Category Archives: Transhuman News

Focusing on Heart Attacks Among the Young

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape. I'm privileged today to speak with Sekar Kathiresan from the Broad Institute, who heads up the Center for Genomic Medicine at Massachusetts General Hospital, which is not even a year old, and who also is on the faculty at Harvard Medical School. Sek, you've done some remarkable things to advance our knowledge in cardiovascular genomics. In fact, you're my go-to guy.

I'd like to start with your background and how you got into this area. You grew up in Pittsburgh, went to Penn for undergrad, and then to Harvard?

Sekar Kathiresan, MD: I graduated from Harvard Medical School in '92 and have stayed there since. I did internal medicine (clinical cardiology) training, and I was a chief resident in medicine at Mass General. I started my research training in 2003 after all those years of medical school and clinical training. It was originally supposed to be just a 2-year stint in genetic epidemiology, but I ended up liking it so much that I spent 5 years as a postdoctoral fellow2 years at the Framingham Heart Study and 3 years at the Broad Institute, learning human genetics. I got all of the foundation for genetics research during that experience.

I started my own lab in 2008. The whole time, we've been focused on trying to understand why some people have heart attacks at a young age, specifically looking at the genetic basis for premature myocardial infarction (MI).

Dr Topol: In addition, you've established worldwide collaborations of people doing similar things. How did you start that?

Dr Kathiresan: That's an interesting story. I started in this work in 1997 as an intern at Mass General, recruiting patients who'd had an MI prior to the age of 50 for men and 60 for women. A faculty member there, Chris O'Donnell, started that project and got me involved. Over the subsequent 6 or 7 years of my clinical training, we recruited about 500 such patients at Mass General. I realized quickly that it wasn't going to be a sufficient sample size to make the kind of observations needed to understand the biology of the disease. It's a complex disease; a few patients were not going to help solve the problem.

In the mid-2000s I worked with David Altshuler. He was my mentor, and he encouraged me to reach out to people around the world who had similar collections of patients. As a postdoctoral fellow, I emailed investigators in Malm, Sweden, who had a similar collection. They had published their findings. I said, "Do you want to work with us?" They invited me to Malm, and I went. We ended up partnering with six or seven other investigators to start what we called the Myocardial Infarction Genetics Consortium. That's been the foundation for all of our work on heart attack genetics.

Around the same time, I started a similar consortium for looking at cholesterol level genetics. That has now expanded to more than 50 centers around the world.

Dr Topol: There is a real misconception that heart attacks and coronary disease are tightly interwoven with lipids and cholesterol, but plenty of people who have virtually normal or even better-than-average lipid profiles wind up having heart attacks. Where do you see this field going in terms of better understanding the non-LDL cholesterolor other lipidfoundation for MIs?

Dr Kathiresan: I'll share with you what we have learned about heart attack genetics over the past 10 years. Doing something unbiased, in the sense of looking across the genome and asking, "Where in the genome is there risk for heart attack in terms of cases versus controls?", we have learned that several previously known pathways show up. For example, one of the top results in any genetic analysis for heart attack is LDL cholesterol and several genes related to LDL cholesterol. In addition, we've been able to clarify some controversies in the lipids area.

It was unclear when I got into the field which of the twoHDL, the so-called "good cholesterol," or triglycerideswas more important. When I was in medical school I was taught that anything that raised the good cholesterol must be good for you. Our genetics have shown that is not the case. Basically, HDL cholesterol is a very good marker of risk but it's unlikely to be a causal factor. We published a genetics study[1] a couple of years ago that challenged the conventional wisdom and suggested that drugs that raise HDL are not going to work. We actually had a hard time publishing that study; it took a couple of years, but since then, there have been five randomized control trials of medicines that have tried to raise HDL cholesterol.

Dr Topol: It's been a big bust.

Dr Kathiresan: It turns out that we probably were on the wrong side of the seesaw. When HDL is down, triglycerides are up. People thought that HDL was what was important. The genetics now strongly point to triglycerides-rich lipoproteins.

We have LDL and we have triglyceride-rich lipoproteins. The other key factor in the lipids space is something called lipoprotein(a). The genetics are compelling that these three things are very important for heart attack. The surprising thing has been that of the 55 gene regions we've identified for heart attack, only about 40% point to things that we already knew about. Another 60% don't relate to any of the known risk factors, like blood pressure or cholesterol, suggesting that there are new mechanisms for atherosclerosis. As a community, we need to figure those out.

