Category Archives: Transhuman News

Joselin Linder and members of the DeMoe family of North Dakota both lost genetic lotteries: They carry harmful inherited mutations that will impair, and likely curtail, their lives.

But the respective protagonists of "The Family Gene" and "The Inheritance" are far more than victims. At some sacrifice to their time, comfort and even health, they have become contributors to cutting-edge genomic medicine a field whose inevitable advances will benefit future generations.

Linder's mutation is exceedingly rare. In fact, it exists only in her family. Its marker is a heart murmur, often barely detectable. Its pre-eminent symptom is leakage of lymphatic fluid into the lungs and other body cavities, resulting in swollen limbs, damaged organs, breathing problems and eventual starvation. The gene, located on an X chromosome, expresses less virulently in women because they carry a second, nonlethal X chromosome that may temper its effects.

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The DeMoes of North Dakota are plagued by early-onset Alzheimer's disease a rare variation of the growing health scourge. Alzheimer's affects as many as 36 million people worldwide and about 5.3 million in the United States, but early-onset Alzheimer's represents just 1 percent of cases. It arises from three genetic mutations and typically presents between ages 30 and 50.

In rural Colombia, one extended family wrestling with this highly heritable dementia calls it "the curse." But for Alzheimer's researchers, the malady represents a scientific windfall an opportunity to test preventive drugs on a population known to be headed for illness.

"The Family Gene" and "The Inheritance," while concerned with explicating the relevant science, also share an unusual emotional intimacy. That intimacy takes different forms. Linder's memoir is a personal tale of loss, illness, ethical dilemmas and emotional fallout. Some of the details are harrowing. But Linder tells her story in a smart, wry voice devoid of self-pity.

"The Inheritance" is more straightforward in style, but ultimately no less involving. A model of immersion journalism, it is especially notable for its specificity and author Niki Kapsambelis' empathy. The DeMoes laid bare their lives, and Kapsambelis repays their candor with a warts-and-all portrait softened by fondness and respect.

"The Family Gene" begins with Linder's discovery of the severity of her father's illness. Dr. William I. Linder was himself a physician. But he would spend years, baffled and increasingly terrified, in a struggle with a nameless disease that could be neither diagnosed nor successfully treated.

At one point, the widow of William Linder's uncle notes that her husband had suffered similar symptoms on his way to a horrific death. Joselin Linder's great-grandmother, Mae, though longer-lived, had also experienced the disease's characteristic swelling. The family history pointed to a genetic link.

Linder uses gentle humor to distance herself, and the reader, from the grim reality of her father's condition. "We were not a family who routinely dealt with catastrophe," she writes. "We lived in Ohio." Recounting a story of a neighbor's disaster, she writes: "It's where we excelled: watching lightning strike other people's houses."

Eventually, the family makes a fortunate connection with Dr. Christine "Kricket" Seidman, a Boston-area genetic researcher with a specialty in cardiology. She recommends screening every family member for the telltale heart murmur. Out of 41 of Mae's descendants, 13 apparently have the murmur, forecasting health troubles ahead. Linder is one of them.

During her father's illness, she tries to maintain "a semblance of normalcy," attending Tufts University, finding her first serious boyfriend. But she soon swerves off course, abandoning her studies, acting out with drugs and men. "The idea of tempering my emotions, seeking any kind of balance at all, just seemed incomprehensible," she writes.

Then her medical and insurance woes begin. Months after her father's death, Linder discovers that her platelets are "alarmingly low," a condition that Seidman diagnoses as anemia. Meanwhile, her family doctor apparently has reported her heart murmur to a medical database, saddling Linder with a pre-existing condition. For a decade, in those pre-Obamacare years, she is unable to buy health insurance a problem solved only by marriage to a man with employer-based insurance.

Meanwhile, more relatives are stricken, the men succumbing "faster and in more devastating ways" than the women. One day, Linder's ankles swell up. Later, she discovers that she has a blocked portal vein, another symptom. Procedures to clear it ultimately fail.

But there are breakthroughs to cheer: A postdoctoral fellow in the Seidman lab maps the variant gene. Technology can now detect it and keep it from being passed to the next generation. Seidman develops a hypothesis about the disease mechanism, which implicates an improperly functioning liver. There is as yet no cure nor even a name for the disease. But Linder, while postponing childbearing, resolves to enjoy her life as best she can.

Like "The Family Gene," "The Inheritance" is partly about the impact a genetic disease has on entire families even relatives who are not afflicted. At the center of Kapsambelis' narrative are two remarkably courageous women: Gail DeMoe and her daughter Karla.

