No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples

Richard Border, Emma C. Johnson, and others
The American Journal of Psychiatry
https://doi.org/10.1176/appi.ajp.2018.18070881

Abstract

Objective:
Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified 18 candidate genes for depression that have been studied 10 or more times and examined evidence for their relevance to depression phenotypes.

Methods:
Utilizing data from large population-based and case-control samples (Ns ranging from 62,138 to 443,264 across subsamples), the authors conducted a series of preregistered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity).

Results:
No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than noncandidate genes. The authors demonstrate that phenotypic measurement error is unlikely to account for these null findings.

Conclusions:
The study results do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, the results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.

The research is here.

Editor's note: Depression is a complex, multivariate experience that is not primarily genetic in its origins.

Precision medicine’s rosy predictions haven’t come true. We need fewer promises and more debate

Michael Joyner and Nigel Paneth
STATnews.com
Originally published February 7, 2019

Here is an excerpt:

While we are occasionally told that we are Luddites or nihilists (generally without much debate of the merits of our position), the most frequent communications we receive have been along the lines of “I agree with you, but can’t speak up publicly for fear of losing my grants, alienating powerful people, or upsetting my dean.” This atmosphere cannot be good for the culture of science.

We are calling for an open debate, in all centers of biomedical research, about the best way forward, and about whether precision medicine is really the most promising avenue for progress. It is time for precision medicine supporters to engage in debate — to go beyond asserting the truism that all individuals are unique, and that the increase in the volume of health data and measurements combined with the decline in the cost of studying the genome constitute sufficient argument for the adoption of the precision medicine program.

Enthusiasts of precision medicine must stop evading the tough questions we raise. The two of us have learned enormously from the free and open exchange of ideas among our small band of dissenters, and we look forward to a vigorous debate engaging an ever-larger fraction of the scientific community.

The info is here.

CRISPR in China: Why Did the Parents Give Consent?

Dena Davis
The Hastings Center
Originally posted December 7, 2018

The global scientific community has been unanimous in condemning Chinese scientist He Jiankui, who announced last week that he used the gene-editing technology called CRISPR to make permanent, heritable changes to the genes of two baby girls who were born this month in China. Criticism has focused on Dr. He’s violation of worldwide acknowledgement that CRISPR has not been proven to be safe and ready to use in humans. Because CRISPR edits the actual germline, there are safety implications not only for these two girls, but for their progeny. There is also fear, expressed by the American Society for Reproductive Medicine, that this one renegade scientist could spark a backlash that would result in overly restrictive regulation.

Largely missing from the discussion is whether the twins’ parents understood what was happening and the unproven nature of the technology.  Was the informed consent process adequate, and if so, why on earth would they have given their consent?

The info is here.

The Amazing Ways Artificial Intelligence Is Transforming Genomics and Gene Editing

Bernard Marr
Forbes.com
Originally posted November 16, 2018

Here is an excerpt:

Another thing experts are working to resolve in the process of gene editing is how to prevent off-target effects—when the tools mistakenly work on the wrong gene because it looks similar to the target gene.

Artificial intelligence and machine learning help make gene editing initiatives more accurate, cheaper and easier.

The future for AI and gene technology is expected to include pharmacogenomics, genetic screening tools for newborns, enhancements to agriculture and more. While we can't predict the future, one thing is for sure: AI and machine learning will accelerate our understanding of our own genetic makeup and those of other living organisms.

The info is here.

'Should we even consider this?' WHO starts work on gene editing ethics

Agence France-Presse
Originally published 3 Dec 2018

The World Health Organization is creating a panel to study the implications of gene editing after a Chinese scientist controversially claimed to have created the world’s first genetically edited babies.

“It cannot just be done without clear guidelines,” Tedros Adhanom Ghebreyesus, the head of the UN health agency, said in Geneva.

The organisation was gathering experts to discuss rules and guidelines on “ethical and social safety issues”, added Tedros, a former Ethiopian health minister.

Tedros made the comments after a medical trial, which was led by Chinese scientist He Jiankui, claimed to have successfully altered the DNA of twin girls, whose father is HIV-positive, to prevent them from contracting the virus.

His experiment has prompted widespread condemnation from the scientific community in China and abroad, as well as a backlash from the Chinese government.

The info is here.