Dr Topol: For example, the common variant of 9p21, a 60 kb noncoding region, has nothing known to do with cholesterol, and we are still working on what it really means, right?

Dr Kathiresan: Yes. At Scripps, you played a big role in trying to sort that out. It's been 10 years and it's been very challenging. None of this is going to be easy. Cholesterol was hypothesized to play a role in heart attack more than 100 years ago, and some people are still debating the role of LDL cholesterol. This isn't going to be straightforward, but it does suggest that there are lots of other mechanisms.

Dr Topol: That's obviously very important because Brown and Goldstein, the famous Nobel Laureates who were instrumental in the development of statins at the turn of the century, published an editorial in Science, "Heart Attacks: Gone With the Century?"[2] That was the notion that statins would be widely used and that we would stamp out heart attacks. That hasn't exactly happened, although there has been a reduction in large ST-elevation infarcts.

Dr Kathiresan: There are a couple of issues. Their hypothesis is sound; it says that if you start treatment early enough, and if the LDL is low over an extended period of time (30-40 years), you won't develop atherosclerosis. They based that hypothesis on model organism work but also on human genetics. People who carry mutations that naturally lower their LDL to very low levels lifelong rarely develop atherosclerosis. Societies like rural China, where LDL is very low, have very little atherosclerosis. It is a very good hypothesis and we still have to test it. We don't know.

Dr Topol: If you could do it at birth...

Dr Kathiresan: If we could do it safely...

Dr Topol: And safelyright.

Dr Kathiresan: Even if you do that, there are still several other elements or pathways. We are seeing now, in the United States at least, a transition from risk that was driven over the past century by blood pressure, smoking, and LDL, to this century, when risk is basically being driven by abdominal adiposity, insulin, and triglyceridesthe cardiometabolic axis. That's what we're seeing with the obesity epidemic. LDL levels are coming down and heart attack rates have come down as a result, but we have the countervailing force of cardiometabolic disease. That's where triglyceride-rich lipoproteins come ininsulin and so forth. This is on an incredible rise in the United States and also worldwide.

Dr Topol: One of the most seminal studies in the three decades during which I studied cardiology and coronary heart disease was one that you and your colleagues published last November in the New England Journal of Medicine.[3] In that study, you had the genetic risk scores, so you knew the various polygenic markers and could separate people into low, moderate or intermediate, and high risk, and you showed the titration of high riskwhich has never been done before, genomicallywith better lifestyle.

A Cell editorial[4] published very soon after your paper said that diet and exercise will save us all.

I want to get your thoughts about this. These days, if people knew that they were at high risk without any connection to family history, blood pressure, or LDL, they could benefit from this knowledge and this could be a way to promote, for them in particular, a healthy lifestyle.

Dr Kathiresan: Thank you for your kind words about the paper. The work started with a very simple observation. In my preventive cardiology clinic at Mass General, we have patients who come in and say, "My father died of a heart attack at age 50. I am doomed." They feel that DNA is destiny for this disease. We wanted to address that if you are at high genetic risk, can you overcome or counterbalance that risk with a favorable, healthy lifestyle? We've known for many years that a favorable lifestyle is associated with a reduced risk for coronary heart disease. In the context of genetic risk, how do they interact?

We found that if you are at high genetic risk, based on 50 different DNA markers, you could cut that risk in half by having a favorable lifestyle that included not smoking, regular fruit and vegetable intake, maintaining an ideal weight, and so forth. It was a very sobering message in some sense and a good public health messagethat if you are at high genetic risk based on, let's say, family history, you should not take this DNA-as-destiny approach. Rather, you do have control over your health, specifically by trying to practice these healthful behaviors.

Dr Topol: It transcends the Framingham Risk Score era because now you have a way to gauge risk and it can be titrated, so it was a big step forward. I also want to get into the idea that you can protect your heart disease risk naturallythat is Mother Nature. Previously you've talked about APOC3 and a startling finding about these homozygotes that you identified in Pakistan. Would you tell us that story?

Dr Kathiresan: You wrote many years ago about protective mutations. When we think about genetics, we think automatically about risk, but actually there is a big value of genetics in finding people who are naturally protected because of a mutation, and the main value is that you could hopefully develop a medicine that might mimic that mutation. If you can do that, then you can transfer the benefit that nature gave just to that one rare person to the entire population. That's the concept.