Gail's husband, Galen "Moe" DeMoe, is "a hard drinker, a harder worker, and one of the best-liked men in the oil fields" of Tioga, N.D. Gail, with her "ribald sense of humor," is an even more popular figure. The couple has six children and a household filled with noise and laughter.

But, by 1973, Moe's forgetfulness and confusion are sufficiently worrisome that Gail takes him to a neurologist, who makes the Alzheimer's diagnosis. Over time, his temper turns violent; his children fear him and regard him as abusive. Gail blames his rages on the disease, saying she remembers a different man. But as his belligerence worsens, she finally sends him to a state mental hospital. He dies in a nursing home.

Carrying a gene associated with early-onset Alzheimer's is a guarantee of disaster: Everyone who has it will develop the disease, and so will approximately half that person's offspring. Moe's family, however, is particularly unfortunate: Of his six children, only Karla has been spared.

Kapsambelis tells the extended family's story in pointillist detail, perhaps too much so for some readers. A DeMoe family tree helps keep the relationships straight, while a generous array of photographs underlines the poignancy of their fate.

"The Inheritance" is equally concerned with the history of Alzheimer's research. Dr. Francisco Lopera, who spent years traveling the dangerous back roads of Colombia to investigate the disease, emerges as an especially sympathetic figure. Kapsambelis is also a fan of the University of Pittsburgh's Dr. Bill Klunk, a pioneer of brain imaging.

The case of Dr. Pearson "Trey" Sunderland III, chief of geriatric psychiatry at the National Institute of Mental Health, is more complicated. For all his brilliance and personal charm, Sunderland was compromised by a consulting relationship with the pharmaceutical company Pfizer, manufacturer of Aricept. Sunderland promoted the Alzheimer's drug without disclosing the extent of his financial ties to Pfizer, and eventually pleaded guilty to a criminal conflict of interest.

Kapsambelis carefully lays out the somewhat arcane internecine disputes within the field between, for instance, those who attribute Alzheimer's primarily to amyloid plaques and those who fault tau tangles.

She notes that early intervention is the holy grail of Alzheimer's research which is why families like the DeMoes, who carry an autosomal dominant gene mutation, are so important. The DeMoes, who worked with both NIMH and Pitt, are now part of the Dominantly Inherited Alzheimer's Network, a major international study aimed at finding drugs to prevent or halt the disease.

Most won't benefit directly from the study, and traveling to Pittsburgh for batteries of tests has at times strained their health. But the DeMoes remain highly motivated. "If their bodies could help science ferret out an answer," Kapsambelis writes, "they might save their children."

The younger DeMoes Gail's grandchildren and their cousins have faced difficult decisions about whether to submit to genetic testing, and whether to have children. Relatives already diagnosed have lost not just memory and jobs, but all but their most steadfast friends. Their caregivers sometimes have had to resort to deception to move them to nursing homes. "No matter what decisions you make, you never feel good about them," Karla says.

To both the Linders and the DeMoes, medical genetics offers the possibility of a reprieve. "We now understand the gene and its impact on our bodies," Linder writes. "For us, this means hope, and the chance to change our fate."

The DeMoes, too, are waiting, as clinical trials of potential Alzheimer's drugs proceed. "Tragedy would intertwine with their blessings," Kapsambelis writes, "until they found the thread that would lead them out of the labyrinth."

Julia M. Klein was a finalist for the 2016 National Book Critics Circle's Nona Balakian Citation for Excellence in Reviewing.

'The Family Gene' | By Joselin Linder, Ecco, 261 pages, $28.99

'The Inheritance' | By Niki Kapsambelis, Simon & Schuster, 344 pages, $26

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'For us, this means hope': Exploring the promise of genomic medicine - Chicago Tribune

A natural system for silencing genes that appears to be a way the bodys genetic material defends itself from unwanted changes is helping develop resistant crops but has not yet translated into many clinical therapies, said a 2006 Nobel Prize for Medicine recipient.

Dr. Andrew Fire, of Stanford University, was the first G. Lombard Kelly Lecturer on Thursday at the Medical College of Georgia at Augusta University. He shared the 2006 Nobel Prizein Physiology or Medicine for discovering the mechanism of RNA interference. Short pieces of double-stranded RNA (molecules that transmit genetic material) coded to a particular gene can block that gene from creating a protein, silencing that gene.

Fire first published on RNA interference in 1998, and in the years since then, RNA interference has attracted a lot of attention from both research and clinical standpoints from researchers who want to use it to target particular genes. The system, which might be a way for cells to defend against things such as viruses that attempt to assert themselves into the genome the total genetic material could also be one of the reasons why many early gene therapy trials failed.