As China Seeks Scientific Greatness, Some Say Ethics Are an Afterthought

Sui-Lee Wee and Elsie Chen
The New York Times
Originally published November 30, 2018

First it was a proposal to transplant a head to a new body. Then it was the world’s first cloned primates. Now it is genetically edited babies.

Those recent scientific announcements, generating reactions that went from unease to shock, had one thing in common: All involved scientists from China.

China has set its sights on becoming a leader in science, pouring millions of dollars into research projects and luring back top Western-educated Chinese talent. The country’s scientists are accustomed to attention-grabbing headlines by their colleagues as they race to dominate their fields.

But when He Jiankui announced on Monday that he had created the world’s first genetically edited babies, Chinese scientists — like those elsewhere — denounced it as a step too far. Now many are asking whether their country’s intense focus on scientific achievement has come at the expense of ethical standards.

The info is here.

Super-smart designer babies could be on offer soon. But is that ethical?

Philip Ball
The Guardian
Originally posted November 19, 2018

Here is an excerpt:


Before we start imagining a Gattaca-style future of genetic elites and underclasses, there’s some context needed. The company says it is only offering such testing to spot embryos with an IQ low enough to be classed as a disability, and won’t conduct analyses for high IQ. But the technology the company is using will permit that in principle, and co-founder Stephen Hsu, who has long advocated for the prediction of traits from genes, is quoted as saying: “If we don’t do it, some other company will.”

The development must be set, too, against what is already possible and permitted in IVF embryo screening. The procedure called pre-implantation genetic diagnosis (PGD) involves extracting cells from embryos at a very early stage and “reading” their genomes before choosing which to implant. It has been enabled by rapid advances in genome-sequencing technology, making the process fast and relatively cheap. In the UK, PGD is strictly regulated by the Human Fertilisation and Embryology Authority (HFEA), which permits its use to identify embryos with several hundred rare genetic diseases of which the parents are known to be carriers. PGD for other purposes is illegal.

The info is here.

First gene-edited babies claimed in China

Marilynn Marchione

Associated Press
Originally posted today

A Chinese researcher claims that he helped make the world’s first genetically edited babies — twin girls born this month whose DNA he said he altered with a powerful new tool capable of rewriting the very blueprint of life.

If true, it would be a profound leap of science and ethics.

A U.S. scientist said he took part in the work in China, but this kind of gene editing is banned in the United States because the DNA changes can pass to future generations and it risks harming other genes.

Many mainstream scientists think it’s too unsafe to try, and some denounced the Chinese report as human experimentation.

The researcher, He Jiankui of Shenzhen, said he altered embryos for seven couples during fertility treatments, with one pregnancy resulting thus far. He said his goal was not to cure or prevent an inherited disease, but to try to bestow a trait that few people naturally have — an ability to resist possible future infection with HIV, the AIDS virus.

The info is here.

Why the Gene Editors of Tomorrow Need to Study Ethics Today

Katie Palmer
www.wired.com
Originally posted September 18, 2018

Two years after biochemist Jennifer Doudna helped introduce the world to the gene-editing tool known as Crispr, a 14-year-old from New Jersey turned it loose on a petri dish full of lung cancer cells, disrupting their ability to multiply. “In high school, I was all on the Crispr bandwagon,” says Jiwoo Lee, who won top awards at the 2016 Intel International Science and Engineering Fair for her work. “I was like, Crisprize everything!” Just pick a snippet of genetic material, add one of a few cut-and-paste proteins, and you’re ready to edit genomes. These days, though, Lee describes her approach as “more conservative.” Now a sophomore at Stanford, she spent part of her first year studying not just the science of Crispr but also the societal discussion around it. “Maybe I matured a little bit,” she says.

Doudna and Lee recently met at the Innovative Genomics Institute in Berkeley to discuss Crispr’s ethical implications. “She’s so different than I was at that age,” Doudna says. “I feel like I was completely clueless.” For Lee’s generation, it is critically important to start these conversations “at as early a stage as possible,” Doudna adds. She warns of a future in which humans take charge of evolution—both their own and that of other species. “The potential to use gene editing in germ cells or embryos is very real,” she says. Both women believe Crispr may eventually transform clinical medicine; Lee even hopes to build her career in that area—but she’s cautious. “I think there’s a really slippery slope between therapy and enhancement,” Lee says. “Every culture defines disease differently.” One country’s public health campaign could be another’s eugenics.

The info is here.