There's a very good example in the cardiovascular space with the gene PCSK9, where this held true. We set out a couple of years ago to ask whether there are other examples. The first that we found was the gene apolipoprotein C3. This is a gene that has been known about for 30 or more years. It's a gene that puts a break on your body's ability to handle dietary fat. When we eat a McDonald's burger, right after the meal, the triglyceride level goes up two- to threefold. The body has to clear that fat and the APOC3 protein actually dampens your ability, or puts a break on your body's ability, to clear it.

We found that about 1 in 150 people in the United States have a favorable mutation that gets rid of one of the two gene copies of APOC3. These individuals have lost a "bad guy" in their blood, and therefore they have lower lifelong triglyceride levels and about a 40% lower risk for heart attacks. That immediately suggested that if you could develop a medicine that got rid of APOC3, you might be able to reduce risk for heart attack.

One of the other key features of this paradigm is finding individuals who lack both copies of that gene. Sometimes you would call them "human knock-outs." Why do you want to know that? If there's a person walking around who naturally lacks both copies of that gene, and they are healthy, then that immediately says that you could pretty safely treat somebody with an inhibitor of that protein and not have a lot of adverse effects. It's not a complete predictor, but it's pretty close.

We set out to find these individuals. We looked at more than 100,000 people in the United Sates of European ancestry and did not find a single person who lacked both copies of APOC3. It turns out that there are people in whom both copies are gone, but that property tends to happen more when the parents of a child are closely related to each otherfor example, first-cousin marriage. In some parts of the world, it is actually fairly common. It's not taboo as it is in the United States. Pakistan is a country with the highest proportion of marriages that involve parents who are closely related. We went to an investigator in Pakistan, a collaborator who had recruited a large study of heart attacks there, and we did sequencing of APOC3 in more than 20,000 people. We found four individuals who completely lacked the gene.

Dr Topol: It was striking that these people, first with low triglycerides, also had no triglyceride elevation when they ate a fatty meal.

Dr Kathiresan: It's fascinating. This was a small fishing village. My collaborator, Danish Saleheen, had a mobile truck to do studies. They went out to the fishing village and recruited family members in whom gene copies were present and those with both copies gone. They gave both groups of individuals a fat challenge and then took blood samples every hour for 6 hours. In all of the people who had APOC3, the triglyceride levels went up (like they would in you and me), but in the people who didn't have the gene, the triglyceride levels did not budge at all after the fatty meal. This gives us some insight as to why people are protected from heart attack.

Dr Topol: It's interesting, because it flies in the face of so many studies where they lowered triglyceride levels and findings were very disappointingthere was little clinical effect. But this is a different target, of course.

Dr Kathiresan: That's the issue. There were lots of studies over the years (particularly with fibrates and fish oils, for example). In randomized controlled trials, those two medicines lowered triglycerides but they were unable to show that they lowered risk for heart attack. The challenge is that we don't really know what the molecular targets are for those two drugs, and triglyceride metabolism is complex. You can imagine waysand there are actually waysthat you can lower the triglyceride level, but counteract that with other bad things where the net effect might be no effect on disease risk. The way you lower the triglycerides will mattermaybe a little less so than for LDL. It looks like almost any way you lower LDL (although there are some exceptions there too) makes a difference in terms of heart disease risk. For triglycerides, it matters how you lower them.

We are seeing that there are several genes (APOC3 and a couple of others) in the pathway where there is naturally occurring genetic variation, pointing to these genes as being the way to lower triglycerides if you want to lower risk for heart attack.

Dr Topol: That's phenomenal. What we are seeing here is starting to really crack the big three: Lp(a), APOC3 (and other triglycerides), and LDL. We're going to see the lipid story become amplified. There is still going to be this other...

Dr Kathiresan: Residual risk.

Dr Topol: That's going to be an interesting enigma.

Dr Topol: Where are you going next? How are you going to keep building this? This foundation of knowledge has been extraordinary. You have been working on it for a decade. What can you do to expand this now?

Dr Kathiresan: The lab has worked on three elements during the past 10 years: discovery of new genes, understanding how they work, and then translating those findings to improve cardiac care. I see genomics and informed cardiac care going in two ways. One is identifying a subset of individuals who are at much higher risk, based on the genome. We are pretty good at that right now and I think there will be broad uptake over the next 10 years.

