derived snippet, the drug candidate NAP, inhibited mutated-ADNP toxicity and enhanced the healthy function of Tau, Gozes said. We hope that new diagnostics and treatment modes will be developed based on our discoveries.

Genetics continues to be a large area of research around Alzheimers and dementia. Recently, researchers discovered that a genetic mutation known as APOE3ch delayed a womans high risk of developing Alzheimers by three decades.

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Alzheimer's and Autism: Researchers Pinpoint Genetic Mutations Overlapping in Both Diseases - Being Patient