For the first time, researchers will release genetically engineered mosquitoes in Africa

Ike Swetlitz
www.statnews.com
Originally posted September 5, 2018

The government of Burkina Faso granted scientists permission to release genetically engineered mosquitoes anytime this year or next, researchers announced Wednesday. It’s a key step in the broader efforts to use bioengineering to eliminate malaria in the region.

The release, which scientists are hoping to execute this month, will be the first time that any genetically engineered animal is released into the wild in Africa. While these particular mosquitoes won’t have any mutations related to malaria transmission, researchers are hoping their release, and the work that led up to it, will help improve the perception of the research and trust in the science among regulators and locals alike. It will also inform future releases.

Teams in three African countries — Burkina Faso, Mali, and Uganda — are building the groundwork to eventually let loose “gene drive” mosquitoes, which would contain a mutation that would significantly and quickly reduce the mosquito population. Genetically engineered mosquitoes have already been released in places like Brazil and the Cayman Islands, though animals with gene drives have never been released in the wild.

The info is here.

The radical moral implications of luck in human life

David Roberts
vox.com
Originally posted August 21, 2018

Here is an excerpt:

So, then, here you are. You turn 18. You are no longer a child; you are an adult, a moral agent, responsible for who you are and what you do.

By that time, your inheritance is enormous. You’ve not only been granted a genetic makeup, an ethnicity and appearance, by accidents of nature and parentage. You’ve also had your latent genetic traits “activated” in a very specific way through a specific upbringing, in a specific environment, with a specific set of experiences.

Your basic mental and emotional wiring is in place; you have certain instincts, predilections, fears, and cravings. You have a certain amount of money, certain social connections and opportunities, a certain family lineage. You’ve had a certain amount and quality of education. You’re a certain kind of person.

You are not responsible for any of that stuff; you weren’t yet capable of being responsible. You were just a kid (or worse, a teen). You didn’t choose your genes or your experiences. Both nature and the vast bulk of the nurture that matters happened to you.

And yet when you turn 18, it’s all yours — the whole inheritance, warts and all. By the time you are an autonomous, responsible moral agent, you have effectively been fired out of a cannon, on a particular trajectory. You wake up, morally speaking, midflight.

The info is here.

Experts outline ethics issues with use of genealogy DNA to solve crimes

Carolyn Crist
Business Insider
Originally published June 1, 2018

With recent revelations that U.S. law enforcement can - and already has - dipped into consumer genealogy DNA databases to help solve crimes, experts say more discussion of the ethical issues raised by this unintended use of personal information is needed.

It's unclear, for instance, whether online genealogy site users know their DNA is available to criminal investigators - and whether they'd object to it being used for that purpose, write the authors of an essay exploring the topic in the Annals of Internal Medicine.

"We're seeing a divide about this right now. On one hand, it's a powerful technology to solve cases, but it also raises questions for consumers," said lead author Benjamin Berkman, who heads the section on the ethics of genetics and new technologies at the National Institutes of Health's Department of Bioethics in Bethesda, Maryland.

"The idea that they upload their data for genealogy purposes and it's used in such a different way really surprises some people," he told Reuters Health in a telephone interview. "The terms of service agreements don't explain this clearly, and even if they did, people wouldn't read it or find it in the dense legalese."

The information is here.

The Next Best Version of Me: How to Live Forever

David Ewing Duncan
Wired.com
Originally published March 27, 2018

Here is an excerpt:

There are also the ethics of using a powerful new technology to muck around with life’s basic coding. Theoretically, scientists could one day manufacture genomes, human or otherwise, almost as easily as writing code on a computer, transforming digital DNA on someone’s laptop into living cells of, say, Homo sapiens. Mindful of the controversy, Church and his HGP-Write colleagues insist that minting people is not their goal, though the sheer audacity of making genome-scale changes to human DNA is enough to cause controversy. “People get upset if you put a gene from another species into something you eat,” says Stanford bioethicist and legal scholar Henry Greely. “Now we’re talking about a thorough rewriting of life? Hairs will stand on end. Hackles will be raised.”

Raised hackles or not, Church and his team are forging ahead. “We want to start with a human Y,” he says, referring to the male sex chromosome, which he explains has the fewest genes of a person’s 23 chromo­somes and is thus easier to build. And he doesn’t want to synthesize just any Y chromosome. He and his team want to use the Y chromosome sequence from an actual person’s genome: mine.

“Can you do that?” I stammer.