We'll then be able to find a subset of individuals early in life, based on their DNA sequence, who are at three-, four-, or 10-fold higher risk for heart attack. Then the question becomes, what do you do for those patients? We've already shown the value of lifestyle and probably a statin, but then the key question is, what else is there? Can we develop a medicine in the nonlipid space that can have dramatic benefit? That's what I see in the next 10 years.

Dr Topol: That would be exciting. We will ultimately get there as we learn more.

Now, you are big on Twitter.

Dr Kathiresan: No bigger than you.

Dr Topol: I enjoy following you. You are great to follow because you are one of my favorite educators. We can learn a lot from Twitter. What do you like about it? Sometimes, of course, you are tweeting about the Steelers, but when you are not tweeting about the Steelers or politics, what do you enjoy about Twitter?

Dr Kathiresan: I love what you just said. Every day I learn something new on Twitter. It's a little bit of a double-edged sword. We all know about social media; it's quite addictive. I could sometimes spend an inordinate amount of time on it. That aside, I learn a lot and it's mostly about science. It's things that I would not have seen. On your feed, you transfer an incredible amount of information daily, and there are lots of other opinions. Often now it is the place for immediate news, whether it's science news or other news.

A good example: A couple of weeks ago, the topline results from the randomized controlled trial of the PCSK9 antibody were announced. I knew they were going to be announced because it was a 4 PM release by Amgen at the close of the market, so I'm waiting.

Dr Topol: The first look is going to be on Twitter.

Dr Kathiresan: Exactly. A day later it will show up in The New York Times.

Dr Topol: The pulse of our field, as you say; the amount of information that you can get through Twitter in science and biomedicineour worldis quite extraordinary, and it's just as surprising that a lot more physicians and researchers don't use it.

Dr Kathiresan: Two of the healthiest areas are genomics and cardiovascular medicine. There's a tremendous amount of cardiology on Twitter, and of course, genomics is way ahead of a lot of other fields.

Dr Topol: It seems that way. It's some of my favorite stuff.

This has been really fun. I just cannot say enough about how much you have accomplished in such a short time to advance the field. [Heart disease is] still right there as the number-one cause of death and disability, and we still have a long way to go, although cancer is catching up and may soon overtake it in the United States.

Thanks so much for joining us. And thanks to all of you for joining us for this conversation. It got a little deep into the pathophysiology and genomics of coronary disease, but it's certainly an area that we are going to continue to build on.

Follow Dr Kathiresan on Twitter @skathire and Dr Topol @EricTopol

The rest is here:
Kathiresan and Topol on Genomics of Heart Disease - Medscape

Epic. Thats the word that comes to mind when you visit the Wellcome Trust Sanger Institute. Its a vast campus just outside Cambridge, with hulking buildings full of data servers, genetic engineers and scientific researchers.

Theres a real sense of history at Sanger, which isnt surprising because its the place where British scientists working with a team in the US decrypted the entire human genetic code in 2003, a momentous event that was compared by President Clinton at the time to the feat of putting a man on the Moon.

Sequencing the human genome for the first time was a massive project it took 13 years, cost more than 2 billion, and involved thousands of scientists, which helps explains the gargantuan scale of the Sanger Institute itself.

But as weve seen with computers, over time technology rapidly falls in price and shrinks in size, and thats no different when it comes to genetics. Today the cost of decoding a whole human genome has dropped to less than 1,000 and can be done in a matter of hours.

As a result, genetic engineering technology is being opened up in much the same way that computers quickly went from something only wealthy organisations could afford to being affordable and commonplace.

This shift matters. All over London start-ups are now working on genetic technologies which previously would have been only possible for major corporations or public-sector bodies to do because the cost would have been prohibitive.

This bottom-up innovation grassroots genetics, if you will is happening in the most unlikely places.If you stroll up Hanbury Street, just off Brick Lane, you come to a fantastic coffee shop called Nude Espresso. Just next door is a little office the kind of place you might expect to find a small charity or arts organisation.

Instead its home to Desktop Genetics, which is at the forefront of genetic engineering, using cutting-edge artificial intelligence to make it easier to manipulate genes and edit DNA, opening up new possibilities for medicine and healthcare.

Its the same story with Lab Genius, founded by James Field, a young graduate from Imperial College. It has come up with a way of re-engineering protein that could enable the creation of entirely new types of drugs, cosmetics and even materials and its doing it all from a typical little office in London, not a fancy laboratory out of town.

Start-ups working on genetic technologies are popping up all over the capital which might sound scary, given media stories about the health risks of genetically engineered foods, as well as legitimate ethical questions about manipulating the building blocks of life.