What researchers hoped were very intelligent, scientific ways of manipulating these systems turned out to be manipulations that were recognized by the organisms as often unwanted information trying to make itself heard, Fire said. The organisms then responded to that. And those mechanisms are very interesting and exciting and one of those mechanisms is RNA interference.

Fires work was in nematode worms and it turns out that it it is much more difficult to get RNA into mammalian or human cells because it gets degraded in the body.

Its been critical to do any of those applications to develop ways of encapsulating and protecting the RNA in order to get a biological effect, he said.

While his lab has not done that work, others have made impressive progress in achieving that, Fire said. For instance, one company is in Phase III clinical trials using a RNA interference drug to combat defective amyloid protein production in the liver that causes fibril tangles to form in organs, where even blocking a significant percentage has a big clinical effect. Such applications might be more realistic for therapies than say something such as cancer, Fire said.

In some of those cases a modest effect can be quite beneficial, he said. That is something that is challenging with cancer because if you have a modest effect on cancer, generally the cancer just evolves to match that.

RNA interference might be useful for more precisely characterizing what genes are active in a tumor, for instance, and points toward ways to more precisely attack it, Fire said. It could also be helpful in moving toward more personalized medicine, he said.

In agriculture, however, RNA interference is proving to be more successful in creating genetically modified organisms that, for instance, could be more resistant to pathogens or extreme conditions, Fire said. That work predates the discovery of the precise mechanisms of RNA interference, he said, but it is still a useful tool for helping to create those organisms.

Some of those strains or species will be useful for mitigating what are really substantial problems in crops, in mitigating hunger, Fire said. So there is a benefit to this in agriculture.

Reach Tom Corwin at (706) 823-3213or tom.corwin@augustachronicle.com.

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Nobel Prize winner discusses gene therapy at AU - The Augusta Chronicle

ABL1, a human gene well-known for its association with cancer now has been linked to a developmental disorder. The study, which was carried out by a team of researchers from institutions around the world, including Baylor College of Medicine, Baylor Genetics and Texas Childrens Hospital, appears in Nature Genetics.

We were reviewing the genomic data, the analysis of all the genes, of six patients who share similar clinical features, but did not find any of the already known disease-associated genes to be involved, said co-first author Dr. Xia Wang, assistant professor of molecular and human genetics at Baylor. Instead, we found that the patients carry novel mutations, not previously described by other researchers, in the ABL1 gene, a gene that until now had been seen to undergo genetic changes in cancer cells.

The genetic changes involving the ABL1 gene in cancer cells consist in the ABL gene fusing with another gene, the BCR gene, in chromosome 22, which is then called the Philadelphia chromosome. This change occurs only in cancer cells, specifically leukemia or blood cancer cells, and not in the other cells of the body. On the other hand, the novel mutations in ABL1 discovered here are different from those described for the Philadelphia chromosome and are present in all the cells of the body at birth.

The new mutations of ABL1 and the similar clinical features are inherited together, which made us think that the gene mutations could be good candidates to explain the patients clinical features, Wang said.

The patients clinical characteristics include heart defects and dilation or widening of the aortic artery, which can predispose to rupture of the aorta, a life-threatening condition, as well as skeletal conditions, such as joint problems and particular facial features, among others.

From studying the clinical and genomic information of immediate relatives of affected individuals, the researchers learned that in some of the patients the ABL1 mutation is de novo or new it is present only in the patient, but not in the parents, said co-senior author Dr. Yaping Yang, associate professor of molecular and human genetics and senior laboratory director of Baylor Genetics. In some of the families, the ABL1 mutation is present in several generations.

Providing answers for families

One of the families in our study has four generations affected with this disorder, said co-senior author Dr. Christian Schaaf, assistant professor of molecular and human genetics at Baylor. Some of the members of the family had been given a diagnosis of Marfan syndrome, a classic genetic disorder that shares clinical similarities with the condition we were studying. They received that diagnosis on the basis of their skeletal features, but more importantly based on the dilation of the aortic arch, which predisposes to rupture of the aorta. Interestingly, it was only a clinical diagnosis; they did not have a genetic diagnosis of Marfan syndrome, which is caused by mutations in a different gene, called FBN1. The condition looked like Marfan syndrome, but it was not.

The scientists think that the findings of this research would help this family in several ways.

By uncovering the genetic cause of this condition we can provide this family with specific clinical considerations, Schaaf said. Family members have been going through testing to determine whether their aorta is dilating, but now we have a genetic test that would let them know who is at risk. Those who carry the mutation in ABL1 are at risk and need routine testing of their aortas; but those that dont carry the mutation are not at the same risk. We know that the ABL1 mutation is dominant having the mutation in one of the two copies of the gene is enough for the individual to have the condition. It means that a person having the mutation has a 50 percent chance of passing it to his or her children.