“Of course we can—with your permission,” he says, reminding me that it would be easy to tap into my genome, since it was stored digitally in his lab’s computers as part of an effort he launched in 2005 called the Personal Genome Project.

The article is here.

What’s Next for Humanity: Automation, New Morality and a ‘Global Useless Class’

Kimiko de Freytas-Tamura
The New York Times
Originally published March 19, 2018

What will our future look like — not in a century but in a mere two decades?

Terrifying, if you’re to believe Yuval Noah Harari, the Israeli historian and author of “Sapiens” and “Homo Deus,” a pair of audacious books that offer a sweeping history of humankind and a forecast of what lies ahead: an age of algorithms and technology that could see us transformed into “super-humans” with godlike qualities.

In an event organized by The New York Times and How To Academy, Mr. Harari gave his predictions to the Times columnist Thomas L. Friedman. Humans, he warned, “have created such a complicated world that we’re no longer able to make sense of what is happening.” Here are highlights of the interview.

Artificial intelligence and automation will create a ‘global useless class.’

Just as the Industrial Revolution created the working class, automation could create a “global useless class,” Mr. Harari said, and the political and social history of the coming decades will revolve around the hopes and fears of this new class. Disruptive technologies, which have helped bring enormous progress, could be disastrous if they get out of hand.

“Every technology has a good potential and a bad potential,” he said. “Nuclear war is obviously terrible. Nobody wants it. The question is how to prevent it. With disruptive technology the danger is far greater, because it has some wonderful potential. There are a lot of forces pushing us faster and faster to develop these disruptive technologies and it’s very difficult to know in advance what the consequences will be, in terms of community, in terms of relations with people, in terms of politics.”

The article is here.

The video is worth watching.

Please read Sapiens and Homo Deus by Yuval Harari.

Deadly gene mutations removed from human embryos in landmark study

Ian Sample
The Guardian
Originally published August 2, 2017

Scientists have modified human embryos to remove genetic mutations that cause heart failure in otherwise healthy young people in a landmark demonstration of the controversial procedure.

It is the first time that human embryos have had their genomes edited outside China, where researchers have performed a handful of small studies to see whether the approach could prevent inherited diseases from being passed on from one generation to the next.

While none of the research so far has created babies from modified embryos, a move that would be illegal in many countries, the work represents a milestone in scientists’ efforts to master the technique and brings the prospect of human clinical trials one step closer.

The work focused on an inherited form of heart disease, but scientists believe the same approach could work for other conditions caused by single gene mutations, such as cystic fibrosis and certain kinds of breast cancer.

The article is here.

The Public’s Distrust of Biotech Is Deepening. Commercialization May Be to Blame.

Jim Kozubek
undark.org
Originally published November 3, 2017

Here is an excerpt:

The high profile patent battle over the CRISPR-Cas9 gene editing tool, often valued commercially at a billion dollars, and the FDA approval of the first genetically modified medicine for $475,000 — a sale price that is 19 times the cost to manufacture it — have displayed the capacity for turning taxpayer-funded research into an aggressive money-making enterprise. More personally, genetics are being used to typify people for cancer risk and age-related diseases, schizophrenia, autism, and intelligence, none of which truly belong to diagnostic categories.

It is therefore no surprise that parents may want to protect their newborns from becoming targets of commercialization.

In truth, genome sequencing is an extension of earlier commercial sequencing tests and standard newborn screening tests. BabySeq has expanded these to 166 genes, which can theoretically predict thousands of disorders and identify several genetic risk variants. For instance, it has identified a dozen newborns to have a genetic variant associated with biotinidase deficiency, which can impact cognition, and be fixed by taking a simple vitamin. Casie Genetti, a researcher at Boston Children’s Hospital, noted researchers found 109 of 125 babies had at least one, and up to six, genetic variants for an autosomal recessive disorder, meaning that if they went on to have children with a partner who had a corresponding gene compromised in a similar way, it could be damaging or life-threatening for their own baby.

Part of the problem is that we all have some measure of genetic variation, and that can be either dangerous or advantageous depending on the cell type or genetic background or environment.

The article is here.