As with other areas of technology, its vital that government oversight keeps pace and adjusts to the fact that these days its not just well-funded big businesses that are doing genetic science, its start-ups that dont have entire teams dedicated to navigating public sector bureaucracy.

But if we can do the right things to support this new wave of London innovation, we all stand to benefit. That requires unlocking more funding for these emerging start-ups, as well as providing shared equipment they may not be able to afford by themselves.

More high-paid jobs, new sources of economic growth and the next generation of medical treatments and drugs these are just some of the potential benefits of the grassroots genetics revolution happening all around us.

So the next time you walk past a non-descript office building in London, just think the future of genetics might be developed right under your nose.

If the summer football transfer rumours are to be believed, the Brazilian striker Neymar, pictured, is set to become the highest-paid footballer in the world if he leaves Barcelona and signs for Paris Saint-Germain. According to reports, Neymar will earn 36 million a year a whopping 300 per cent pay rise.

No doubt this salary will spark a debate about whether footballers are paid too much and whether there should be a salary cap, like in American sports. But the problem with a salary cap is that it doesnt restrict the amount of money coming into the sport from TV deals, tickets and merchandise it simply means the owners of sports clubs earn more because they can pay their players less.

Surely its better that the workers the footballers get to keep more of the money they generate from their labour rather than the men in suits making fatter profits off the back of their hard work? Its just a thought but I cant imagine Comrade Corbyn making the same point.

Visit link:
Rohan Silva: The genetic revolution is happening in a tiny office or coffee shop near you - Evening Standard

Charlie Gard would have turned one year old tomorrow.

The day before the British infant died of a mitochondrial disease on July 27, a short article inMIT Technology Reviewteased that Shoukhrat Mtalipov and his team at Oregon Health & Science University and colleagues had used CRISPR-Cas9 to replace a mutation in human embryos, a titillating heads-up that didnt actually name the gene or disease.

Yesterday Naturepublished the details of what the researchers call gene correction, not editing, because it uses natural DNA repair. I covered the news conference, with a bit of perspective, forGenetic Literacy Project.

Might gene editing enable Charlies parents, who might themselves develop mild symptoms as they age, to have another child free of the familys disease? Could anything have saved the baby?

A TRAGIC CASE

The court hearing testimonyon the case between Great Ormond Street Hospital (GOSH) and the family, published April 11, chronicles the sad story. The hospital had requested discontinuing life support based on the lack of tested treatment.

Charlie was born August 4, 2016, at full term and of a good weight, but by a few weeks of age, his parents noticed that he could no longer lift his head nor support any part of his body. By the October 2 pediatrician visit, Charlie hadnt gained any weight, despite frequent breastfeeding. After an MRI and EEG, Charlie had a nasogastric tube inserted to introduce high-caloric nutrition.

By October 11, the baby was lethargic, his breathing shallow. So his parents, Connie Yates and Chris Gard, took him to GOSH. There, physicians noted Charlies persistently elevated lactate. It was an ominous sign.

Remember Bio 101? When cellular respiration in the mitochondria fails, an alternate pathway releases lactic acid this is what causes muscle cramps in a sprinter right after a race. Its what was happening to the thousands of mitochondria in Charlies muscle cells; they werent extracting enough ATP energy from digested nutrients, and so the baby was limp, unable to reach or react much. His brain was running out of energy too.

On October 25, a muscle biopsy indicated only 6% of the normal amount of mitochondrial DNA, well below the 35% that indicates a mitochondrial DNA depletion syndrome (MDDS). But which one did Charlie have? Which gene was mutant? Thats important. With a judge discussing strains of the syndrome, as if it is a bacterial infection and not a monogenic disease, confusion loomed.

In mid November, sequencing of Charlies genome found two mutations in the gene RRM2B, causing infantile onset encephalomyopathic MDDS. It affected the brain and muscles that was obvious but he was also deaf and had heart and kidney abnormalities. With these findings, the Ethics Committee at GOSH advised against a ventilator.

Charlies disease is a block to the machinery in charge of supplying nucleotide building blocks for mitochondrial DNA synthesis, Fernando Scaglia, professor of medical and human genetics at Baylor College of Medicine, told me when I picked his brain on whether gene editing might help Charlies parents.