Interestingly, according to the information we have, there is no history of cancer in these families, Schaaf said. Vice versa, patients with cancer associated with the Philadelphia chromosome are not at increased risk for heart disease or aortic dilation, because in their case the mutation is limited to the cancer cells.

The power of an unbiased comprehensive approach to study the genetic causes of diseases

This is a rare condition, Yang said. By the end of this study we had sequenced the genes of 7,000 patients, most of whom have developmental problems. We found seven patients who carry a disease-causing mutation in ABL1. Six patients were included in the publication; the seventh patient was not included due to lack of interest in participating in this research.

The discovery that ABL1 also is associated with human developmental disorders would not have surfaced had the researchers taken a targeted approach to determine the genetic cause of their patients condition.

If instead of looking at all the genes in the genome we had looked only at genes we know are involved in cardiac and skeletal conditions, features associated with this syndrome, we would have never seen that ABL1, a gene that until now had only been linked to cancer, is involved in this condition, Schaaf said. Taking the unbiased approach often times pays off.

ABL1 is an important gene that has been studied extensively in cancer; I noted more than 1,500 papers in a PUBMED search. However, this is the first time inherited mutations have been identified and connected to a newly described specific syndrome unrelated to cancer, said co-author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. This work illustrates the wonderful collaborative synergy between clinical, clinical diagnostic and basic scientists here at Baylor.

Although this finding was a complete surprise, the extensive prior research on ABL1 changes and function in cancer should accelerate the research by geneticists to understand this new disorder, said co-author Dr. Sharon Plon professor of pediatrics - oncology and molecular and human genetics at Baylor and director of the Cancer Genetics Clinical and Research Programs at Texas Children's Hospital.

A full list of the authors of this study and their affiliations as well as the financial support for this project can be found here.

See more here:
Gene ABL1 implicated in cancer, developmental disorder - Baylor College of Medicine News (press release)

What happened

Shares of gene-editing pioneer Editas Medicine (NASDAQ:EDIT) rose over 17% today before settling near gains of 5% in the last hour of trading, after the company announced a strategic research-and-development collaboration with Allergan (NYSE:AGN). The pair will team up to advance and develop Editas' lead drug candidate, taking aim at a rare group of eye diseases collectively called Leber Congenital Amaurosis, or LCA. The rare inherited disease is detected at (or within months after) birth and can cause severe loss of vision or blindness.

Allergan, already a leader in treating and developing novel treatments for eye diseases, will also have exclusive access to license up to five of the gene-editing platform's ocular programs. Editas Medicine will receive $90 million up front, plus potential milestones and royalty payments. Of course, it's worth pointing out that even the lead program has yet to enter clinical trials.

Image source: Getty Images.

The partnership announcement specifically mentioned LCA10, which is one of 18 recognized types of LCA. Each type of the disease affects a different single gene, an important consideration for early gene-editing therapeutic candidates. That's because it will be easier to treat diseases with simpler genetic mutations affecting one gene (such as Friedreich's ataxia, sickle-cell anemia, and LCA) than it will be to treat diseases with more complex genetic influences (such as heart disease).

More specifically, there are good reasons for the company to initially focus on diseases affecting vision. CRISPR, the gene-editing technology used by Editas Medicine, has been shown in the past 18 months to restore sight in blind lab animals. Those external studies did not achieve very high efficiency rates and focused on diseases other than LCA, but there are encouraging similarities.

In the short term, given the early-stage nature of the technology and the company's pipeline, investors should focus more on the financial aspects of the deal. The $90 million up-front payment will provide a nice boost to the balance sheet, which showed $185 million in cash at the end of 2016. Plus, investors could expect additional up-front payments should Allergan license programs aside from LCA10.

It's also important to note that Allergan will be responsible for all expenses related to the development and commercialization of each program licensed, unless Editas Medicine exercises its option to co-develop and co-market up to two of the programs licensed by its new partner. That will allow the gene-editing pioneer to avoid significant clinical, regulatory, and marketing expenses while developing and commercializing its platform.

This may not be a blockbuster deal for investors, but there could be more deals on the way, now that the company's technology platform is no longer operating under the fog of uncertainty caused by a recently settled legal dispute. Either way, Allergan is a deep-pocketed and experienced partner that can shield Editas Medicine from development risks as the latter prepares to bring a CRISPR therapeutic into the clinic for the first time.

Maxx Chatsko has no position in any stocks mentioned. The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy.

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Here's Why Editas Medicine Gained as Much as 17.2% Today - Motley Fool