Differential inter-subject correlation of brain activity when kinship is a variable in moral dilemma

Mareike Bacha-Trams, Enrico Glerean, Robin Dunbar, Juha M. Lahnakoski, and others
Scientific Reports 7, Article number: 14244

Abstract

Previous behavioural studies have shown that humans act more altruistically towards kin. Whether and how knowledge of genetic relatedness translates into differential neurocognitive evaluation of observed social interactions has remained an open question. Here, we investigated how the human brain is engaged when viewing a moral dilemma between genetic vs. non-genetic sisters. During functional magnetic resonance imaging, a movie was shown, depicting refusal of organ donation between two sisters, with subjects guided to believe the sisters were related either genetically or by adoption. Although 90% of the subjects self-reported that genetic relationship was not relevant, their brain activity told a different story. Comparing correlations of brain activity across all subject pairs between the two viewing conditions, we found significantly stronger inter-subject correlations in insula, cingulate, medial and lateral prefrontal, superior temporal, and superior parietal cortices, when the subjects believed that the sisters were genetically related. Cognitive functions previously associated with these areas include moral and emotional conflict regulation, decision making, and mentalizing, suggesting more similar engagement of such functions when observing refusal of altruism from a genetic sister. Our results show that mere knowledge of a genetic relationship between interacting persons robustly modulates social cognition of the perceiver.

The article is here.

Genetic testing of embryos creates an ethical morass

 Andrew Joseph
STAT news
Originally published October 23, 2017

Here is an excerpt:

The issue also pokes at a broader puzzle ethicists and experts are trying to reckon with as genetic testing moves out of the lab and further into the hands of consumers. People have access to more information about their own genes — or, in this case, about the genes of their potential offspring — than ever before. But having that information doesn’t necessarily mean it can be used to inform real-life decisions.

A test can tell prospective parents that their embryo has an abnormal number of chromosomes in its cells, for example, but it cannot tell them what kind of developmental delays their child might have, or whether transferring that embryo into a womb will lead to a pregnancy at all. Families and physicians are gazing into five-day-old cells like crystal balls, seeking enlightenment about what might happen over a lifetime. Plus, the tests can be wrong.

“This is a problem that the rapidly developing field of genetics is facing every day and it’s no different with embryos than it is when someone is searching Ancestry.com,” said Judith Daar, a bioethicist and clinical professor at University of California, Irvine, School of Medicine. “We’ve learned a lot, and the technology is marvelous and can be predictive and accurate, but we’re probably at a very nascent stage of understanding the impact of what the genetic findings are on health.”

Preimplantation genetic testing, or PGT, emerged in the 1990s as a way to study the DNA of embryos before they’re transferred to a womb, and the technology has grown more advanced with time. Federal data show it has been used in about 5 percent of IVF procedures going back several years, but many experts pin the figure as high as 20 or 30 percent.

The article is here.

Human Gene Editing Marches On

bioethics.net
Originally published October 6, 2017

Here is an excerpt:

In all three cases, the main biologic approach, and the main ethical issues, are the same.  The main differences were which genes were being edited, and how the embryos were obtained.

This prompted Nature to run an editorial to say that it is “time to take stock” of the ethics of this research.  Read the editorial here.  The key points:  This is important work that should be undertaken thoughtfully.  Accordingly, donors of any embryos or cells should be fully informed of the planned research.  Only as many embryos should be created as are necessary to do the research.  Work on embryos should be preceded by work on pluripotent, or “reprogrammed,” stem cells, and if questions can be fully answered by work with those cells, then it may not be necessary to repeat the studies on whole, intact human embryos, and if that is not necessary, perhaps it should not be done.  Finally, everything should be peer reviewed.

I agree that editing work in non-totipotent cells should be at all times favored over work on intact embryos, but if one holds that an embryo is a human being that should have the benefits of protections afforded human research subjects, then Nature’s ethical principles are rather thin, little more than an extension of animal use provisions for studies in which early humans are the raw materials for the development of new medical treatments.

The article is here.

First 'three person baby' born using new method

By Michelle Roberts
BBC News online

Originally published September 27, 2016

The world's first baby has been born using a new "three person" fertility technique, New Scientist reveals.

The five-month-old boy has the usual DNA from his mum and dad, plus a tiny bit of genetic code from a donor.

US doctors took the unprecedented step to ensure the baby boy would be free of a genetic condition that his Jordanian mother carries in her genes.

Experts say the move heralds a new era in medicine and could help other families with rare genetic conditions.

But they warn that rigorous checks of this new and controversial technology, called mitochondrial donation, are needed.

It's not the first time scientists have created babies that have DNA from three people - that breakthrough began in the late 1990s - but it is an entirely new and significant method.

The article is here.