(A quasi-technical aside: RRM2B encodes an enzyme [ribonucleotide reductase] that, with three other subunits, removes an oxygen from the sugar part of nucleic acid building blocks, leaving deoxyribose as the sugar rather than ribose, with two phosphates attached. This happens just outside the mitochondria. Once these precursors get into the mitochondria, a third phosphate is added, forming the DNA nucleotide building blocks of the 37 mitochondrial genes. Charlie inherited a RRM2B mutation from each parent the gene is in the nucleus, but it is essential to supply the mitochondria with nucleotides. RRM2Bs enzyme works only in cells that arent dividing hence the extreme effects on Charlies muscles and brain.)

Charlies seizures started on December 15 and never let up. Experts began weighing in, including by the end of the month Michio Hirano from Columbia University, who had experience using nucleoside bypass therapy on 18 patients with MDDS due to mutations in a different gene, TK2. A ray of hope?

Nucleoside bypass therapy provides precursors to the DNA building blocks that have only one of the three phosphates, to circumvent the disabled enzyme, and because the full forms are too highly charged to easily enter cells. But the paper analyzingthe strategy, from 2012, clearly showed that it didnt work in an experimental system for Charlies disease myotubes, bits of non-dividing muscle in a dish:

First we suggest that not only myotubes (post-mitotic cells), but also myoblasts and possibly other dividing cells can show mtDNA depletion in RRM2B deficiency. Second, supplementation with dNMPs, as expected, had no beneficial effect in RRM2B deficiency. Based on the function of this protein supplementation with dNDPs could be tried as an alternative strategy in RRM2B deficiency. (This isnt a sentence, albeit the crucial one for the case; it means trying two phosphates instead of one.)

Im guessing that these three sentences are what catalyzed the parents GoFundMeeffort and desire to take their baby to the US. But theres never been a proper clinical trial for nucleoside therapy, said Dr. Scaglia, although 18 patients in Spain and Italy with mutations in a different gene, TK2, have so far tolerated it. But that form only affects muscle. The treatment might not have crossed the blood-brain barrier to reach Charlies more extensive disease.

Justice Francis knew the limitations of what some in the media called the pioneering treatment, if not the difference between a microbe and a gene. In fact, this type of treatment has not even reached the experimental stage on mice let alone been tried on humans with this particular strain of MDDS, he wrote.

From January 9th until the 27th, Charlie had an unrelenting storm of seizures, his EEG erratic even when he wasnt obviously seizing. This setback caused postponement of an ethics committee meeting and all but Dr. Hirano to give up. Perhaps he thought it a theoretical possibility because of that one sentence in the 2012 paper that suggested giving DNA precursors with 2 phosphates instead of one.

For a time, Columbia University considered treating Charlie, with what I dont know. Meanwhile, nurses noted and then testified that the baby was gaining weight but making no obvious progress, countering the parents observations that Charlie felt pain, distress, pleasure, and subtly communicated with them.

Then an EEG from March 30 convinced even Dr. Hirano that an attempt at any treatment would be futile a term that so dominated the court hearing that Justice Francis defined it: for the avoidance of any doubt, the word futile in this context means pointless or of no effective benefit.Goals began to focus on preventing suffering.

Yet the Pope and the Presidentweighed in circa July 4, offering to welcome the baby for unspecified treatment to the Vatican or US. What did they know that the English doctors didnt? And I had to wonder, where are these notables when similar things happen to many other babies born with rare genetic diseases? (See No Ice Buckets or Pink Ribbons for Very Rare Genetic Diseases)

For a time, discussion at the hearing devolved into a UK vs US scenario of the Brits taking a more reasoned approach in denying a futile therapy whereas US docs would try anything if parents could just raise enough money. The single-payer system in the UK was a factor too.

As the Pope and President were making their kind offers, pretty much all the experts were reaching agreement that Charlie should be taken off life support. Still, and understandably, the parents grabbed at any hope. We truly believe that these medicines will work, the father told the court, although nucleoside bypass was more an untested hypothesis than a medicine. Belief cant alter biochemistry.

And so Charlie passed away on July 27.

COULD ANYTHING HAVED SAVED CHARLIE?

It was too soon for nucleoside bypass therapy, nor were approaches for other mitochondrial diseases such as cofactor supplementation (which I wrote abouthere), liver transplant, or stem cell transplant applicable. Nor can a recently-described peptide-like moleculethat silences mitochondrial genes help, because Charlies mutant genes are in the nucleus. (A mitochondrion only houses 37 genes.)

Gene therapy or gene editing couldnt have saved Charlie, because the intervention would have to have infiltrated his many muscle and brain cells, damaged beyond repair. But could either approach enable his parents to avoid having another child with two doses of the RRM2B mutation? (Gene therapy introduces a functioning copy of a gene; gene editing can replace it.)

Couples who are carriers of the same recessive condition already have options to avoid passing on the disease: prenatal genetic testing to identify an affected fetus and ending the pregnancy, or preimplantation genetic diagnosis (PGD) following IVF and selecting healthy embryos to continue development in the uterus.

Unfortunately, yesterdays Nature paper about gene correction of a heart condition doesnt apply to Charlies family. The researchers used CRISPR-Cas9 to snip a dominant mutation from sperm at the brink of fertilizing an egg, jumpstarting a natural DNA repair mechanism that copies a normal version of the gene from the egg to reconstitute two functioning copies a little like me giving my husband a Womens March tee-shirt to match mine and replace his Jets tee-shirt. The approach wouldnt work for a sperm and an egg each bearing a recessive mutation in the same gene, the scenario for Charlie and 1 in 4 of his potential siblings, because there wouldnt be a healthy gene to copy.

Its easier to do PGD and select those embryos that would not have a mutation in the particular gene, as is done for many other conditions, Dr. Scaglia said. However, editing-out mutations can potentially help older women undergoing PGD by upping the percentage of okay embryos both the number of eggs and their quality decline precipitously with age. A more pressing problem, Dr. Scaglia added, is controlling the cost of PGD and getting insurance to cover it, rather than pursuing gene editing.

DID LIMITED UNDERSTANDING OF GENETICS PROLONG CHARLIES SUFFERING?

How should Charlie Gard have been treated? Given my experience as a hospice volunteer and cat owner, plus my knowledge of genetics and the pathways of cellular respiration, I think that he should have been taken off life support, which began in October, and given only love and palliative care, as soon as his mutation was identified from genome sequencing in November.

Sometimes we are kinder to our pets than we are to people.

In May I had to ask the vet to help my cat Panda cross the rainbow bridge. Panda had been losing weight for months, his kidneys failing. I knew the end was near when on a Sunday night he wandered to a spot in the garden where hed never gone before, curled up under a shrub, and stayed there. Cats do this. The next morning I took him to the vet for hydration and further treatment, and he had to stay there. But by Wednesday morning, when Panda backed into the cave of his cage even for me, I knew he was ready, even if I wasnt.

The kind vet gently added a barbiturate to Pandas IV. I didnt have to pull the plug on an invasive medical device, as had to happen for little Charlie. But I held tightly onto my kitty as life left him.

It was the right thing to do.

Here is the original post:
Charlie Gard Post-Mortem: Could He Have Been Saved? - PLoS Blogs (blog)

Once editing of genetic mutations in embryos is allowed, it will be impossible to avoid a "dystopian" world of "consumer eugenics."

That's the view ofwatchdog group Human Genetics Alert, whose founding director even raised the scourge of Nazism in a fiery interview with Julia Hartley-Brewer.

Dr David King spoke to talkRADIO after aUS study showedscientists may soon be able to edit out genetic mutations in order to prevent babies from being born with diseases. It is also thought that the technique could remove inherited conditions from embryos.

King told Julia Hartley-Brewer: "Once we allow this, allow them to start making genetically modified babies, then it will be basically impossible to avoid getting into that dystopian world of consumer eugenics and designer babies."

King said that the sort of eugenic theories espoused by the Nazis in the 1930s demonstrate the evil which could eventually arise from gene-editing - a claim which drew short shrift from Julia.

The intervieww also suggestedthat "actually theres no medical case" for eradicating diseases by editing embryo DNA,claiming there are plenty of ways of preventing genetic diseases.

"The media always skip over [the fact that]we already have perfectly good techniques for avoiding the birth of those children [with genetic diseases]. Once you've got the gene, you can do genetic testing of either embryos or foetuses if the pregnancy has been established.

"The number of cases that occur around the world where you cant use preimplantation genetic diagnosis, you can count them on the fingers of one hand.

"We can do it now, the reason why science keeps on investing in new technologies that are actually uneccessary is because basically of this really rather mindless belief of technology as progress."

Listen to the full interview above

Original post:
Designer babies: Watchdog claims editing out gene mutations is first step to 'dystopian eugenics' - talkRADIO (press release)